Compositions for delivery of hepatic antigens and related methods

Abstract

The present disclosure provides compositions (e.g., pharmaceutical compositions) and related techniques (e.g., components thereof and / or methods related thereto) for delivering plasmodium protein antigens. The present disclosure provides, among other things, polyribonucleotides encoding plasmodium protein antigens.

Description

Background Art

[0001] Malaria is a mosquito-borne infectious disease caused by protozoan parasites of the genus Plasmodium. According to the World Health Organization, it is estimated that 3.4 billion people in 92 countries are at risk of being infected with malaria parasites and developing the disease. Summary of the Invention

[0002] The present disclosure provides pharmaceutical compositions (e.g., immunogenic compositions, e.g., vaccines) and related technologies (e.g., methods) for delivering specific Plasmodium antigens (e.g., Plasmodium T cell antigens) to a subject (e.g., a patient). The Plasmodium antigens may also be referred to herein as "malaria antigens". In particular, the present disclosure provides malaria vaccine compositions and related technologies (e.g., methods). The present disclosure includes the unexpected finding that the antigens and fragments thereof disclosed herein are particularly advantageous for preventing or treating malaria, e.g., when used in antigen constructs and / or vaccines, as further disclosed herein.

[0003] In some embodiments, the present disclosure provides a polynucleotide encoding a polypeptide, wherein the polypeptide comprises one or more Plasmodium T cell antigens. In some embodiments, the one or more Plasmodium T cell antigens include at least 2 and at most 10 Plasmodium T cell antigens. In some embodiments, the encoded polypeptide comprises at least 25 amino acids and at most 1100 amino acids. In some embodiments, the encoded polypeptide comprises at least 25 amino acids and at most 500 amino acids.

[0004] In some embodiments, the polynucleotide disclosed herein encodes one or more Plasmodium T cell antigens, which antigens comprise two or more of the following:

[0005] (i) an antigenic Plasmodium CSP polypeptide fragment;

[0006] (ii) an antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0007] (iii) an antigenic Plasmodium LSA-1(b) polypeptide fragment;

[0008] (iv) an antigenic Plasmodium TRAP polypeptide fragment;

[0009] (v) an antigenic Plasmodium LSAP2 polypeptide fragment;

[0010] (vi) an antigenic Plasmodium UIS3 polypeptide fragment;

[0011] (vii) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0012] (viii) an antigenic Plasmodium LISP-1 polypeptide fragment;

[0013] (ix) Antigenic Plasmodium LISP-2 polypeptide fragment; and

[0014] (x) Antigenic Plasmodium LSA-3 polypeptide fragment.

[0015] In some embodiments, the polynucleotides disclosed herein encode one or more Plasmodium T cell antigens, said antigens comprising:

[0016] (i) Antigenic Plasmodium CSP polypeptide fragment;

[0017] (ii) Antigenic Plasmodium TRAP polypeptide fragment;

[0018] (iii) Antigenic Plasmodium UIS3 polypeptide fragment;

[0019] (iv) Antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and

[0020] (v) Antigenic Plasmodium LSAP2 polypeptide fragment.

[0021] In some embodiments, the polynucleotide encodes an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:15.

[0022] In some embodiments, the polynucleotide encodes a polypeptide comprising one or more Plasmodium T cell antigens, said Plasmodium T cell antigens comprising:

[0023] (i) Antigenic Plasmodium CSP polypeptide fragment;

[0024] (ii) Antigenic Plasmodium TRAP polypeptide fragment;

[0025] (iii) Antigenic Plasmodium UIS3 polypeptide fragment;

[0026] (iv) Antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0027] (v) Antigenic Plasmodium LSAP2 polypeptide fragment;

[0028] (vi) Antigenic Plasmodium LSA-3 polypeptide fragment;

[0029] (vii) Antigenic Plasmodium LSA-1(a) polypeptide fragment; and

[0030] (viii) Antigenic Plasmodium LSA-1(b) polypeptide fragment.

[0031] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:18 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:18.

[0032] In some embodiments, the polynucleotide encodes one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0033] (i) an antigenic Plasmodium CSP polypeptide fragment;

[0034] (ii) an antigenic Plasmodium TRAP polypeptide fragment;

[0035] (iii) an antigenic Plasmodium UIS3 polypeptide fragment;

[0036] (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0037] (v) an antigenic Plasmodium LSAP2 polypeptide fragment;

[0038] (vi) an antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0039] (vii) an antigenic Plasmodium LSA-1(b) polypeptide fragment;

[0040] (viii) an antigenic Plasmodium LISP-2 polypeptide fragment; and

[0041] (ix) an antigenic Plasmodium LISP-1 polypeptide fragment.

[0042] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:24 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:24.

[0043] In some embodiments, the polynucleotide encodes one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0044] (i) an antigenic Plasmodium CSP polypeptide fragment;

[0045] (ii) an antigenic Plasmodium TRAP polypeptide fragment;

[0046] (iii) an antigenic Plasmodium UIS3 polypeptide fragment;

[0047] (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0048] (v) An antigenic Plasmodium LSAP2 polypeptide fragment;

[0049] (vi) An antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0050] (vii) An antigenic Plasmodium LSA-1(b) polypeptide fragment; and

[0051] (viii) An antigenic Plasmodium LISP-1 polypeptide fragment.

[0052] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:27 or consisting of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:27.

[0053] In some embodiments, the polynucleotide encodes a polypeptide comprising one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0054] (i) An antigenic Plasmodium CSP polypeptide fragment;

[0055] (ii) An antigenic Plasmodium TRAP polypeptide fragment;

[0056] (iii) An antigenic Plasmodium UIS3 polypeptide fragment;

[0057] (iv) An antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0058] (v) An antigenic Plasmodium LSAP2 polypeptide fragment;

[0059] (vi) An antigenic Plasmodium LISP-2 polypeptide fragment; and

[0060] (vii) An antigenic Plasmodium LISP-1 polypeptide fragment.

[0061] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:30 or consisting of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:30.

[0062] In some embodiments, the polynucleotide encodes a polypeptide that encodes one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0063] (i) An antigenic Plasmodium CSP polypeptide fragment;

[0064] (ii) Antigenic Plasmodium TRAP polypeptide fragment;

[0065] (iii) Antigenic Plasmodium UIS3 polypeptide fragment;

[0066] (iv) Antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0067] (v) Antigenic Plasmodium LSAP2 polypeptide fragment;

[0068] (vi) Antigenic Plasmodium LSA-1(b) polypeptide fragment; and

[0069] (vii) Antigenic Plasmodium LISP-1 polypeptide fragment.

[0070] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:33 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:33.

[0071] In some embodiments, the polynucleotide encodes one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0072] (i) Antigenic Plasmodium CSP polypeptide fragment;

[0073] (ii) Antigenic Plasmodium TRAP polypeptide fragment;

[0074] (iii) Antigenic Plasmodium UIS3 polypeptide fragment;

[0075] (iv) Antigenic Plasmodium ETRAMP10.3 polypeptide fragment;

[0076] (v) Antigenic Plasmodium LSAP2 polypeptide fragment;

[0077] (vi) Antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0078] (vii) Antigenic Plasmodium LSA-1(b) polypeptide fragment;

[0079] (viii) Antigenic Plasmodium LISP-2 polypeptide fragment;

[0080] (ix) Antigenic Plasmodium LISP-1 polypeptide fragment; and

[0081] (x) Antigenic Plasmodium LSA-3 polypeptide fragment.

[0082] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:36 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:36.

[0083] In some embodiments, the polynucleotide encodes a polypeptide comprising one or more Plasmodium T cell antigens or consisting of one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0084] (i) an antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0085] (ii) an antigenic Plasmodium LSA-1(b) polypeptide fragment;

[0086] (iii) an antigenic Plasmodium LISP-2 polypeptide fragment;

[0087] (iv) an antigenic Plasmodium LISP-1 polypeptide fragment; and

[0088] (v) an antigenic Plasmodium LSA-3 polypeptide fragment.

[0089] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:48 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:48.

[0090] In some embodiments, the polynucleotide encodes a polypeptide of one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising:

[0091] (i) an antigenic Plasmodium LSA-1(a) polypeptide fragment;

[0092] (ii) an antigenic Plasmodium LSA-1(b) polypeptide fragment;

[0093] (iii) an antigenic Plasmodium LISP-2 polypeptide fragment; and

[0094] (iv) an antigenic Plasmodium LISP-1 polypeptide fragment.

[0095] In some embodiments, the polynucleotide encodes a polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:45 or consisting of an amino acid sequence having at least 85% sequence identity to the amino acid sequence according to SEQ ID NO:45.

[0096] In some embodiments, the polynucleotide encodes one or more Plasmodium T cell antigens, the Plasmodium T cell antigens comprising an antigenic Plasmodium CSP polypeptide fragment, wherein the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment further comprises a Plasmodium CSP N-terminal end region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment further comprises a Plasmodium CSP junction region.

[0097] In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:133 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:133.

[0098] In some embodiments, one or more Plasmodium T cell antigens do not comprise an antigenic Plasmodium berghei CSP polypeptide fragment.

[0099] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LSA-1(a) polypeptide fragment, wherein the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:144 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:144.

[0100] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LSA-1(b) polypeptide fragment, wherein the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:155 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:155.

[0101] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium TRAP polypeptide fragment, wherein the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:171 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:171.

[0102] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 198 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 198.

[0103] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium UIS3 polypeptide fragment, wherein the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 212 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 212.

[0104] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium ETRAMP10.3 polypeptide fragment, wherein the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 219 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 219.

[0105] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LISP-1 polypeptide fragment, wherein the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 229 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 229.

[0106] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LISP-2 polypeptide fragment, wherein the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 238 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 238.

[0107] In some embodiments, one or more Plasmodium T cell antigens comprise an antigenic Plasmodium LSA-3 polypeptide fragment, wherein the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:249 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:249.

[0108] In some embodiments, each of one or more Plasmodium T cell antigens comprises one or more T cell epitopes.

[0109] In some embodiments, the polynucleotide encodes a polypeptide that does not comprise an antigenic fragment of a bacterial polypeptide. In some embodiments, the encoded polypeptide does not comprise an antigenic Bacillus Calmette-Guérin (BCG) polypeptide fragment, optionally wherein the antigenic BCG polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:461. In some embodiments, the encoded polypeptide does not comprise an antigenic tetanus toxin (TT) polypeptide fragment, optionally wherein the antigenic TT polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:462.

[0110] In some embodiments, one or more Plasmodium T cell antigens do not comprise an antigenic Plasmodium sporozoite threonine-asparagine-rich protein (STARP) polypeptide fragment, optionally wherein the antigenic Plasmodium STARP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:463.

[0111] In some embodiments, the polynucleotide encodes a polypeptide that further comprises a MHC class I transport signal (MITD). In some embodiments, the MITD comprises the amino acid sequence according to SEQ ID NO:479 or consists of the amino acid sequence according to SEQ ID NO:479.

[0112] In some embodiments, the polynucleotide encodes a polypeptide that comprises a secretion signal.

[0113] In some embodiments, the secretion signal comprises a Plasmodium secretion signal or consists of a Plasmodium secretion signal. In some embodiments, the Plasmodium secretion signal comprises a Plasmodium CSP secretion signal or consists of a Plasmodium CSP secretion signal. In some embodiments, the Plasmodium CSP secretion signal comprises the amino acid sequence according to SEQ ID NO:397 or consists of the amino acid sequence according to SEQ ID NO:397.

[0114] In some embodiments, the secretion signal comprises a heterologous secretion signal or consists of a heterologous secretion signal. In some embodiments, the heterologous secretion signal comprises a non-human secretion signal or consists of a non-human secretion signal.

[0115] In some embodiments, the heterologous secretion signal comprises or consists of a viral secretion signal.

[0116] In some embodiments, the viral secretion signal comprises or consists of an HSV secretion signal. In some embodiments, the HSV secretion signal comprises or consists of an HSV-1 or HSV-2 secretion signal. In some embodiments, the HSV secretion signal comprises or consists of an HSV glycoprotein D (gD) secretion signal. In some embodiments, the HSV gD secretion signal comprises the amino acid sequence according to SEQ ID NO:382 or consists of the amino acid sequence according to SEQ ID NO:382. In some embodiments, the HSV gD secretion signal comprises the amino acid sequence according to SEQ ID NO:388 or consists of the amino acid sequence according to SEQ ID NO:388.

[0117] In some embodiments, the secretion signal comprises or consists of an Ebola virus secretion signal. In some embodiments, the Ebola virus secretion signal comprises or consists of an Ebola virus spike glycoprotein (SGP) secretion signal. In some embodiments, the Ebola virus SGP secretion signal comprises the amino acid sequence according to SEQ ID NO:400 or consists of the amino acid sequence according to SEQ ID NO:400.

[0118] In some embodiments, the secretion signal is located at the N-terminus of the polypeptide.

[0119] In some embodiments, the polypeptide comprises a transmembrane region.

[0120] In some embodiments, the transmembrane region comprises or consists of a Plasmodium transmembrane region. In some embodiments, the Plasmodium transmembrane region comprises or consists of a Plasmodium circumsporozoite protein (CSP) glycosylphosphatidylinositol (GPI) anchor region.

[0121] In some embodiments, the Plasmodium CSP GPI anchor region comprises the amino acid sequence according to SEQ ID NO:444 or consists of the amino acid sequence according to SEQ ID NO:444.

[0122] In some embodiments, the heterologous transmembrane region comprises or consists of a human transmembrane region. In some embodiments, the heterologous transmembrane region does not comprise a hemagglutinin transmembrane region. In some embodiments, the heterologous transmembrane region comprises or consists of a non-human transmembrane region. In some embodiments, the heterologous transmembrane region comprises or consists of a viral transmembrane region.

[0123] In some embodiments, the heterologous transmembrane region comprises or consists of an HSV transmembrane region. In some embodiments, the HSV transmembrane region comprises or consists of an HSV-1 or HSV-2 transmembrane region. In some embodiments, the HSV transmembrane region comprises or consists of an HSV gD transmembrane region. In some embodiments, the HSV gD transmembrane region comprises the amino acid sequence according to SEQ ID NO:447 or consists of the amino acid sequence according to SEQ ID NO:447.

[0124] In some embodiments, the transmembrane region comprises or consists of a human transmembrane region. In some embodiments, the human transmembrane region comprises or consists of a human decay-accelerating factor glycosylphosphatidylinositol (hDAF-GPI) anchor region. In some embodiments, the hDAF-GPI anchor region comprises the amino acid sequence according to SEQ ID NO:450 or consists of the amino acid sequence according to SEQ ID NO:450.

[0125] In some embodiments, the polypeptide does not comprise a secretion signal.

[0126] In some embodiments, the polypeptide does not comprise a transmembrane region.

[0127] In some embodiments, the polypeptide comprises one or more linkers. In some embodiments, the one or more linkers comprise the amino acid sequence according to SEQ ID NO:452 or consist of the amino acid sequence according to SEQ ID NO:452. In some embodiments, the one or more linkers comprise the amino acid sequence according to SEQ ID NO:459 or consist of the amino acid sequence according to SEQ ID NO:459. In some embodiments, the one or more linkers comprise the amino acid sequence according to SEQ ID NO:456 or consist of the amino acid sequence according to SEQ ID NO:456. In some embodiments, the one or more linkers comprise the amino acid sequence according to SEQ ID NO:460 or consist of the amino acid sequence according to SEQ ID NO:460.

[0128] In some embodiments, the polypeptide comprises a linker between two Plasmodium T cell antigens.

[0129] In some embodiments, one or more Plasmodium T cell antigens are one or more Plasmodium falciparum T cell antigens. In some embodiments, one or more Plasmodium falciparum T cell antigens are from the Plasmodium falciparum isolate 3D7. In some embodiments, one or more Plasmodium T cell antigens are from Plasmodium species capable of infecting humans.

[0130] In some embodiments, each of the one or more Plasmodium T cell antigens comprises at least 21 amino acids.

[0131] In some embodiments, the polynucleotide is an isolated polynucleotide.

[0132] In some embodiments, the polynucleotide is an engineered polynucleotide.

[0133] In some embodiments, the polynucleotide is a codon-optimized polynucleotide.

[0134] In some embodiments, provided herein is an RNA construct that comprises, in 5' to 3' order:

[0135] (i) a 5' UTR that comprises or consists of a modified human alpha globin 5'-UTR;

[0136] (ii) a polynucleotide of any one of claims 1-82;

[0137] (iii) a 3' UTR that comprises or consists of a first sequence and a second sequence, the first sequence from a split amino-terminal enhancer (AES) messenger RNA and the second sequence from mitochondrially-encoded 12S ribosomal RNA; and

[0138] (iv) a polyA tail sequence.

[0139] In some embodiments, the 5' UTR comprises or consists of a ribonucleic acid sequence according to SEQ ID NO:465.

[0140] In some embodiments, the 3' UTR comprises or consists of a ribonucleic acid sequence according to SEQ ID NO:471.

[0141] In some embodiments, the polyA tail sequence is a split polyA tail sequence.

[0142] In some embodiments, the split polyA tail sequence comprises or consists of a ribonucleic acid sequence according to SEQ ID NO:467.

[0143] In some embodiments, the RNA construct comprises a 5' cap.

[0144] In some embodiments, the RNA construct comprises a cap-proximal sequence that includes positions +1, +2, +3, +4, and +5 of a polynucleotide.

[0145] In some embodiments, the RNA construct comprises a 5' cap that comprises or consists of: m7(3’OMeG)(5’)ppp(5’)(2’OMeA1)pG2, where A1 is position +1 of the polynucleotide and G2 is position +2 of the polynucleotide. In some embodiments, the RNA construct further comprises: a cap-proximal sequence that includes A1 and G2 of a Cap1 structure; and a sequence comprising A3A4U5 (SEQ ID NO:480) at positions +3, +4, and +5, respectively, of the polynucleotide.

[0146] In some embodiments, compositions are disclosed herein that comprise one or more polynucleotides (e.g., one or more polynucleotides disclosed herein).

[0147] In some embodiments, compositions are disclosed herein that comprise one or more RNA constructs (e.g., one or more RNA constructs disclosed herein).

[0148] In some embodiments, the compositions disclosed herein comprise lipid nanoparticles, polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes. In some embodiments, one or more polynucleotides are fully or partially encapsulated within lipid nanoparticles, polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes.

[0149] In some embodiments, the compositions disclosed herein further comprise lipid nanoparticles, wherein the one or more polynucleotides are encapsulated within the lipid nanoparticles. In some embodiments, the lipid nanoparticles target hepatocytes. In some embodiments, the lipid nanoparticles target secondary lymphoid organ cells. In some embodiments, the lipid nanoparticles are cationic lipid nanoparticles.

[0150] In some embodiments, each of the lipid nanoparticles comprises:

[0151] (a) a polymer-conjugated lipid;

[0152] (b) a cationic ionizable lipid; and

[0153] (c) one or more neutral lipids.

[0154] In some embodiments, the polymer-conjugated lipid comprises a PEG-conjugated lipid. In some embodiments, the polymer-conjugated lipid comprises 2-[(polyethylene glycol)-2000]-N,N-ditetradecylethanamide.

[0155] In some embodiments, one or more neutral lipids comprise 1,2-distearoyl-sn-glycero-3-phosphocholine (DPSC).

[0156] In some embodiments, one or more neutral lipids comprise cholesterol.

[0157] In some embodiments, the cationic ionizable lipid comprises [(4-hydroxybutyl)azanediyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate).

[0158] In some embodiments, the lipid nanoparticle has an average diameter of about 50 - 150 nm.

[0159] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a composition (e.g., a composition disclosed herein) and at least one pharmaceutically acceptable excipient. In some embodiments, the drug comprises a cryoprotectant, optionally wherein the cryoprotectant is sucrose. In some embodiments, the drug comprises a buffered aqueous solution, optionally wherein the buffered aqueous solution comprises one or more of Tris base, Tris HCl, NaCl, KCl, Na2HPO4, and KH2PO4.

[0160] In some embodiments, the present disclosure provides a combination comprising:

[0161] (i) a first pharmaceutical composition comprising a first polynucleotide, wherein the first polynucleotide encodes a first polypeptide, and the first polypeptide comprises one or more Plasmodium T cell antigens; and

[0162] (ii) a second pharmaceutical composition comprising a second polynucleotide, wherein the second polynucleotide encodes a second polypeptide, and the second polypeptide comprises one or more Plasmodium antigenic polypeptide regions or portions thereof.

[0163] In some embodiments, the combination comprises a first pharmaceutical composition, the first pharmaceutical composition comprising a polynucleotide disclosed herein.

[0164] In some embodiments, the combination disclosed herein comprises a second polynucleotide encoding a polypeptide that comprises one or more Plasmodium antigenic polypeptide regions or portions thereof, and comprises one or more Plasmodium CSP regions or portions thereof.

[0165] In some embodiments, the combination comprises:

[0166] (i) A first pharmaceutical composition comprising a polynucleotide encoding a first polypeptide, wherein the first polypeptide comprises one or more Plasmodium T cell antigens, and wherein the one or more Plasmodium T cell antigens comprise a Plasmodium N-terminal region or a portion thereof, but do not comprise a Plasmodium C-terminal region or a portion thereof; and

[0167] (ii) A second pharmaceutical composition comprising a polynucleotide encoding a second polypeptide, wherein the second polypeptide comprises one or more Plasmodium CSP polypeptide regions or a portion thereof, and wherein the one or more Plasmodium CSP polypeptide regions or a portion thereof comprise a Plasmodium CSP C-terminal region or a portion thereof, but do not comprise a Plasmodium CSP N-terminal region or a portion thereof.

[0168] In some embodiments, the combination disclosed herein comprises a first pharmaceutical composition and a second pharmaceutical composition, wherein the first and second pharmaceutical compositions are not in the same composition.

[0169] In some embodiments, the present disclosure provides a combination comprising:

[0170] (i) A first pharmaceutical composition comprising a first polynucleotide; and

[0171] (ii) A second pharmaceutical composition comprising a second polynucleotide, wherein the second polynucleotide.

[0172] In some embodiments, the present disclosure provides a method comprising administering a polynucleotide (e.g., a polynucleotide disclosed herein) to a subject.

[0173] In some embodiments, the present disclosure provides a method comprising administering an RNA construct (e.g., an RNA construct disclosed herein) to a subject.

[0174] In some embodiments, the present disclosure provides a method comprising administering a composition (e.g., a composition disclosed herein) to a subject.

[0175] In some embodiments, the present disclosure provides a method comprising administering one or more doses of a pharmaceutical composition (e.g., a pharmaceutical composition disclosed herein) to a subject.

[0176] In some embodiments, the present disclosure provides a pharmaceutical composition for treating a malaria infection, wherein the method comprises administering one or more doses of the pharmaceutical composition to a subject.

[0177] In some embodiments, the present disclosure provides a pharmaceutical composition for preventing a malaria infection, comprising administering one or more doses of the pharmaceutical composition to a subject.

[0178] In some embodiments, the methods disclosed herein or the pharmaceutical compositions for the uses disclosed herein include administering to a subject two or more doses of the pharmaceutical composition.

[0179] In some embodiments, the method includes administering to a subject three or more doses of the pharmaceutical composition disclosed herein. In some embodiments, the pharmaceutical composition for use includes administering to a subject three or more doses of the pharmaceutical composition disclosed herein. In some embodiments, the second dose of the three or more doses is administered to the subject at least 4 weeks after the first dose of the three or more doses is administered to the subject. In some embodiments, the third dose of the three or more doses is administered to the subject at least 4 weeks after the second dose of the three or more doses is administered to the subject.

[0180] In some embodiments, the method includes administering to a subject a fourth dose of the pharmaceutical composition disclosed herein. In some embodiments, the pharmaceutical composition for use includes administering to a subject a fourth dose of the pharmaceutical composition disclosed herein. In some embodiments, the fourth dose is administered to the subject at least one year after the third dose of the three or more doses is administered to the subject.

[0181] In some embodiments, the method includes administering a combination (e.g., the combination disclosed herein). In some embodiments, the method includes administering a combination comprising a first pharmaceutical composition and a second pharmaceutical composition. In some embodiments, the first and second pharmaceutical compositions are administered on the same day. In some embodiments, the first and second pharmaceutical compositions are administered on different days. In some embodiments, the first and second pharmaceutical compositions are administered to the subject at different locations on the subject's body.

[0182] In some embodiments, the present disclosure provides methods of treating a malaria infection.

[0183] In some embodiments, the present disclosure provides methods of preventing a malaria infection.

[0184] In some embodiments, the subject has a malaria infection or is at risk of developing a malaria infection. In some embodiments, the subject is a human.

[0185] In some embodiments, administering a pharmaceutical composition disclosed herein, a combination disclosed herein, or a polynucleotide disclosed herein induces an anti-malarial immune response in a subject. In some embodiments, the anti-malarial immune response in the subject includes an adaptive immune response. In some embodiments, the anti-malarial immune response includes a T cell response. In some embodiments, the T cell response is or includes a CD4+ T cell response, a CD8+ T cell response, and / or a B cell response. In some embodiments, the anti-malarial immune system response includes the production of antibodies against one or more malarial antigens.

[0186] In some embodiments, the present disclosure provides for the use of a pharmaceutical composition (e.g., a pharmaceutical composition described herein) in the treatment of a malarial infection.

[0187] In some embodiments, the present disclosure provides for the use of a pharmaceutical composition (e.g., a pharmaceutical composition described herein) in the prevention of a malarial infection.

[0188] In some embodiments, the present disclosure provides for the use of a pharmaceutical composition (e.g., a pharmaceutical composition disclosed herein) in inducing an anti-malarial immune response in a subject.

[0189] In some embodiments, the present disclosure provides a polypeptide encoded by a polynucleotide described herein.

[0190] In some embodiments, the present disclosure provides a polypeptide encoded by an RNA construct described herein.

[0191] In some embodiments, the present disclosure provides a host cell comprising a polynucleotide (e.g., a polynucleotide described herein).

[0192] In some embodiments, the present disclosure includes a host cell (e.g., a host cell comprising a polynucleotide disclosed herein, an RNA construct described herein, and / or a polypeptide disclosed herein). BRIEF DESCRIPTION OF THE DRAWINGS

[0193] Figure 1 An exemplary workflow for identifying, selecting, and / or characterizing an antigen (e.g., a malarial protein, including specific variants and / or epitopes thereof, particularly T cell epitopes) for use in accordance with the present disclosure is shown.

[0194] Figures 2A - 2K The immunological characterization of eleven malarial proteins (specifically, CSP, TRAP, EXP1, UIS3, ETRAMP10.3, LISP-1, LISP-2, LSA-1, LSA-3, LSAP1, and LSAP2) is shown, and also depicts the fragments selected for inclusion in an antigen (e.g., a tandem construct antigen) for use in accordance with the present disclosure.

[0195] Figure 2L Display antigenic fragments of Plasmodium polypeptides encoded by the exemplary RNA constructs described herein.

[0196] Figure 2M Display antigenic fragments of the Plasmodium protein LSA-3.

[0197] Figure 3 Show a schematic diagram of an exemplary Plasmodium T cell string polypeptide construct containing an antigen as described herein.

[0198] Figures 4A - 4F Depict the activation of T cells as evaluated by the secretion of IFN-γ. Figure 4A Show an exemplary study design including administration and peptide string construct design. Figures 4B - 4D Show the evaluation of IFN-γ secretion using isolated splenocytes (from mice immunized with different T cell peptide string constructs) incubated with a construct-specific antigenic peptide pool (15-mer, 11 aa overlap across antigens). Figure 4E Depict a comparison of the responses of isolated splenocytes (from mice in groups 2 and 3, and splenocytes isolated from mice in group 4) to a specific antigenic peptide pool. Figure 4F Depict a comparison of the responses of isolated splenocytes (from mice in group 2, and splenocytes isolated from mice in group 1) to a specific antigenic peptide pool.

[0199] Figures 5A - 5I Depict the activation of T cells as evaluated by the secretion of IFN-γ. Figure 5A Show an exemplary study design including administration and peptide string construct design. Figures 5B - 5I Show the evaluation of IFN-γ secretion using isolated splenocytes (from mice immunized with different T cell peptide string constructs) incubated with a construct-specific antigenic peptide pool (15-mer, 11 aa overlap across antigens).

[0200] Figures 6A - 6B Depict the evaluation of the activation of T cells as evaluated by the secretion of IFN-γ using isolated splenocytes (from mice immunized alone with a T cell peptide string construct or with a combination of T cell string constructs).

[0201] Figures 7A - 7B Depict the evaluation of the activation of T cells as evaluated by the secretion of IFN-γ using isolated splenocytes (from mice immunized with a shorter T cell peptide string construct or a longer T cell peptide string with the same antigen content).

[0202] Figure 8Depicts the transfection of a combination of RNA constructs 55 and 57 into cells to produce a detectable protein product. Relative protein expression at 24 h after co-transfection of 2.5 μg of each drug product into the HEK293T cell line is shown.

[0203] Definitions

[0204] The compounds of the present disclosure include those substantially described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. In addition, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Edition, Editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0205] Unless otherwise indicated, the structures depicted herein are intended to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structures, as well as all geometric or conformational isomeric forms of the structures. For example, the R and S configurations of each stereogenic center are considered to be part of the present disclosure. Accordingly, the individual stereochemical isomers of the provided compounds, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the present disclosure. For example, in some instances, the provided compounds depict one or more stereoisomers of the compound and, unless otherwise indicated, represent each stereoisomer individually and / or as a mixture. Unless otherwise indicated, all tautomeric forms of the provided compounds are within the scope of the present disclosure.

[0206] Unless otherwise indicated, the structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present disclosure (including replacement of hydrogen by deuterium or tritium or replacement of carbon by 13C-enriched carbon or 14C-enriched carbon) are within the scope of the present disclosure.

[0207] About: As used herein, the term "about" when referring to a value means a value similar to the indicated value in the context. Generally, one of ordinary skill in the art familiar with the context will understand the relevant degree of variation covered by "about" in that context. For example, in some embodiments, the term "about" may cover a range of values within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the indicated value.

[0208] Agent: As used herein, the term "agent" can refer to a physical entity. In some embodiments, an agent can be characterized by specific features and / or effects. For example, as used herein, the term "therapeutic agent" refers to a physical entity having a therapeutic effect and / or causing a desired biological and / or pharmacological effect. In some embodiments, an agent can be a compound, molecule, or entity of any chemical class, including, for example, small molecules, polypeptides, nucleic acids, sugars, lipids, metals, or combinations or complexes thereof.

[0209] Amino acid: In the broadest sense, as used herein, the term "amino acid" refers to a compound and / or substance that can be, has been, or is being incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. A "standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than a standard amino acid, whether synthetically prepared or obtained from a natural source. In some embodiments, the amino acids in a polypeptide (including the carboxyl and / or amino-terminal amino acids) may contain structural modifications compared to the above general structure. For example, in some embodiments, compared to the general structure, an amino acid can be modified by methylation, amidation, acetylation, polyethylene glycolylation, glycosylation, phosphorylation, and / or substitution (e.g., of an amino group, a carboxylic acid group, one or more protons, and / or a hydroxyl group). In some embodiments, such modifications may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide containing the modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid. It will be clear from the context that, in some embodiments, the term "amino acid" can be used to refer to a free amino acid; in some embodiments, it can be used to refer to an amino acid residue of a polypeptide.

[0210] Antigen: As used herein, the term "antigen" refers to an agent that elicits an immune response; and / or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody.

[0211] Anti-malaria immune response: As used herein, the term "anti-malaria immune response" refers to an immune response against one or more antigens derived from Plasmodium.

[0212] Correlated: When used herein, two events or entities are "correlated" with each other if the presence, level, degree, type, and / or form of one event or entity is related to the presence, level, degree, type, and / or form of another event or entity. For example, if the presence, level, and / or form of a particular entity (e.g., a polypeptide, a genetic trait, a metabolite, a microorganism, etc.) is related to the incidence, susceptibility, severity, stage, etc. of a particular disease, disorder, or condition (e.g., among a relevant population), it is considered to be correlated with the disease, disorder, or condition. In some embodiments, if two or more entities interact directly or indirectly such that they are physically close to each other and / or remain physically close to each other, they are "associated" physically with each other. In some embodiments, two or more entities that are physically associated with each other are covalently linked to each other; in some embodiments, two or more entities that are physically associated with each other are not covalently linked, but are non-covalently associated, e.g., by hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetic forces, and combinations thereof.

[0213] C-terminal domain: As used herein, the term "C-terminal domain" refers to the region of the CSP polypeptide corresponding to amino acids 273-397 of the wild-type CSP sequence of Plasmodium falciparum (isolate 3D7) (SEQ ID NO:1).

[0214] C-terminal region: As used herein, the term "C-terminal region" refers to the region of the CSP polypeptide corresponding to amino acids 273-375 of the wild-type CSP sequence (SEQ ID NO:1). In some embodiments, serine follows immediately after the C-terminal region. In some embodiments, serine and valine follow immediately after the C-terminal region.

[0215] Central domain: As used herein, the term "central domain" refers to the region of the CSP polypeptide corresponding to amino acids 105-272 of the wild-type CSP sequence (SEQ ID NO:1).

[0216] Combination Therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents (e.g., two or more antibody agents)). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered followed by any dose of a second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, the administration of combination therapy may involve administering one or more agents or modalities to a subject who is receiving other agents or modalities in the combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), but in some embodiments, two or more agents or their active portions may be combined and administered together in a composition.

[0217] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, sets of conditions, etc. that may not be identical to one another, but are sufficiently similar to permit comparison between them such that one of ordinary skill in the art will understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, comparable sets of conditions, environments, individuals, or groups are characterized by a plurality of substantially identical features and one or a small number of varying features. One of ordinary skill in the art will understand, in context, what degree of identity between two or more such agents, entities, situations, sets of conditions, etc. is required in any given case to be considered comparable. For example, one of ordinary skill in the art will recognize that sets of environments, individuals, or groups are comparable to one another when they are characterized by a sufficient number and type of substantially identical features to warrant the reasonable conclusion that differences in results or phenomena observed under different sets of environments, individuals, or groups are caused or indicated by variations in those different features.

[0218] Corresponds to: As used herein, the term "corresponds to" refers to a relationship between two or more entities. For example, the term "corresponds to" can be used to indicate the position / identity of a structural element in a compound or composition relative to another compound or composition (e.g., relative to a suitable reference compound or composition). For example, in some embodiments, monomer residues in a polymer (e.g., amino acid residues in a polypeptide or nucleic acid residues in a polynucleotide) can be identified as "corresponding to" residues in a suitable reference polymer. For example, one of ordinary skill in the art will understand that, for simplicity, residues in a polypeptide are typically designated using a canonical numbering system based on a reference related polypeptide such that, for example, the amino acid that "corresponds to" the residue at position 190 does not actually have to be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue seen at 190 in the reference polypeptide; one of ordinary skill in the art can readily understand how to identify the "corresponding" amino acid. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE, which can be used to, for example, identify "corresponding" residues in polypeptides and / or nucleic acids according to the present disclosure. Those skilled in the art will also understand that, in some cases, the term "corresponds to" can be used to describe an event or entity that shares a relevant similarity with another event or entity (e.g., a suitable reference event or entity). Just to give one example, a gene or protein in one organism can be described as "corresponding to" a gene or protein from another organism in order to, in some embodiments, indicate that it plays a similar role or performs a similar function and / or that it exhibits a particular degree of sequence identity or homology, or shares particular characteristic sequence elements.

[0219] Dosage regimen: One of ordinary skill in the art will understand that the term "dosage regimen" (or "treatment regimen") can be used to refer to a set of unit doses (usually more than one) that are typically administered to a subject individually at intervals over a period of time. In some embodiments, a given therapeutic agent has a recommended dosage regimen, which can involve one or more doses.

[0220] Encoding: As used herein, the term "encode / encoding" refers to the sequence information of a first molecule that directs the production of a second molecule having a defined nucleotide sequence (e.g., a polynucleotide) or a defined amino acid sequence. For example, a DNA molecule can encode an RNA molecule (e.g., by a transcription process involving DNA-dependent RNA polymerase). An RNA molecule can encode a polypeptide (e.g., by a translation process). Thus, if transcription and translation of an RNA corresponding to a gene results in a polypeptide in a cell or other biological system, the gene, cDNA, or RNA molecule encodes the polypeptide. In some embodiments, the coding region of a polynucleotide encoding a target antigen refers to the coding strand, the nucleotide sequence of which is identical to the polynucleotide sequence of such target antigen. In some embodiments, the coding region of a polynucleotide encoding a target antigen refers to the non-coding strand of such target antigen, which can be used as a template for gene or cDNA transcription.

[0221] Expression: As used herein, the "expression" of a nucleic acid sequence refers to the production of a gene product from the nucleic acid sequence. In some embodiments, the gene product can be a transcript, such as the polynucleotides provided herein. In some embodiments, the gene product can be a polypeptide. In some embodiments, the expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of the RNA transcript (e.g., by splicing, editing, etc.); (3) translation of the RNA into a polypeptide or protein; and / or (4) post-translational modification of the polypeptide or protein.

[0222] Heterologous: As used herein, the term "heterologous" with respect to a secretion signal or transmembrane region refers to a secretion signal or transmembrane region from a virus or an organism other than Plasmodium.

[0223] Homology: As used herein, the term "homology" or "homolog" refers to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules are considered to be "homologous" to each other if their sequences are at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% identical. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules are considered to be "homologous" to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% similar (e.g., contain residues with chemically related properties at corresponding positions). For example, as is well known to those of ordinary skill in the art, certain amino acids are generally classified as "hydrophobic" or "hydrophilic" amino acids that are similar to each other, and / or have "polar" or "nonpolar" side chains. Substituting one amino acid for another of the same type is generally considered a "homologous" substitution.

[0224] Identity: As used herein, the term "identity" refers to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules are considered to be "substantially identical" to each other if their sequences are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical. The percent identity between two nucleic acid or polypeptide sequences can be calculated, for example, by aligning the two sequences for optimal comparison (e.g., gaps can be introduced in one or both of the first and second sequences for optimal alignment, and non-identical sequences can be ignored for comparison purposes). In certain embodiments, the length of the sequences aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or substantially 100% of the length of the reference sequence. The nucleotides at the corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap, which are introduced for optimal alignment of the two sequences. Mathematical algorithms can be used to accomplish the comparison of the sequences and the determination of the percent identity between two sequences. For example, the algorithm of Meyers and Miller, 1989, incorporated into the ALIGN program (version 2.0), can be used to determine the percent identity between two nucleotide sequences. In some exemplary embodiments, nucleic acid sequence comparison using the ALIGN program uses the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Alternatively, the GAP program in the GCG software package can be used, using the NWSgapdna.CMP matrix, to determine the percent identity between two nucleotide sequences.

[0225] Increased, induced, or decreased: As used herein, these terms or grammatically comparable comparative terms indicate a value relative to a comparable reference measurement. For example, in some embodiments, an evaluated value obtained with the provided composition (e.g., a pharmaceutical composition) can be "increased" relative to an evaluated value obtained with a comparable reference composition. Alternatively or additionally, in some embodiments, an evaluated value obtained in a subject can be "increased" relative to an evaluated value obtained in the same subject under different conditions (e.g., before or after an event; or in the presence or absence of an event, such as administration of a composition as described herein (e.g., a pharmaceutical composition)) or in different comparable subjects (e.g., in a comparable subject different from the subject of interest, the subject of interest having been previously exposed to conditions such as the absence of administration of a composition as described herein (e.g., a pharmaceutical composition)). In some embodiments, the comparative term refers to a statistically relevant difference (e.g., a prevalence and / or magnitude sufficient to achieve statistical relevance). One of ordinary skill in the art will recognize or will be able to readily determine, in a given context, the degree and / or prevalence of difference required or sufficient to achieve such statistical significance. In some embodiments, the term "decreased" or equivalent terms refer to a reduction in the level of the evaluated value by at least 5%, at least 10%, at least 20%, at least 50%, at least 75% or more as compared to a comparable reference. In some embodiments, the term "decreased" or equivalent terms refer to complete or substantially complete inhibition, i.e., a reduction to zero or substantially a reduction to zero. In some embodiments, the term "increased" or "induced" refers to an increase in the level of the evaluated value by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 80%, at least 100%, at least 200%, at least 500% or more as compared to a comparable reference.

[0226] Sequential: As used herein with respect to a polynucleotide or polyribonucleotide, "sequential" refers to the order of features along the polynucleotide or polyribonucleotide from 5' to 3'. As used herein with respect to a polypeptide, "sequential" refers to the order of features moving from the feature closest to the N-terminus to the feature closest to the C-terminus along the polypeptide. "Sequential" does not mean that there cannot be additional features among the listed features. For example, if features A, B, and C of a polynucleotide are described herein as "sequentially feature A, feature B, and feature C", such a description does not exclude, for example, feature D being located between features A and B.

[0227] Isolated: The term "isolated" means altered or removed from its natural state. For example, a nucleic acid or peptide that occurs naturally in a living animal is not "isolated", but the same nucleic acid or peptide that is partially or completely separated from the coexisting materials in its natural state is "isolated". An isolated nucleic acid or protein may exist in a substantially purified form or may exist in a non-natural environment (e.g., a host cell).

[0228] Junction region: As used herein, the term "junction region" refers to the region of the CSP polypeptide corresponding to amino acids 93 - 104 of the wild-type CSP sequence (SEQ ID NO:1).

[0229] Junction region variant: As used herein, the term "junction region variant" refers to a junction region that contains one or more substitution mutations compared to amino acids 93 - 104 of the wild-type CSP sequence (SEQ ID NO:1).

[0230] Linker: As used herein, the term "linker" refers to a portion of a polypeptide that connects different regions, parts, or antigens to each other.

[0231] Lipid: As used herein, the terms "lipid" and "lipid-like substance" are broadly defined as molecules that contain one or more hydrophobic moieties or groups and optionally also contain one or more hydrophilic moieties or groups. Molecules that contain both hydrophobic and hydrophilic moieties are often also referred to as amphiphilic molecules.

[0232] Major repeat region: As used herein, the term "major repeat region" refers to the region of the CSP polypeptide corresponding to amino acids 129 - 272 of the wild-type CSP sequence (SEQ ID NO:1) and containing 35 repeats of the amino acid sequence NANP (SEQ ID NO:108). The 35 repeats of the amino acid sequence NANP (SEQ ID NO:108) are divided into two consecutive segments, the first segment containing 17 repeats of the amino acid sequence NANP (SEQ ID NO:108), and the second segment containing 18 repeats of the amino acid sequence NANP (SEQ ID NO:108), which flank the amino acid sequence of NVDP (SEQ ID NO:105). A portion of the major repeat region contains at least the amino acid sequence NPNA (SEQ ID NO:104). Preferably, a portion of the major repeat region contains at least the amino acid sequences NANPNA (SEQ ID NO:114) and NPNANP (SEQ ID NO:111). As used herein, a "repeat" of sequence A means that sequence A occurs once, and "one or more repeats" of sequence A means that sequence A occurs once or more.

[0233] Merozoite stage-specific Plasmodium antigen: As used herein, the term "merozoite stage-specific Plasmodium antigen" refers to an antigen that is expressed during the merozoite stage of the Plasmodium life cycle.

[0234] Minor repeat region: As used herein, the term "minor repeat region" refers to the region of the CSP polypeptide corresponding to amino acids 105-128 of the wild-type CSP sequence (SEQ ID NO:1) and containing three repeats of the amino acid sequence NANPNVDP (SEQ ID NO:477). The minor repeat region does not contain the amino acid sequence NPNA (SEQ ID NO:104), and does not contain the amino acid sequence NANPNA (SEQ ID NO:114) or NPNANP (SEQ ID NO:111). As used herein, a "repeat" of sequence A refers to sequence A occurring once, and three repeats of sequence A refers to sequence A occurring three times.

[0235] N-terminal domain: As used herein, the term "N-terminal domain" refers to the region of the CSP polypeptide corresponding to amino acids 19-92 of the wild-type CSP sequence (SEQ ID NO:1).

[0236] N-terminal end region: As used herein, the term "N-terminal end region" refers to the region of the CSP polypeptide corresponding to amino acids 81-92 of the wild-type CSP sequence (SEQ ID NO:1).

[0237] N-terminal region: As used herein, the term "N-terminal region" refers to the region of the CSP polypeptide corresponding to amino acids 19-80 of the wild-type CSP sequence (SEQ ID NO:1).

[0238] RNA lipid nanoparticles: As used herein, the term "RNA lipid nanoparticle" refers to a nanoparticle comprising at least one lipid and an RNA molecule (e.g., one or more polynucleotides provided herein). In some embodiments, the RNA lipid nanoparticle comprises at least one cationic amino lipid. In some embodiments, the RNA lipid nanoparticle comprises at least one cationic amino lipid, at least one helper lipid, and at least one polymer-conjugated lipid (e.g., PEG-conjugated lipid). In various embodiments, the RNA lipid nanoparticles as described herein may have an average size (e.g., Z-average) of about 100 nm to 1000 nm or about 200 nm to 900 nm or about 200 nm to 800 nm or about 250 nm to about 700 nm. In some embodiments of the present disclosure, the RNA lipid nanoparticles may have a particle size (e.g., Z-average) of about 30 nm to about 200 nm or about 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 to about 90 nm, about 80 nm to about 90 nm, or about 70 nm to about 80 nm. In some embodiments, the average size of the lipid nanoparticle is determined by measuring the average particle diameter. In some embodiments, the RNA lipid nanoparticles can be prepared by mixing the lipid with the RNA molecule as described herein.

[0239] Neutralization: As used herein, the term "neutralization" refers to an event in which a binder (such as an antibody) binds to a biologically active site of a parasite (such as a receptor-binding protein), thereby inhibiting parasite infection of a cell. In some embodiments, the term "neutralization" refers to an event in which the binder eliminates or significantly reduces the ability to infect a cell.

[0240] Nucleic Acid / Polynucleotide: As used herein, the term "nucleic acid" refers to a polymer of at least 10 or more nucleotides. In some embodiments, the nucleic acid is or comprises DNA. In some embodiments, the nucleic acid is or comprises RNA. In some embodiments, the nucleic acid is or comprises peptide nucleic acid (PNA). In some embodiments, the nucleic acid is or comprises single-stranded nucleic acid. In some embodiments, the nucleic acid is or comprises double-stranded nucleic acid. In some embodiments, the nucleic acid comprises both single-stranded and double-stranded portions. In some embodiments, the nucleic acid comprises a backbone containing one or more phosphodiester linkages. In some embodiments, the nucleic acid comprises a backbone containing both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, the nucleic acid may comprise a backbone containing one or more phosphorothioate or 5'-N-phosphoramidite linkages and / or one or more peptide bonds, such as in "peptide nucleic acid". In some embodiments, the nucleic acid comprises one or more or all of the natural residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, the nucleic acid comprises one or more or all of the unnatural residues. In some embodiments, the unnatural residues comprise nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 6-O-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, the unnatural residues comprise one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared to those sugars in the natural residues. In some embodiments, the nucleic acid has a nucleotide sequence encoding a functional gene product, such as RNA or polypeptide. In some embodiments, the nucleic acid has a nucleotide sequence containing one or more introns. In some embodiments, nucleic acids can be prepared by isolation from natural sources, enzymatic synthesis (e.g., by polymerization based on a complementary template, such as in vivo or in vitro), replication in a recombinant cell or system, or chemical synthesis.In some embodiments, the nucleic acid has a length of at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500 or 20,000 or more residues or nucleotides.

[0241] Pharmaceutically effective amount: The term "pharmaceutically effective amount" or "therapeutically effective amount" refers to the amount that, alone or in combination with additional doses, achieves the desired response or desired effect. In the case of treating a particular disease (e.g., malaria), the desired response in some embodiments involves inhibiting the progression of the disease (e.g., malaria). In some embodiments, such inhibition can include slowing the progression of the disease (e.g., malaria) and / or interrupting or reversing the progression of the disease (e.g., malaria). In some embodiments, the desired response in the treatment of a disease (e.g., malaria) can be or include delaying or preventing the onset of the disease (e.g., malaria) or a condition (e.g., malaria-related conditions). The effective amount of the compositions (e.g., pharmaceutical compositions) described herein will depend on, for example, the disease (e.g., malaria) or condition (e.g., malaria-related conditions) to be treated, the severity of such disease (e.g., malaria) or condition (e.g., malaria-related conditions), the individual parameters of the patient (including, for example, age, physiological condition, body size and weight), the duration of treatment, the type of concomitant therapy (if any), the particular route of administration, and similar factors. Thus, the dosage of the compositions (e.g., pharmaceutical compositions) described herein can depend on various such parameters. In cases where the patient's response to an initial dose is inadequate, higher doses (or effectively higher doses obtained by a different, more localized route of administration) can be used.

[0242] Polypeptide: As used herein, the term "polypeptide" refers to a polymeric chain of amino acids. In some embodiments, the polypeptide has a naturally occurring amino acid sequence. In some embodiments, the polypeptide has an amino acid sequence that is not naturally occurring. In some embodiments, the polypeptide has an engineered amino acid sequence as the sequence is designed and / or produced through artificial means. In some embodiments, the polypeptide may comprise, or consist of, natural amino acids, unnatural amino acids, or both. In some embodiments, the polypeptide may consist of only natural amino acids or only unnatural amino acids. In some embodiments, the polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, the polypeptide may consist of only D-amino acids. In some embodiments, the polypeptide may consist of only L-amino acids. In some embodiments, the polypeptide may include one or more side groups or other modifications, such as modifications or attachments at the N-terminus of the polypeptide, at the C-terminus of the polypeptide, or any combination thereof, or to one or more amino acid side chains. In some embodiments, such side groups or modifications include acetylation, amidation, lipidation, methylation, polyethylene glycolation, etc., including combinations thereof. In some embodiments, the polypeptide may be cyclic and / or may include a cyclic moiety. In some embodiments, the polypeptide is not cyclic and / or does not include any cyclic moieties. In some embodiments, the polypeptide is linear. In some embodiments, the polypeptide may be or include a tethered polypeptide. In some embodiments, the term "polypeptide" may be appended to the name, activity, or structure of a reference polypeptide; in such cases, it is used herein to refer to polypeptides that share the relevant activity or structure and may thus be considered members of the same class or family of polypeptides. For each such class, the present specification provides and / or one of ordinary skill in the art will be aware of exemplary polypeptides with known amino acid sequences and / or functions within the class; in some embodiments, such exemplary polypeptides are reference polypeptides of the polypeptide class or family. In some embodiments, members of a polypeptide class or family exhibit significant sequence homology or identity with the reference polypeptide of the class, share common sequence motifs (e.g., characteristic sequence elements) with the reference polypeptide of the class, and / or share a common activity (in some embodiments at a comparable level or within a specified range) with the reference polypeptide of the class; in some embodiments for all polypeptides within the class).For example, in some embodiments, the member polypeptide exhibits a degree of overall sequence homology or identity with a reference polypeptide of at least about 30-40%, and typically greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, and / or includes at least one region (e.g., a conserved region that may be or contain characteristic sequence elements in some embodiments), which region exhibits a very high sequence identity, typically greater than 90% or even 95%, 96%, 97%, 98% or 99%. Such conserved regions typically span at least 3-4 and typically up to 35 or more amino acids; in some embodiments, the conserved region spans at least one segment of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more contiguous amino acids. In some embodiments, the related polypeptide may comprise or consist of a fragment of a parental polypeptide. In some embodiments, the polypeptide is a Plasmodium T cell string polypeptide construct as described herein. A Plasmodium T cell string polypeptide construct is a polypeptide comprising one or more T cell antigens or one or more portions thereof from one or more Plasmodium proteins. In some embodiments, the Plasmodium T cell string polypeptide construct further comprises one or more additional amino acid sequences, such as a secretion signal (e.g., a heterologous secretion signal), a transmembrane region (e.g., a heterologous transmembrane region), a trafficking signal and / or a linker, as described herein.

[0243] Prevention: As used herein, the term "prevent / prevention" when used in connection with the occurrence of a disease, disorder, and / or condition refers to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention can be considered complete when the onset of the disease, disorder, or condition has been delayed for a predetermined period of time. In some embodiments, prevention refers to reducing the risk of developing clinical malaria.

[0244] Reference: As used herein, the term "reference" describes the standard or control to which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or assayed substantially contemporaneously with the test or assay of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Generally, as will be understood by those skilled in the art, the reference or control is assayed or characterized under conditions or circumstances comparable to those being evaluated. Those skilled in the art will appreciate when there is sufficient similarity to justify reliance on a particular possible reference or control and / or comparison to a particular possible reference or control.

[0245] Ribonucleic acid (RNA) or polynucleotide: As used herein, the terms "ribonucleic acid", "RNA", or "polynucleotide" refer to a polymer of ribonucleotides. In some embodiments, the RNA is single-stranded. In some embodiments, the RNA is double-stranded. In some embodiments, the RNA contains both single-stranded and double-stranded portions. In some embodiments, the RNA may contain a backbone structure as described in the definition of "nucleic acid / polynucleotide" above. The RNA can be a regulatory RNA (e.g., siRNA, microRNA, etc.) or messenger RNA (mRNA). In some embodiments, the RNA is mRNA. In some embodiments in which the RNA is mRNA, the RNA typically contains a poly(A) region at its 3' end. In some embodiments in which the RNA is mRNA, the RNA typically contains a cap structure recognized in the art at its 5' end, e.g., for identifying the mRNA and linking it to a ribosome to initiate translation. In some embodiments, the RNA is synthetic RNA. Synthetic RNA includes RNA synthesized in vitro (e.g., by enzymatic synthesis methods and / or by chemical synthesis methods). In some embodiments, the polynucleotide encodes a polypeptide, which is preferably a Plasmodium T cell string polypeptide construct.

[0246] Ribonucleotides: As used herein, the term "ribonucleotide" encompasses unmodified ribonucleotides and modified ribonucleotides. As used herein, unmodified ribonucleotides include the purine bases adenine (A) and guanine (G) and the pyrimidine bases cytosine (C) and uracil (U). Modified ribonucleotides can include one or more modifications, including but not limited to, for example, (a) end modifications, such as 5'-end modifications (e.g., phosphorylation, dephosphorylation, conjugation, reverse linkage, etc.), 3'-end modifications (e.g., conjugation, reverse linkage, etc.), (b) base modifications, such as replacement with a modified base, a stabilizing base, a destabilizing base, or a base that pairs with an expanded library of ligands or a conjugated base, (c) sugar modifications (e.g., at the 2'-position or 4'-position) or replacement of the sugar, and (d) internucleoside linkage modifications, including modifications or replacements of the phosphodiester linkage. The term "ribonucleotide" also encompasses ribonucleotide triphosphates, including modified and unmodified ribonucleotide triphosphates.

[0247] Secretory signal: As used herein, the term "secretory signal" refers to an amino acid sequence motif that targets a relevant polypeptide for translocation into the secretory pathway.

[0248] Subject: As used herein, the term "subject" refers to an organism to which a composition described herein is to be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, domestic pets, etc.) and humans. In a preferred embodiment, the subject is a human subject. In some embodiments, the subject has a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, the subject is predisposed to a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, the subject exhibits one or more non-specific symptoms of a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, the subject is a human who is predisposed to a disease, disorder, or condition (e.g., malaria and / or malaria-related conditions) or has one or more characteristics that place the subject at risk of a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who has received and / or has been receiving a diagnosis and / or treatment.

[0249] Having: An individual "having" a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions) has been diagnosed with and / or exhibits one or more symptoms of the disease, disorder, and / or condition.

[0250] Prone: An individual who is "prone" to a disease, disorder, and / or condition (e.g., malaria, malaria-related conditions) is an individual who has a higher risk of developing the disease, disorder, and / or condition (e.g., malaria, malaria-related conditions) than a member of the general public. In some embodiments, an individual who is prone to a disease, disorder, and / or condition (e.g., malaria, malaria-related conditions) may not have been diagnosed with the disease, disorder, and / or condition (e.g., malaria, malaria-related conditions). In some embodiments, an individual who is prone to a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions) may exhibit symptoms of the disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, an individual who is prone to a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions) may not exhibit symptoms of the disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, an individual who is prone to a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions) will develop the disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, an individual who is prone to a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions) will not develop the disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions).

[0251] Therapy: As used herein, the term "therapy" refers to the administration or delivery of an agent or intervention that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect (e.g., has been shown to have such an effect statistically likely when administered to a relevant population). In some embodiments, a therapeutic agent or therapy is any substance that can be used to alleviate, improve, relieve, inhibit, prevent one or more symptoms or features of a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions), delay its onset, reduce its severity, and / or reduce its incidence. In some embodiments, a therapeutic agent or therapy is a medical intervention that can be performed to alleviate, relieve, inhibit, prevent one or more symptoms or features of a disease, disorder, and / or condition, delay its onset, reduce its severity, and / or reduce its incidence.

[0252] Transmembrane region: As used herein, the term "transmembrane region" refers to a region of a polypeptide that spans a biological membrane (such as the plasma membrane of a cell).

[0253] Treatment: As used herein, the terms "treat / treatment / treating" refer to any method for partially or completely alleviating, ameliorating, relieving, inhibiting, preventing one or more symptoms or characteristics of a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions), delaying its onset, reducing its severity, and / or reducing its incidence. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions). In some embodiments, treatment can be administered to a subject who exhibits only early signs of a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions), for example, for the purpose of reducing the risk of developing pathologies associated with the disease, disorder, and / or condition. In some embodiments, treatment can be administered to a subject in the advanced stage of a disease, disorder, and / or condition (e.g., malaria and / or malaria-related conditions).

[0254] Variant: As used herein, the term "variant" refers to a molecule that exhibits significant structural (e.g., primary or secondary) identity to a reference molecule but is structurally different from the reference molecule. For example, a variant polypeptide or nucleic acid can differ from a reference polypeptide or nucleic acid due to one or more differences in the amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalently attached components of the polypeptide or nucleic acid (e.g., attached to the polypeptide or nucleic acid backbone). Detailed Description

[0255] I. Malaria

[0256] Malaria is a mosquito-borne infectious disease caused by the unicellular eukaryotic parasite Plasmodium, which is transmitted through the bite of mosquitoes of the genus Anopheles (Phillips, M. et al., Malaria. Nat Rev Dis Primers 3, 17050 (2017), which is incorporated herein by reference in its entirety). Mosquitoes that transmit malaria must be infected by taking a previous blood meal from an infected subject (e.g., a human). When a mosquito bites an infected subject, a small amount of blood containing malaria parasites is ingested. The infected mosquito can then subsequently bite an uninfected subject, thereby infecting that subject.

[0257] Malaria remains one of the most serious infectious diseases, causing approximately 200 million clinical cases and 500,000 - 600,000 deaths annually. Although a great deal of effort has been devoted to developing treatments for malaria, many malaria parasites have developed resistance to available treatments. According to the Malaria Eradication Research Agenda initiative, malaria can only be eradicated through effective vaccination.

[0258] In 2015, the European Medicines Agency gave a positive opinion on a candidate malaria vaccine called "RTS,S", which was a milestone in malaria vaccine development. In 2019, the World Health Organization launched a pilot project to provide RTS,S to children at least 5 months old in parts of three sub-Saharan African countries. RTS,S / AS01 is an adjuvanted protein subunit vaccine composed of a part of the major repeat region of Plasmodium falciparum fused to hepatitis B surface antigen (HBsAg) and the C-terminus of CSP. The vaccine is a mixture of this PfCSP-HBsAg compound and HBsAg, which forms virus-like particles (RTS,S / AS01; Mosquirix TM ). RTS,S is administered according to a four-dose regimen: the initial three doses are scheduled to be administered at least 1 month apart, and the fourth dose is given 15 - 18 months after the third dose (see, for example, Vandoolaeghe & Schuerman Expert Rev Vaccines. 15:1481, 2016; PATH_MVI_RTSS_FactSheet_042019, each of the foregoing documents is incorporated herein by reference in its entirety). Reports indicate that RTS,S protected approximately 30% to 50% of children from clinical disease within 18 months. It has been reported that RTS,S induces protective antibody and CD4+ T cell responses, but only a negligible CD8+ T cell response (see, for example, Moris et al., Hum Vaccin Immunother 14:17, 2018, which is incorporated herein by reference in its entirety). A phase III study of RTS,S delivered as a three-dose series with a booster after 1 yr (year) showed moderate vaccine efficacy in children 5 to 17 months of age, preventing 36% of clinical malaria cases over the entire study period, with a median follow-up of 4 years, ranging from 20% in high-transmission settings to 66% in low-transmission settings. In addition, published literature indicates that the protective effect wanes over time, including reports of potential negative efficacy after 5 years in children with high malaria exposure (Olotu et al., 2016, N. Engl. J. Med. 374:2519 - 29, which is incorporated herein by reference in its entirety). Thus, an effective malaria vaccine remains a critically important and unmet medical need for global health.

[0259] A. Life cycle

[0260] During blood feeding, the infected mosquito injects sporozoites, called hepatic stage Plasmodium sporozoites, along with their anticoagulant saliva, and their journey through the skin reaches the lymphatic vessels and enters the hepatocytes of the liver. This journey occurs very quickly; it can be completed in only a few minutes (Sinnis et al., Parasitol Int. September 2007; 56(3):171-8, which is incorporated herein by reference in its entirety). This is the bottleneck stage of malaria infection known to be most favorable for therapeutic intervention, because the mosquito injects only a small number (thought to be at most a few hundred) of sporozoites, and only a small fraction of them establish an infection in the liver and develop into mature live-stage parasites (Flores-Garcia et al., mBio. November 20, 2018; 9(6):e02194-18, which is incorporated herein by reference in its entirety). Thus, subjects in whom the immune system is primed to clear sporozoites before they enter hepatocytes can effectively clear the infection.

[0261] A particular challenge associated with clearing malaria infection during this bottleneck period is that the most abundant and immunogenic protein on the surface of sporozoites, circumsporozoite protein (CSP), is exposed to the immune system only in small amounts and for a short duration, due to variable and low inoculation from the mosquito and the kinetics of hepatocyte infection after inoculation. After establishing liver infection, the parasite differentiates into a stage that no longer expresses CSP, but is a chimera with different surface antigens. In addition, due to the density and close proximity of adjacent CSPs on the parasite surface and the bivalent nature of antibodies, the binding of antibodies to CSP can produce a phenomenon called CSP precipitation, whereby antibodies can cross-link adjacent CSPs and cause them to precipitate and detach from the parasite surface, leaving a string of precipitated antibody-bound CSPs that the parasite can replace through its normal CSP translocation process (Livingstone et al., Sci Rep 11, 5318 (2021); Steward et al., J Protozool. July-August 1991; 38(4):411-21, the above-mentioned literature is incorporated herein by reference in its entirety).

[0262] When sporozoites move from the inoculation site in the skin to the liver, they traverse host cells (Mota et al., Science Jan. 5, 2001; 291(5501):141 - 4, which is incorporated herein by reference in its entirety). Sporozoites cross different types of host cells in the dermis, including fibroblasts and phagocytes (Amino et al., Cell Host Microbe. Feb. 14, 2008; 3(2):88 - 96, which is incorporated herein by reference in its entirety), as well as the hepatic sinusoidal barrier containing liver endothelial cells and Kupffer cells (Frevert et al., PLoS Biol 3(6):e192.2005, which is incorporated herein by reference in its entirety) and sinusoidal endothelial cells (Tavares et al., J Exp Med May 6, 2013; 210(5):905 - 15, which is incorporated herein by reference in its entirety) to gain access to hepatocytes. Sporozoites preferentially cross cells with low - sulfated heparan sulfate proteoglycan (HSPG), but preferentially invade cells with highly sulfated HSPG (Coppi et al., Cell Host & Microbe 2, 316–327, November 2007, which is incorporated herein by reference in its entirety).

[0263] The first observed cell traversal was the non - phagocytic entry of Plasmodium berghei sporozoites into macrophages, followed by "escape" from these cells (Vanderberg et al., J.Euk.Microbiol. 37:528 - 536, 1990, which is incorporated herein by reference in its entirety). The biochemical, biophysical, and step - by - step processes of traversal are still being explored. However, electron microscopy has shown that host cell rupture occurs upon entry and exit from host cells (Mota et al., 2001; Tavares et al., 2013, the above - mentioned literature is incorporated herein by reference in its entirety). It has also been shown that Plasmodium yoelii sporozoites can enter hepatocytes via transient vacuoles, and host membrane rupture occurs upon cell exit rather than cell entry (Risco - Castillo et al., Cell Host Microbe Nov. 11, 2015; 18(5):593 - 603, which is incorporated herein by reference in its entirety).

[0264] Sporozoites also cross hepatocytes before establishing an effective hepatocyte infection (Mota et al., 2001, which is incorporated herein by reference in its entirety). There are several possibilities as to why this occurs. The first hypothesis proposes that migration across hepatocytes primes the parasite for invasion by activating apical exocytosis (Mota et al., Nat Med November 2002;8(11):1318-22, which is incorporated herein by reference in its entirety). The second theory proposes that crossing releases hepatocyte growth factor (HGF), making adjacent hepatocytes more susceptible to infection (Carrolo et al., Nat Med. November 2003;9(11):1363-9, which is incorporated herein by reference in its entirety). Finally, other studies have shown that sporozoites require some time to switch off the crossing machinery and activate the invasion machinery (Amino et al., 2008; Coppi et al., 2007, the above-mentioned literature is incorporated herein by reference in its entirety), and the main function of crossing is to penetrate the cellular barrier and avoid being phagocytosed on the way to the liver (Amino et al., 2008; Coppi et al., 2007; Tavares et al., 2013, the above-mentioned literature is incorporated herein by reference in its entirety).

[0265] Although sporozoite crossing of human cells has been shown (Behet et al., Malar J April 5, 2014;13:136; Cha et al., J Exp Med August 24, 2015;212(9):1391-403; Dumoulin et al., PLoS One June 12, 2015;10(6):e0129623; van Schaijk et al., PLoS ONE,3(10).e3549 2008, the above-mentioned literature is incorporated herein by reference in its entirety), the molecular basis of the crossing process has been largely unstudied. Antibodies against circumsporozoite protein (CSP) attenuate crossing (Dumoulin et al., 2015, which is incorporated herein by reference in its entirety), but this could be due to inhibition of motility rather than a direct effect (Cha et al., J Exp Med September 19, 2016;213(10):2099-112, which is incorporated herein by reference in its entirety). In addition, antibodies induced by chloroquine prophylaxis with sporozoites interfere with cell crossing, and these antibodies can also target CSP (Behet et al., 2014). Recently, it has been shown that during crossing, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) on the parasite surface interacts with CD 68 on Kupffer cells (Cha et al., 2015; Cha et al., 2016, the above-mentioned literature is incorporated herein by reference in its entirety).

[0266] In rodent malaria parasites such as *Plasmodium berghei*, two microneme proteins have been identified that appear to be essential for cell traversal (the sporozoite microneme protein essential for cell traversal [SPECT1; Ishino et al., PLoS Biol., 2 (2004), pp. 77-84] and SPECT2 [Ishino et al., Cell Microbiol., 7 (2005), pp. 199-208], also known as perforin-like protein 1 [PLP1] [Kaiser et al., Mol. Biochem. Parasitol., 133 (2004), pp. 15-26], which is incorporated herein by reference in its entirety). Even though genetic disruption of either SPECT1 or SPECT2 renders sporozoites unable to traverse murine cells, they can still invade hepatocytes in vitro (Ishino et al., 2004; Ishino et al., 2005, which are incorporated herein by reference in their entirety). When sporozoites lacking SPECT1 or SPECT2 are injected into rodents, their liver infectivity is impaired, but a small number of sporozoites can still establish liver infections, resulting in subsequent patency. However, depletion of Kupffer cells allows mutants to establish liver infections at levels comparable to those of wild-type parasites (Ishino et al., 2004; Ishino et al., 2005, which are incorporated herein by reference in their entirety). This data indicates that traversal of rodent-infected sporozoites is important for crossing the sinusoidal layer, but not for hepatocyte invasion, development of the exoerythrocytic form of malaria, or growth within erythrocytes (Ishino et al., 2004; Ishino et al., 2005, which are incorporated herein by reference in their entirety).

[0267] An ortholog of SPECT2 in *Plasmodium yoelii* PLP1 has been shown to play a role in cell traversal. Although this protein is not required for entry into hepatocytes, it plays a role in its expulsion from transient vacuoles during traversal (Risco-Castillo et al., 2015, which is incorporated herein by reference in its entirety). Thus, sporozoites infecting rodents can traverse host cells by generating vacuoles during the entry step and utilize perforin-like proteins (e.g., SPECT2 / PLP1) to escape from this compartment and / or the host cell during cell exit.

[0268] Once sporozoites invade liver cells, they differentiate into merozoites, which are the replicative forms of the parasite capable of lysing liver cells after multiple rounds of replication. Within a few days, hundreds of sporozoites can give rise to hundreds of thousands of merozoites. When the infected liver cells rupture, they release merozoites into the bloodstream, where they invade red blood cells and initiate the asexual replication stage, which is the symptomatic stage of the disease. Within just a few days, millions of merozoites will appear in the blood.

[0269] Malaria symptoms typically appear 4 - 8 days after the initial red blood cell invasion. The replication cycle of merozoites within red blood cells lasts 36 - 72 hours until hemolysis occurs, releasing merozoites for another round of red blood cell infection. Thus, in synchronous infections (infections resulting from a single infectious bite), fever occurs every 36 - 72 hours when the infected red blood cells lyse and release large amounts of endotoxin.

[0270] Plasmodium parasites gain entry into red blood cells through specific ligand - receptor interactions mediated by proteins on the surface of the parasite that interact with receptors on host red blood cells (mature red blood cells) or reticulocytes (immature red blood cells). While Plasmodium falciparum can invade both red blood cells and reticulocytes and replicate within them, Plasmodium vivax and other species mainly invade reticulocytes, which are less abundant than red blood cells. Most of the red blood cell - binding or reticulocyte - binding proteins associated with invasion are redundant or expressed as families of variant forms; however, for Plasmodium falciparum, two essential red blood cell receptors (basigin and decay - accelerating factor of complement, also known as CD55) have been identified.

[0271] Plasmodium vivax and Plasmodium ovale can also enter a dormant state in the liver, known as hypnozoites.

[0272] Merozoites released from red blood cells can invade other red blood cells and continue to replicate, or in some cases differentiate into male or female gametocytes. Gametocytes accumulate in the skin capillaries and are then taken up by the mosquito vector during another blood meal. In the mosquito gut, each male gametocyte produces eight small gametes after three rounds of mitosis; the female gametocyte matures into a macrogamete. The male microgametes are flagellated and motile forms and seek out the female macrogamete. The male and female gametes fuse to form a diploid zygote, which elongates into an ookinete; this motile form secretes chitinase in order to enter the peritrophic matrix and cross the midgut epithelium to reach the basolateral side of the midgut, where it establishes itself as an oocyst in the basal lamina. The oocyst matures over 14 - 15 days, undergoes a replication cycle to form sporozoites, which are eventually released into the hemocoel, an environment rich in sugars and substrates favorable for parasite survival. Thousands of sporozoites can be formed from a single oocyst and are randomly distributed throughout the hemocoel. These sporozoites are motile and rapidly disrupt the hemolymph, with only approximately 20% successfully invading the salivary glands. After invading the salivary glands, the sporozoites are reprogrammed via an unknown mechanism in preparation for invasion of the liver. Evidence of this reprogramming has been demonstrated by the inability of midgut sporozoites (directly from oocysts) to invade hepatocytes, and also by the fact that sporozoites that have successfully invaded the salivary glands cannot invade another salivary gland (if any). Salivary gland sporozoites alter mosquito behavior and salivary gland function, as less saliva is produced, leading to an increase in mosquito biting behavior, increasing the chance of transmission to the human host via mosquito bites.

[0273] Some drugs that prevent Plasmodium invasion of the liver or its replication in the liver have prophylactic activity, drugs that block the erythrocytic stage are necessary for the symptomatic stage of the disease treatment, and compounds that inhibit gametocyte formation or their development in the mosquito (including drugs that kill blood - feeding mosquitoes) are transmission blockers (Phillips et al., Malaria. Nat Rev Dis Primers 3, 17050 (2017), which is incorporated herein by reference in its entirety).

[0274] B. Genome

[0275] Since the first sequence of the Plasmodium falciparum 3D7 genome was completed in 2002, genomic studies of malaria parasites have advanced rapidly. Except for a short diploid stage after fertilization in the mosquito midgut, Plasmodium parasites are haploid throughout their life cycle. The genome sizes of different species vary from 20 to 35 megabases, containing 14 chromosomes, a circular plastid genome of approximately 35 kilobases, and multiple copies of 6 - kilobase mitochondrial DNA. Comparison of genomes from different species shows that homologous genes are usually present in syntenic blocks, which are arranged in different orders among different chromosomes.

[0276] The adenine-thymine (AT) content of Plasmodium species can also vary widely, e.g., ~80% AT in Plasmodium falciparum, Plasmodium reichenowi, and Plasmodium gallinaceum; ~75% AT in rodent malaria parasites; and ~60% AT in Plasmodium vivax, Plasmodium knowlesi, and Plasmodium cynomolgi. The AT content in introns and intergenic non-coding regions is generally higher than that in protein-coding exons, with an average of 80.6% AT for the entire Plasmodium falciparum genome and 86.5% for non-coding sequences. The high AT content of Plasmodium falciparum reflects a large number of low-complexity regions, simple sequence repeats and microsatellites, and highly skewed codon usage bias. The polymorphism of AT-rich repeat sequences provides abundant markers for linkage mapping of drug resistance genes and for tracking the evolution and structure of parasite populations.

[0277] Malaria parasite genomes carry multigene families that play important roles in the interaction of parasites with their hosts, including, for example, antigenic variation, signal transduction, protein trafficking, and adhesion. Among these gene families, the most extensively studied is the gene encoding Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Each individual Plasmodium falciparum parasite carries a unique set of 50 to 150 copies of var genes, and switching of gene expression can give rise to antigenic variation. PfEMP1 plays an important role in the pathogenesis of clinical manifestations such as cerebral malaria and placental malaria, where it mediates the cytoadhesion of infected red blood cells (iRBCs) in deep tissues. Different PfEMP1 molecules bind to various host molecules, including α2-macroglobulin, CD36, chondroitin sulfate A (CSA), complement 1q, CR1, E-selectin, and P-selectin, endothelial protein C receptor (EPCR), heparan sulfate, ICAM1, IgM, IgG, PECAM1, thrombospondin (TSP), and VCAM1. This binding leads to the activation of various host inflammatory responses. Hemoglobinopathies (including hemoglobin C and hemoglobin S trait conditions) interfere with the display of PfEMP1 in the knob structure of iRBCs. This poor display of PfEMP1 on the host cell surface provides antimalarial protection by reducing cytoadhesion and activating inflammatory processes that promote the development of severe disease.

[0278] Members of the Plasmodium falciparum dispersed repetitive sequence (pir) multigene family are named differently according to the parasite species, such as yir in Plasmodium yoelii, bir in Plasmodium berghei, and vir in Plasmodium vivax. Several Plasmodium falciparum gene families (stevor, rif, and PfMC-2TM) are grouped with pir based on their similar gene structures, which characteristically include a short first exon, a long second exon, and a third exon encoding a transmembrane domain. In recent studies, pir genes from Plasmodium chabaudi (cir) have been shown to be expressed at different cellular locations, on the inside and surface of iRBCs, as well as in merozoites. Malaria parasites devote much of their genome to gene families that ensure evasion of host immune defenses and protect molecular processes crucial for infection. These families highlight the importance of studying them in parasite-host interactions and virulence, despite the inherent difficulties in their study.

[0279] Another exemplary polymorphic gene family contains a set of 14 genes that encode proteins with six cysteines (6-Cys). These proteins are generally located on the parasite surface where they interact with host proteins and are expressed at different parasite developmental stages. 6-Cys proteins also exhibit diverse functions and have been shown to play roles in, for example, parasite fertilization, mating interactions, evasion of the immune response, and invasion of hepatocytes. Proteins expressed during the asexual stage are generally polymorphic and / or under selective pressure, suggesting that they may be targets of the host immune response; however, their functions in parasite development remain largely unknown.

[0280] The Plasmodium genome can be highly polymorphic. Early studies have shown that polymorphisms involve tens to hundreds of kilobases, and the chromosomal structure in Plasmodium falciparum is largely conserved in the central region but has extensive polymorphisms in length and sequence near the telomeres. Most subtelomeric variations can be explained by recombination within repetitive sequence blocks and gene families.

[0281] The frequency of simple sequence repeats (microsatellites) in Plasmodium falciparum is estimated to be approximately one polymorphic microsatellite per kb of DNA. Without being bound by any theory, this high rate may reflect the AT-rich nature of the genome. In other Plasmodium species with lower genomic AT content, the frequency of microsatellites appears to be lower. In addition to the high polymorphism and repetitive structure of the Plasmodium genome, there are also a large number of single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) (Su et al., Plasmodium Genomics and Genetics: New Insights into Malaria Pathogenesis, Drug Resistance, Epidemiology, and Evolution. Clin Microbiol Rev. July 31, 2019; 32(4), which is incorporated herein by reference in its entirety).

[0282] C. Plasmodium proteins

[0283] Plasmodium parasites are known to express various proteins at different stages of their life cycle. Exemplary Plasmodium proteins are described below, and exemplary amino acid sequences are provided in Table 2.

[0284] Circumsporozoite protein (CSP) is a multifunctional protein involved in the Plasmodium life cycle as it is required for sporozoite formation in the mosquito midgut, sporozoite release from oocysts, invasion of the salivary gland, attachment of sporozoites to hepatocytes in the liver, and sporozoite invasion of hepatocytes (see, e.g., Zhao et al., (2016) PLoS ONE 11(8):e0161607). CSP is present in all Plasmodium species and while there are amino acid sequence differences between species, the overall domain structure of the central repeat region and the non-repetitive sequence flanking regions is highly conserved (see, e.g., Zhao et al., (2016) PLoS ONE 11(8):e0161607; Wahl et al., (2022) J. Exp. Med. 219:e20201313, which are incorporated herein by reference in their entireties). CSP sequences are known (see, e.g., UniProt accession numbers A0A2L1C F52, A0A2L, 1CF88, C6FGZ3, C6FH2,7C6FHG7, M1V060, M1V0A3, M1V0B0, M1V0C4, M1V0E0, M1V9I4, M1VFN9, M1VKZ2, P02893, Q5EIJ9, Q5EIK2, Q5EIK8, Q5EIL3, Q5EIL5, Q5EI L8, Q5R2L2, Q7K740, Q8I9G5, Q8I9J3, Q8I9J4), and Table 1 includes exemplary sequences of CSP Plasmodium falciparum isolates from Asia, South America, and Africa.

[0285] Table 1: Exemplary sequences of CSP Plasmodium falciparum isolates from Asia, South America, and Africa

[0286]

[0287]

[0288]

[0289] An exemplary CSP amino acid sequence is provided in SEQ ID NO:1.

[0290] RH5 is found in Plasmodium falciparum, but not in other Plasmodium species that infect humans. RH5 orthologs are also found in other species belonging to the Lavarenia subgenus, which includes parasites that infect chimpanzees and gorillas, indicating that it plays a unique role in the invasion of human red blood cells by Plasmodium falciparum. See, for example, Ragotte et al., Trends Parasitol. 36(6) 2020, which is incorporated herein by reference in its entirety. RH5 is expressed during the mature schizont stage and can complex with cysteine-rich protective antigen (CyRPA) and RH5 interacting protein (Ripr) to form an elongated protein trimer on the merozoite surface that binds to the erythrocyte surface protein basigin. See, for example, Ragotte Trends Parasitol June 2020; 36(6):545-559, which is incorporated herein by reference in its entirety).

[0291] In humans, RH5 that binds to basigin plays a crucial role in invasion, acting downstream of membrane deformation. Binding of RH5 to basigin is required to induce a calcium peak within the erythrocyte, and induction of the calcium peak is blocked when merozoites attempt to invade in the presence of anti-RH5, anti-Ripr, or anti-basigin antibodies or soluble basigin. See, for example, Ragotte (2020).

[0292] RH5 is a 63 kDa protein expressed during the mature schizont stage. It is processed and cleaved into a 45 kDa form that is shed by the parasite. The structure of PfRH5 presents a kite-like architecture formed by two three-helix bundles joined together. See, for example, Ragotte (2020).

[0293] RH5 sequences are known (see, for example, UniProt accession numbers A0A159SK44, A0A159SK99, A0A159SKS8, A0A159SKW8, A0A159SL23, A0A159SL78, A0A159SL96, A0A159SLM7, A0A159SMC8, A0A159SMR9, A0A161FQT0, A0A1B1UZE2, A0A1B1UZE4, A0A1B1UZE5, A0A346RCI1, A0A346RCJ0, A0A346RCJ2, A0A346RCJ3, A0A346RCJ4, A0A346RCK4, A0A346RCK5, A0A346RCK6, A0A346RCK9, B2L3N7, Q8IFM5), and an exemplary RH5 amino acid sequence is provided in SEQ ID NO:365.

[0294] P113 is a glycosylphosphatidylinositol (GPI)-anchored protein that directly interacts with the N-terminus of unprocessed RH5, providing a mechanism for tethering the RH5 invasion complex to the merozoite surface. See, e.g., Ragotte (2020). Orthologs of P113 have been found in all Plasmodium species sequenced to date, indicating a common and conserved function (Bullen et al., (2022) Molecular Microbiology 117:1245-1262, which is incorporated herein by reference in its entirety). Nevertheless, in a rodent model of malaria (Plasmodium berghei), p113 knockout parasites are still viable, indicating that the protein is not essential for asexual blood stage growth and invasion. However, the knockout parasites do exhibit a defect in natural sporozoite transmission, resulting in an extended latency period in infected mice (Offeddu et al., (2014) Mol. Biochem. Parasitology 193:101-109, which is incorporated herein by reference in its entirety).

[0295] The Plasmodium P113 sequence is known (see, e.g., Uniprot accession number Q8ILP3). An exemplary P113 amino acid sequence is provided in SEQ ID NO:326.

[0296] Cysteine-rich protective antigen (CyRPA) is a 43 kDa protein with a predicted N-terminal secretion signal. CyRPA is part of a multi-protein complex that includes RH5 and Ripr, which are important for triggering Ca 2+ release and establishing tight junctions. PfCyRPA is highly conserved, with only a single SNP with an incidence greater than 5%, is essential for invasion (since conditional knockdown results in loss of invasion activity), and has poor seroreactivity to natural exposure (see, e.g., Ragotte (2020)).

[0297] The Plasmodium CyRPA sequence is known (see, e.g., Uniprot accession numbers A0A2S1Q7P0, A0A2S1Q7P5, A0A2S1Q7Q4, Q8IFM8). An exemplary CyRPA amino acid sequence is provided in SEQ ID NO:329.

[0298] The RH5 interacting protein (Ripr) is a protein of approximately 120 kDa and localizes to the micronemes during the schizont stage of the Plasmodium falciparum life cycle. The full-length 120 kDa protein is processed into two similarly sized fragments, namely the N-terminal fragment (including EGF domains 1 and 2) and the C-terminal fragment (including EGF domains 3-10). During parasite invasion, Ripr co-localizes with RH5 and CyRPA at the junction between the merozoite and the erythrocyte. Parasites with conditional knockout of PfRipr induce membrane deformation but cannot complete invasion (see, for example, Ragotte (2020)).

[0299] The Plasmodium Ripr sequences are known (see, for example, UniProt accession numbers A0A193PDI9, A0A193PDK3, A0A193PDK8, A0A193PDL3, A0A193PDL9, A0A193PDP4, A0A193PDQ8, A0A193PE01, A0A193PE05, A0A193PE07, O97302, A0A193PE17). An exemplary Ripr amino acid sequence is provided in SEQ ID NO:332.

[0300] E140 is found in every Plasmodium species for which a genomic sequence is available and is highly conserved, with the range of amino acid identity between species being 34-92%. See, for example, Smith et al., PLoS one 15.5 (2020):e0232234; http: / / doi:10.1371 / journal.pone.023223; and US Patent Publication No. US2019 / 0117752; the above documents are incorporated herein by reference in their entirety. E140 is also highly conserved (95-99%) among Plasmodium falciparum isolates worldwide and exhibits a low mutation frequency. E140 is expressed at different life stages of the malaria parasite (specifically, E140 has been detected in sporozoites, liver and blood stage parasites).

[0301] Protein structure algorithms predict that the E140 protein has five transmembrane domains, possibly spanning membranes of parasite or host origin. E140 exhibits different protein expression patterns at the mature sporozoite, late liver and late schizont stages. It travels to the front and rear ends of the sporozoite, the parasitophorous vacuole space in the late liver, and around the merozoites developing in the late schizont stage. It is also known to be expressed in mature salivary gland sporozoites as well as sporozoites and oocysts derived from oocysts.

[0302] The E140 sequence is known (see, for example, UniProt accession numbers A0A650D649, A0A650D653, A0A650D672, A0A650D687, A0A650D690, A0A650D694, A0A650D6A3, A0A650D6B8, A0A650D6L3, A0A650D6L7, Q8I299), and an exemplary E140 amino acid sequence is provided in SEQ ID NO: 335.

[0303] CelTOS is required for sporozoites to cross Kupffer cells during liver invasion. CelTOS forms pores within cells, allowing sporozoites to be discharged into the liver. Antibody epitopes have been characterized in immunized mice and infected populations (Pf and Pv). In mouse studies, it has been shown that immunization with CelTOS provides protection and resistance to challenge. Vaccination with CelTOS generates antibodies that can bind to the extracellular domain of the pore-forming complex, preventing the complete formation of pores and preventing sporozoite traversal into the liver. See, for example, Jimah et al., Elife Dec 1, 2016;5:e20621.doi:10.7554 / eLife.20621, which is incorporated herein by reference in its entirety.

[0304] The Plasmodium CelTOS sequence is known (see, for example, Uniprot accession numbers M1ETJ8, Q53UB7, A0A2R4QLA5, A0A2R4QLI0, A0A2R4QLI5, A0A2R4QLJ1, A0A2R4QLJ4, M1ETJ8, Q53UB8, Q8I5P1). An exemplary CelTOS amino acid sequence is provided in SEQ ID NO: 350.

[0305] SPECT1 and SPECT2 (the latter sometimes also referred to as perforin-like protein 1 (PLP1)) are essential Plasmodium proteins that may play a role in cell traversal. See Yang et al., Cell Rep. Mar 28, 2017;18(13):3105-3116.doi:10.1016 / j.celrep.2017.03.017, which is incorporated herein by reference in its entirety. Targeted disruption of Plasmodium falciparum SPECT1 or SPECT2 has been shown to reduce the infectivity of sporozoites during hepatic stage development in humanized mice. However, the mechanism of cell traversal by these two proteins in Plasmodium falciparum remains to be determined. See Yang et al.

[0306] SPECT1 and SPECT2 are considered attractive pre-erythrocytic immune targets because they are thought to play a key role in traversing the dermis and hepatic sinusoidal wall prior to invasion of hepatocytes by the malaria parasite. Recombinant Plasmodium falciparum SPECT2 has been shown to cause lysis of erythrocytes in a Ca 2+ -dependent manner, similar to the MACPF / CDC domain of PfSPECT2. PfSPECT2 is also associated with the Ca2+-dependent egress of Plasmodium falciparum merozoites from erythrocytes.

[0307] The Plasmodium SPECT1 and SPECT2 sequences are known (see, for example, UniProt accession numbers Q8IDR4 and Q9U0J9), and exemplary amino acid sequences are provided in SEQ ID NO:353 and SEQ ID NO:356, respectively.

[0308] Exported protein 1 (EXP1) is a single-pass transmembrane protein with an N-terminal signal peptide that is expressed during the intra-erythrocytic and hepatic stages (see, for example, Spielmann et al., Int J Med Microbiol. October 2012;302(4-5):179-86, which is incorporated herein by reference in its entirety). EXP1 has been shown to be initially localized to dense granules in merozoites and then transported to the parasitophorous vacuole membrane (PVM) after invasion (see, for example, Iriko et al., Parasitol Int. October 2018;67(5):637-639, which is incorporated herein by reference in its entirety). Once localized to the PVM, EXP1 forms homotypic oligomers with its N-terminus exposed to the parasitophorous vacuole lumen and its C-terminus exposed to the erythrocyte cytosol (see, for example, Mesén-Ramírez et al., PLoS Biol. September 30, 2019;17(9):e3000473, which is incorporated herein by reference in its entirety).

[0309] EXP1 has been shown to have glutathione S-transferase (GST) activity, which can protect the malaria parasite from oxidative damage (see, for example, Mesén-Ramírez et al., PLoS Biol 17(9) September 30, 2019;17(9):e3000473, which is incorporated herein by reference in its entirety). Recently, it has been demonstrated that EXP1 is important for parasite survival by maintaining the correct localization of the nutrient-permeable channel EXP2 in the PVM (see, for example, Mesén-Ramírez et al., 2020).

[0310] The polypeptide sequence of Plasmodium falciparum EXP1 is known (see, e.g., UniProt accession numbers Q8IIF0, W7JTD3, Q25840, Q548U2, Q5VKK2, Q5VKK5, Q5WRH8, Q6V9G4, Q6V9G6, Q6V9G9, Q6V9H1, Q6V9H2, Q9U590, P04923, P04926). Exemplary EXP1 amino acid sequences are provided in SEQ ID NO: 314.

[0311] Upregulated in infective sporozoites 3 (UIS3) is a membrane-bound protein localized to the parasitophorous vacuole membrane (PVM) of sporozoites in infected hepatocytes. UIS3 has been shown to interact with liver fatty acid-binding protein (L-FABP) and is involved in fatty acid and / or lipid import during the growth stages of the malaria parasite (see, e.g., Sharma et al., J Biol Chem. Aug 29, 2008; 283(35):24077–24088; Mikolajczak et al., Int J Parasitol. Apr 2007; 37(5):483-9, which are incorporated herein by reference in their entireties).

[0312] After the sporozoites invade host hepatocytes, they synthesize extremely important structural features of the malaria parasite (e.g., the parasitophorous vacuole membrane). During the hepatocyte stage, the malaria parasite relies on host fatty acids to rapidly synthesize its membranes (see, e.g., Sharma et al., J Biol Chem. Aug 29, 2008; 283(35):24077–24088, which is incorporated herein by reference in its entirety). Insertion of UIS3 into the PVM provides the malaria parasite with a means of importing essential fatty acids and / or lipids during the rapid sporozoite growth stage (see, e.g., Sharma et al., 2008).

[0313] Immunization with UIS3-deficient Plasmodium berghei sporozoites can protect against malaria in a rodent malaria model (see, e.g., Mueller et al., Nature. Jan 13, 2005; 433(7022):164-7, which is incorporated herein by reference in its entirety). UIS3-deficient Plasmodium berghei can initiate the transformation process in the liver; however, they show severe defects during transformation into trophozoites (see, e.g., Mueller et al., 2005). UIS3-deficient Plasmodium berghei are also unable to develop into mature liver schizonts and thus interrupt malaria infection within the liver itself (see, e.g., Mueller et al., 2005). Further, it has previously been shown that UIS3 from Plasmodium berghei and UIS3 from Plasmodium falciparum exhibit low (i.e., 34%) amino acid sequence identity (see, e.g., Mueller et al., 2005).

[0314] The Plasmodium UIS3 sequences are known (see, for example, UniProt accession numbers A0A509ARS3, A0A1C6YLP3, Q8IEU1, A0A384KLI1, A0A1G4H423, A0A077YB01, Q9NFU4). Exemplary UIS3 amino acid sequences are provided in SEQ ID NO: 359.

[0315] Upregulated in infective sporozoites 4 (UIS4) contains a single transmembrane domain and localizes to the secretory organelles of sporozoites and the parasitophorous vacuole membrane (PVM) of the liver stage. UIS4 is not expressed in blood stage or early sporozoites produced in oocysts (see, for example, Mackellar et al., Eukaryot Cell. May 2010;9(5):784 - 794, which is incorporated herein by reference in its entirety).

[0316] Deletion of the UIS4 gene is associated with arrest of early liver development (see, for example, Vaughan and Kappe, Cold Spring Harb Perspect Med. Jun 1, 2017;7(6):a025486, which is incorporated herein by reference in its entirety). Recently, it has been shown that UIS4 is involved in Plasmodium berghei survival by evading host actin structures deployed as part of the host cytosolic defense (see, for example, Bana et al., iScience. Apr 22, 2022;25(5):104281.doi:10.1016 / j.isci.2022.104281.eCollection May 20, 2022, which is incorporated herein by reference in its entirety). Plasmodium falciparum has an ortholog of UIS4, named ETRAMP10.3, which cannot function as a complement to P. yoelii UIS4, suggesting that it may have a different function in the Plasmodium falciparum life cycle (see Mackellar et al., Eukaryot. Cell 9:784 - 94 (2010), which is incorporated herein by reference in its entirety).

[0317] Plasmodium falciparum early transcribed membrane protein 10.3 (ETRAMP10.3) is a protein of approximately 10 kDa and is a member of the early transcribed membrane protein multigene family, which is conserved among Plasmodium species and includes proteins located in the parasitophorous vacuole. Several ETRAMP proteins are specific to Plasmodium falciparum and are not found in Plasmodium species that infect other organisms. ETRAMP10.3 is an example that is expressed in both liver and blood stage Plasmodium falciparum parasites. It has been found that ETRAMP10.3 transcription peaks during the transition of Plasmodium falciparum blood stage infection in the human host from the ring to the trophozoite stage. ETRAMP10.3 localizes to the parasitophorous vacuole and is exported to the host red blood cell during blood stage infection. Although ETRAMP10.3 is sometimes mentioned as being upregulated in the infective sporozoite gene 4 (UIS4), it should be understood that based on synteny and structural similarity, ETRAMP10.3 is an ortholog of UIS4. However, ETRAMP10.3 is not a functional ortholog of UIS4 and may play a different biological role. Although the biological function of ETRAMP10.3 has not been fully determined, its localization to vesicular structures in the host red blood cell suggests that it plays a role in host-parasite interactions or the remodeling of infected red blood cells. ETRAMP10.3 appears to play a key role in the Plasmodium life cycle. When ETRAMP10.3 is deleted, the deletion can lead to disruption of mouse liver stage development and asexual blood stage progression.

[0318] Although the terms "UIS4" and "ETRAMP10.3" in the literature are sometimes used to refer to different proteins, in the context of the present disclosure, the terms "UIS4" and "ETRAMP10.3" can be used interchangeably to refer to ETRAMP10.3.

[0319] The Plasmodium ETRAMP10.3 sequence is known (see, for example, UniProt accession number Q8IJM9, which is incorporated herein by reference in its entirety). An exemplary ETRAMP10.3 amino acid sequence is provided in SEQ ID NO: 362.

[0320] Liver-specific protein 1 (LISP-1) is expressed during Plasmodium development in hepatocytes and localizes to the parasitophorous vacuole membrane (PVM) (see, for example, Ishino et al., Cell Microbiol. September 2009; 11(9):1329–1339). LISP-1 is shown to be expressed at high levels during late liver development and is involved in PVM breakdown and subsequent merozoite release (see, for example, Ishino et al., Cell Microbiol. September 2009; 11(9):1329-1339, which is incorporated herein by reference in its entirety).

[0321] Intracellular malaria parasites lacking LISP-1 develop into hepatic merozoites and exhibit normal infectivity to red blood cells (see, for example, Ishino et al., Cell Microbiol. September 2009; 11(9):1329-1339, which is incorporated herein by reference in its entirety). However, LISP1-deficient liver-stage malaria parasites do not disrupt the PVM and remain trapped inside hepatocytes (see, for example, Ishino et al., 2009).

[0322] The malaria parasite LISP-1 sequences are known (see, for example, UniProt accession numbers A0A2I0C2X6, Q8ILR5). Exemplary LISP-1 amino acid sequences are provided in SEQ ID NO:308.

[0323] Liver-specific protein 2 (LISP-2) contains a modified 6-cys domain and is expressed during malaria parasite development in hepatocytes (see, for example, Orito et al., Mol Microbiol. January 2013; 87(1):66-79, which is incorporated herein by reference in its entirety). LISP-2 is shown to be expressed by liver-stage malaria parasites, exported to hepatocytes, and distributed throughout the host cell, including the nucleus (see, for example, Orito et al., 2013).

[0324] Intracellular malaria parasites lacking LISP2 do not mature efficiently during merozoite development (see, for example, Orito et al., 2013).

[0325] The malaria parasite LISP-2 sequences are known (see, for example, UniProt accession numbers A0A2I0BZR4, Q8I1X6, Q9U0D4). Exemplary LISP-2 amino acid sequences are provided in SEQ ID NO:311.

[0326] Thrombospondin-related adhesive protein (TRAP) contains an N-terminal domain commonly referred to as the von Willebrand factor A domain, although it is most similar to the integrin I domain in that it contains Mg required for sporozoite motility in vitro and infection in vivo 2+The metal ion-dependent adhesion site (MIDAS) of the ion (see, for example, Lu et al., PLoS One. 2020;15(1):e0216260, which is incorporated herein by reference in its entirety). The I domain is inserted into a β-sheet belt, followed by a thrombospondin repeat (TSR) domain, a C-terminal proline-rich segment, a single transmembrane domain, and a cytoplasmic domain (see, for example, Lu et al., 2020). Sequence analysis of the proline-rich segment revealed the presence of an SH3 domain-binding PxxP motif in Plasmodium TRAP (Akhouri et al., Malar J. April 22, 2008;7:63. doi:10.1186 / 1475-2875-7-63, which is incorporated herein by reference in its entirety).

[0327] TRAP is stored in micronemes and is exposed on the surface at the sporozoite front when the parasite makes contact with the host cell (Akhouri et al., Malar J. April 22, 2008;7:63. doi:10.1186 / 1475-2875-7-63, which is incorporated herein by reference in its entirety). TRAP also plays an important role in sporozoite invasion of hepatocytes by helping the sporozoite gliding motility and recognizing host receptors on mosquito salivary glands and hepatocytes (Akhouri et al., Malar J. April 22, 2008;7:63. doi:10.1186 / 1475-2875-7-63, which is incorporated herein by reference in its entirety).

[0328] The Plasmodium TRAP sequence is known (see, for example, UniProt accession numbers A0A5Q2E XK8, A0A5Q2EZD7, A0A5Q2F1F6, A0A5Q2F2B8, A0A5Q2F2H6, A0A5Q2F4G9, O76110, P16893, Q01507, Q26020, Q76NM2, W8VNB6), and an exemplary TRAP amino acid sequence is provided in SEQ ID NO:287.

[0329] The liver stage-associated protein (LSAP-1) has been shown to be mainly seen in the periphery of intracellular liver parasites throughout development, but not in blood stage parasites, and may be seen in small amounts in salivary gland sporozoites (see, for example, Siau et al., PLoS Pathog. August 8, 2008;4(8):e1000121, which is incorporated herein by reference in its entirety). LSAP-1 is one of the most abundant transcripts in the salivary gland transcriptome, but has not been detected in proteomic examinations of sporozoites. Instead, expression is detected only in the liver stage (see, for example, Siau et al., 2008).

[0330] The Plasmodium LSAP-1 sequence is known (see, e.g., UniProt accession numbers Q8I632, W7JR53). Exemplary LSAP-1 amino acid sequences are provided in SEQ ID NO: 302.

[0331] Like LSAP-1, LSAP-2 is also one of the most abundant transcripts in the salivary gland transcriptome but has not been detected in proteomic surveys of sporozoites. LSAP-2 has shown some efficacy as a vaccine when combined with other antigens. See, e.g., Halbroth et al., Infect Immun. January 22, 2020; 88(2):e00573-19. doi:10.1128 / IAI.00573-19. Published January 22, 2020, which is incorporated herein by reference in its entirety.

[0332] The Plasmodium LSAP-2 sequence is known (see, e.g., UniProt accession numbers Q8I632, W7JR53). Exemplary LSAP-2 amino acid sequences are provided in SEQ ID NO: 305.

[0333] Liver stage antigen 1 (LSA-1) is expressed after Plasmodium has invaded hepatocytes and the antigen accumulates in the parasitophorous vacuole (see, e.g., Tucker, K. et al., 2016, ‘Pre-Erythrocytic Vaccine Candidates in Malaria’, in A.J. Rodriguez-Morales (ed.), Current Topics in Malaria, IntechOpen, London. 10.5772 / 65592, which is incorporated herein by reference in its entirety). The function of LSA-1 is currently unknown (see, e.g., Tucker, K. et al., 2016).

[0334] LSA-1 is a 230 kDa pre-erythrocytic stage protein containing a large central region composed of more than eighty 17-amino acid residue repeat units flanked by highly conserved C- and N-termini (Richie, T.L. and Parekh, F.K. (2009) Malaria, in Vaccines for Biodefense and Emerging and Neglected Diseases (Barrett, A.D.T. and Stanberry L.R., eds.), pp. 1309-1364, Elsevier, which is incorporated herein by reference in its entirety). LSA1 is expressed only by liver-stage malaria parasites and not by sporozoites (Richie, T.L. and Parekh, F.K. (2009) Malaria, which is incorporated herein by reference in its entirety). In Vaccines for Biodefense and Emerging and Neglected Diseases (Barrett, A.D.T. and Stanberry L.R., eds., pp. 1309-1364, Elsevier, which is incorporated herein by reference in its entirety). The repeat region results in significant variation in the protein between Plasmodium falciparum strains (see, e.g., Tucker, K. et al., 2016).

[0335] The Plasmodium LSA-1 sequences are known (see, e.g., UniProt accession numbers Q25886, Q25887, Q25893, Q26028, Q9GTX5, O96125). Exemplary LSA-1 amino acid sequences are provided in SEQ ID NO:290.

[0336] Liver stage antigen 3 (LSA-3) is a 200-kDa protein composed of three non-repetitive regions (NR-A, NR-B, and NR-C) flanked by two short repeat regions and one long repeat region (see, e.g., Tucker, K. et al., 2016). The non-repetitive sequence regions are highly conserved among geographically diverse Plasmodium falciparum strains (see, e.g., Tucker, K. et al., 2016). The most significant variation is in the repeat regions, which is due to the organization and number of repeat subunits rather than the composition of the repeat regions (see, e.g., Tucker, K. et al., 2016).

[0337] Recently, in vitro data have shown that antibodies against LSA-3, particularly the C-terminal portion of LSA-3, can provide some protection (see, e.g., Morita et al., Sci Rep. April 5, 2017; 7:46086. doi:10.1038 / srep46086, which is incorporated herein by reference in its entirety).

[0338] The Plasmodium LSA-3 sequences are known (see, e.g., UniProt accession numbers C7DU21, C7DU22, C7DU23, C7DU24, C7DU25, C7DU26, C7DU27, C7D U28, C7DU29, C7DU32, C7DU33, C7DU34, C7DU36, C7DU37, C7DU38, C7DU39, C7DU40, Q8I042, Q8I0A5, Q8I0D0, Q8IFR1, Q8IFR2, Q8IFR3, Q8IFR4, Q8IFR5, Q8IFR6, Q8IFR7, Q8IFR8, Q8IFR9, Q8IFS0, Q8IFS1, Q8IFS2, Q8IFS3, Q8IFS4, Q8IFS5, Q8IFS6, Q8IFS7, Q8IFS8, Q8IFS9, Q8IFT0, Q8IFT1, Q8IFT2, Q8IFT3, Q8IFT4, Q9U0N9, Q9U0P0, A0A2I0BVD6, A0PFM9, O96275). An exemplary LSA-3 amino acid sequence is provided in SEQ ID NO:299.

[0339] Glutamate-rich protein (GARP) is an 80 kDa protein, the name of which is derived from its glutamate-rich amino acid sequence, which accounts for 24% of all its residues. GARP is mainly expressed in the ring stage and trophozoites, and is shown to be a non-essential gene in cell culture, but is highly immunogenic in animal models (Hon et al., Trends Parasitol. August 2020; 36(8):653-655, which is incorporated herein by reference in its entirety). Although GARP is not essential in cell culture, its localization to the periphery of infected red blood cells may indicate its role in the sequestration of infected red blood cells. It has been proposed that GARP participates in sequestration via binding to a chloride / bicarbonate anion exchanger (Lau et al., PLoS Pathog. 10, e1004135. 2014, which is incorporated herein by reference in its entirety). Antibodies against GARP have been proposed as markers for protection against severe malaria and have shown efficacy in experimental trials in monkeys. See, for example, Hon et al., Trends in Paras August 2020; 36(8):653-655.doi:10.1016 / j.pt.2020.05.012 and Laue et al., Plos Path. 2014 10, e1004135, the above-mentioned literature is incorporated herein by reference in its entirety. The GARP sequence is known (see, for example, UniProt accession numbers Q9GTW3, Q9U0N1), and an exemplary GARP amino acid sequence is provided in SEQ ID NO: 341.

[0340] Parasite-infected erythrocyte-specific protein 2 (PIESP2) (see, for example, UniProt accession number Q8I488) is a highly immunogenic protein that is first expressed in the trophozoite stage and is thought to be important for the clinical progression of cerebral malaria. Although this protein is mainly found inside red blood cells, it has been shown to be present on the surface of red blood cells, enabling them to adhere to the endothelial cells of cerebral blood vessels. Antibodies against PIESP2 have been shown to prevent the vascular adhesion of malaria parasites and can be demonstrated to be valuable in preventing inflammatory responses and blood-brain barrier damage in the brain during the progression of cerebral malaria (see, for example, Liu et al., Int J BiolMacromol. April 30, 2021; 177:535-547.doi:10.1016 / j.ijbiomac.2021.02.145, which is incorporated herein by reference in its entirety). The PIESP2 sequence is known (see, for example, UniProt accession number Q8I488), and an exemplary PIESP2 amino acid sequence is provided in SEQ ID NO: 344.

[0341] Sporozoite egress antigen-1 (SEA1) is a large 244 kDa protein that lacks a transmembrane domain or known targeting signal. The function of SEA1 is unknown; however, it has been shown to be effective in rodent vaccine studies and has even been proposed as a target for protective antibodies seen in children. SEA1 got its name because antibodies against this protein were reported to inhibit the egress of Plasmodium merozoites. SEA1 localizes tightly to the centromere during nuclear division, suggesting that it plays a role in the fundamental process of replication. To date, various studies have proposed that SEA1 plays a role not only in egress but also in the mitosis of the nucleus during replication. (See, for example, Perrin et al., mBio. Mar 9, 2021;12(2):e03377-20.doi:10.1128 / mBio.03377-20, which is incorporated herein by reference in its entirety). The SEA1 sequence is known (see, for example, UniProt accession number A0A143ZXM2), and an exemplary SEA1 amino acid sequence is provided in SEQ ID NO:347.

[0342] D. Embodiments of Malaria Sequences

[0343] The exemplary full-length CSP polypeptide amino sequence from the Plasmodium falciparum isolate 3D7 corresponds to SEQ ID NO:1 and includes the following: a secretion signal (amino acids 1-18); an N-terminal domain (amino acids 19-104); a junction region (amino acids 93-104), a central domain (amino acids 105-272); and a C-terminal domain (amino acids 273-397). In the exemplary SEQ ID NO:1, the N-terminal domain includes an N-terminal region (amino acids 19-80); an N-terminal end region (amino acids 81-92); and a junction region (amino acids 93-104). In the exemplary SEQ ID NO:1, the junction region includes an R1 region (amino acids 93-97) and the amino acids ADGNPDP (SEQ ID NO:93) at positions 98-104. In the exemplary SEQ ID NO:1, the central domain includes a minor repeat region (amino acids 105-128) and a major repeat region (amino acids 129-272). In the exemplary SEQ ID NO:1, the minor repeat region includes three repeats of the amino acid sequence NANPNVDP (SEQ ID NO:477). In the exemplary SEQ ID NO:1, the major repeat region includes 35 repeats of the amino acid sequence NANP (SEQ ID NO:108), where the 35 repeats of the amino acid sequence NANP are divided into two consecutive segments, and one segment includes 17 repeats of the amino acid sequence NANP, and one segment includes 18 repeats of the amino acid sequence NANP flanked by NVDP (SEQ ID NO:105). The major repeat region includes the amino acid sequences NPNANP (SEQ ID NO:111) and NANPNA (SEQ ID NO:114). In the exemplary SEQ ID NO:1, the C-terminal domain includes a C-terminal region (amino acids 273-375) and a transmembrane domain (amino acids 376-397). In the exemplary SEQ ID NO:1, the C-terminal region includes a Th2R region (amino acids 314-327) and a Th3R region (amino acids 352-363).

[0344] Table 2: Exemplary Amino Acid Sequences

[0345]

[0346]

[0347] II. Plasmodium T - cell string polypeptide constructs

[0348] Among other aspects, the present disclosure utilizes RNA technology as a modality to express one or more Plasmodium T cell string polypeptide constructs (also referred to as "malaria T cell string polypeptide constructs" or "malaria T cell peptide string constructs"), which comprise one or more T cell antigens or one or more portions thereof (e.g., one or more antigenic fragments) from one or more Plasmodium proteins described herein. The Plasmodium T cell string polypeptide constructs as described herein may comprise one or more T cell antigens or one or more portions thereof (e.g., one or more antigenic fragments) from one or more Plasmodium polypeptides as described herein. In some embodiments, the Plasmodium T cell string polypeptide constructs as described herein comprise one or more Plasmodium liver stage antigens that elicit a T cell response. As understood in the art, a "T cell antigen" as described herein can induce a T cell response in a subject or a model system. In some embodiments, the Plasmodium T cell string polypeptide constructs targeting the liver stage of Plasmodium infection comprise polypeptides or antigenic portions thereof that are expected to be relatively abundant in infected hepatocytes and elicit a T cell response. The polynucleotides encoding the Plasmodium T cell string polypeptide constructs as described herein and the Plasmodium T cell string polypeptide constructs as described herein are designed to deliver polypeptides to a subject and, in turn, for proteolytic degradation and processing for presentation in the subject such that the subject mounts an immune response (e.g., a T cell response). Methods for determining the presence of a T cell response are well known in the art and are described in the Examples. In a preferred embodiment, the Plasmodium T cell string polypeptide constructs as described herein comprise more than one T cell antigen and / or epitope or one or more portions thereof from Plasmodium liver stage polypeptides. In some preferred embodiments, one or more Plasmodium liver stage polypeptides or antigenic portions thereof comprise between 2 and 20 liver stage polypeptides or antigenic portions thereof (e.g., antigenic portions that induce a T cell response). In some embodiments, the Plasmodium T cell string polypeptide construct comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 (preferably 4, 5, 6, 7, 8, 9, 10, 11, or 12) different liver stage polypeptides or antigenic portions thereof (e.g., each of which is capable of eliciting a T cell response).

[0349] For example, in some embodiments, the Plasmodium T cell string polypeptide construct comprises one or more Plasmodium T cell antigens from CSP, LSA-1(a), LSA-1(b), TRAP, LSAP2, UIS3, ETRAMP10.3, LISP-1, LISP-2, LSA-3, EXP1, LSAP1 and / or polypeptide regions or portions thereof (e.g., one or more antigenic fragments thereof). In some embodiments, the Plasmodium T cell string polypeptide construct comprises between about 25 and about 1200 amino acids, such as between about 25 and about 1100 amino acids, such as between about 25 and about 1000 amino acids, such as between about 25 and about 750 amino acids, such as between about 25 and about 500 amino acids. In some embodiments, the Plasmodium T cell string polypeptide construct comprises about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150 or about 1200 amino acids. In some embodiments, the Plasmodium T cell string polypeptide construct further comprises one or more additional amino acid sequences, such as a secretion signal (e.g., a heterologous secretion signal), a transmembrane region (e.g., a heterologous transmembrane region), a trafficking signal and / or a linker, as described herein.

[0350] A. Selection of T cell antigens

[0351] In some embodiments, the T cell antigens utilized in the Plasmodium T cell string polypeptide constructs described herein include Plasmodium protein sequences identified and / or characterized by one or more of the following:

[0352] HLA-I or HLA-II binding (e.g., to HLA alleles present in a relevant population);

[0353] HLA ligandomics data identified by mass spectrometry;

[0354] Relatively high expression;

[0355] Sequence conservation;

[0356] Expression during the early liver stage of the parasite life cycle;

[0357] Localization to the parasitophorous vacuole membrane;

[0358] Seroreactivity;

[0359] Immunogenicity (e.g., the presence of one or more B cell and / or T cell epitopes; evidence of the ability to induce sterile protection in model systems including, for example, humans, non-human primates, and / or mice); and

[0360] Sequences of eight or more amino acids that do not overlap with the human proteome, unless six or more amino acids are from linker sequences.

[0361] In some embodiments, such characteristics are evaluated experimentally or computationally. In some embodiments, such characteristics are evaluated by consulting published reports.

[0362] For example, in some embodiments, HLA-I and / or HLA-II binding is evaluated experimentally; in some embodiments, it is predicted. In some embodiments, algorithms such as neonmhc 1 and / or neonmhc 2 are used to evaluate predicted HLA-I or HLA-II binding, which algorithms predict and / or characterize the likelihood of MHC class I and MHC class II binding, respectively. Alternatively or additionally, in some embodiments, the MHC-peptide presentation prediction algorithm or MHC-peptide presentation predictor is or includes NetMHCpan or NetMHCIIpan. In some embodiments, a hidden Markov model approach can be used for MHC-peptide presentation prediction and / or characterization. In some embodiments, the peptide prediction model MARIA can be used. In some embodiments, NetMHCpan is not used to predict or characterize the MHC binding likelihood of peptides as described herein. In some embodiments, the peptide prediction model MARIA can be used. In some embodiments, NetMHCIIpan is not used to predict or characterize the MHC binding likelihood of peptides as described herein. In some embodiments, neither NetMHCpan nor NetMHCIIpan is used to predict or characterize the MHC binding likelihood of peptides as described herein. In some embodiments, the MHC-peptide presentation prediction algorithm or MHC-peptide presentation predictor is or includes (Real-time Epitope Computation in Oncology), which provides high-quality MHC-peptide presentation prediction based on expression, processing, and binding capabilities. See, for example, Abelin et al., Immunity 21:315, 2017; Abelin et al., Immunity 15:766, 2019, each of which is incorporated herein by reference in its entirety.

[0363] In some embodiments, HLA binding and / or ligandomics assessment may take into account the geographical region of the subject to be immunized. For example, in some embodiments, HLA allele diversity may be considered. In some embodiments, when considered together, the T cell antigens comprise peptides (e.g., epitopes) that are expected or determined to bind to a significant percentage (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more) of the HLA alleles that are expected or known to be present in the relevant region or population. In some embodiments, when considered together, the T cell antigens comprise peptides that are expected or determined to bind to the most prevalent (e.g., the 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 most prevalent, or at least 1, 2, 3, 4 or 5 of the 10 most prevalent, etc.) HLA alleles that are expected or known to be present in the relevant region or population.

[0364] In some embodiments, the expression level is determined experimentally (e.g., in a model system or in an infected human). In some embodiments, the expression level is a reported level (e.g., in a published or submitted report). In some embodiments, the expression level is assessed in terms of RNA (e.g., via RNASeq). In some embodiments (and typically preferably), the expression level is assessed in terms of protein.

[0365] In some embodiments, sequence conservation is assessed, for example, using publicly available sequence assessment software (such as, for example, the multiple sequence alignment programs MAFFT, Clustal Omega, etc.). In some embodiments, sequence conservation is determined by consulting published resources (e.g., sequences). In some embodiments, sequence conservation includes taking into account currently or recently detected strains (e.g., in an active outbreak).

[0366] In some embodiments, surface exposure is assessed by reference to publicly available databases and / or software. In some embodiments, surface exposure is assessed by reference to publicly available data, such as, for example, as described in Swearingen et al., “Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics” PLoS Pathog (2016), the contents of which are incorporated herein by reference for the purposes described herein.

[0367] In some embodiments, serum reactivity is evaluated by contacting a serum sample from an infected individual with a polypeptide comprising the sequence of interest (e.g., display can be via, for example, phage display or peptide arrays; see, e.g., Whittemore et al., PlosOne, 2016, which is incorporated herein by reference in its entirety). In some embodiments, serum reactivity is evaluated by consulting literature reports and / or database data indicating serum-recognized sequences.

[0368] In some embodiments, the evaluation of immunoreactivity and / or the presence of epitopes can be or include consulting the Immune Epitope Database (IEDB), which is known to those skilled in the art as a free resource funded by NIAID that catalogs experimental data on antibody and T cell epitopes (see iedb.org).

[0369] In some embodiments, the ability to induce sterile protection is evaluated, e.g., as described in one or more of the following: Schofield et al., “γ Interferon, CD8 +T cells and antibodies required for immunity to malaria sporozoites” Nature 330, 664-666 (1987); Weiss et al., (1988), “CD8+ T cells (cytotoxic / suppressors) are required for protection in mice immunized with malaria sporozoites” Proc. Natl. Acad. Sci. U.S.A. 85, 573-576; Romero et al., “Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria.” Nature 341, 323-326 (1989); Rodrigues et al., (1991) “CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria.” Int. Immunol. 3, 579-585; Chakravarty et al., “CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes.” Nat Med. September 2007; 13(9):1035-41. Epub August 19, 2007, each of the foregoing documents is incorporated herein by reference in its entirety).

[0370] In some embodiments, T cell antigens are characterized by dendritic cell presentation, which in turn can indicate HLA binding and / or immunogenicity. Without being bound by any particular theory, it is proposed that dendritic cell presentation (e.g., in peripheral lymph nodes) can induce CD8+ T cells that migrate to the liver, such as those that can eliminate parasite-infected hepatocytes. See, e.g., Chakravarty et al., “CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes.” Nat Med. September 2007;13(9):1035-41. Epub August 19, 2007, the entire content of which is incorporated herein for the purposes described herein.

[0371] B. Exemplary T Cell Antigens

[0372] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more Plasmodium T cell antigens from Plasmodium proteins selected from CSP, LSA-1(a), LSA-1(b), TRAP, LSAP2, UIS3, IS4, LISP-1, LISP-2, LSA-3, EXP1, and LSAP1.

[0373] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include from 2 to about 20 Plasmodium T cell antigens (e.g., from about 2 to about 15, from about 2 to about 10, from about 2 to about 9, from about 2 to about 8, from about 2 to about 7, from about 2 to about 6, or from about 2 to about 5 Plasmodium T cell antigens). In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include four Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include five Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include six Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include seven Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include eight Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include nine Plasmodium T cell antigens. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include ten Plasmodium T cell antigens. In some embodiments, the malaria T cell peptide string constructs described herein contain only one or more immunogenic portions of the included Plasmodium T cell antigens.

[0374] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP, such as Plasmodium falciparum CSP, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium CSP polypeptide fragment. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal region and a junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal end region and a junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises a Plasmodium CSP N-terminal domain and a junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acids according to SEQ ID NO:133 or consists of the amino acids according to SEQ ID NO:133.In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142. In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142.

[0375] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide, such as a Plasmodium LSA-1(a) polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising the amino acid sequence of SEQ ID NO:293 or consisting of the amino acid sequence of SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(a) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises the amino acids according to SEQ ID NO:144 or consists of the amino acids according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153.In some embodiments, the antigenic Plasmodium falciparum LSA-1(a) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153 or consists of the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153.

[0376] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide, such as a Plasmodium LSA-1(b) polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising the amino acid sequence of SEQ ID NO:296 or consisting of the amino acid sequence of SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(b) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises the amino acids according to SEQ ID NO:155 or consists of the amino acids according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.In some embodiments, the antigenic Plasmodium falciparum LSA-1(b) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.

[0377] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide, such as a Plasmodium TRAP polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising the amino acid sequence of SEQ ID NO: 287 or consisting of the amino acid sequence of SEQ ID NO: 287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 287 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium TRAP polypeptide fragment. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 171 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acids according to SEQ ID NO: 171 or consists of the amino acids according to SEQ ID NO: 171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.

[0378] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an LSAP1 polypeptide, such as a Plasmodium LSAP1 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an LSAP1 polypeptide comprising the amino acid sequence of SEQ ID NO: 302 or consisting of the amino acid sequence of SEQ ID NO: 302. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an LSAP1 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 302 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 302. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an antigenic Plasmodium LSAP1 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 192 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 192. In some embodiments, the antigenic Plasmodium LSAP1 polypeptide fragment comprises the amino acids according to SEQ ID NO: 192 or consists of the amino acids according to SEQ ID NO: 192.

[0379] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide, such as a Plasmodium LSAP2 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising the amino acid sequence of SEQ ID NO: 305 or consisting of the amino acid sequence of SEQ ID NO: 305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 305 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 198 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises the amino acids according to SEQ ID NO: 198 or consists of the amino acids according to SEQ ID NO: 198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210 or consists of the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.

[0380] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include the UIS3 polypeptide, such as the Plasmodium UIS3 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising the amino acid sequence of SEQ ID NO:359 or consisting of the amino acid sequence of SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium UIS3 polypeptide fragment. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acids according to SEQ ID NO:212 or consists of the amino acids according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:217 or consists of the amino acid sequence according to SEQ ID NO:217.

[0381] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide, such as a Plasmodium ETRAMP10.3 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising the amino acid sequence of SEQ ID NO:362 or consisting of the amino acid sequence of SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium ETRAMP10.3 polypeptide fragment. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acids according to SEQ ID NO:219 or consists of the amino acids according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227.In some embodiments, the antigenic Plasmodium falciparum ETRAMP10.3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227 or consists of the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227.

[0382] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a LISP-1 polypeptide, such as a Plasmodium LISP-1 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a LISP-1 polypeptide comprising the amino acid sequence of SEQ ID NO:308 or consisting of the amino acid sequence of SEQ ID NO:308. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a LISP-1 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LISP-1 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises the amino acids according to SEQ ID NO:229 or consists of the amino acids according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises the amino acids SEQ ID NO:234, 235 or 236 or consists of the amino acids SEQ ID NO:234, 235 or 236.

[0383] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LISP-2 polypeptide, such as a Plasmodium LISP-2 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LISP-2 polypeptide comprising the amino acid sequence of SEQ ID NO:311 or consisting of the amino acid sequence of SEQ ID NO:311. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LISP-2 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:311 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:311. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LISP-2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:238 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises the amino acids according to SEQ ID NO:238 or consists of the amino acids according to SEQ ID NO:238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:243, 244, 245, 246 or 247 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:243, 244, 245, 246 or 247. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:243, 244, 245, 246 or 247 or consists of the amino acid sequence according to SEQ ID NO:243, 244, 245, 246 or 247.

[0384] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide, such as a Plasmodium LSA-3 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising the amino acid sequence of SEQ ID NO:299 or consisting of the amino acid sequence of SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-3 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises the amino acids according to SEQ ID NO:249 or consists of the amino acids according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262.In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262 or consists of the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262.

[0385] In some embodiments, the Plasmodium T cell string polypeptide construct described herein includes an EXP1 polypeptide, such as a Plasmodium EXP1 polypeptide. In some embodiments, the Plasmodium T cell string polypeptide construct described herein includes an EXP1 polypeptide comprising the amino acid sequence according to SEQ ID NO: 314 or consisting of the amino acid sequence according to SEQ ID NO: 314. In some embodiments, the Plasmodium T cell string polypeptide construct described herein includes an EXP1 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 314 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 314. In some embodiments, the Plasmodium T cell string polypeptide construct described herein includes an antigenic Plasmodium EXP1 polypeptide fragment. In some embodiments, the antigenic Plasmodium EXP1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 263 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 263. In some embodiments, the antigenic Plasmodium EXP1 polypeptide fragment comprises the amino acids according to SEQ ID NO: 263 or consists of the amino acids according to SEQ ID NO: 263.

[0386] C. Transport signal

[0387] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a trafficking signal. For example, in some embodiments, the trafficking signal is a MHC class I trafficking determinant (MITD). In some embodiments, the MITD comprises or consists of the amino acid sequence according to SEQ ID NO:479.

[0388] D. Secretion signal

[0389] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a secretion signal, such as a secretion signal that is functional in mammalian cells. In some embodiments, the secretion signal comprises or consists of a Plasmodium secretion signal. In some embodiments, the Plasmodium secretion signal comprises or consists of a Plasmodium CSP secretion signal.

[0390] In some embodiments, the secretion signal utilized is a heterologous secretion signal. In some embodiments, the heterologous secretion signal comprises or consists of a non-human secretion signal. In some embodiments, the heterologous secretion signal comprises or consists of a viral secretion signal. In some embodiments, the viral secretion signal comprises or consists of a HSV secretion signal (e.g., a HSV-1 or HSV-2 secretion signal). In some embodiments, the HSV secretion signal comprises or consists of a HSV glycoprotein D (gD) secretion signal. In some embodiments, the secretion signal comprises or consists of an Ebola virus secretion signal. In some embodiments, the Ebola virus secretion signal comprises or consists of an Ebola virus spike glycoprotein (SGP) secretion signal.

[0391] In some embodiments, the secretion signal is characterized by a length of about 15 to 30 amino acids.

[0392] In many embodiments, the secretion signal is located at the N-terminus of the Plasmodium T cell string polypeptide constructs described herein. In some embodiments, the secretion signal preferably permits trafficking of the associated Plasmodium T cell string polypeptide construct to a defined cellular compartment, preferably the cell surface, endoplasmic reticulum (ER) or endosome-lysosome compartment.

[0393] In some embodiments, the secretion signal is selected from the S1S2 secretion signal (aa 1-19), the immunoglobulin secretion signal (aa 1-22), the human SPARC secretion signal, the human insulin isoform 1 secretion signal, the human albumin secretion signal, etc. Those skilled in the art will know other secretion signals, such as those disclosed in WO2017 / 081082 (e.g., SEQ ID NO: 1-1115 and 1728 or fragment variants thereof), which is incorporated herein by reference in its entirety. In some embodiments, the Plasmodium T cell string polypeptide construct described herein does not contain a secretion signal.

[0394] In some embodiments, the secretion signal is the secretion signal listed in Table 3 or a secretion signal having 1, 2, 3, 4, or 5 amino acid differences relative thereto. In some embodiments, the signal sequence is selected from those included in Table 3 below and / or those encoded by the sequences in Table 4 below.

[0395] Table 3: Exemplary Secretion Signals

[0396]

[0397] Table 4: Exemplary Polynucleotide Sequences Encoding Secretion Signals

[0398]

[0399] E. Transmembrane Region

[0400] In some embodiments, the Plasmodium T cell string polypeptide construct described herein includes a transmembrane region. In some embodiments, the transmembrane region includes or consists of a Plasmodium transmembrane region. In some embodiments, the transmembrane region utilized is a region that is typically CSP-related in nature. In some embodiments, the Plasmodium transmembrane region contains or consists of the Plasmodium CSP glycosylphosphatidylinositol (GPI) anchor region, such as amino acids 374-397 of SEQ ID NO: 1. In some embodiments, the transmembrane region utilized is a heterologous transmembrane region.

[0401] In some embodiments, the transmembrane region is located at the N-terminus of the Plasmodium T cell string polypeptide construct. In some embodiments, the transmembrane region is located at the C-terminus of the Plasmodium T cell string polypeptide construct. In some embodiments, the transmembrane region is not located at the N-terminus or C-terminus of the Plasmodium T cell string polypeptide construct.

[0402] Transmembrane regions are known in the art, and any of them can be used in the Plasmodium T cell string polypeptide constructs described herein. In some embodiments, the transmembrane region comprises or is the transmembrane region of hemagglutinin (HA) of influenza virus, Env of HIV-1, equine infectious anemia virus (EIAV), murine leukemia virus (MLV), mouse mammary tumor virus, G protein of vesicular stomatitis virus (VSV), rabies virus or a seven-transmembrane domain receptor.

[0403] In some embodiments, the heterologous transmembrane region does not include the hemagglutinin transmembrane region. In some embodiments, the heterologous transmembrane region comprises or consists of a non-human transmembrane region. In some embodiments, the heterologous transmembrane region comprises or consists of a viral transmembrane region. In some embodiments, the heterologous transmembrane region comprises or consists of an HSV transmembrane region, such as an HSV-1 or HSV-2 transmembrane region. In some embodiments, the HSV transmembrane region comprises or consists of an HSV gD transmembrane region, such as comprising or consisting of the amino acid sequence according to SEQ ID NO: 447.

[0404] In some embodiments, the heterologous transmembrane region comprises or consists of a human transmembrane region. In some embodiments, the human transmembrane region comprises or consists of the human decay-accelerating factor glycosylphosphatidylinositol (hDAF-GPI) anchor region. In some embodiments, the hDAF-GPI anchor region comprises or consists of the amino acid sequence according to SEQ ID NO: 450.

[0405] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein do not comprise a transmembrane region.

[0406] F. Linker

[0407] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more linkers. In some embodiments, the linker is or comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids. In some embodiments, the linker is or comprises no more than about 30, 25, 20, 15, 10 or fewer amino acids. The linker can comprise any amino acid sequence and is not limited to any particular amino acid. In some embodiments, the linker comprises one or more glycine (G) amino acids. In some embodiments, the linker comprises one or more serine (S) amino acids. In some embodiments, the linker comprises amino acids selected based on cleavage predictors to produce a highly cleavable linker.

[0408] In some embodiments, the linker is or comprises S-G4-S-G4-S. In some embodiments, the linker is or comprises the amino acid sequence according to SEQ ID NO:455. In some embodiments, the linker is or comprises the amino acid sequence according to SEQ ID NO:452. In some embodiments, the linker is a linker according to any one of SEQ ID NO:453, 455, 452, 458 (GGS), 459 (GGGS), 456, 460, 454 or 457. In some embodiments, the linker is or comprises the sequence as shown in WO2017 / 081082, which is incorporated herein by reference in its entirety (see SEQ ID NO:1509-1565, or fragments or variants thereof).

[0409] In some embodiments, the Plasmodium T cell tandem polypeptide construct described herein comprises a linker between two Plasmodium T cell antigens.

[0410] G. Embodiments of the Plasmodium T cell tandem polypeptide construct

[0411] In some embodiments, the Plasmodium T cell tandem polypeptide construct described herein comprises two or more of the following: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (iii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (iv) an antigenic Plasmodium TRAP polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium UIS3 polypeptide fragment; (vii) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (viii) an antigenic Plasmodium LISP-1 polypeptide fragment; (ix) an antigenic Plasmodium LISP-2 polypeptide fragment; and (x) an antigenic Plasmodium LSA-3 polypeptide fragment.

[0412] In some embodiments, the Plasmodium T cell tandem polypeptide construct described herein comprises one or more Plasmodium polypeptides or portions thereof from Plasmodium falciparum. In some embodiments, the one or more Plasmodium polypeptides or portions thereof are one or more Plasmodium falciparum T cell antigens. In some embodiments, the one or more Plasmodium falciparum T cell antigens are from the Plasmodium falciparum isolate 3D7.

[0413] In some embodiments, the Plasmodium T cell tandem polypeptide construct described herein does not comprise one or more Plasmodium polypeptides or portions thereof from Plasmodium berghei (e.g., an antigenic Plasmodium berghei CSP polypeptide fragment).

[0414] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein do not include antigenic fragments of bacterial polypeptides. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein do not include antigenic Bacillus Calmette-Guérin (BCG) polypeptide fragments. In some embodiments, the antigenic BCG polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 461. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein do not include antigenic tetanus toxin (TT) polypeptide fragments. In some embodiments, the antigenic TT polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 462.

[0415] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein do not include antigenic Plasmodium sporozoite threonine-asparagine-rich protein (STARP) polypeptide fragments. In some embodiments, the antigenic Plasmodium STARP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 463.

[0416] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more Plasmodium polypeptide regions or portions thereof (e.g., antigenic fragments) as described above. Exemplary combinations are described below.

[0417] Constructs including CSP, TRAP, LSA-1(a), LSA-1(b), LSA-3, LSAP2

[0418] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a Plasmodium circumsporozoite protein (CSP) polypeptide (or one or more antigenic Plasmodium CSP polypeptide fragments), a Plasmodium thrombospondin-related anonymous protein (TRAP) polypeptide (or one or more antigenic Plasmodium TRAP polypeptide fragments), a Plasmodium liver stage antigen 1 (LSA-1)(a) polypeptide (or one or more antigenic Plasmodium LSA-1(a) polypeptide fragments), a Plasmodium LSA-1(b) polypeptide (or one or more antigenic Plasmodium LSA-1(b) polypeptide fragments), a Plasmodium LSA-3 polypeptide (or one or more antigenic Plasmodium LSA-3 polypeptide fragments), and a Plasmodium LSAP2 polypeptide (or one or more antigenic Plasmodium LSAP2 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0419] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP polypeptide, such as a Plasmodium falciparum CSP polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more antigenic Plasmodium CSP polypeptide fragments, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal end region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment does not contain the N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acids according to SEQ ID NO:133 or consists of the amino acids according to SEQ ID NO:133.In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142. In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142.

[0420] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide, such as a Plasmodium TRAP polypeptide, such as a Plasmodium falciparum TRAP polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising the amino acid sequence of SEQ ID NO:287 or consisting of the amino acid sequence of SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium TRAP polypeptide fragment. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acids according to SEQ ID NO:171 or consists of the amino acids according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.

[0421] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide, such as a Plasmodium LSA-1(a) polypeptide, such as a Plasmodium falciparum LSA-1(a) polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising the amino acid sequence of SEQ ID NO:293 or consisting of the amino acid sequence of SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(a) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises the amino acids according to SEQ IDNO:144 or consists of the amino acids according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153.In some embodiments, the antigenic Plasmodium falciparum LSA-1(a) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153 or consists of the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153.

[0422] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide, such as a Plasmodium LSA-1(b) polypeptide, such as a Plasmodium falciparum LSA-1(b) polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(b) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.In some embodiments, the antigenic Plasmodium falciparum LSA-1(b) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.

[0423] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide, such as a Plasmodium LSA-3 polypeptide, such as a Plasmodium falciparum LSA-3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising the amino acid sequence of SEQ ID NO:299 or consisting of the amino acid sequence of SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-3 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises the amino acids according to SEQ ID NO:249 or consists of the amino acids according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262.In some embodiments, the antigenic Plasmodium falciparum LSA-3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262 or consists of the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262.

[0424] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide, such as a Plasmodium LSAP2 polypeptide, such as a Plasmodium falciparum LSAP2 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210.In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210 or consists of the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.

[0425] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (iv) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (v) an antigenic Plasmodium LSA-3 polypeptide fragment; and (vi) an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein sequentially include: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (iv) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (v) an antigenic Plasmodium LSA-3 polypeptide fragment; and (vi) an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:3. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include the amino acid sequence of SEQ ID NO:3. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein sequentially include: (i) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (ii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (iii) an antigenic Plasmodium LSAP2 polypeptide fragment; (iv) an antigenic Plasmodium CSP polypeptide fragment; (v) an antigenic Plasmodium LSA-3 polypeptide fragment; and (vi) an antigenic Plasmodium TRAP polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:6. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include the amino acid sequence of SEQ ID NO:6.

[0426] Constructs including LSAP1, EXP1, UIS3, ETRAMP10.3, LISP-1, LISP-2

[0427] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a Plasmodium LSAP1 polypeptide (or one or more antigenic Plasmodium LSAP1 polypeptide fragments), a Plasmodium EXP1 polypeptide (or one or more antigenic Plasmodium EXP1 polypeptide fragments), a Plasmodium UIS3 polypeptide (or one or more antigenic Plasmodium UIS3 polypeptide fragments), a Plasmodium ETRAMP10.3 polypeptide (or one or more antigenic Plasmodium ETRAMP10.3 polypeptide fragments), a Plasmodium LISP-1 polypeptide (or one or more antigenic Plasmodium LISP-1 polypeptide fragments), and a Plasmodium LISP-2 polypeptide (or one or more antigenic Plasmodium LISP-2 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0428] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP1 polypeptide, such as a Plasmodium LSAP1 polypeptide, such as a Plasmodium falciparum LSAP1 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP1 polypeptide comprising the amino acid sequence of SEQ ID NO:302 or consisting of the amino acid sequence of SEQ ID NO:302. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP1 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:302 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:302. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP1 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:192 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:192. In some embodiments, the antigenic Plasmodium LSAP1 polypeptide fragment comprises the amino acids according to SEQ ID NO:192 or consists of the amino acids according to SEQ ID NO:192.

[0429] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an EXP1 polypeptide, such as a Plasmodium EXP1 polypeptide, such as a Plasmodium falciparum EXP1 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an EXP1 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 314. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an EXP1 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 314 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 314. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium EXP1 polypeptide fragment. In some embodiments, the antigenic Plasmodium EXP1 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 263 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 263. In some embodiments, the antigenic Plasmodium EXP1 polypeptide fragment comprises the amino acids according to SEQ ID NO: 263 or consists of the amino acids according to SEQ ID NO: 263.

[0430] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include the UIS3 polypeptide, such as the Plasmodium UIS3 polypeptide, such as the Plasmodium falciparum UIS3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising the amino acid sequence of SEQ ID NO:359 or consisting of the amino acid sequence of SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium UIS3 polypeptide fragment. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acids according to SEQ ID NO:212 or consists of the amino acids according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:217 or consists of the amino acid sequence according to SEQ ID NO:217.

[0431] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide, such as a Plasmodium ETRAMP10.3 polypeptide, such as a Plasmodium falciparum ETRAMP10.3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising the amino acid sequence of SEQ ID NO:362 or consisting of the amino acid sequence of SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium ETRAMP10.3 polypeptide fragment. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acids according to SEQ ID NO:219 or consists of the amino acids according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227.In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227 or consists of the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227.

[0432] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide, such as a Plasmodium LISP-1 polypeptide, such as a Plasmodium falciparum LISP-1 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:308. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium LISP-1 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO:234, 235 or 236.

[0433] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide, such as a Plasmodium LISP-2 polypeptide, such as a Plasmodium falciparum LISP-2 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 311. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 311 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 311. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium LISP-2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 238 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO: 238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 243, 244, 245, 246 or 247 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 243, 244, 245, 246 or 247.In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 243, 244, 245, 246 or 247.

[0434] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises: (i) an antigenic Plasmodium LSAP1 polypeptide fragment; (ii) an antigenic Plasmodium EXP1 polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LISP-1 polypeptide fragment; and (vi) an antigenic Plasmodium LISP-2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises, in order: (i) an antigenic Plasmodium EXP1 polypeptide fragment; (ii) an antigenic Plasmodium UIS3 polypeptide fragment; (iii) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (iv) an antigenic Plasmodium LSAP1 polypeptide fragment; (v) an antigenic Plasmodium LISP-2 polypeptide fragment; and (vi) an antigenic Plasmodium LISP-1 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence according to SEQ ID NO: 9. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises, in order: (i) an antigenic Plasmodium UIS3 polypeptide fragment; (ii) an antigenic Plasmodium LSAP1 polypeptide fragment; (iii) an antigenic Plasmodium LISP-1 polypeptide fragment; (iv) an antigenic Plasmodium EXP1 polypeptide fragment; (v) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and (vi) an antigenic Plasmodium LISP-2 polypeptide fragment. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence according to SEQ ID NO: 12. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 12.

[0435] Constructs comprising CSP, TRAP, LSAP2, UIS3, ETRAMP10.3

[0436] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein comprise a CSP polypeptide (or one or more antigenic Plasmodium CSP polypeptide fragments), a Plasmodium TRAP polypeptide (or one or more antigenic Plasmodium TRAP polypeptide fragments), a Plasmodium LSAP2 polypeptide (or one or more antigenic Plasmodium LSAP2 polypeptide fragments), a Plasmodium UIS3 polypeptide (or one or more antigenic Plasmodium UIS3 polypeptide fragments), and a Plasmodium ETRAMP10.3 polypeptide (or one or more antigenic Plasmodium ETRAMP10.3 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0437] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP polypeptide, such as a Plasmodium falciparum CSP polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more antigenic Plasmodium CSP polypeptide fragments, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal end region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment does not contain the N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acids according to SEQ ID NO:133 or consists of the amino acids according to SEQ ID NO:133.In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141, or 142. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142 or consists of the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141, or 142.

[0438] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide, such as a Plasmodium TRAP polypeptide, such as a Plasmodium falciparum TRAP polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising the amino acid sequence of SEQ ID NO:287 or consisting of the amino acid sequence of SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium TRAP polypeptide fragment. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acids according to SEQ ID NO:171 or consists of the amino acids according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190.In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of an amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.

[0439] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide, such as a Plasmodium LSAP2 polypeptide, such as a Plasmodium falciparum LSAP2 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210.In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises or consists of an amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.

[0440] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include the UIS3 polypeptide, such as a Plasmodium UIS3 polypeptide, such as a Plasmodium falciparum UIS3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising the amino acid sequence of SEQ ID NO:359 or consisting of the amino acid sequence of SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium UIS3 polypeptide fragment. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acids according to SEQ ID NO:212 or consists of the amino acids according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:217 or consists of the amino acid sequence according to SEQ ID NO:217.

[0441] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide, such as a Plasmodium ETRAMP10.3 polypeptide, such as a Plasmodium falciparum ETRAMP10.3 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising the amino acid sequence of SEQ ID NO:362 or consisting of the amino acid sequence of SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium ETRAMP10.3 polypeptide fragment. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acids according to SEQ ID NO:219 or consists of the amino acids according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227.In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 224, 225, 226, or 227.

[0442] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and (v) an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises in sequence: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and (v) an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 15. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 15.

[0443] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises in sequence: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and (v) an antigenic Plasmodium LSAP2 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 57. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 57.

[0444] Constructs comprising CSP, TRAP, LSA-1(a), LSA-1(b), LSA-3, LSAP2, UIS3, ETRAMP10.3

[0445] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein comprise a CSP polypeptide (or one or more antigenic Plasmodium CSP polypeptide fragments), a Plasmodium TRAP polypeptide (or one or more antigenic Plasmodium TRAP polypeptide fragments), a Plasmodium LSA-1(a) polypeptide (or one or more antigenic Plasmodium LSA-1(a) polypeptide fragments), a Plasmodium LSA-1(b) polypeptide (or one or more antigenic Plasmodium LSA-1(b) polypeptide fragments), a Plasmodium LSA-3 polypeptide (or one or more antigenic Plasmodium LSA-3 polypeptide fragments), a Plasmodium LSAP2 polypeptide (or one or more antigenic Plasmodium LSAP2 polypeptide fragments), a Plasmodium UIS3 polypeptide (or one or more antigenic Plasmodium UIS3 polypeptide fragments), and a Plasmodium ETRAMP10.3 polypeptide (or one or more antigenic Plasmodium ETRAMP10.3 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0446] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP polypeptide, such as a Plasmodium falciparum CSP polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more antigenic Plasmodium CSP polypeptide fragments, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal end region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment does not contain the N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acids according to SEQ ID NO:133 or consists of the amino acids according to SEQ ID NO:133.In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141 or 142 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141 or 142. In some embodiments, the antigenic Plasmodium falciparum CSP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141 or 142 or consists of the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141 or 142.

[0447] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide, such as a Plasmodium TRAP polypeptide, such as a Plasmodium falciparum TRAP polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium TRAP polypeptide fragment. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.

[0448] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide, such as a Plasmodium LSA-1(a) polypeptide, such as a Plasmodium falciparum LSA-1(a) polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising the amino acid sequence of SEQ ID NO:293 or consisting of the amino acid sequence of SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(a) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises the amino acids according to SEQ IDNO:144 or consists of the amino acids according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153.In some embodiments, the antigenic Plasmodium falciparum LSA-1(a) polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153.

[0449] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide, such as a Plasmodium LSA-1(b) polypeptide, such as a Plasmodium falciparum LSA-1(b) polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising the amino acid sequence of SEQ ID NO:296 or consisting of the amino acid sequence of SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(b) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises the amino acids according to SEQ ID NO:155 or consists of the amino acids according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.In some embodiments, the antigenic Plasmodium falciparum LSA-1(b) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.

[0450] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide, such as a Plasmodium LSA-3 polypeptide, such as a Plasmodium falciparum LSA-3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising the amino acid sequence of SEQ ID NO:299 or consisting of the amino acid sequence of SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:299. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-3 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises the amino acids according to SEQ ID NO:249 or consists of the amino acids according to SEQ ID NO:249. In some embodiments, the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:254, 255, 256, 257, 258, 259, 260, 261 or 262.In some embodiments, the antigenic Plasmodium falciparum LSA-3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262 or consists of the amino acid sequence according to SEQ ID NO: 254, 255, 256, 257, 258, 259, 260, 261 or 262.

[0451] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide, such as a Plasmodium LSAP2 polypeptide, such as a Plasmodium falciparum LSAP2 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210.In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210 or consists of the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.

[0452] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a UIS3 polypeptide, such as a Plasmodium UIS3 polypeptide, such as a Plasmodium falciparum UIS3 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a UIS3 polypeptide comprising the amino acid sequence of SEQ ID NO:359 or consisting of the amino acid sequence of SEQ ID NO:359. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a UIS3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:359. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium UIS3 polypeptide fragment. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acids according to SEQ ID NO:212 or consists of the amino acids according to SEQ ID NO:212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:217. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:217 or consists of the amino acid sequence according to SEQ ID NO:217.

[0453] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide, such as a Plasmodium ETRAMP10.3 polypeptide, such as a Plasmodium falciparum ETRAMP10.3 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising the amino acid sequence of SEQ ID NO:362 or consisting of the amino acid sequence of SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium ETRAMP10.3 polypeptide fragment. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acids according to SEQ ID NO:219 or consists of the amino acids according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227.In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227.

[0454] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-3 polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(a) polypeptide fragment; and (viii) an antigenic Plasmodium LSA-1(b) polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-3 polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(a) polypeptide fragment; and (viii) an antigenic Plasmodium LSA-1(b) polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 18. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 18.

[0455] Constructs including CSP, TRAP, LSA-1(a), LSA-1(b), LSAP2, UIS3, ETR AMP10.3, LISP-1, LISP-2

[0456] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide (or one or more antigenic Plasmodium CSP polypeptide fragments), a Plasmodium TRAP polypeptide (or one or more antigenic Plasmodium TRAP polypeptide fragments), a Plasmodium LSA-1(a) polypeptide (or one or more antigenic Plasmodium LSA-1(a) polypeptide fragments), a Plasmodium LSA-1(b) polypeptide (or one or more antigenic Plasmodium LSA-1(b) polypeptide fragments), a Plasmodium LSAP2 polypeptide (or one or more antigenic Plasmodium LSAP2 polypeptide fragments), a Plasmodium UIS3 polypeptide (or one or more antigenic Plasmodium UIS3 polypeptide fragments), a Plasmodium ETRAMP10.3 polypeptide (or one or more antigenic Plasmodium ETRAMP10.3 polypeptide fragments), a Plasmodium LISP-1 polypeptide (or one or more antigenic Plasmodium LISP-1 polypeptide fragments), and a Plasmodium LISP-2 polypeptide (or one or more antigenic Plasmodium LISP-2 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0457] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP polypeptide, such as a Plasmodium falciparum CSP polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more antigenic Plasmodium CSP polypeptide fragments, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal end region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment does not contain the N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:133. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acids according to SEQ ID NO:133 or consists of the amino acids according to SEQ ID NO:133.In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141 or 142 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 138, 139, 140, 141 or 142. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141 or 142 or consists of the amino acid sequence according to SEQ ID NO: 138, 139, 140, 141 or 142.

[0458] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide, such as a Plasmodium TRAP polypeptide, such as a Plasmodium falciparum TRAP polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising the amino acid sequence of SEQ ID NO:287 or consisting of the amino acid sequence of SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a TRAP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:287. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium TRAP polypeptide fragment. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acids according to SEQ ID NO:171 or consists of the amino acids according to SEQ ID NO:171. In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.In some embodiments, the antigenic Plasmodium TRAP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190 or consists of the amino acid sequence according to SEQ ID NO: 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 or 190.

[0459] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide, such as a Plasmodium LSA-1(a) polypeptide, such as a Plasmodium falciparum LSA-1(a) polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising the amino acid sequence of SEQ ID NO:293 or consisting of the amino acid sequence of SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(a) polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:293. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(a) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises the amino acids according to SEQ IDNO:144 or consists of the amino acids according to SEQ ID NO:144. In some embodiments, the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:149, 150, 151, 152 or 153.In some embodiments, the antigenic Plasmodium falciparum LSA-1(a) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153 or consists of the amino acid sequence according to SEQ ID NO: 149, 150, 151, 152 or 153.

[0460] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide, such as a Plasmodium LSA-1(b) polypeptide, such as a Plasmodium falciparum LSA-1(b) polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSA-1(b) polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296 or consisting of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:296. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSA-1(b) polypeptide fragment. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:155. In some embodiments, the antigenic Plasmodium LSA-1(b) polypeptide fragment comprises an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.In some embodiments, the antigenic Plasmodium falciparum LSA-1(b) polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169 or consists of the amino acid sequence according to SEQ ID NO: 160, 161, 162, 163, 164, 165, 166, 167, 168 or 169.

[0461] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide, such as a Plasmodium LSAP2 polypeptide, such as a Plasmodium falciparum LSAP2 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising the amino acid sequence of SEQ ID NO:305 or consisting of the amino acid sequence of SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an LSAP2 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:305. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium LSAP2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises the amino acids according to SEQ ID NO:198 or consists of the amino acids according to SEQ ID NO:198. In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:203, 204, 205, 206, 207, 208, 209 or 210.In some embodiments, the antigenic Plasmodium LSAP2 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 203, 204, 205, 206, 207, 208, 209 or 210.

[0462] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide, such as a Plasmodium UIS3 polypeptide, such as a Plasmodium falciparum UIS3 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a UIS3 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 359 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium UIS3 polypeptide fragment. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 212 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO: 212. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 217 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 217. In some embodiments, the antigenic Plasmodium UIS3 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 217.

[0463] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide, such as a Plasmodium ETRAMP10.3 polypeptide, such as a Plasmodium falciparum ETRAMP10.3 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising the amino acid sequence of SEQ ID NO:362 or consisting of the amino acid sequence of SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an ETRAMP10.3 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:362. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include an antigenic Plasmodium ETRAMP10.3 polypeptide fragment. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises the amino acids according to SEQ ID NO:219 or consists of the amino acids according to SEQ ID NO:219. In some embodiments, the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227 or consists of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:224, 225, 226 or 227.In some embodiments, the antigenic Plasmodium falciparum ETRAMP10.3 polypeptide fragment comprises the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227 or consists of the amino acid sequence according to SEQ ID NO: 224, 225, 226 or 227.

[0464] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide, such as a Plasmodium LISP-1 polypeptide, such as a Plasmodium falciparum LISP-1 polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:308. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-1 polypeptide comprising an amino acid sequence having at least 85% (such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:308. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium LISP-1 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises or consists of the amino acids according to SEQ ID NO:229. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236 or consisting of an amino acid sequence having at least 85% (such as, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO:234, 235 or 236. In some embodiments, the antigenic Plasmodium LISP-1 polypeptide fragment comprises or consists of the amino acid sequence according to SEQID NO:234, 235 or 236.

[0465] In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide, such as a Plasmodium LISP-2 polypeptide, such as a Plasmodium falciparum LISP-2 polypeptide, preferably from the Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide comprising the amino acid sequence of SEQ ID NO: 311 or consisting of the amino acid sequence of SEQ ID NO: 311. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include a LISP-2 polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 311 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 311. In some embodiments, the Plasmodium T cell epitope polypeptide constructs described herein include an antigenic Plasmodium LISP-2 polypeptide fragment. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 238 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises the amino acids according to SEQ ID NO: 238 or consists of the amino acids according to SEQ ID NO: 238. In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 243, 244, 245, 246 or 247 or consists of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to SEQ ID NO: 243, 244, 245, 246 or 247.In some embodiments, the antigenic Plasmodium LISP-2 polypeptide fragment comprises or consists of the amino acid sequence according to SEQ ID NO: 243, 244, 245, 246 or 247.

[0466] In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (viii) an antigenic Plasmodium LISP-2 polypeptide fragment; and (ix) an antigenic Plasmodium LISP-1 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises, in order: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (viii) an antigenic Plasmodium LISP-2 polypeptide fragment; and (ix) an antigenic Plasmodium LISP-1 polypeptide fragment, wherein the Plasmodium is preferably Plasmodium falciparum, more preferably Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO: 24. In some embodiments, the Plasmodium T cell string polypeptide construct described herein comprises the amino acid sequence of SEQ ID NO: 24.

[0467] Constructs including CSP, TRAP, LSA-1(a), LSA-1(b), LSAP2, UIS3, ETR AMP10.3, LISP-1

[0468] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide (or one or more antigenic Plasmodium CSP polypeptide fragments), a Plasmodium TRAP polypeptide (or one or more antigenic Plasmodium TRAP polypeptide fragments), a Plasmodium LSA-1(a) polypeptide (or one or more antigenic Plasmodium LSA-1(a) polypeptide fragments), a Plasmodium LSA-1(b) polypeptide (or one or more antigenic Plasmodium LSA-1(b) polypeptide fragments), a Plasmodium LSAP2 polypeptide (or one or more antigenic Plasmodium LSAP2 polypeptide fragments), a Plasmodium UIS3 polypeptide (or one or more antigenic Plasmodium UIS3 polypeptide fragments), a Plasmodium ETRAMP10.3 polypeptide (or one or more antigenic Plasmodium ETRAMP10.3 polypeptide fragments), and a Plasmodium LISP-1 polypeptide (or one or more antigenic Plasmodium LISP-1 polypeptide fragments), wherein the Plasmodium is preferably Plasmodium falciparum, more preferably the Plasmodium falciparum isolate 3D7.

[0469] In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide, such as a Plasmodium CSP polypeptide, such as a Plasmodium falciparum CSP polypeptide, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising the amino acid sequence of SEQ ID NO:1 or consisting of the amino acid sequence of SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include a CSP polypeptide comprising an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1 or consisting of an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence according to SEQ ID NO:1. In some embodiments, the Plasmodium T cell string polypeptide constructs described herein include one or more antigenic Plasmodium CSP polypeptide fragments, preferably from Plasmodium falciparum isolate 3D7. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal end region and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal domain and the junction region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment containing at least some portions of the N-terminal domain does not contain the C-terminal region. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment does not contain the N-terminal domain. In some embodiments, the antigenic Plasmodium CSP polypeptide fragment comprises an amino acid sequence having at least 85% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% ...

Claims

1. A polyribonucleotide encoding a polypeptide, wherein the polypeptide comprises one or more Plasmodium T cell antigens, and wherein the one or more Plasmodium T cell antigens comprise two or more of the following: (i) An antigenic Plasmodium CSP polypeptide fragment; (ii) An antigenic Plasmodium LSA-1(a) polypeptide fragment; (iii) An antigenic Plasmodium LSA-1(b) polypeptide fragment; (iv) An antigenic Plasmodium TRAP polypeptide fragment; (v) An antigenic Plasmodium LSAP2 polypeptide fragment; (vi) An antigenic Plasmodium UIS3 polypeptide fragment; (vii) An antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (viii) An antigenic Plasmodium LISP-1 polypeptide fragment; (ix) An antigenic Plasmodium LISP-2 polypeptide fragment; and (x) An antigenic Plasmodium LSA-3 polypeptide fragment.

2. The polyribonucleotide according to claim 1, wherein the one or more Plasmodium T cell antigens comprise or consist of the following: (i) An antigenic Plasmodium CSP polypeptide fragment; (ii) An antigenic Plasmodium TRAP polypeptide fragment; (iii) An antigenic Plasmodium UIS3 polypeptide fragment; (iv) An antigenic Plasmodium ETRAMP10.3 polypeptide fragment; and (v) An antigenic Plasmodium LSAP2 polypeptide fragment.

3. The polyribonucleotide according to claim 1 or 2, wherein the polypeptide comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:15 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

15.

4. The polyribonucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of the following: (i) An antigenic Plasmodium CSP polypeptide fragment; (ii) An antigenic Plasmodium TRAP polypeptide fragment; (iii) An antigenic Plasmodium UIS3 polypeptide fragment; (iv) An antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) An antigenic Plasmodium LSAP2 polypeptide fragment; (vi) An antigenic Plasmodium LSA-3 polypeptide fragment; (vii) An antigenic Plasmodium LSA-1(a) polypeptide fragment; and (viii) An antigenic Plasmodium LSA-1(b) polypeptide fragment.

5. The polyribonucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of the following: (i) An antigenic Plasmodium CSP polypeptide fragment; (ii) An antigenic Plasmodium TRAP polypeptide fragment; (iii) An antigenic Plasmodium UIS3 polypeptide fragment; (iv) An antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) An antigenic Plasmodium LSAP2 polypeptide fragment; (vi) An antigenic Plasmodium LSA-1(a) polypeptide fragment; (vii) An antigenic Plasmodium LSA-1(b) polypeptide fragment; (viii) An antigenic Plasmodium LISP-2 polypeptide fragment; and (ix) An antigenic Plasmodium LISP-1 polypeptide fragment.

6. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; and (viii) an antigenic Plasmodium LISP-1 polypeptide fragment.

7. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LISP-2 polypeptide fragment; and (vii) an antigenic Plasmodium LISP-1 polypeptide fragment.

8. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-1(b) polypeptide fragment; and (vii) an antigenic Plasmodium LISP-1 polypeptide fragment.

9. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium CSP polypeptide fragment; (ii) an antigenic Plasmodium TRAP polypeptide fragment; (iii) an antigenic Plasmodium UIS3 polypeptide fragment; (iv) an antigenic Plasmodium ETRAMP10.3 polypeptide fragment; (v) an antigenic Plasmodium LSAP2 polypeptide fragment; (vi) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (vii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (viii) an antigenic Plasmodium LISP-2 polypeptide fragment; (ix) an antigenic Plasmodium LISP-1 polypeptide fragment; and (x) an antigenic Plasmodium LSA-3 polypeptide fragment.

10. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (ii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (iii) an antigenic Plasmodium LISP-2 polypeptide fragment; (iv) an antigenic Plasmodium LISP-1 polypeptide fragment; and (v) an antigenic Plasmodium LSA-3 polypeptide fragment.

11. The polynucleotide according to claim 1 or 2, wherein the one or more Plasmodium T cell antigens comprise or consist of: (i) an antigenic Plasmodium LSA-1(a) polypeptide fragment; (ii) an antigenic Plasmodium LSA-1(b) polypeptide fragment; (iii) an antigenic Plasmodium LISP-2 polypeptide fragment; and (iv) an antigenic Plasmodium LISP-1 polypeptide fragment.

12. The polynucleotide according to claim 11, wherein the polypeptide comprises or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

45.

13. The polynucleotide according to any one of claims 1-9, wherein the one or more Plasmodium T cell antigens comprise the antigenic Plasmodium CSP polypeptide fragment, and wherein the antigenic Plasmodium CSP polypeptide fragment comprises the Plasmodium CSP N-terminal region.

14. The polynucleotide according to claim 13, wherein the antigenic Plasmodium CSP polypeptide fragment further comprises the Plasmodium CSP N-terminal end region.

15. The polynucleotide according to claim 13 or 14, wherein the antigenic Plasmodium CSP polypeptide fragment further comprises the Plasmodium CSP junction region.

16. The polynucleotide according to any one of claims 13-15, wherein the antigenic Plasmodium CSP polypeptide fragment comprises or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

133.

17. The polynucleotide according to any one of claims 1-9, wherein the one or more Plasmodium T cell antigens do not comprise the antigenic Plasmodium berghei CSP polypeptide fragment.

18. The polynucleotide according to any one of claims 1, 4-6 and 9-17, wherein the one or more Plasmodium T cell antigens comprise the antigenic Plasmodium LSA-1(a) polypeptide fragment, and wherein the antigenic Plasmodium LSA-1(a) polypeptide fragment comprises or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

144.

19. The polynucleotide according to any one of claims 1, 4 - 6, and 8 - 18, wherein the one or more Plasmodium T - cell antigens comprise the antigenic Plasmodium LSA - 1(b) polypeptide fragment, and wherein the antigenic Plasmodium LSA - 1(b) polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:155 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

155.

20. The polynucleotide according to any one of claims 1 - 9 and 13 - 19, wherein the one or more Plasmodium T - cell antigens comprise the antigenic Plasmodium TRAP polypeptide fragment, and wherein the antigenic Plasmodium TRAP polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:171 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

171.

21. The polynucleotide according to any one of claims 1 - 9 and 13 - 20, wherein the one or more Plasmodium T - cell antigens comprise the antigenic Plasmodium LSAP2 polypeptide fragment, and wherein the antigenic Plasmodium LSAP2 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:198 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

198.

22. The polynucleotide according to any one of claims 1 - 9 and 13 - 21, wherein the one or more Plasmodium T - cell antigens comprise the antigenic Plasmodium UIS3 polypeptide fragment, and wherein the antigenic Plasmodium UIS3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:212 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

212.

23. The polynucleotide according to any one of claims 1 - 9 and 13 - 22, wherein the one or more Plasmodium T - cell antigens comprise the antigenic Plasmodium ETRAMP10.3 polypeptide fragment, and wherein the antigenic Plasmodium ETRAMP10.3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:219 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

219.

24. The polynucleotide according to any one of claims 1 and 5 - 23, wherein the one or more Plasmodium T cell antigens comprise the antigenic Plasmodium LISP-1 polypeptide fragment, and wherein the antigenic Plasmodium LISP-1 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:229 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

229.

25. The polynucleotide according to any one of claims 1, 5, 7 and 9 - 24, wherein the one or more Plasmodium T cell antigens comprise the antigenic Plasmodium LISP-2 polypeptide fragment, and wherein the antigenic Plasmodium LISP-2 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:238 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

238.

26. The polynucleotide according to any one of claims 1, 4, 9, 10 and 13 - 25, wherein the one or more Plasmodium T cell antigens comprise the antigenic Plasmodium LSA-3 polypeptide fragment, and wherein the antigenic Plasmodium LSA-3 polypeptide fragment comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:249 or consists of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO:

249.

27. The polynucleotide according to any one of claims 1 - 26, wherein the polypeptide does not comprise an antigenic fragment of a bacterial polypeptide.

28. The polynucleotide according to any one of claims 1 - 27, wherein the one or more Plasmodium T cell antigens do not comprise an antigenic Plasmodium sporozoite threonine-asparagine-rich protein (STARP) polypeptide fragment, optionally wherein the antigenic Plasmodium STARP polypeptide fragment comprises the amino acid sequence according to SEQ ID NO:

463.

29. The polynucleotide according to any one of claims 1 - 28, wherein the polynucleotide further comprises a sequence encoding a MHC class I transport signal (MITD).

30. The polynucleotide according to any one of claims 1 - 29, wherein the polypeptide comprises a secretion signal.

31. The polynucleotide according to claim 30, wherein the secretion signal comprises or consists of a Plasmodium secretion signal, preferably the Plasmodium CSP secretion signal.

32. The polynucleotide according to claim 30, wherein the secretion signal comprises or consists of a heterologous secretion signal.

33. The polynucleotide according to claim 32, wherein the heterologous secretion signal comprises or consists of a non-human secretion signal.

34. The polyribonucleotide according to claim 32, wherein the heterologous secretion signal comprises or consists of a viral secretion signal, preferably wherein the viral secretion signal comprises or consists of the following: (a) an HSV-1 or HSV-2 secretion signal, even more preferably wherein the viral secretion signal comprises or consists of the HSV glycoprotein D (gD) secretion signal, or (b) an Ebola virus secretion signal, even more preferably wherein the viral secretion signal comprises or consists of the Ebola virus spike glycoprotein (SGP) secretion signal.

35. The polyribonucleotide according to any one of claims 1-34, wherein the polypeptide comprises a transmembrane region.

36. The polyribonucleotide according to claim 35, wherein the transmembrane region comprises or consists of a Plasmodium transmembrane region, preferably wherein the Plasmodium transmembrane region comprises or consists of the Plasmodium circumsporozoite protein glycosylphosphatidylinositol (GPI) anchor region.

37. The polyribonucleotide according to claim 35, wherein the transmembrane region comprises or consists of a heterologous transmembrane region, preferably wherein the heterologous transmembrane region: (a) does not include a hemagglutinin transmembrane region, (b) comprises or consists of a viral transmembrane region, preferably wherein the viral transmembrane region comprises or consists of an HSV-1 or HSV-2 transmembrane region, even more preferably wherein the HSV transmembrane region comprises or consists of the HSV gD transmembrane region, or (c) comprises or consists of a human transmembrane region, preferably wherein the human transmembrane region comprises or consists of the human decay-accelerating factor glycosylphosphatidylinositol (hDAF-GPI) anchor region.

38. The polyribonucleotide according to any one of claims 1-29 and 35-37, wherein the polypeptide does not comprise a secretion signal.

39. The polyribonucleotide according to any one of claims 1-34, wherein the polypeptide does not comprise a transmembrane region.

40. The polyribonucleotide according to any one of claims 1-39, wherein the one or more Plasmodium T cell antigens are one or more Plasmodium falciparum T cell antigens, preferably wherein the one or more Plasmodium falciparum T cell antigens are from the Plasmodium falciparum isolate 3D7.

41. The polyribonucleotide according to any one of claims 1-40, wherein the polyribonucleotide is an isolated polyribonucleotide.

42. The polyribonucleotide according to any one of claims 1-41, wherein the polyribonucleotide is an engineered polyribonucleotide.

43. The polyribonucleotide according to any one of claims 1-42, wherein the polyribonucleotide is a codon-optimized polyribonucleotide.

44. An RNA construct that comprises, in 5' to 3' order: (i) A 5’UTR which comprises a modified human alpha globin 5’-UTR or consists of a modified human alpha globin 5’-UTR; (ii) A polyribonucleotide according to any one of claims 1 - 43; (iii) A 3’UTR which comprises or consists of a first sequence and a second sequence, wherein the first sequence is from a split amino-terminal enhancer (AES) messenger RNA and the second sequence is from mitochondrially encoded 12S ribosomal RNA; and (iv) A polyA tail sequence.

45. The RNA construct according to claim 44, which further comprises a 5’ cap.

46. A composition which comprises one or more polyribonucleotides according to any one of claims 1 - 43 or an RNA construct according to claim 44 or 45.

47. The composition according to claim 46, which further comprises a lipid nanoparticle, a polyplex (PLX), a lipidated polyplex (LPLX) or a liposome, wherein the one or more polyribonucleotides are fully or partially encapsulated within the lipid nanoparticle, the polyplex (PLX), the lipidated polyplex (LPLX) or the liposome.

48. A pharmaceutical composition which comprises the composition according to claim 46 or 47 and at least one pharmaceutically acceptable excipient.

49. A combination which comprises: (i) A first pharmaceutical composition which comprises a first polyribonucleotide, wherein the first polyribonucleotide encodes a first polypeptide and the first polypeptide comprises one or more Plasmodium T cell antigens; and (ii) A second pharmaceutical composition which comprises a second polyribonucleotide, wherein the second polyribonucleotide encodes a second polypeptide and the second polypeptide comprises one or more Plasmodium antigenic polypeptide regions or portions thereof.

50. The combination according to claim 49, wherein the first polyribonucleotide is a polyribonucleotide according to any one of claims 1 - 43.

51. The combination according to claim 49 or 50, wherein the one or more Plasmodium antigenic polypeptide regions or portions thereof of the second polypeptide comprise one or more Plasmodium CSP regions or portions thereof.

52. A combination which comprises: (i) A first pharmaceutical composition which comprises a polyribonucleotide encoding a first polypeptide, wherein the first polypeptide comprises one or more Plasmodium T cell antigens and wherein the one or more Plasmodium T cell antigens comprise a Plasmodium N-terminal region or a portion thereof but do not comprise a Plasmodium C-terminal region or a portion thereof; and (ii) A second pharmaceutical composition which comprises a polyribonucleotide encoding a second polypeptide, wherein the second polypeptide comprises one or more Plasmodium CSP polypeptide regions or portions thereof and wherein the one or more Plasmodium CSP polypeptide regions or portions thereof comprise a Plasmodium CSP C-terminal region or a portion thereof but do not comprise a Plasmodium CSP N-terminal region or a portion thereof.

53. A combination which comprises: (i) A first pharmaceutical composition which comprises a first polyribonucleotide, wherein the first polyribonucleotide is a polyribonucleotide according to claim 2 or 3; and (ii) A second pharmaceutical composition comprising a second polynucleotide, wherein the second polynucleotide is a polynucleotide according to claim 11 or 12.

54. A method of treating or preventing malaria infection, comprising administering to a subject a polynucleotide according to any one of claims 1-43, an RNA construct according to claim 44 or 45, a composition according to claim 46 or 47, a pharmaceutical composition according to claim 48, or a combination according to any one of claims 49-53.

55. The pharmaceutical composition according to claim 48, for treating or preventing malaria infection, comprising administering to a subject one or more doses of the pharmaceutical composition.

56. The combination according to any one of claims 49-53, for treating or preventing malaria infection, comprising administering to a subject one or more doses of the combination.

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