Immunotherapy compositions and methods for treatment of tauopathy, neuroinflammation, and synaptic loss

Abstract

This disclosure describes, in one aspect, a method comprising administering to a subject in need thereof a pharmaceutical composition. The pharmaceutical composition comprising pharmaceutically acceptable carrier and an antigen presentation component. The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

Description

[0001] IMMUNOTHERAPY COMPOSITIONSAND METHODS FOR TREATMENT OF TAUOPATHY, NEUROINFLAMMATION, AND SYNAPTIC LOSS

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 639,047 filed April 26, 2024, the entire contents of which are incorporated herein by reference.

[0004] INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0005] This application contains a Sequence Listing which has been submitted in .XML format via Patent Center and is hereby incorporated by reference in its entirety. Said .XML copy, created on April 23, 2025, is named pT217.xml and is 5,658 kilobytes in size.

[0006] BACKGROUND

[0007] Alzheimer's disease and other tauopathic diseases are progressive neurodegenerative disorders that causes memory loss and serious mental deterioration. Methods for treating an afflicted subject or reducing symptoms in the subject, vaccinating the subject, and for creating of antibodies for use in the same is needed.

[0008] SUMMARY

[0009] This disclosure describes antigen presentation components comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a phosphorylated fragment of Tau, e.g., comprising a phosphorylation at the threonine residue at position 217 (T217).

[0010] An aspect of the present disclosure is a method comprising administering to a subject in need thereof a pharmaceutical composition. The pharmaceutical composition comprising pharmaceutically acceptable carrier and an antigen presentation component. The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group. Another aspect of the present disclosure is an antibody obtained by any herein-disclosed method.

[0011] In embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

[0012] A further aspect of the present disclosure is pharmaceutical composition comprising a pharmaceutically acceptable carrier and a herein-disclosed isolated antibody.

[0013] An additional aspect of the present disclosure is composition comprising an antigen presentation component comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0014] In an aspect, the present disclosure provides a use of any herein-disclosed composition in a method for vaccinating a subj ect in need thereof.

[0015] In another aspect, the present disclosure provides a use of any herein-disclosed composition in a method for treating a symptom of a tauopathic condition in a subject in need thereof.

[0016] In a further aspect, the present disclosure provides a use of any herein-disclosed composition in a method for reducing a symptom of a tauopathic condition in a subject in need thereof.

[0017] In an additional aspect, the present disclosure provides a use of any herein-disclosed composition in a method for screening the presence of an antibody in a sample.

[0018] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising pharmaceutically acceptable carrier and any herein-disclosed composition.

[0019] In yet a further aspect, the present disclosure provides a use of any herein-disclosed pharmaceutical composition in a method for vaccinating a subject in need thereof.

[0020] In yet an additional aspect, the present disclosure provides a use of any herein-disclosed pharmaceutical composition in a method for treating a tauopathic condition in a subject in need thereof.

[0021] An aspect of the present disclosure is a use of any herein-disclosed pharmaceutical composition in a method for reducing a symptom of a tauopathic condition in a subject in need thereof. Another aspect of the present disclosure is a method for screening for the presence of an antibody in a sample. The method comprising a step of contacting a sample suspected of comprising the antibody with any herein-disclosed composition comprising an antigen presentation component. The method further comprises a step of detecting binding of the antigen presentation component and the antibody.

[0022] Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] FIG. 1A and FIG. IB show the chemical conjugation of peptides to QP virus-like particles (VLPs). FIG. 1A is schematic representation of the conjugation protocol. The bifunctional cross-linker (SMPH; Pierce, Thermo Fisher Scientific, Inc., Waltham, Mass.) reacts with primary amine groups on the surface of QP VLPs (indicated in (FIG. IB)). After purification, the phage is reacted with target peptides containing cysteine. In embodiments, any one of SEQ ID NO: 1 to SEQ ID NO: 4, or variants thereof may be a MAPT peptide. FIG. 1C is a schematic diagram illustrating conjugation of MAPT peptides to VLPs.

[0025] FIG. 2A show the location of the pT217 peptide within Tau protein. A 13 -amino acid peptide sequence containing the phosphorylated Thr217 (pT217) site and a Gly-Gly-Cys spacer sequence was chemically conjugated to fully assembled QP bacteriophage virus-like particles (VLPs) using succinimidyl 6-((beta-maleimidopropionamido) hexanoate) (SMPH). FIG. 2B is a schematic of vaccination scheme with one embodiment (carrying SEQ ID NO: 1) used in vaccination and confirmation of successful conjugation of pT217 to QP VLPs. FIG. 2C is a gel mobility shift image showing increase in size of a conjugated VLP.

[0026] FIG. 3A to FIG. 3D shows that vaccination with pT217-QP induces a robust antibody response in young PS 19 mice. FIG. 3A is a graph showing that serum IgG antibody titers were elevated in pT217-QP vaccinated mice assessed by ELISA at 8-, 12-, and 16-weeks after vaccination. FIG. 3B is a graph showing brain IgG antibody titers in the cortical parenchyma were elevated in pT217-QP vaccinated mice assessed by ELISA at 6-months of age. FIG. 3C is a graph showing serum IgG titers against the non-phosphorylated T217 peptide were significantly lower at 8-, 12-, and 16-weeks compared to the pT217 antibody titer response. FIG. 3D is a graph showing that antibody avidity for both the pT217 and non-phosphorylated T217 peptides were not significantly different. All data presented here is as mean ± SEM. *p<0.05; **p<0.01; LOD=Limit of Detection.

[0027] FIG. 4A to FIG. 4F shows engagement of antibodies generated in the serum of the immunized mice with pathological tau in human brain postmortem samples from Alzheimer's patients. FIG. 4A includes photomicrographs showing Human Alzheimer’s disease (AD) Braak III and healthy human control hippocampal tissue sections stained using AT8 antibody to confirm the presence or absence of tau pathology or stained with immune sera from pT217-QP or unconjugated QP vaccinated mice demonstrating specific detection of pathological tau by pT217-targeted antibodies in human AD but not in healthy control. FIG. 4B are western blots showing Human AD Braak III, Human AD Braak VI, and Frontotemporal dementia (FTD) hippocampal lysates stained using either a commercial antibody against pT217, purified IgG from pT217-QP vaccinated mice, or commercial Taul2 antibody. FIG. 4C incudes graphs showing that purified IgG from pT217-QP vaccinated mice successfully detected pathological tau in human AD and FTD and were able to successfully differentiate Human AD Braak VI from Braak III and FTD while commercial pT217 antibody only preferentially stained FTD but was unable to differentiate human AD Braak VI from Braak III. ANOVA. *p<0.05; **p<0.01; ****p<0.0001. FIG. 4D is a wester blow showing immunoprecipitation of human AD Braak VI hippocampal lysates using purified IgG from either unconjugated QP or pT217-QP vaccinated immune sera stained with Tau5-HRP antibody. FIG. 4E is a graph showing the quantification of Tau5+ bands with pT217-QP IgG but not QP IgG successfully precipitating tau from human AD lysates. FIG. 4F includes western blots uncropped western blot images of commercial pT217 antibody, purified IgG from pT217-QP vaccinated immune sera, and purified IgG from unconjugated QP vaccinated immune sera staining of human AD and FTD samples. This data shows that pT217-QP derived IgG has better specificity for tau than a commercially available anti-pT217 antibody In these figures, FT=Flow through; IP=immunoprecipitated.

[0028] FIG. 5A to FIG. 51 shows that immunization with pT217-QP provides protection against early memory deficits in six-month-old PS 19 mice. FIG. 5A and FIG. 5B are graphs of results from open field tests assessing anxiety behaviors based on time spent in the center region or the border regions of the arena which showed no differences in PS 19 mice compared to non- transgenic mice regardless of vaccination. FIG. 5C and FIG. 5D are graphs of results from Y- maze spontaneous alternation test which showed no significant differences in spontaneous alternations or percentage of repeated arm entries in PS 19 mice compared to non-transgenic mice regardless of vaccination. FIG. 5E is a graph of results from a novel object recognition test which showed a significantly increased nose touch discrimination index for the novel object in pT217-QP vaccinated PS 19 mice and non-transgenic mice but not QP vaccinated PS 19 mice. FIG. 5F is a graph showing that all groups had a significantly increased discrimination index in time spent with the novel object. Two-way ANOVA with Sidak’s multiple comparisons. FIG. 5G are cumulative heatmaps of the novel object recognition test day for QP and pT217-QP vaccinated mice showing increased cumulative duration of time near the novel object (upper right quadrant) compared to the familiar object (lower left quadrant). FIG. 5H includes graphs showing that PS 19 mice spend less time moving compared to non- transgenic mice regardless of vaccine condition (left), showing that PS 19 mice have a lower average velocity than non-transgenic mice (middle), and that PS 19 mice have a decreased overall distance traveled compared to non-transgenic mice (right). One-way ANOVA with Tukey’s multiple comparisons. FIG. 51 includes cumulative heatmaps for all groups in the open field test of FIG. 5H. Two-way ANOVA with Sidak’s multiple comparisons were used in FIG. 5E and FIG. 5F. All data presented as mean ± SEM. . *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. B6=non-transgenic. n=7-8.

[0029] FIG. 6A to FIG. 6D show the result of Barnes maze trials on mice immunized with the control and pT217-QP VLP composition. FIG. 6A is a graph of Barnes maze training trials learning curves for latency to finding the escape hole showing a non-significantly difference in the PS 19 mice compared to the non-transgenic mice regardless of vaccination. FIG. 6B is a graph of the time spent in the target quadrant during the Barnes maze test day showing a significantly increased time compared to the average time spent in the off-target quadrants for pT217-QP vaccinated PS 19 mice and non-transgenic mice but not QP vaccinated PS 19 mice. FIG. 6C includes cumulative heatmaps of the Barnes maze test day showing increased cumulative duration of time spent in the target quadrant (lower right quadrant) in pT217-QP treated mice but not QP treated mice. a-d. One-way ANOVA with Tukey’s multiple comparisons. Two-way ANOVA with Sidak’s multiple comparisons were used in FIG. 6A and FIG. 6B. All data presented as mean ± SEM. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. FIG. 6D is a graph showing that there is no significant difference in the number of incorrect holes investigated prior to reaching the target escape hole during the training trials of the Barnes maze test between PS 19 mice and non-transgenic mice regardless of vaccine condition. Two-way ANOVA with Sidak’s multiple comparisons. Data presented as mean ± SEM. *p<0.05. n=7-8. FIG. 7A to FIG. 7D show that immunization with pT217-QP reduces early tau phosphorylation in 6-month-old PS 19 mice. FIG. 7A is an illustrative western blot of hippocampal pT217 levels showing reduction by pT217-QP vaccination. FIG. 7B is a graph quantifying western blot data and showing pT217-QP vaccinated mice showed significantly reduced levels of the pT217 tau protein compared to QP vaccinated mice. FIG. 7C includes western blots of hippocampal pathological (AT180, AT8, AT270, Taul2) and physiologic (Tau5) tau showing reduction in pathological tau by pT217-QP vaccination. FIG. 7D includes graphs quantifying the western blot data of FIG. 7C. In these figures, Student’s t-test was used. All data presented as mean ± SEM. *p<0.05; **p<0.01; ***p<0.001. (n=6-7 per group).

[0030] FIG. 8A and FIG. 8B show that pT217-QP vaccination protects against synapse loss in 6- month-old PS 19 mice. FIG. 8A is a western blot of hippocampal lysates from 6-month-old PS 19 mice immunized with either unconjugated QP or pT217-QP vaccines. FIG. 8B includes graphs showing that pT217-QP vaccination significantly increased the levels of synaptophysin (SYP) but failed to significantly increase the levels of postsynaptic density protein 95 (PSD- 95). In these figures, Student’s t-test was used. All data presented as mean ± SEM. *p<0.05. (n=6 per group).

[0031] FIG. 9 is a working model showing extracellular tau acting as a primary driver of inflammation (similar to other known inflammasome activators — ATP, K+ efflux, and mitochondrial- reactive oxygen species (ROS), which are released in response to cell death) in IL-ip-mediated neuroinflammation and neurotoxicity.

[0032] FIG. 10A to FIG. IOC show that pT217-QP vaccination reduces inflammasome activation in 6-month-old PS 19 mice. FIG. 10A is a western blot of hippocampal lysates from 6-month-old PS19 mice vaccinated with either unconjugated QP or pT217-Qp. FIG. 10B includes graphs showing that pT217-QP vaccination did not affect the levels of the inflammasome protein ASC but significantly reduced active caspase-1 (Caspl) and reduced the levels of mature interleukin- ip (IL-ip). The levels of active (p-P65) and total NF-KB (t-P65) as well as inhibitor of KB (IxB-a) were all significantly reduced by pT217-QP vaccination. FIG. IOC is a graph summarizing ELISA of mature IL-ip levels in cortical brain lysates shows significant reduction by pT217-QP vaccination. In FIG. 10A and FIG. 10B, Student’s t-test was used. All data presented as mean ± SEM. *p<0.05; **p<0.01. (n=6-8 per group). DETAILED DESCRIPTION

[0033] Introduction

[0034] In aspects, this disclosure describes compositions and methods for prophylactic and / or therapeutic treatment of tauopathy. Specifically, this disclosure describes a highly efficient, safe, economical, and state-of-the-art immunotherapy approach based on a Virus-Like Particle (VLP)-platform to target a disease-related modification in microtubule-associated protein tau (MAPT), as a potential therapy for MAPT pathology, highly associated with neurodegenerative tauopathies such as Alzheimer's disease and related tauopathies and traumatic brain injury (TBI).

[0035] Pathological misfolding and aggregation of microtubule-associated protein tau (MAPT) into neurofibrillary tangles (NFTs) is a neuropathological hallmark of several neurodegenerative tauopathies. In addition, hyperphosphorylation and aggregation of MAPT occur following TBI and chronic traumatic encephalopathy (CTE), either or both of which can occur in athletes following repeated concussions.

[0036] The accumulation of these pathological modifications to MAPT is responsible for its dissociation from neuronal microtubules and eventual misfolding and aggregation into tau paired helical filaments which accumulate in neurons as neurofibrillary tangles. One early pathological tau (pTau) epitope of rising interest is the phospho-Thr 217 (pT217) site.

[0037] The MAPTpT217 site has been recently identified as an early biofluid-based biomarker of Alzheimer’s pathology that strongly predicts the presence of Ap and tau pathology in the brain with the potential to predict the clinical course of disease progression. The MAPTpT217 site is secreted into the CSF at much higher concentrations compared to other leading tau biomarkers and continues to increase along with Braak staging of the disease. A unique feature of the MAPTpT217-site compared to other pTau epitopes includes its abundant distribution in post-synaptic dendritic spines, indicating a potential role for early synaptic dysfunction, and in pre-tangle pathology suggesting a role for early tau tangle development.

[0038] One promising therapeutic strategy currently being tested in Alzheimer's disease is immunotherapy. There are several challenges with this approach. First, it is often difficult to elicit strong antibody responses against self-antigens like MAPT. Second, immune responses against self-antigens have the potential to cause substantial side effects (e.g., in the case of Ap vaccination, they can lead to encephalitis, vasogenic edema, and / or microhemorrhage in 5% of immunized patients). Furthermore, while the administration of purified MAPT antibodies (passive immunization) shows promising trends in reducing pathological MAPT in recent studies, the therapy is not cost-effective due to the prohibitively expensive process of making purified antibodies. Finally, in the context of MAPT pathology, neuroinflammation, which can ensue in response to brain trauma, accelerates MAPT pathology and cognitive impairment in an hTau mouse model of tauopathy (Bhaskar et al., 2010, Neuron 68: 19-31). It is, therefore, important to develop a MAPT-targeted immunotherapy that can successfully elicit a targeted immune response against neurofibrillary tangles while limiting the inflammatory consequences.

[0039] This disclosure describes exploiting a unique VLP-based platform technology to develop vaccines against tauopathies. This strategy uses non-infectious VLPs to display antigens at high valency on the surface of a highly immunogenic particulate antigen (FIG. 1A to FIG. 1C). FIG. 1A shows chemical conjugation protocol of peptides to QP virus-like particles (VLPs). The bifunctional cross-linker (SMPH; Pierce, Thermo Fisher Scientific, Inc., Waltham, Mass.) reacts with primary amine groups on the surface of QP VLPs (indicated in FIG. IB). After purification, the phage is reacted with target peptides containing cysteine. In embodiments, any one of SEQ ID NO: 1 to SEQ ID NO: 4, or variants thereof may be a MAPT peptide. A schematic diagram illustrating conjugation of MAPT peptides to VLPs shown in FIG. 1C.

[0040] Thus, this disclosure describes, in aspects, a viable, safe, and comprehensive immunotherapy approach to treat and, in some cases, reverse MAPT pathology, neurodegeneration, and / or cognitive decline in neurodegenerative tauopathies such as Alzheimer's disease or TBI. In some cases, neurodegeneration can include brain atrophy. In some cases, the immunotherapy also can minimize undesirable inflammatory response and possible targeting of non-pathological MAPT.

[0041] Generally, the treatment involves administering to a subject having or at risk of having a condition associated with tauopathy a composition that includes an antigen presentation component and / or immunogenic component linked to a MAPT component. In some embodiments, the antigen presentation component and / or immunogenic component preferably includes a virus-like particle (VLP)-based immunogenic component and / or a virus-like particle (VLP). In some embodiments, the MAPT component includes a MAPT antigen epitope.

[0042] This disclosure describes conjugating a peptide hyperphosphorylated at T217 (MAPTpT217 or pTau) to VLP derived from QP RNA bacteriophage (FIG. 1A to FIG. 1C, FIG. 2A, and FIG. 2B). MAPTpT217 is an early stage, disease-associated MAPT peptide and its presence in cerebrospinal fluid (CSF) has been used to diagnose Alzheimer’s disease (Barthelemy et al., 2023, Nat Aging 3, 391-401).

[0043] As disclosed herein, immunizations with QP-MAPTpT217 provides >105mean antibody titers than conventional active immunotherapy. Thus, VLP-display of self-antigens can overcome the mechanisms of immunological tolerance. Notably, QP-MAPTpT217 immunotherapy reduced neurofibrillary tangle pathology and improved spatial memory in Barnes Maze test without inducing unwanted neuroinflammation in a PS 19 transgenic mouse model of tauopathy. These results complement a recent study on the direct infusion of anti-MAPT antibodies, which was shown to clear pathological MAPT and improve cognitive function in a mouse model of tauopathy. Taken together, an antibody-mediated approach to block the onset and propagation of neurofibrillary tangle pathology following traumatic brain injury represents a feasible therapeutic approach.

[0044] Methods

[0045] An aspect of the present disclosure is a method comprising administering to a subject in need thereof a pharmaceutical composition. The pharmaceutical composition comprising pharmaceutically acceptable carrier and an antigen presentation component. The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0046] In embodiments, the antigen presentation component comprises a virus-like particle (VLP). In some cases, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage.

[0047] A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0048] In some embodiments, the antigen presenting component and the MAPT component are linked covalently. In some cases, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage.

[0049] In various embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0050] In numerous embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0051] In additional embodiments, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0052] In many embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1.

[0053] By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0054] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0055] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0056] In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0057] In several embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0058] In any embodiment, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0059] In embodiments, the MAPT component consists of SEQ ID NO: 1.

[0060] In some embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0061] In various embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0062] As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0063] In numerous embodiments, the pharmaceutical composition further comprises an adjuvant.

[0064] In additional embodiments, administering the pharmaceutical composition induces pT217- reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject. In preferred embodiments, administering the pharmaceutical composition induces pT217-reactive IgGs in the subject.

[0065] In many embodiments, administering the pharmaceutical composition vaccinates a subject in need thereof against a tauopathic condition. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0066] In several embodiments, administering the pharmaceutical composition reduces a symptom of a tauopathic condition in a subject in need thereof and / or treats a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0067] In any embodiment, the subject in need thereof is a human.

[0068] Another aspect of the present disclosure is an antibody obtained by any herein-disclosed method.

[0069] In embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

[0070] A further aspect of the present disclosure is pharmaceutical composition comprising a pharmaceutically acceptable carrier and a herein-disclosed isolated antibody.

[0071] In embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

[0072] In an aspect, the present disclosure provides a use of any herein-disclosed composition in a method for vaccinating a subj ect in need thereof.

[0073] In another aspect, the present disclosure provides a use of any herein-disclosed composition in a method for treating a symptom of a tauopathic condition in a subject in need thereof.

[0074] In a further aspect, the present disclosure provides a use of any herein-disclosed composition in a method for reducing a symptom of a tauopathic condition in a subject in need thereof.

[0075] In an additional aspect, the present disclosure provides a use of any herein-disclosed composition in a method for screening the presence of an antibody in a sample. In embodiments, the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma. In many embodiments, the sample is a tissue sample, e.g., from a biopsy. In several embodiments, the sample comprises tissue from the nervous system of a subject. In any embodiment, the tissue is obtained from the brain. In embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group. A MAPT-VLP can, therefore, be formulated with a pharmaceutically acceptable carrier. As used herein, “carrier” includes any solvent, dispersion medium, vehicle, coating, diluent, antibacterial, and / or antifungal agent, isotonic agent, absorption delaying agent, buffer, carrier solution, suspension, colloid, and the like. The use of such media and / or agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions. As used herein, “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with MAPT-VLP without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0076] A MAPT-VLP may therefore be formulated into a pharmaceutical composition. The pharmaceutical composition may be formulated in a variety of forms adapted to a preferred route of administration. Thus, a composition can be administered via known routes including, for example, oral, parenteral (e.g., intradermal, transcutaneous, subcutaneous, intramuscular, intravenous, intraperitoneal, intrathecal etc.), or topical (e.g., intranasal, intrapulmonary, intramammary, intravaginal, intrauterine, intradermal, transcutaneous, rectally, etc.). A pharmaceutical composition can be administered to a mucosal surface, such as by administration to, for example, the nasal or respiratory mucosa (e.g., by spray or aerosol). A composition also can be administered via a sustained or delayed release.

[0077] A formulation may be conveniently presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Methods of preparing a composition with a pharmaceutically acceptable carrier include the step of bringing the MAPT-VLP into association with a carrier that constitutes one or more accessory ingredients. In general, a formulation may be prepared by uniformly and / or intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.

[0078] A MAPT-VLP may be provided in any suitable form including but not limited to a solution, a suspension, an emulsion, a spray, an aerosol, or any form of mixture. The composition may be delivered in formulation with any pharmaceutically acceptable excipient, carrier, or vehicle. For example, the formulation may be delivered in a conventional topical dosage form such as, for example, a cream, an ointment, an aerosol formulation, a non-aerosol spray, a gel, a lotion, and the like. The formulation may further include one or more additives including such as, for example, an adjuvant, a skin penetration enhancer, a colorant, a fragrance, a flavoring, a moisturizer, a thickener, and the like. The formulations can be administered as a single dose or in multiple doses.

[0079] The amount of MAPT-VLP administered can vary depending on various factors including, but not limited to, the specific MAPT-VLP being administered, the weight, physical condition, and / or age of the subject, and / or the route of administration. Thus, the absolute weight of MAPT-VLP included in a given unit dosage form can vary widely and depends upon factors such as the particular MAPT-VLP being administered, the species, age, sex, weight and physical condition of the subject, and / or the method of administration. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of a MAPT-VLP effective for all possible applications. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.

[0080] In some embodiments, the method can include administering sufficient MAPT-VLP to provide a dose of, for example, from about 100 ng to about 50 mg to the subject, although in some embodiments the methods may be performed by administering MAPT-VLP in a dose outside this range. In some of these embodiments, the method includes administering sufficient MAPT- VLP to provide a dose of from about 10 pg to about 5 mg to the subject, for example, a dose of from about 100 pg to about 1 mg. In one specific embodiment, the method includes administering sufficient MAPT-VLP to provide a dose of from about 25 pg to about 300 pg.

[0081] Alternatively, the dose may be calculated using actual body weight obtained just prior to the beginning of a treatment course. For the dosages calculated in this way, body surface area (m2) can be calculated prior to the beginning of the treatment course using the Dubois method: m2=(wt kg0 425* height cm0 725)* 0.007184.

[0082] In some embodiments, the method can include administering sufficient MAPT-VLP to provide a dose of, for example, from about 0.01 mg / m2to about 10 mg / m2.

[0083] In some embodiments, a MAPT-VLP may be administered, for example, from a single dose to multiple doses per week, although in some embodiments the method can be performed by administering the MAPT-VLP at a frequency outside this range. In certain embodiments, the MAPT-VLP can be administered on an as needed basis. Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0084] Compositions

[0085] An additional aspect of the present disclosure is composition comprising an antigen presentation component comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0086] In some embodiments, the antigen presentation component comprises a virus-like particle (VLP).

[0087] A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0088] In various embodiments, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage.

[0089] In numerous embodiments, the antigen presenting component and the MAPT component are linked covalently. The VLP may comprise surface lysines which attach to the covalent linkage.

[0090] In additional embodiments, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage. In many embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0091] In several embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0092] In any embodiment, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0093] In embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1.

[0094] By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0095] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0096] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0097] In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0098] In some embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0099] In various embodiments, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0100] In numerous embodiments, the MAPT component consists of SEQ ID NO: 1. In additional embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0101] In many embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0102] As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0103] In several embodiments, the composition further comprises an adjuvant.

[0104] In additional embodiments, administering the pharmaceutical composition induces pT217- reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject. In preferred embodiments, administering the pharmaceutical composition induces pT217-reactive IgGs in the subject.

[0105] In embodiments, administering the composition vaccinates a subject in need thereof against a tauopathic condition.

[0106] In some embodiments, administering the composition reduces a symptom of a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the composition improves cognitive function. In various cases, administering the composition does not produce unwanted neuroinflammation. In some cases, administering the composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0107] In various embodiments, administering the composition for treating a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP- 17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the composition improves cognitive function. In various cases, administering the composition does not produce unwanted neuroinflammation. In some cases, administering the composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0108] In numerous embodiments, the subject in need thereof is a human.

[0109] In an aspect, the present disclosure provides a use of any herein-disclosed composition in a method for vaccinating a subj ect in need thereof. In another aspect, the present disclosure provides a use of any herein-disclosed composition in a method for treating a symptom of a tauopathic condition in a subject in need thereof.

[0110] In a further aspect, the present disclosure provides a use of any herein-disclosed composition in a method for reducing a symptom of a tauopathic condition in a subject in need thereof.

[0111] In an additional aspect, the present disclosure provides a use of any herein-disclosed composition in a method for screening the presence of an antibody in a sample. In embodiments, the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma. In many embodiments, the sample is a tissue sample, e.g., from a biopsy. In several embodiments, the sample comprises tissue from the nervous system of a subject. In any embodiment, the tissue is obtained from the brain. In embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

[0112] Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0113] Pharmaceutical Compositions

[0114] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising pharmaceutically acceptable carrier and any herein-disclosed composition, e.g., a composition comprising an antigen presentation component comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0115] In some embodiments, the antigen presentation component comprises a virus-like particle (VLP).

[0116] A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0117] In various embodiments, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage.

[0118] In numerous embodiments, the antigen presenting component and the MAPT component are linked covalently. The VLP may comprise surface lysines which attach to the covalent linkage.

[0119] In additional embodiments, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage.

[0120] In many embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0121] In several embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0122] In any embodiment, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0123] In embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1.

[0124] By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0125] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0126] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0127] In some embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0128] In various embodiments, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0129] In numerous embodiments, the MAPT component consists of SEQ ID NO: 1.

[0130] In additional embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0131] In many embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0132] As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0133] In several embodiments, the composition further comprises an adjuvant.

[0134] In additional embodiments, administering the pharmaceutical composition induces pT217- reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject. In preferred embodiments, administering the pharmaceutical composition induces pT217-reactive IgGs in the subject.

[0135] In yet a further aspect, the present disclosure provides a use of any herein-disclosed pharmaceutical composition in a method for vaccinating a subject in need thereof. In yet an additional aspect, the present disclosure provides a use of any herein-disclosed pharmaceutical composition in a method for treating a tauopathic condition in a subject in need thereof.

[0136] In various embodiments, administering the pharmaceutical composition for treating a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0137] An aspect of the present disclosure is a use of any herein-disclosed pharmaceutical composition in a method for reducing a symptom of a tauopathic condition in a subject in need thereof.

[0138] In embodiments, administering the pharmaceutical composition reduces a symptom of a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0139] In numerous embodiments, the subject in need thereof is a human.

[0140] In an aspect, the present disclosure provides a use of any herein-disclosed composition in a method for vaccinating a subj ect in need thereof.

[0141] A MAPT-VLP can, therefore, be formulated with a pharmaceutically acceptable carrier. As used herein, “carrier” includes any solvent, dispersion medium, vehicle, coating, diluent, antibacterial, and / or antifungal agent, isotonic agent, absorption delaying agent, buffer, carrier solution, suspension, colloid, and the like. The use of such media and / or agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions. As used herein, “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with MAPT-VLP without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. A MAPT-VLP may therefore be formulated into a pharmaceutical composition. The pharmaceutical composition may be formulated in a variety of forms adapted to a preferred route of administration. Thus, a composition can be administered via known routes including, for example, oral, parenteral (e.g., intradermal, transcutaneous, subcutaneous, intramuscular, intravenous, intraperitoneal, intrathecal etc.), or topical (e.g., intranasal, intrapulmonary, intramammary, intravaginal, intrauterine, intradermal, transcutaneous, rectally, etc.). A pharmaceutical composition can be administered to a mucosal surface, such as by administration to, for example, the nasal or respiratory mucosa (e.g., by spray or aerosol). A composition also can be administered via a sustained or delayed release.

[0142] A formulation may be conveniently presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Methods of preparing a composition with a pharmaceutically acceptable carrier include the step of bringing the MAPT-VLP into association with a carrier that constitutes one or more accessory ingredients. In general, a formulation may be prepared by uniformly and / or intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.

[0143] A MAPT-VLP may be provided in any suitable form including but not limited to a solution, a suspension, an emulsion, a spray, an aerosol, or any form of mixture. The composition may be delivered in formulation with any pharmaceutically acceptable excipient, carrier, or vehicle. For example, the formulation may be delivered in a conventional topical dosage form such as, for example, a cream, an ointment, an aerosol formulation, a non-aerosol spray, a gel, a lotion, and the like. The formulation may further include one or more additives including such as, for example, an adjuvant, a skin penetration enhancer, a colorant, a fragrance, a flavoring, a moisturizer, a thickener, and the like. The formulations can be administered as a single dose or in multiple doses.

[0144] The amount of MAPT-VLP administered can vary depending on various factors including, but not limited to, the specific MAPT-VLP being administered, the weight, physical condition, and / or age of the subject, and / or the route of administration. Thus, the absolute weight of MAPT-VLP included in a given unit dosage form can vary widely and depends upon factors such as the particular MAPT-VLP being administered, the species, age, sex, weight, and physical condition of the subject, and / or the method of administration. Accordingly, it is not practical to set forth generally the amount that constitutes an amount of a MAPT-VLP effective for all possible applications. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.

[0145] In some embodiments, the method can include administering sufficient MAPT-VLP to provide a dose of, for example, from about 100 ng to about 50 mg to the subject, although in some embodiments the methods may be performed by administering MAPT-VLP in a dose outside this range. In some of these embodiments, the method includes administering sufficient MAPT- VLP to provide a dose of from about 10 pg to about 5 mg to the subject, for example, a dose of from about 100 pg to about 1 mg. In one specific embodiment, the method includes administering sufficient MAPT-VLP to provide a dose of from about 25 pg to about 300 pg.

[0146] Alternatively, the dose may be calculated using actual body weight obtained just prior to the beginning of a treatment course. For the dosages calculated in this way, body surface area (m2) can be calculated prior to the beginning of the treatment course using the Dubois method: m2=(wt kg0 425* height cm0 725)* 0.007184.

[0147] In some embodiments, the method can include administering sufficient MAPT-VLP to provide a dose of, for example, from about 0.01 mg / m2to about 10 mg / m2.

[0148] In some embodiments, a MAPT-VLP may be administered, for example, from a single dose to multiple doses per week, although in some embodiments the method can be performed by administering the MAPT-VLP at a frequency outside this range. In certain embodiments, the MAPT-VLP can be administered on an as needed basis.

[0149] Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0150] Screening Samples for Antibodies

[0151] Another aspect of the present disclosure is a method for screening for the presence of an antibody in a sample. The method comprising a step of contacting a sample suspected of comprising the antibody with any herein-disclosed composition comprising an antigen presentation component. The method further comprises a step of detecting binding of the antigen presentation component and the antibody.

[0152] In some embodiments, the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma.

[0153] In various embodiments, the sample is a tissue sample, e.g., from a biopsy. In numerous embodiments, the sample comprises tissue from the nervous system of a subject.

[0154] In additional embodiments, the tissue is obtained from the brain.

[0155] In many embodiments, the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

[0156] Conjugating MAPT to VLPs

[0157] MAPT peptide can be covalently linked to a VLP. For example, a MAPT peptide containing an N-terminal or C-terminal cysteine residue can be linked to VLPs (e.g., QP VLPs, MS2, PP7, AP205, or any phage in the Leviviridae family) using a bi-functional cross-linker. One exemplary suitable bi-functional cross-linker is succinimidyl 6-((beta- maleimidopropionamido)hexanoate) (SMPH). The pT217-containing peptide (e.g., comprising any one of SEQ ID NO: 1 to SEQ ID NO: 4, or variants thereof) are custom-synthesized peptides from commercial sources or are expressed recombinantly. These peptides are designed to incorporate phosphorylated S / T residues that are spaced approximately at the center of the peptide chain. In some embodiments, the peptides are engineered to include a cysteine residue at the N-terminus for easy conjugation with the free lysines of the VLPs. One can insert a cysteine (linker) at the N-terminus of the protein for VLP conjugation using site-directed mutagenesis. The extent of conjugation of MAPT to QP VLPs can be analyzed by SUS-PAGE, Western blot analysis with respective immunized sera, and / or ELISA. Following production of MAPT-VLPs, immunogenicity can be assessed by immunizing C57B1 / 6 mice using previously described protocol (Chackerian et al., 2006, Vaccine 24:6321-6331).

[0158] While occasionally described in the context of exemplary embodiments in which the MAPT peptide is displayed using a VLP, an immunogen as described herein may be constructed, a composition as described herein may be prepared, and a method as described herein may be practiced using any suitable platform for displaying the MAPT peptide. Suitable platforms for displaying an immunogenic peptide include, for example, any synthetic and / or biocompatible platform that can display an immunogenic peptide in a multivalent format and / or array for presentation to the immune system. Such platforms can involve the use of a virus, a virosome, and / or nanoparticles. Definitions

[0159] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0160] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.”

[0161] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. In some cases, the term “about” refers to ±10% of a stated number or value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0162] As used herein, the phrases “at least one”, “one or more”, and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and / or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.

[0163] As used herein, “or” may refer to “and”, “or,” or “and / or” and may be used both exclusively and inclusively. For example, the term “A or B” may refer to “A or B”, “A but not B”, “B but not A”, and “A and B”. In some cases, context may dictate a particular meaning. The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative, or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0164] The terms “increased”, “increasing”, or “increase” are used herein to generally mean an increase by a statically significant amount. In some aspects, the terms “increased,” or “increase,” mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, standard, or control. Other examples of “increase” include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more as compared to a reference level.

[0165] The terms “decreased”, “decreasing”, or “decrease” are used herein generally to mean a decrease by a statistically significant amount. In some aspects, “decreased” or “decrease” means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level or non-detectable level as compared to a reference level), or any decrease between 10-100% as compared to a reference level. In the context of a marker or symptom, by these terms is meant a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without a given disease.

[0166] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0167] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subj ect at risk of developing a particular disease, or to a subj ect reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0168] The term “therapeutically effective amount” or “effective amount” refers to the amount of a compound or composition that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound or composition that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0169] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. By “MAPT-VLPs of the present disclosure” is meant any MAPT-VLP as described herein and comprising a MAPT component comprising a sequence that is at least 90% identical to SEQ ID NO: 1, as described herein. And VLP described herein may be used in a MAPT-VLP. Any linkage method described herein or known in the art may be used to conjugate a MAPT to a VLP. The term “pTau-VLP” is equivalent to “MAPT-VLPs of the present disclosure”.

[0170] MAPT-VLPs of the present disclosure are capable of inducting expression of pT217-reactive IgGs in a subject and / or inducing T217-reactive IgGs in the subject. The number “217” corresponds to the threonine (T) located at position 217 of SEQ ID NO: 5 and position seven (7) of SEQ ID NO: 1. Thus, the term “pT217-reactive IgGs” are antibodies that bind to a sequence comprising a phosphorylated fragment of Tau, e.g., comprising a phosphorylation at the T217 position, with respect to SEQ ID NO: 5. And, the term “T217-reactive IgGs” are antibodies that bind to a sequence comprising a non-phosphorylated fragment of Tau, e.g., comprising a phosphorylation at the T217 position, with respect to SEQ ID NO: 5.

[0171] Any composition or method disclosed herein is applicable to any herein-disclosed composition or method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0172] Teachings relevant to the present disclosure may be found in WO2016154522A1, WO2024049946A1, and WO2020242963A1, the contents of each of which is incorporated herein by reference in their entireties.

[0173] EXAMPLES

[0174] Example 1: Methods

[0175] Behavioral Analysis

[0176] 1. Spatial Alternation in the Y-Maze:

[0177] Spontaneous alternation in the Y-maze is a rapid and accurate measure of working spatial memory (Hughes, R. N., 2004, Neurosci Biobehav Rev 28:497-505) in mouse models of Alzheimer's disease. Each animal is placed in the center of the Y-maze and allowed free exploration for five minutes. The total number of arm choices and number of spontaneous alternations, where the previous two arm choices differed from the third, is calculated from the videotaped session. 2. Novel Object Recognition Test

[0178] After the Y-maze test, Novel Object Recognition test, a measure of recognition memory, which is significantly impaired in hTau mice at 12 months of age, is completed over three days as previously described (Oliveira et al., 2010, LearnMem 17:155-160) with minor modifications. Briefly, on day one, animals are placed in an open arena (60 cm><50 cm><40 cm) for a 10-minute habituation. On day two, animals are placed in the same open arena and exposed to two similar objects for 10 minutes. On day three, animals are placed in the same open arena and exposed to one familiar object (exactly the same as the objects from day two) and one novel object (distinct in shape and texture from the familiar object) for 10 minutes. A video tracking system (ETHOVISION, Noldus Information Technology, Leesburg, Va.) is used to calculate the percentage of time spent on object exploration.

[0179] 3. Barnes Maze

[0180] The Barnes Maze test involved a three-day paradigm for assessment of learning and short-term spatial memory consolidation following a previously published protocol. (Blackmer-Raynolds, L., Krout, I. N. & Sampson, T. Barnes Maze Protocol. (2024)). The Barnes maze (MazeEngineers) was a 92 cm diameter table with 20 holes (5 cm diameter) evenly positioned around the outer perimeter and a 20 cm x 11.5 cm x 4 cm black nesting box with fresh bedding anchored beneath one of the escape holes. All animals were trained for 2 days (three trials on each day; approximately 15 min inter-trial intervals) to find a hidden escape box using spatial cues in the room. The location of the escape hole remained the same for all training trials. The escape box and table surface were cleaned with 70% EtOH between all trials and the table surface was randomly rotated between all trials to eliminate scent cues. Animals were guided to the escape box only for the first trial and were allowed to acclimate to the escape box for two-minutes without any aversive stimuli. Bright white overhead lighting and loud white-noise were utilized as aversive stimuli to encourage the animals to search for the escape box during each trial. Each training trial was completed when the animals found the escape box and the latency to escape and number of incorrect holes investigated were recorded. 72-hours after the final training trial, a probe trial was performed where the escape box was removed and the percentage of time the animals spent in the target vs. other quadrants was recorded over a 90 second interval.

[0181] Neuropathological Analysis of mice and human brain tissues

[0182] Fixed brain tissue is cryoprotected (a 20% glycerol solution) and frozen before preparing coronal free-floating sections for immunohistochemistry. For studies of MAPT pathology, sections are processed to detect early (AT8, AT180, and MCI) and late (PHF1, Alz50) diseasespecific MAPT epitopes, truncated (AD421), and MAPT aggregates (detected using Galiyas silver staining; Bhaskar et al., 2010, Neuron 68: 19-31). Additional sections are used to identify neurodegeneration (annexin V, caspase 3, and Tunnel) via double immunofluorescence with a neuron-specific antigen NeuN. Neuroinflammation is detected via specific antibodies (microglia / macrophage by Ibal, CD45, CD68, F4 / 80; astrocytes by GFAP). Images will be captured in the ZEISS Meta inverted fluorescent microscope, and the quantifications will be performed utilizing Stereo Investigator® (MBF Bioscience, Williston, Vt.).

[0183] Biochemical Analysis

[0184] Antibody responses in the serum are quantified as previously described (Chackerian et al., 2006, Vaccine 24:6321-6331). For MAPT biochemistry, proteins from the frozen brains are extracted in Tissue-Protein Extraction Reagent (T-PER, Pierce, Thermo Fisher Scientific, Inc., Waltham, Mass.) with protease and phosphatase inhibitor cocktails and Western blot analysis performed. Specific antibodies to phosphorylated MAPT pS199 / S202 (AT8), pT231 (AT180), pS396 / pS404 (PHF1*, Dickson et al., 1987, Acta Neuropathol 73:254-258), conformational epitopes (Alz50*, Carmel et al., 1996, J Boil Chem 271 :32789-32795; MCI*, Jicha et al., 1997, JNeurosci Res 48: 128-132), truncated MAPT (AD421, Millipore MAB5430), and total MAPT (Taus and Taul2 — a human MAPT specific antibody) are used to detect respective phosphorylated MAPT. Appropriate secondary antibodies are used for immunodetection on Western blots (Bhaskar et al., 2010, Neuron 68: 19-31).

[0185] Example 2: Inoculation of PS19 Mice with MAPT-VLPs:

[0186] To assess the effectiveness of MAPT-VLPs in reducing the levels of truncated-MAPT, hyperphosphorylated-MAPT, and conformationally disordered-MAPT in hTau expressing mice (P301S, also referred to here as PS 19) once they age and display robust MAPT pathology, as described in Example 1 and as characterized in the art. Three weeks prior to peak MAPT pathology, PS19 mice are inoculated intramuscularly with respective MAPT-VLPs (e.g., pT217-VLPs) once weekly for two to three weeks.

[0187] After last serum collection, the mice are subjected to behavioral analysis, Barnes maze analysis (as characterized in the art) and sacrificed via transcardial perfusion with ice-cold phosphate buffer. The brains from half the mice in each group are microdissected into CX, HP, and ROB, weighed and frozen in liquid nitrogen for later biochemical analysis as described in Example 1. The brains from the other half of the mice in each group are immersion fixed in 4% paraformaldehyde for later neuropathological analysis.

[0188] Example 3: Vaccination Studies

[0189] Two-month-old P19 mice were vaccinated with either unconjugated QP VLPs (n=7 mice; 3 males, 4 females) or QP VLPs displaying pT217 tau peptide (n=8 mice; 4 males, 4 females). The mice received two intramuscular doses, 3-weeks apart (5 pg of VLP / dose; 50 pL per injection) in the right hind limb. See FIG. 2B for schematic. Retro-orbital blood collection was performed at 4-months, 5-months, and 6-months of age. Blood samples were allowed to clot at room temperature for 30 minutes and then centrifuged at 4000 x g for 10 minutes twice to isolate sera. Serum samples were frozen at -80°C for further analysis. Behavior analyses were performed at 6-months of age prior to sacrifice. The animals were sacrificed by Avertin anesthetization followed by transcardial perfusion with ice cold phosphate buffer pH 7.4. Left brain hemispheres were fixed in 4% paraformaldehyde (PFA) and the right cortex, hippocampus, and remaining brain tissue were weighed, snap frozen on dry ice and stored at - 80°C for further analysis.

[0190] To assess the brain penetrance of pT217-VLP-directed IgG, ELISA was performed on serum and brain (cortex) lysates of mice immunized with pT217-VLPs of the present disclosure or QP (without MAPT) alone. Notably, the level of pT217-reactive IgG in the brain lysates of mice immunized with pT217-VLPs of the present disclosure was compared to the mice immunized with QP alone. Furthermore, the presence of pT217 IgGs in the brain were confirmed by performing reverse immunohistochemistry. The brain sections were first incubated with biotinylated-T217 peptide and then incubated with streptavi din-conjugated to horse-radish peroxidase. Following developing the color reaction with a substrate, the presence of brown precipitation within several cells in the hippocampal dentate gyrus region were observed.

[0191] To assess the effect of vaccination on cognitive function, the novel object recognition test and Barnes maze assay were performed as described in Example 1. Briefly, wild type mice typically spend about 80% of their time with the novel object. In contrast, untreated PS 19 mice typically spend relatively equal amounts of time with both the novel object and the familiar object. Mice vaccinated with pT217-VLPs of the present disclosure were compared with vaccinated PS 19 mice to assay their preference to the novel object (compared to a familiar object). Proteins from frozen brains of PS 19 mice vaccinated with pT217-VLPs of the present disclosure or QP were extracted using Tissue-Protein Extraction Reagent (T-PER, Pierce, Thermo Fisher Scientific, Inc., Waltham, Mass.) with protease and phosphatase inhibitor cocktails, and Western blot analysis will be performed. Western Blot and immunohistochemistry were conducted.

[0192] Example 4: pT217-Q0VLPs induce a robust immune response in PS19 mice

[0193] The pT217-QPVLP vaccine was produced by conjugating pT217 tau peptides to pre-formed QP VLPs using a bifunctional crosslinker (FIG. 2A). By assessing the upward mobility shift in bands of QP-conjugated to pT217 peptides compared to unconjugated QP on a denaturing SDS-PAGE gel, it was estimated that 132 copies of the pT217 peptide are displayed per assembled QPVLP, which is composed of 180 monomers of the QP coat protein (FIG. 2C). PS 19 mice were vaccinated at 2-months of age with either unconjugated QP or pT217- QPVLPs, received a booster immunization 2-weeks later, and were monitored for 4-months with repeated blood collections followed by memory / behavior testing prior to sacrifice (FIG. 2B)

[0194] Serum IgG antibody titer levels against the pT217 tau peptide were assessed at 8-, 12-, and 16- weeks after the initial vaccine dose in both QPVLP and pT217-QPVLP vaccinated mice to evaluate the antibody response (FIG. 3A). At all three timepoints, pT217-QP VLP vaccinated mice showed significantly elevated serum IgG antibody titers against the pT217 peptide compared to the QPVLP vaccinated group which was below the detection level (FIG. 3A). Thus, pT217-QPVLP induced a robust antibody response which remained persistently elevated for at least 4-months. At the time of sacrifice, 16-weeks after the initial vaccination, anti-pT217 antibodies were significantly elevated within the brain parenchyma of pT217-QPVLP vaccinated mice; thus, anti-pT217 antibodies are brain penetrant albeit at several orders of magnitude lower than in the peripheral circulation (FIG. 3B)

[0195] To determine if pT217-QPVLP vaccination elicits antibodies against the non-phosphorylated T217 tau site, serum IgG antibody titers against the non-phosphorylated T217 tau peptide were measured and compared to the pT217 tau peptide. At 8-, 12-, and 16-weeks after the initial vaccine dose, serum titers against the non-phosphorylated T217 peptide were significantly lower than the titers against the pT217 peptide (FIG. 3C). Thus, pT217-Q0VLP vaccination elicits a robust antibody response that preferentially targets the pathological phosphorylation site, though some antibodies may show some binding to the T217 epitope regardless of the presence of the pT217 phosphorylation site in vitro.

[0196] Next, an antibody avidity assay using 6M urea was performed to determine the strength of antibody binding to either the pT217 peptide or the non-phosphorylated T217 peptide. There was no significant difference observed in the avidity index of the anti-pT217 antibodies and the anti-T217 antibodies; thus, all antibodies tested bind with high avidity to the peptide target (FIG. 3D). Notably, there was a higher variability in the avidity index for antibodies against the non-phosphorylated T217 peptide with some animals showing low avidity antibodies (one animal did not show any binding at all to the non-phosphorylated T217 peptide but was excluded from the analysis) whereas the antibodies against the pT217 peptide were all high avidity (FIG. 3D).

[0197] Example 5: pT217-QpVLP induced antibody responses engage pathological tau in human AD samples

[0198] To demonstrate that pT217-QpVLP vaccine induced antibodies which engage their pathological tau target in human AD tissue samples, IHC of human AD Braak stage III hippocampal brain sections was performed using the immune sera from pT217-QpVLP vaccinated mice and were compared to QPVLP vaccinated immune sera or a commercial AT8 antibody. The AT8 antibody was used as a positive control to confirm the presence of tau pathology in the AD hippocampal sections and the absence of pathology in healthy human control hippocampal tissue (FIG. 4A). The immune sera from the pT217-QpVLP vaccinated mice robustly detected tau pathology in the AD hippocampal tissue compared to the QPVLP immune sera which did not detect any tau pathology (FIG. 4A). Notably, the pT217-QpVLP immune sera did not show any staining in the healthy human control hippocampal tissue; thus, pT217-QPVLP induced antibodies which have preferential binding to pathological tau and not to healthy tau in human brain tissue ex vivo (FIG. 4A). The staining pattern of pT217-QPVLP immune sera in the AD brain showed preferential detection of pyramidal neuron pre-tangle pathology, abundant neuritic plaque detection, and puncta / neuropil thread-like structures across numerous regions. Comparatively, the AT8 antibody detected all of these tau structures but showed preferential detection of mature tangle pathology over pre-tangles.

[0199] Next, Western blot analysis of hippocampal lysates from human AD Braak stage III (n=9), human AD Braak stage VI (n=9), human frontotemporal dementia (FTD) (n=3), and mice deficient in the tau gene (mTau- / -) (n=3) was performed to further validate the ability of pT217- QPVLP induced antibodies to detect pathological tau. A commercially available anti-pT217 antibody showed minimal binding and was unable to distinguish human AD Braak stage III or VI samples but showed significantly higher binding in human FTD which typically does not have high pT217 levels (FIG. 4B and FIG. 4C). Conversely, antibodies purified from pT217- QPVLP immune sera distinguished AD patient samples from FTD and showed significant increase in detection between AD Braak stage III and Braak stage VI (FIG. 4B and FIG. 4C), despite total tau levels in each sample being equal (FIG. 4B and FIG. 4C). Furthermore, the commercially available anti-pT217 antibody showed significantly higher non-specific binding in mTau- / - samples around 55 kDa. On the other hand, the purified IgG from pT217-QPVLP vaccinated immune sera staining of mTau- / - around 55 kDa was not statistically significant from the Taul2 antibody which showed no tau present in the mTau- / - samples. Thus, the antibodies generated by pT217-QPVLP vaccination have a higher specificity for the pathological pT217-tau site and outperform a commercially available antibody for this site.

[0200] Uncropped western blots for the commercial pT217 antibody and the IgG purified from pT217- QPVLP and unconjugated QP sera further highlight the enhanced specificity of the herein- disclosed vaccine derived sera over the commercial antibody which showed high non-specific staining especially in mTau- / - samples. (FIG. 4F). The non-specific band at 39 kDa in the purified IgG from pT217-QP vaccine sera also appears in the purified IgG from QP vaccine sera indicating that this non-specific band is shared among mice and not a unique antibody induced by the pT217-QP vaccine.

[0201] Finally, immunoprecipitation of tau from human AD Braak stage VI hippocampal lysates was performed using purified IgG from either unconjugated QP vaccinated mouse sera and pT217- QPVLP vaccinated mouse sera (FIG. 4D). Western blot analysis of the flow through (FT) and immunoprecipitate (IP) from both groups using HRP-conjugated Tau5 antibody showed abundant presence of tau in the QPVLP FT but not in the QP IP (FIG. 4 E) and abundant tau in the pT217-QpVLP IP but not in the pT217-QpVLP FT. Thus, pT217-QpVLP induced IgG successfully immunoprecipitate pathological tau from human AD brain lysate indicating direct target engagement in human tissue samples.

[0202] Example 6: pT217-Q0VLP vaccination provides protection against early memory deficits in PS19 mice

[0203] The PS 19 tauopathy mouse model has been previously well characterized demonstrating an age dependent increase in tau pathology associated with decreasing cognitive and behavioral performance on a variety of validated cognitive / behavioral assessments. Early mild cognitive changes and synaptic dysfunction have been observed as early as 3-months of age preceding tau pathology including changes in anxiety behaviors. Deficits in long-term spatial and recognition memory appear around 6-months of age but are typically severe around 9-months. In this study, 6-month-old PS 19 mice as a model of early cognitive and memory deficits was assessed using a battery of assessments including the open field test, Y-maze spontaneous alternations test, novel object recognition test, and Barnes maze to determine if pT181- Q0 vaccination prevents early cognitive and memory deficits.

[0204] The open field test was performed to assess for changes in anxiety behaviors between unconjugated Q0VLP sham vaccinated and pT217-Q0VLP vaccinated PS 19 mice. No significant differences were observed in the amount of time spent in the center of the open field or in the borders of the open field between Q0 VLP or pT217-Q0VLP vaccinated PS 19 mice or non-transgenic control mice (FIG. 5A and FIG. 5B) suggesting a lack of increased anxiety behaviors at the 6-month timepoint in PS 19 mice. During the open field test, the PS 19 mice had significantly decreased movement velocity, distance traveled, and time spent moving compared to the non-transgenic control mice regardless of vaccine condition (FIG. 5H and FIG. 51)

[0205] The Y-maze spontaneous alternation test was performed to assess for differences in short-term spatial working memory between unconjugated Q0VLP sham vaccinated and pT217-Q0VLP vaccinated PS 19 mice. There were no significant differences in the percentage of spontaneous alternations or the percentage of repeated arm entries between the Q0VLP and pT2 l 7-QPVLP vaccinated PS 19 mice and non-transgenic control mice suggesting no impairment in spatial working memory at the 6-month time point in PS 19 mice (FIG. 5C and FIG. 5D).

[0206] The novel object recognition test was performed to assess changes in delay-dependent recognition memory between Q0VLP and pT217-Q0VLP vaccinated PS 19 mice. During the familiarization day, no groups exhibited a preference for either of the two identical objects. During the test day, 24-hours after familiarization, the Q0VLP vaccinated PS 19 mice exhibited a deficiency in recognition memory indicated by no preference for either the novel object or the familiar object in the frequency of nose touches to investigate each object (FIG. 5E). Contrastingly, the pT217-Q0VLP vaccinated mice exhibited a significantly increased preference for the novel object indicated by a positive discrimination index in the frequency of nose touches to investigate the novel object (FIG. 5E). Similarly, the non-transgenic mice also exhibited a preference for the novel object over the familiar object in nose touch frequency (FIG. 5E). When the amount of time each animal spent within the vicinity of the novel object and the familiar object werew assessed, all groups spent significantly more time with the novel object compared to the familiar object (FIG. 5F and FIG. 5G). Thus, the delay-dependent recognition memory deficits observed in the Q0VLP vaccinated PS 19 mice may be minimal at this timepoint.

[0207] Finally, the Barnes maze test was performed to assess for changes in spatial learning and longterm spatial memory formation between Q0VLP and pT217-Q0VLP vaccinated PS 19 mice following a previously published protocol.32 The five training trials demonstrated no deficits in spatial learning in either of the PS 19 vaccine conditions compared to non-transgenic animals. During each of the five training trials, there were no significant differences observed in the latency to finding the escape hole or the number of mistakes made prior to finding the escape hole between Q0VLP or pT217-Q0VLP vaccinated PS 19 mice or non-transgenic mice (FIG. 6A and FIG. 6D) 72-hours later, the escape box was removed and the animals’ long-term spatial memory was assessed revealing deficits in long-term spatial memory in the Q0VLP vaccinated PS 19 group. As expected, the non-transgenic mice spent significantly more time in the target quadrant than the off-target quadrants indicating intact long-term spatial memory formation whereas the QB vaccinated PS 19 mice spent an equal amount of time in the target quadrant as the off-target quadrants (FIG. 6B and FIG. 6C). Contrastingly, the pT2 l 7-QPVLP vaccinated PS 19 mice spent significantly more time in the target quadrant compared to the off- target quadrants indicating rescue of long-term spatial memory deficits (FIG. 6B and FIG. 6C). Furthermore, 5 out of 8 of the pT217-Q0VLP vaccinated mice utilized a direct search strategy to the escape hole during the probe trial while only one of the QB vaccinated mice used a direct search strategy.

[0208] Overall, at 6-months of age, PS 19 mice only display deficits in long-term spatial and recognition memory compared to non-transgenic mice suggesting that cognitive impairment is mild at this stage. Furthermore, these deficits are rescued by pT217-Q0VLP vaccination.

[0209] Example 7: pT217-QP vaccinations reduces early tan phosphorylation in 6-month-old PS19 mice

[0210] To assess for target engagement of pT217-Q0VLP induced antibodies in vivo, the levels of serum pT217 was measured using a validated singleplex electrochemiluminescence assay in serum collected from Q0VLP and pT217-Q0VLP vaccinated mice at 4-, 5-, and 6-months of age.

[0211] Next, the levels of pT217 phosphorylated tau protein was assessed in hippocampal lysates of 6-month old Q0VLP and pT217-Q0VLP vaccinated mice by western blot using a commercially available antibody against the pT217 site. pT217-QpVLP vaccinated mice showed significantly reduced levels of the pT217 tau protein compared to QP vaccinated mice suggesting target engagement by the pT217-QPVLP induced antibodies (FIG. 7A and FIG. 7B).

[0212] To further assess the effects of pT217-QP on tau pathology in 6-month-old PS19 mice, levels of several pathological tau markers was evaluated by western blot. The ATI 80 antibody, corresponding with the pT231 site, and the AT8 antibody, corresponding with the pS202 / pT205 sites, showed a reduction of about 27% and 66% respectively in the pT217- QPVLP vaccinated mice compared to the unconjugated QP group although these reductions were not statistically significant (FIG. 7C and FIG. 7D). The AT270 antibody, corresponding with the pT181 site, detected monomeric tau at 55 kDa and multimeric tau at -140 kDa which were both significantly reduced in the pT217-QPVLP group compared to the unconjugated QPVLP group (FIG. 7C and FIG. 7D). Taul2, a marker for total human tau, was significantly reduced by pT217-QPVLP vaccination but Tau5, a marker of normal physiologic tau at 55 kDa was unchanged (FIG. 7C and FIG. 7D). Like the AT270 antibody, multimeric tau detected by the Tau5 antibody was also significantly reduced by pT217-QPVLP vaccination (FIG. 7C and FIG. 7D)

[0213] These data demonstrate that pT217-QPVLP vaccination engages the pT217 site on pathological tau in vivo. The reduction of pT217+ tau also resulted in an associated reduction in pT181+ tau, pathological multimeric tau species, and overall human mutant tau from the brain.

[0214] Example 8: pT217-Q0VLP vaccination protects against early synapse loss in 6-month-old PS19 mice

[0215] Synaptic dysfunction and synapse loss are early neuropathologic changes in the PS 19 mouse model that precede neurodegeneration. To determine if pT217-QPVLP vaccination can protect against synapse loss, western blot analysis of hippocampal lysate from 6-month-old PS 19 mice vaccinated with either unconjugated QPVLP or pT217-Q0VLP was performed and changes in synaptic markers were assessed (FIG. 8A). The levels of synaptophysin, a marker of pre- synaptic vesicles, was significantly increased in pT217-QPVLP vaccinated PS 19 mice compared to unconjugated QPVLP vaccinated PS 19 mice (FIG. 8B). Similarly, postsynaptic density protein 95 (PSD-95), a post-synaptic marker for excitatory synapses, showed a 70% increase in pT217-Q0VLP vaccinated mice though this difference was not statistically significant (p=0.20) (FIG. 8B).

[0216] Example 9: Vaccination with pT217-Q0VLP reduces activity of biomarkers of inflammation pathway

[0217] Pathological tau contributes to neuroinflammation through activation of the NLRP3 inflammasome complex. Upon activation of the inflammasome, the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) recruits pro- caspase-1 to the inflammasome complex, pro-caspase-1 is then cleaved to its active form, caspase- 1, which then matures the inflammatory cytokine interleukin- ip (IL-ip) (FIG. 9). Western blot analysis of hippocampal lysates from unconjugated QPVLP vaccinated and pT217-QPVLP vaccinated PS 19 mice was performed to determine if tau reduction by pT217- QPVLP vaccination can reduce NLRP3 inflammasome activation (FIG. 10A). The levels of ASC protein were not significantly altered in pT217-QPVLP vaccinated mice compared to the unconjugated QPVLP vaccinated group (FIG. 10B). However, the levels of activated caspase- 1 were significantly decreased in the pT217-QP vaccinated group compared to the unconjugated QPVLP vaccinated group. Similarly, the levels of mature IL-ip were reduced by 37% but this failed to meet statistical significance (p=0.07) (FIG. 10C).

[0218] The transcription factor nuclear factor-kappa B (NF-KB) regulates the transcription of many inflammatory response genes in response to pathological tau including the inflammasome complex. NF-KB is inhibited by the protein inhibitor of kappa-B-alpha (IKB-C / .) but becomes activated when these proteins are phosphorylated. Western blot assessment of total NF-KB (t- P65), active NF-KB (p-P65), and IxB-a showed that pT217-QPVLP vaccination significantly reduced the levels of all three of these proteins in 6-month-old PS 19 mice compared to unconjugated QP vaccinated PS 19 mice (FIG. 10B). Thus, pT217-QPVLP vaccination reduces the priming of inflammatory response genes by NF-KB potentially through reducing the levels of pathological tau.

[0219] Example 10: Methods for Treating or Reducing a Symptom of a Tauopathic Condition The present disclosure provides a method comprising administering to a subject in need thereof a pharmaceutical composition for treating or reducing a symptom of a tauopathic condition. The pharmaceutical composition comprising pharmaceutically acceptable carrier and an antigen presentation component. The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0220] In several embodiments, administering the pharmaceutical composition reduces a symptom of a tauopathic condition in a subject in need thereof and / or treats a tauopathic condition in a subject in need thereof. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site. In embodiments, the antigen presentation component comprises a virus-like particle (VLP). In some cases, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage.

[0221] A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0222] In some embodiments, the antigen presenting component and the MAPT component are linked covalently. In some cases, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage.

[0223] In various embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0224] In numerous embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0225] In additional embodiments, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0226] In many embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1.

[0227] By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0228] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0229] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0230] In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0231] In several embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0232] In any embodiment, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0233] In embodiments, the MAPT component consists of SEQ ID NO: 1.

[0234] In some embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0235] In various embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0236] As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0237] In numerous embodiments, the pharmaceutical composition further comprises an adjuvant. In additional embodiments, administering the pharmaceutical composition induces pT217- reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject. In preferred embodiments, administering the pharmaceutical composition induces pT217-reactive IgGs in the subject.

[0238] In any embodiment, the subject in need thereof is a human.

[0239] Example 11 Methods for Vaccination a Subject Against a Tauopathic Condition

[0240] The present disclosure provides a method comprising administering to a subject in need thereof a pharmaceutical composition for vaccination a subject in need thereof against a tauopathic condition. The pharmaceutical composition comprising pharmaceutically acceptable carrier and an antigen presentation component. The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0241] In many embodiments, administering the pharmaceutical composition vaccinates a subject in need thereof against a tauopathic condition. In some cases, the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome-17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE). The symptom of the tauopathic condition may comprise cognitive impairment in the subject and / or neuroinflammation. In many cases, administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury. In some cases, administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss. In numerous cases, administering the pharmaceutical composition improves cognitive function. In various cases, administering the pharmaceutical composition does not produce unwanted neuroinflammation. In some cases, administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB. In various cases, administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject. In many cases, administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject. In multiple cases, administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some cases, the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

[0242] In embodiments, the antigen presentation component comprises a virus-like particle (VLP). In some cases, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage.

[0243] A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0244] In some embodiments, the antigen presenting component and the MAPT component are linked covalently. In some cases, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage.

[0245] In various embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0246] In numerous embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0247] In additional embodiments, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0248] In many embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1. By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0249] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0250] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0251] In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0252] In several embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0253] In any embodiment, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0254] In embodiments, the MAPT component consists of SEQ ID NO: 1.

[0255] In some embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0256] In various embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0257] In numerous embodiments, the pharmaceutical composition further comprises an adjuvant.

[0258] In additional embodiments, administering the pharmaceutical composition induces pT217- reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject. In preferred embodiments, administering the pharmaceutical composition induces pT217-reactive IgGs in the subject.

[0259] In any embodiment, the subject in need thereof is a human.

[0260] Example 12: Methods for Screening for the Presence of an Antibody in a Sample

[0261] The present disclosure provides a method for screening for the presence of an antibody in a sample. The method comprising a step of contacting a sample suspected of comprising the antibody with any herein-disclosed composition comprising an antigen presentation component. The method further comprises a step of detecting binding of the antigen presentation component and the antibody.

[0262] The antigen presentation component comprises a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component. The MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

[0263] In some embodiments, the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma.

[0264] In various embodiments, the sample is a tissue sample, e.g., from a biopsy.

[0265] In numerous embodiments, the sample comprises tissue from the nervous system of a subject.

[0266] In additional embodiments, the tissue is obtained from the brain.

[0267] In embodiments, the antigen presentation component comprises a virus-like particle (VLP). In some cases, the VLP comprises bacteriophage QP or MS2. Alternately, the VLP can be a PP7, AP205, or any phage in the Leviviridae family. The VLP may comprise surface lysines which attach to the covalent linkage. A VLP (e.g., a QP bacteriophage VLP) can be chemically conjugated to a pathological MAPT peptide through either N-terminal or C-terminal cysteine residues. One can use a mouse model to immunize normal mice with the conjugated VLPs and measure antibody responses to the targeted peptides (e.g., by ELISA). While other bacteriophage VLPs may be used, QP VLPs are composed of a single coat protein that self-assembles into a 27 nm-diameter icosahedral particle consisting of 90 coat-protein dimers. Moreover, MAPT peptides containing single free cysteine residues easily link to primary amine groups on surface-exposed lysines on VLPs via a bi-functional cross-linker with amine- and sulfhydryl-reactive arms. These residues allow conjugation of several MAPT peptides per VLP molecule, increasing the antibody response that is induced, and overcoming possible immune tolerance against a self-antigen like MAPT.

[0268] In some embodiments, the antigen presenting component and the MAPT component are linked covalently. In some cases, the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage. The VLP may comprise surface lysines which attach to the covalent linkage.

[0269] In various embodiments, the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

[0270] In numerous embodiments, the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

[0271] In additional embodiments, the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

[0272] In many embodiments, the MAPT component comprises a sequence that is at least 90% identical to SEQ ID NO: 1.

[0273] By “90% identical to SEQ ID NO: 1”, means that a sequence comprises at least 11 or 12 amino acids that are identical to those in SEQ ID NO: 1, which includes 13 amino acids. Thus, a sequence that is “90% identical to SEQ ID NO: 1” has one amino acid is substituted with another amino acid and / or may have one or two amino acids substituted with respect to SEQ ID NO: 1. As examples, a sequence that is 90% identical to SEQ ID NO: 1 may have the N- terminal arginine (R) of SEQ ID NO: 1 substituted with any of the other 19 standard amino acids that make up proteins, i.e., alanine (A), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V) and / or the sequence that is 90% identical to SEQ ID NO: 1 may also have the second amino acid (threonine (T)) substituted with any one of the other 19 standard amino acids that make up proteins, i.e., alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), tryptophan (W), tyrosine (Y), or valine (V). The substitution may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1 ; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two substitutions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0274] In some cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may have one or two amino acids deleted with respect to SEQ ID NO: 1. The deletion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two deletions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0275] In others cases, rather than a substitution, in which one amino acid is replaced with another amino acid, a sequence that is “90% identical to SEQ ID NO: 1”, may one or two amino acids inserted with respect to SEQ ID NO: 1. The insertion may be at any one or two amino acids in SEQ ID NO: 1, except the threonine (T) located at position seven (7) of SEQ ID NO: 1; this threonine corresponds to T217 of SEQ ID NO: 5. In other words, “90% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 or can have two insertions at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. The inserted amino acid may be any one of alanine (A), arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), serine (S), threonine (T), tryptophan (W), tyrosine (Y), or valine (V). Similarly, a sequence that is “95% identical to SEQ ID NO: 1”, can have one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1. In various cases, a sequence that is “90% identical to SEQ ID NO: 1”, may have a combination of substitutions, deletions, and insertions. As examples, the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; the sequence may have one substitution at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1; or the sequence may have one deletion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1 and one insertion at any of positions 1 to 6 or 8 to 13 with respect to SEQ ID NO: 1.

[0276] In several embodiments, the MAPT component comprises the sequence of SEQ ID NO: 1.

[0277] In any embodiment, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

[0278] In embodiments, the MAPT component consists of SEQ ID NO: 1.

[0279] In some embodiments, the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

[0280] In various embodiments, the MAPT component comprises a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4. The MAPT component may comprise the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In various cases, the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The MAPT component may consist of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

[0281] As mentioned above with respect to the term “90% identical to SEQ ID NO: 1”, a sequence that is at least 95% identical to SEQ ID NO: 2 , SEQ ID NO: 3 , or SEQ ID NO: 4, may have one or two substitutions, deletions, or insertions or may have a combination of one or two substitutions, deletions, and insertions.

[0282] INCORPORATION BY REFERENCE

[0283] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. In particular, the entire contents of PCT / US2016 / 024174; PCT / IB2010 / 053313, and US20080050383A1 are incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

[0284] SEQUENCES

[0285] SEQ ID NO: 1

[0286] RTPSLPTPPTREP

[0287] SEQ ID NO: 2

[0288] RTPSLPTPPTREPGGC

[0289] SEQ ID NO: 3

[0290] GGCRTPSLPTPPTREP

[0291] SEQ ID NO: 4

[0292] GGCRTPSLPTPPTREPGGC

[0293] SEQ ID NO: 5

[0294] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTP TEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEA GIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAA PPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPS LPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQ PGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKC GSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKL TFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVD

Claims

CLAIMSWhat is claimed is:

1. A method comprising administering to a subject in need thereof a pharmaceutical composition comprising: an antigen presentation component comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component; and wherein the MAPT component: comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group; and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the antigen presentation component comprises a virus-like particle (VLP).

3. The method of claim 2, wherein the VLP comprises bacteriophage QP, MS2, PP7, AP205, or any phage in the Leviviridae family.

4. The method of any one of claims 1 to 3, wherein the antigen presenting component and the MAPT component are linked covalently.

5. The method of claim 4, wherein the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage.

6. The method of any one of claims 3 to 5, wherein the VLP comprises surface lysines which attach to the covalent linkage.

7. The method of any one of claims 1 to 6, wherein the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

8. The method of any one of claims 1 to 7, wherein the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

9. The method of any one of claims 1 to 8, wherein the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

10. The method of any one of claims 1 to 9, wherein the MAPT component comprises a sequence that is at least 90% identical or is at least 95% identical to SEQ ID NO: 1.

11. The method of any one of claims 1 to 10, wherein the MAPT component comprises the sequence of SEQ ID NO: 1.

12. The method of any one of claims 1 to 11, wherein the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

13. The method of any one of claims 1 to 12, wherein the MAPT component consists of SEQ ID NO: 1.

14. The method of any one of claims 1 to 13, wherein the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

15. The method of claim 14, wherein the MAPT component comprises a sequence that is at least 90% identical to or is at least 95% identical to SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

16. The method of claim 14 or claim 15, wherein the MAPT component comprises the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

17. The method of any one of claims 14 to 16, wherein the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

18. The method of any one of claims 14 to 17, wherein the MAPT component consists of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

19. The method of any one of claims 1 to 18, wherein the pharmaceutical composition further comprises an adjuvant.

20. The method of any one of claims 1 to 19, wherein administering the pharmaceutical composition induces pT217-reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject.

21. The method of any one of claims 1 to 20, wherein administering the pharmaceutical composition vaccinates a subject in need thereof against a tauopathic condition.

22. The method of any one of claims 1 to 21, wherein administering the pharmaceutical composition reduces a symptom of a tauopathic condition in a subject in need thereof and / or treats a tauopathic condition in a subject in need thereof.

23. The method of any claim 21 or claim 22, wherein the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome- 17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE).

24. The method of claim 22 or claim 23, wherein the symptom of the tauopathic condition comprises cognitive impairment in the subject and / or neuroinflammation.

25. The method of any one of claims 22 to 24, wherein administering the pharmaceutical composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury.

26. The method of any one of claims 22 to 25, wherein administering the pharmaceutical composition reduces neurodegeneration and / or neuronal loss and / or brain atrophy and / or synaptic loss.

27. The method of any one of claims 22 to 26, wherein administering the pharmaceutical composition improves cognitive function.

28. The method of any one of claims 22 to 27, wherein administering the pharmaceutical composition does not produce unwanted neuroinflammation.

29. The method of any one of claims 22 to 28, wherein administering the pharmaceutical composition reduces the priming of inflammatory response genes by NF-KB.

30. The method of any one of claims 22 to 29, wherein administering the pharmaceutical composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject.

31. The method of any one of claims 22 to 30, wherein administering the pharmaceutical composition reduces the amount of mutant tau from the brain of the subject.

32. The method of any one of claims 1 to 31, wherein administering the pharmaceutical composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months.

33. The method of claim 32, wherein the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

34. The method of any one of claims 1 to 33, wherein the subject in need thereof is a human.

35. An antibody obtained by the method of any one of claims 1 to 34.

36. The antibody of claim 35, wherein the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

37. A pharmaceutical composition comprising an isolated antibody of claim 35 or claim 29 and a pharmaceutically acceptable carrier.

38. A composition comprising: an antigen presentation component comprising a multivalent immunogen display vaccine format and a microtubule associated tau protein (MAPT) component linked to at least a portion of the antigen presentation component; and wherein the MAPT component: comprises a sequence that is at least 90% identical to SEQ ID NO: 1; comprises no more than 30 amino acids; and comprises at least one amino acid residue modified to comprise a PO3H2 group.

39. The composition of claim 38, wherein the antigen presentation component comprises a virus-like particle (VLP).

40. The composition of claim 39, wherein the VLP comprises bacteriophage QP, MS2, PP7, AP205, or any phage in the Leviviridae family.

41. The composition of any one of claims 38 to 40, wherein the antigen presenting component and the MAPT component are linked covalently.

42. The composition of claim 41, wherein the covalent link comprises a succinimidyl-6-[P- maleimidopropionamido]hexanoate (SMPH) linkage.

43. The composition of any one of claims 40 to 42, wherein the VLP comprises surface lysines which attach to the covalent linkage.

44. The composition of any one of claims 38 to 43, wherein the at least one amino acid residue modified to comprise a PO3H2 group is a threonine.

45. The composition of any one of claims 38 to 44, wherein the threonine comprising the PO3H2 group is at position 2, 7, and / or 10 with respect to SEQ ID NO: 1.

46. The composition of any one of claims 38 to 45, wherein the threonine comprising the PO3H2 group is at position 7 with respect to SEQ ID NO: 1.

47. The composition of any one of claims 38 to 46, wherein the MAPT component comprises a sequence that is at least 90% identical or is at least 95% identical to SEQ ID NO: 1.

48. The composition of any one of claims 38 to 47, wherein the MAPT component comprises the sequence of SEQ ID NO: 1.

49. The composition of any one of claims 38 to 48, wherein the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 1.

50. The composition of any one of claims 38 to 49, wherein the MAPT component consists of SEQ ID NO: 1.

51. The composition of any one of claims 38 to 48, wherein the MAPT component comprises or is covalently linked to one or more N-terminal and / or C-terminal glycines and / or cysteines.

52. The composition of claim 51, wherein the MAPT component comprises a sequence that is at least 90% identical or is at least 95% identical to SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

53. The composition of claim 51 or claim 47, wherein the MAPT component comprises the sequence or SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

54. The composition of any one of claims 51 to 53, wherein the MAPT component consists essentially of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

55. The met composition hod of any one of claims 51 to 54, wherein the MAPT component consists of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

56. The composition of any one of claims 38 to 55, wherein the composition further comprises an adjuvant.

57. The composition of any one of claims 38 to 56, wherein administering the composition induces pT217-reactive IgGs in the subject and / or administering the pharmaceutical composition induces T217-reactive IgGs in the subject.

58. The composition of any one of claims 38 to 57, wherein administering the composition vaccinates a subject in need thereof against a tauopathic condition.

59. The composition of any one of claims 38 to 58, wherein administering the composition reduces a symptom of a tauopathic condition in a subject in need thereof.

60. The composition of any one of claims 38 to 59, wherein administering the composition for treating a tauopathic condition in a subject in need thereof.

61. The composition of any claim 59 or claim 53, wherein the tauopathic condition comprises Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), frontotemporal dementia and Parkinsonism linked to chromosome- 17 Tau Type (FTDP-17T), argyrophilic grain dementia (AGD), traumatic brain injury (TBI), or chronic traumatic encephalopathy (CTE).

62. The composition of any one of claims 59 to 61, wherein the symptom of the tauopathic condition comprises cognitive impairment in the subject in need thereof.

63. The composition of any one of claims 59 to 62, wherein the symptom of the tauopathic condition comprises neuroinflammation.

64. The composition of any one of claims 59 to 63, wherein administering the composition delays or prevents the onset and / or propagation of neurofibrillary tangle pathology following traumatic brain injury.

65. The composition of any one of claims 59 to 64, wherein administering the composition reduces neurodegeneration and / or neuronal loss and / or synaptic loss.

66. The composition of any one of claims 59 to 65, wherein administering the composition reduces brain atrophy.

67. The composition of any one of claims 59 to 66, wherein administering the composition improves cognitive function.

68. The composition of any one of claims 59 to 67, wherein administering the composition does not produce unwanted neuroinflammation.

69. The composition of any one of claims 59 to 68, wherein administering the composition reduces the priming of inflammatory response genes by NF-KB.

70. The composition of any one of claims 59 to 69, wherein administering the composition reduces the amount of disease associated MAPT peptide in in cerebrospinal fluid (CSF) of the subject in need thereof.

71. The composition of any one of claims 59 to 70, wherein administering the composition reduces the amount of mutant tau from the brain of the subject.

72. The composition of any one of claims 59 to 71, wherein administering the composition induces an antibody response which remains elevated for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months.

73. The composition of claim 72, wherein the induced antibody response has a higher specificity for the pathological pT217-tau site relative to the unphosphorylated T217 tau site.

74. The composition of any one of claims 38 to 73, wherein the subject in need thereof is a human.

75. Use of the composition of any one of claims 38 to 74 in a method for vaccinating a subject in need thereof or for treating or reducing a symptom of a tauopathic condition in a subject in need thereof.

76. Use of the composition of any one of claims 38 to 74 in a method for screening the presence of an antibody in a sample.

77. The use of claim 76, wherein the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma.

78. The use of claim 77, wherein the sample is a tissue sample, e.g., from a biopsy.

79. The use of claim 77 or claim 64, wherein the sample comprises tissue from the nervous system of a subject.

80. The use of claim 79, wherein the tissue is obtained from the brain.

81. The use of any one of claims 76 to 80, wherein the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

82. A pharmaceutical composition comprising the composition of any one of claims 38 to 74 and a pharmaceutically acceptable carrier.

83. Use of the pharmaceutical composition of claim 82 in a method for vaccinating a subject in need thereof or for treating or reducing a symptom of a tauopathic condition in a subject in need thereof.

84. A method for screening for the presence of an antibody in a sample, the method comprising contacting a sample suspected of comprising the antibody with a composition of any one of claims 38 to 74 and detecting binding of the antigen presentation component and the antibody.

85. The method of claim 84, wherein the sample is obtained from a subject and is selected from cerebrospinal fluid (CSF), urine, saliva, and whole blood or a blood product, e.g., serum and plasma.

86. The method of claim 85, wherein the sample is a tissue sample, e.g., from a biopsy.

87. The method of claim 85 or claim 72, wherein the sample comprises tissue from the nervous system of a subject.

88. The method of claim 87, wherein the tissue is obtained from the brain.

89. The method of any one of claims 84 to 88, wherein the antibody binds to SEQ ID NO: 1 comprising at least one amino acid residue modified to comprise a PO3H2 group and / or the antibody binds to SEQ ID NO: 1 lacking an amino acid residue modified to comprise a PO3H2 group.

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