Methods of delaying dementia

Abstract

Described are methods of delaying the onset or progression of dementia or mild cognitive impairment in a subject comprising administering to the subject a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or a recombinant nucleic acid encoding a VZV gE polypeptide.

Description

[0001] METHODS OF DELAYING DEMENTIA

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to methods of delaying the onset or progression of dementia or mild cognitive impairment in a subject comprising administering to the subject a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or a recombinant nucleic acid encoding a N N gE polypeptide.

[0004] BACKGROUND OF THE INVENTION

[0005] Dementia is a growing public health concern, characterized by impaired cognitive ability including memory and thinking problems, which interfere with social abilities and everyday activities of affected individuals. Alzheimer's disease accounts for up to 80% of cases of dementia. Additional conditions associated with dementia include vascular disease, Lewy body disease, frontotemporal degeneration and Parkinson’s disease. Mild cognitive impairment (MCI) is an early stage of memory loss characterized by symptoms that are not as severe as dementia. While affected individuals are often able to carry out everyday activities, MCI can be an early stage in the progression to dementia.

[0006] Several retrospective studies of electronic databases and clinical records have found that vaccination against herpes zoster (HZ; shingles) is associated with a reduced risk of newly diagnosed dementia. Two studies in older adults (aged >65 or >70 years at sampling) (Scherrer et al., PLoS One 16, e0257405, doi: 10.1371 / joumal.pone.0257405 (2021); Schnier et al., Alzheimers Dement (NY) 8, e 12293, doi: 10. 1002 / trc2. 12293 (2022) and one study in adults aged 40-69 years (Lophatananon et al. BMJ Open 11, e045871, doi: 10.1136 / bmjopen-2020-045871 (2021)) found that the risk of dementia was reduced by up to 30% in those vaccinated against HZ. More recently, Eyting et al. claimed a causal link between HZ vaccination and a 20% lower risk of dementia.

[0007] The published studies reporting an association between HZ vaccination and dementia risk are limited in several aspects. First, the evidence is primarily based on patients who received a live -attenuated zoster vaccine (Zostavax) which was first licensed for use in 2006, but does not consider the more recently authorized recombinant zoster vaccine (RZV) containing the recombinant VZV glycoprotein E (Shingrix, first licensed in 2017). Second, many studies to date fail to account for the healthy patient selection bias: people that choose to pursue or can afford elective adult vaccines may in general be healthier with fewer lifestyle-associated risk factors than people who do not (or cannot) choose elective vaccines. Thus there is a need in the art for methods of delaying the onset or progression of dementia or mild cognitive impairment in human subjects.

[0008] SUMMARY OF THE INVENTION

[0009] The present disclosure provides methods for delaying the onset or progression of dementia or mild cognitive impairment in a human subject.

[0010] In one aspect, the present disclosure provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

[0011] In another aspect the present disclosure provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

[0012] In another aspect the present disclosure provides recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptides, and compositions comprising such polypeptides, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide or composition.

[0013] In another aspect the present disclosure provides recombinant nucleic acids encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and compositions comprising such recombinant nucleic acids, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide or composition.

[0014] In another aspect the present disclosure provides methods of treating a human subject at least 50 years old, comprising: - administering to the human subject a therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide.

[0015] In another aspect the present disclosure provides methods of treating a human subject at least 50 years old, comprising:

[0016] - administering to the human subject a therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of the recombinant nucleic acid encoding the recombinant N N gE polypeptide.

[0017] In another aspect the present disclosure provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising:

[0018] - administering to the human subject at least one therapeutically effective dose of a vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier.

[0019] In another aspect the present disclosure provides methods of treating a human subject at least 50 years old, comprising:

[0020] - administering to the human subject a first therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0021] - administering to the human subject a second therapeutically effective dose of a recombinant N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0022] In another aspect the present disclosure provides methods of treating a human subject at least 50 years old, comprising: - administering to the human subject a first therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0023] - administering to the human subject a second therapeutically effective dose of a recombinant nucleic acid encoding a N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0024] BRIEF DESCRIPTION OF THE FIGURES

[0025] FIG. 1A-1E: Incidence and relative risk of all-cause dementia over time in matched RZV- 2D (A-C) and ZVL (D-E) compared to comparator cohorts. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia diagnosis) until each timepoint. Abbreviations: CI, confidence interval; NE, non-exposed (not exposed to either RZV or ZVL); PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV-2D, at least 2 administered doses of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live-attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0026] FIG. 2A-2D: Incidence and relative risk of mild cognitive impairment over time in matched RZV-2D (A, B) and ZVL (C, D) cohorts compared to comparator cohorts. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (mild cognitive impairment) until each timepoint. Abbreviations: CI, confidence interval; NE, non-exposed (not exposed to either RZV or ZVL); PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV-2D, at least 2 administered doses of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live-attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals. FIGS. 3A-3C: Incidence and relative risk of dementia over time in matched RZV (at least one dose) compared to ZVL (FIG. 3A), PPSV23 (FIG. 3B) or non-exposed (FIG. 3C) cohorts. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia) until each timepoint. Abbreviations: CI, confidence interval; NE, non-exposed (not exposed to either RZV or ZVL); PPSV23, 23- valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV (>1 dose), at least 1 administered dose of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live- attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0027] FIGS. 4A-4B: Incidence and relative risk of mild cognitive impairment over time in matched RZV (at least one dose) compared to PPSV23 (FIG. 4A) or non-exposed (FIG. 4B) cohorts. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia) until each timepoint. Abbreviations: CI, confidence interval; NE, non-exposed (not exposed to either RZV or ZVL); PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV (>1 dose), at least 1 administered dose of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live-attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0028] FIGS 5A-5B: Incidence and relative risk of Alzheimer’s disease (FIG. 5A) or Vascular dementia (FIG. 5B) in matched RZV (top panels) and ZVL (bottom panel) cohorts, compared to the PPSV23 comparator cohort. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia) until each timepoint. Abbreviations: CI, confidence interval; NE, non-exposed (not exposed to either RZV or ZVL); PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV (>1 dose), at least 1 administered dose of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live-attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0029] FIGS 6A-6B: Incidence and relative risk of all-cause dementia over time in matched RZV and ZVL cohorts, compared to the PPSV23 comparator cohort, stratified by sex. “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia) until each timepoint. Abbreviations: CI, confidence interval; PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV (>1 dose), at least 1 administered dose of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live -attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0030] FIGS. 7A-C: Incidence and relative risk of all -cause dementia over time in matched RZV and ZVL cohorts, compared to the PPSV23 comparator cohort, stratified by age: 60-69 years (FIG. 7A), 70-79 years (FIG. 7B); and 80-89 years (FIG. 7C). “At risk” indicates the total number of match individuals in each cohort, at each time point. “Censored” indicates the cumulative number of individuals who were lost to follow-up or had died until each timepoint. “Events” indicates the cumulative numbers of individuals with the event of interest (dementia) until each timepoint. Abbreviations: CI, confidence interval; PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR, relative risk; RZV (>1 dose), at least 1 administered dose of the recombinant zoster vaccine (brand name SHINGRIX); ZVL, live-attenuated zoster vaccine (brand name ZOSTAVAX). Shaded areas in cumulative hazard plots represent confidence intervals.

[0031] FIGS. 8A-C: Alignment of ectodomains of VZV gE proteins. Amino acids differing from the consensus sequence (Q9J3M8) are boxed. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present disclosure provides methods for delaying the onset or progression of dementia or mild cognitive impairment in a human subject comprising administering to a human subject at least one dose of a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide. In certain aspects the N N gE polypeptide is a recombinant polypeptide. On other aspects the N N gE polypeptide is delivered as a recombinant nucleic acid encoding the polypeptide.

[0033] Also provided are recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptides, recombinant nucleic acids encoding such polypeptides, and compositions comprising such recombinant polypeptides or nucleic acids, for use in the disclosed methods.

[0034] I. DEFINITIONS

[0035] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0036] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term “at least one” refers to one or more.

[0037] Unless specifically stated, as used herein, the term "about" is understood as within a range of normal tolerance in the art. In one embodiment, the term "about" means within 10% of the reported numerical value of the number with which it is being used, such as within 5% of the reported numerical value. For example, the term "about" can be immediately understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01 % of the stated value.

[0038] The term "and / or" as used in a phrase such as "A and / or B" is intended to include "A and B," "A or B," "A," and "B." Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). Additionally, numerical limitations given with respect to concentrations or levels of a substance, such as solution component concentrations or ratios thereof, and reaction conditions such as temperatures, pressures, and cycle times are intended to be approximate. Unless specified otherwise, where a numerical range is provided, it is inclusive, i.e., the endpoints are included.

[0039] “Comprise” (“comprising” or “comprises”) as used herein is open-ended and means “including, but not limited to.” “Having” is used herein as a synonym of comprising. It is understood that wherever embodiments are described herein with the language “comprising,” such embodiments encompass those described in terms of “consisting of’ and / or “consisting essentially of.”

[0040] For the purposes of the descriptions herein, the abbreviations used for the genetically encoded amino acids are conventional and are as follows:

[0041] ASPARAGINE ASN N

[0042] ASPARTATE ASP D

[0043] CYSTEINE CYS C

[0044] GLUTAMATE GLU E

[0045] GLUTAMINE GLN Q

[0046] GLYCINE GLY G

[0047] HISTIDINE HIS H

[0048] ISOLEUCINE ILE I

[0049] LEUCINE LEU L

[0050] LYSINE LYS K

[0051] METHIONINE MET M

[0052] PHENYLALANINE PHE F

[0053] PROLINE PRO P

[0054] SERINE SER S

[0055] THREONINE THR T AMINO ACID THREE-LETTER ONE-LETTER

[0056] TRYPTOPHAN TRP W

[0057] TYROSINE TYR Y

[0058] VALINE VAL V

[0059] “Amino acid” or “residue” as used in the context of the polypeptides disclosed herein refers to the specific monomer at a sequence position (e.g.., P5 indicates that the “amino acid” or “residue” at position 5 is a proline.)

[0060] “Amino acid difference” or “residue difference” or “amino acid substitution” refers to a change in the residue at a specified position of a polypeptide sequence when compared to a reference sequence (e.g. P5Y indicates that the proline at position 5 of a reference sequence is changed to tyrosine).

[0061] “Corresponding to,” “reference to,” or “relative to” when used in the context of the numbering of a given amino acid or polynucleotide sequence refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. Methods of comparing a sequence with a specified reference sequence are known to a skilled person. For example, the Needleman Wunsch method can be used to compare any amino acid or polynucleotide sequence with a reference sequence. “Corresponding amino acid position” is a term that is widely used and well-understood by a skilled person. A corresponding amino acid position can be identified by aligning the amino acid sequences using any of the well-known amino acid alignment methods. For example, the NCBI BLAST algorithm method can be used to identify a corresponding amino acid position.

[0062] “Dementia” as used herein means a significant cognitive decline from a previous level of performance across one or more cognitive domains, including attention, executive function, learning and memory, language, perceptual-motor, social cognition, psychomotor speed, visuo-perceptual and visuo-spatial abilities. The cognitive deficits characteristic of dementia are sufficiently severe to interfere with independence in everyday activities. Dementia can be further characterized by age of onset (early onset dementia [<65 years], late onset dementia [>65 years]), by severity (mild / moderate / severe), and by underlying etiology (e.g., Alzheimer’s disease, Frontotemporal degeneration, Lewy body disease, Vascular disease, Parkinson’s disease, Huntington’s disease). Well-established frameworks exist for diagnosing dementia in a clinical setting, including the Diagnostic and Statistical Manual (currently in the 5th Edition, DSM-5) and the International Classification of Diseases (ICD, currently in the 11thEdition, ICD-11). Dementia is also referred to in the medical field as Major Neurocognitive Disorder.

[0063] “Mild Cognitive Impairment” or “MCI” as used herein means a modest cognitive decline from a previous level of performance across one or more cognitive domains, including attention, executive function, learning and memory, language, perceptual-motor, social cognition, psychomotor speed, visuo-perceptual and visuo-spatial abilities. The cognitive deficits are not sufficiently severe to interfere with independence in everyday activities. MCI can be further characterized by underlying etiology (e.g., Alzheimer’s disease, Frontotemporal degeneration, Lewy body disease, Vascular disease, Parkinson’s disease, Huntington’s disease). Well-established frameworks exist for diagnosing MCI in a clinical setting, including the Diagnostic and Statistical Manual (currently in the 5th Edition, DSM-5) and the International Classification of Diseases (ICD, currently in the 11thEdition, ICD-11). Mild Cognitive Impairment (MCI) is also referred to in the medical field as Minor Neurocognitive Disorder or Mild Neurocognitive Disorder.

[0064] “N N gE hydrophobic domain”, or “N N gE transmembrane domain” as used herein refers to the portion of the N N gE protein corresponding to about amino acids 547 to 559 of SEQ ID NOs: 1-5 or amino acids 585 to 597 of SEQ ID NOs: 6-7. “About” in this context means that the N N gE hydrophobic domain may start at any one of amino acids 545, 546, 547, 548 or 549 of SEQ ID NOs: 1-5 or amino acids 583, 584, 585, 586 or 587 of SEQ ID NOs: 6-7; and may end at any one of amino acids 557, 558, 559, 560, or 561 of SEQ ID NOs: 1-5 or amino acids 595, 596, 597, 598, or 598.

[0065] “N N gE intravirion domain” as used herein refers to the portion of the N N gE protein corresponding to about amino acids 560 to 623 of SEQ ID NOs: 1-5 or amino acids 598 to 661 of SEQ ID NOs: 6-7. “About” in this context means that the N N gE intravirion domain may start at any one of amino acids 558, 559, 560, 561 and 562 of SEQ ID NOs: 1- 5 or amino acids 596, 597, 598, 599, or 600 of SEQ ID NOs: 6-7; and may end at any one of amino acids 621, 622, 623, 624, or 625 of SEQ ID NOs: 1-5 or amino acids 659, 660, 661, 662, or 663 of SEQ ID NOs: 6-7. Recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) include, but are not limited to, vaccines comprising recombinant N N gE polypeptides, such as SHINGRIX, and vaccines comprising recombinant nucleic acids encoding N N gE polypeptides, including RNA vaccines. Such recombinant means do not include live-attenuated varicella zoster virus vaccines.

[0066] Methods

[0067] The present disclosure provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising, in one independent aspect, administering to the subject at least one dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide; or in another independent aspect administering to the subject at least one dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

[0068] In one aspect, the method comprises administering to the human subject at least one dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide derived from a wild-type N N gE protein sequence. A wild-type N N gE protein is a glycoprotein E protein from Varicella Zoster Virus having an amino acid sequence found in naturally circulating strains of N7N, such as the N N gE proteins disclosed in Genbank Accession numbers Q9J3M8, ABF21714, AAT07749, AEW88980, AQT34120, and ANS12941, the contents of which are hereby incorporated by reference in their entireties.

[0069] Wild-type N N gE comprises a transmembrane glycoprotein of 623 or 661 amino acids (depending on the variant), including an N-terminal signal sequence of about 30 or about 68 amino acids, respectively, followed by an ectodomain which is exposed on the virion surface, a hydrophobic transmembrane domain and a C-terminal intravirion domain.

[0070] The wild-type signal peptide comprises the amino acid sequence MGTVNKPVVGVLMGFGIITGTLRITNPVRA (SEQ ID NO: 9) or MFYEALKAELVYTRAVHGFRPRANCVVLSDYIPRVACNMGTVNKPVVGVLMGF GIITGTLRITNPVRA (SEQ ID NO: 10). Heterologous signal peptides can readily be used in place of the wild-type signal peptides for expression of recombinant N N gE polypeptides. Expression of VZV gE from host cells results in the cleavage of the signal peptide from the rest of the protein.

[0071] “The N N gE ectodomain” as used herein refers to portion of the N N gE protein comprising the portion of the glycoprotein exposed on the virion surface, located between the N-terminal signal peptide and the hydrophobic transmembrane domain and C-terminal intravirion domain. Exemplary N N gE ectodomain sequences include the polypeptides provided in SEQ ID NOs: 12-18, and polypeptides at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. An alignment of these ectodomain amino acid sequences is shown in FIG. 8.

[0072] Thus, in certain embodiments, recombinant N7N gE polypeptides suitable for use in the methods of the present disclosure includes polypeptides comprising amino acids 31 to 546 of SEQ ID NOs: 1-5, or amino acids 69 to 584 of SEQ ID NOs: 6-7, and polypeptides at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0073] In some embodiments the recombinant N7N gE polypeptide is truncated by 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids at the N- and / or C-terminus relative to the N N gE ectodomain sequence. Exemplary recombinant N N gE polypeptides suitable for use in the methods of the present disclosure include polypeptides comprising amino acids 32 to 546, 33 to 546, 34 to 546, 35 to 546, 35 to 546, 37 to 546, 38 to 546, 39 to 546, or 40 to 546 of any one of SEQ ID NOs. 1-5, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. Additional recombinant N N gE polypeptides suitable for use in the methods of according the present disclosure include polypeptides comprising amino acids 31 to 545, 31 to 544, 31 to 543, 31 to 542, 31 to 541, 31 to 540, 31 to 539, 31 to 538, or 31 to 537 of any one of SEQ ID NOs. 1 to 5, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. In addition embodiments, the recombinant VZV gE polypeptide is a polypeptide comprising amino acids 31 to 546, 30 to 545, 29 to 544, 28 to 543, 27 to 542, or 26 to 541 of any one of SEQ ID NOs. 1-5, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. Polypeptides comprising corresponding truncations with reference to the N N gE sequences of SEQ ID Nos: 6-7 are also provided. In some embodiments the recombinant N7N gE polypeptide suitable for use in the methods of the present disclosure comprise an amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1. In specific aspects the N N gE polypeptide comprises at least 2, at least 3, or all of the amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1. In specific aspects the substitution is one or more of MOT, D150N, A 186V, or T496Y.

[0074] In some aspects the recombinant N N gE polypeptide further comprises a heterologous sequence, such as human immunoglobulin Fc polypeptide. In certain embodiments the human immunoglobulin Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 11, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. In some aspects the N-terminus of the human immunoglobulin Fc polypeptide is genetically fused to the C-terminus of the N N gE polypeptide.

[0075] Adjuvants

[0076] In certain embodiments, methods of the present disclosure further comprise administering an adjuvant to the human subject. An adjuvant as used herein refers to a composition that enhances the immune response to an immunogen, such as the recombinant N N gE polypeptides or nucleic acids encoding N N gE polypeptides of the present disclosure.

[0077] Specific examples of adjuvants include, but are not limited to, aluminum salts (alum) (such as aluminum hydroxide, aluminum phosphate, and aluminum sulfate), Monophosphoryl Lipid A (MPL), 3 De-O-acylated monophosphoryl lipid A (3D-MPL), MF59 (Novartis), AS03 (GlaxoSmithKline), AS04 (GlaxoSmithKline), and saponins, such as QS21 (see Kensil et al. in Vaccine Design: The Subunit and Adjuvant Approach (eds. Powell & Newman, Plenum Press, NY, 1995); U.S. Pat. No. 5,057,540). In some embodiments, the adjuvant is Freund’s adjuvant (complete or incomplete). Other adjuvants include oil in water emulsions (such as squalene or peanut oil), optionally in combination with immune stimulants, such as monophosphoryl lipid A (see Stoute et al. N. Engl. J. Med. 336, 86-91 (1997)). In one embodiment the adjuvant comprises Lipid A or a synthetic Lipid A derivative. In one embodiment the adjuvant comprises glucopyranosyl lipid adjuvant (GLA; Coler et al. (2011) PLoS ONE 6(1)).

[0078] In one embodiment an adjuvant suitable for use in the present disclosure comprises a saponin and a TLR4 agonist. In one aspect the saponin is QS21. In one aspect the TLR4 agonist is 3D-MPL. In one embodiment, the saponin and TLR-4 agonist are formulated with liposomes. Liposomes may contain a neutral lipid, for example phosphatidylcholine, which is suitably non-crystalline at room temperature, for example egg yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine. In a one embodiment, the liposomes of the present disclosure contain DOPC. The liposomes may also contain a charged lipid which increases the stability of the lipsome-QS21 structure for liposomes composed of saturated lipids.

[0079] In one embodiment, the adjuvant comprises a saponin, wherein the saponin is QS21 and / or QS7. In one embodiment, the saponin may be formulated in the form of a cage-like particle referred to as an ISCOM (Immune Stimulating COMplex) particle. ISCOMs may be prepared as described in EP0109942B1, EP0242380B1 and EP0180S46B1. In one embodiment, the ISCOM comprises at least one saponin and a lipid, optionally wherein the lipid is at least a sterol, such as cholesterol. In one embodiment, the ISCOM also contains a phospholipid, such as phosphatidylcholine. In one embodiment, the saponin may be formulated in at least two ISCOM particles. In one embodiment, the first ISCOM particle comprises QS7 and not QS21; and the second ISCOM particle comprises QS21 and not QS7.

[0080] In some embodiments the adjuvant is a TLR9 agonist. In some aspects the TLR9 agonist is an oligonucleotide comprising an unmethylated cytidine-phospho-guanosine (CpG) motif. In certain aspects the TLR9 agonist oligonucleotide comprises the sequence 5’- AACGTTCGAG-3’ (SEQ ID NO: 19) or 5 -TGACTGTGAACGTTCGAGATGA-3’ (SEQ ID NO: 20).

[0081] In certain aspects the recombinant N7N gE polypeptide and the adjuvant are administered to the human subject concurrently, such as simultaneously or consecutively. Dosage and Formulation

[0082] In some embodiments the recombinant N7N gE polypeptide is administered in an amount effective to induce a N7N gE immune response in the human subject. The N7N gE immune response may be an antigen-specific B cell response which produces neutralizing antibodies to N7N gE. The N7N gE immune response may be an antigen-specific T cell response. The antigen-specific T cell response may comprise a CD4+ T cell response, such as a response involving CD4+ T cells expressing a plurality of cytokines, e.g. IFNgamma, TNFalpha and / or IL2. Alternatively, or additionally, the antigen-specific T cell response comprises a CD8+ T cell response, such as a response involving CD8+ T cells expressing a plurality of cytokines, e.g., IFNgamma, TNFalpha and / or IL2. In some embodiments, the N7N gE polypeptide is administered in a “therapeutically effective amount” or “therapeutically effective dose”, meaning that the amount or dose administered elicits an immune response sufficient to produce a desired therapeutic effect, such as delaying the onset or progression of dementia or mild cognitive impairment. In certain aspects of the disclosed methods, the recombinant N7N gE polypeptide is the only N N polypeptide administered to the subject. In certain aspects, the recombinant N7N gE polypeptide is co-administered with a heterologous antigen to the subject, such as with a pneumococcal polysaccharide antigen, a SARS-CoV-2 antigen, an RSV antigen, or with a Mycobacterium tuberculosis antigen. “Heterologous antigen” as used herein refers to an antigen that is different from a N7N gE polypeptide.

[0083] In some aspects, the method comprises administering to the human subject at least 10 micrograms of the recombinant N7N gE polypeptide per dose. In certain embodiments the recombinant N7N gE polypeptide is administered in an amount selected from about 10 micrograms to about 100 micrograms per dose, such as about 25, about 50, about 75, about 100, about 125, about 150, about 175 or about 200 micrograms per dose.

[0084] In some embodiments the recombinant N7N gE polypeptide is administered in a composition comprising the N7N gE polypeptide and optionally a pharmaceutically- acceptable excipient or carrier. Pharmaceutically acceptable excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co. Easton, PA, 5th Edition (975). Pharmaceutically acceptable excipients can include a buffer, such as a phosphate buffer (e.g. sodium phosphate). Pharmaceutically acceptable excipients can include a salt, for example sodium chloride. Pharmaceutically acceptable excipients can include a solubilizing / stabilizing agent, for example, polysorbate (e.g. TWEEN 80). Pharmaceutically acceptable excipients can include a preservative, for example 2-phenoxyethanol or thiomersal. Pharmaceutically acceptable excipients can include a carrier such as water or saline.

[0085] In some embodiments the method comprises administering at least one dose of the recombinant N N gE polypeptide to the human subject, such as a single dose. In some aspects the recombinant N N gE polypeptide is administered as a first dose and a second dose wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose, such as one, two, three, four, five or six months after the first dose.

[0086] Nucleic Acids

[0087] The present disclosure also provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant nucleic acid encoding a N N gE polypeptide, such as a N N gE polypeptide described herein.

[0088] Thus, in certain embodiments, recombinant nucleic acids suitable for use in the methods of the present disclosure include recombinant nucleic acids, such as RNA or DNA, encoding a polypeptide comprising amino acids 31 to 546 of SEQ ID NOs: 1-5 (or amino acids 69 to 584 of SEQ ID NOs: 6-7), or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0089] In some embodiments the recombinant nucleic acid encodes a N N gE polypeptide which is truncated by 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids at the N- and / or C-terminus relative to the N N gE ectodomain sequence. Exemplary recombinant nucleic acids suitable for use in the methods of the present disclosure include RNA or DNA encoding polypeptides comprising amino acids 32 to 546, 33 to 546, 34 to 546, 35 to 546, 35 to 546, 37 to 546, 38 to 546, 39 to 546, or 40 to 546 of any one of SEQ ID NOs. 1-5, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. Additional recombinant nucleic acids suitable for use in the methods of according the present disclosure include RNA or DNA- encoding polypeptides comprising amino acids 31 to 545, 31 to 544, 31 to 543, 31 to 542, 31 to 541, 31 to 540, 31 to 539, 31 to 538, or 31 to 537 of any one of SEQ ID NOs. 1-5, or a polypeptide at least 85%, 86%,

[0090] 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. In addition embodiments, recombinant nucleic acid encodes a polypeptide comprising amino acids 31 to 546, 30 to 545, 29 to 544, 28 to 543, 27 to 542, or 26 to 541 of any one of SEQ ID NOs. 1-5, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0091] In some embodiments the recombinant nucleic acids suitable for use in the methods of the present disclosure include RNA or DNA encoding a N N gE polypeptide comprising an amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1. In specific aspects the recombinant nucleic acid encodes a N N gE polypeptide comprising at least 2, at least 3, or all of the amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1. In specific aspects the N N gE polypeptide comprises an amino acid substitution corresponding one or more of MOT, D150N, A186V, or T496Y, according to the numbering of SEQ ID NO: 1.

[0092] In some embodiments the recombinant nucleic acid further encodes a signal peptide linked to a N N gE polypeptide. In certain embodiments the signal peptide comprises a native N N gE signal peptide, such as a signal peptide comprising the amino acid sequence of SEQ ID NOs: 9-10. In other aspects the recombinant nucleic acid further comprises a heterologous signal peptide.

[0093] In some embodiments the recombinant nucleic acid further encodes the transmembrane and cytoplasmic tail portion of a full-length N N gE protein. For example, in certain embodiments the recombinant nucleic acid further comprises amino acids 547 to 623 of SEQ ID Nos: 1-5 (or amino acids 585 to 661 of SEQ ID NOs: 6-7), or polypeptides at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto. In particular embodiments the encoded cytoplasmic tail and intravirion domain is truncated by about 10, about 20, about 30, about 40, about 50, or about 60 C- terminal amino acids. In a specific embodiment, the recombinant nucleic acid encodes a polypeptide comprising amino acids 31 to 573 of SEQ ID NOs: 1 to 5, for example a recombinant nucleic acid encoding the polypeptide of SEQ ID NO: 8. The intravirion domain of N7N gE contains a targeting sequence (residues 568-571 of SEQ ID NOs: 1-5; residues 606 to 609 of SEQ ID NOs: 6-7) which causes expressed N7N gE protein to localize in the trans-golgi network. Zhu et al., J. Virol. (1996) 6563-6575. Thus, in some embodiments the N N gE polypeptide suitable for use in the methods of the present disclosure comprise an amino acid substitution corresponding to one or more of residues 568 to 571 of SEQ ID NOs: 1-5; or residues 606 to 609 of SEQ ID NO: 6-7. In specific aspects the N N gE polypeptide comprises the amino acid substitution Y569A (relative to the numbering of SEQ ID NO. 1) or Y607A (relative to the numbering of SEQ ID NOs: 6-7). In one embodiment the recombinant nucleic acids suitable for use in the methods of the present disclosure encodes the polypeptide of SEQ ID NO: 8, or a polypeptide at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0094] The recombinant nucleic acids of the present disclosure may be DNA or RNA (including hybrids thereof), preferably RNA. DNA and RNA analogues, such as those containing modified backbones (e.g. peptide nucleic acids (PNAs) or phosphorothioates) or modified bases, are within the scope of the present disclosure. The recombinant nucleic acid may be linear, circular and / or branched, but will generally be linear. Typically, the recombinant nucleic acid will be in recombinant form, i.e. a form which does not occur in nature.

[0095] The recombinant nucleic acid may be for the expression of a N N gE polypeptide in vitro from a host cell (i.e. the recombinant nucleic acid is, or is part of, an expression vector). Suitable recombinant nucleic acid expression vectors (in particular, DNA expression vectors) can comprise, for example, (1) an origin of replication; (2) a selectable marker gene; (3) one or more expression control elements, such as a transcriptional control element (e.g., a promoter, an enhancer, or a terminator), and / or one or more translation signals; and (4) a signal sequence or leader sequence for targeting to the secretory pathway in a selected host cell.

[0096] In an alternative embodiment, the recombinant nucleic acid is for the expression of a VZV gE polypeptide of the present disclosure in vivo in a subject (i.e. the nucleic acid is, or is part of, a nucleic acid-based vaccine). In such embodiments, in addition to a sequence encoding the N N gE polypeptide, the recombinant nucleic acid may comprise one or more heterologous sequences, such as a sequence encoding a further protein and / or a control sequence, in particular a promoter or an internal ribosome entry site.

[0097] Recombinant nucleic acids of the present disclosure may be codon optimized. In some embodiments, recombinant nucleic acids of the present disclosure may be codon optimized for expression in human cells. Codon optimization refers to the use of specific codons, which, while not altering the sequence of the expressed protein (given genetic code redundancy), may increase translation efficacy and / or half-life of the nucleic acid. Embodiments of codon optimized RNA are discussed in more detail in the subsection entitled RNA below.

[0098] In some embodiments, recombinant nucleic acids of the present disclosure are in the form of a viral vector, such as a replicating or replication-deficient viral vector; including both DNA and RNA-based viral vectors. Suitable examples of viral vectors for use in the methods of the present disclosure include, for example: adenovirus vectors; pox virus vectors; Alphavirus vectors, such as Sindbis virus, Semlike Forest virus (SFV), Ross River virus, Venezuelan equine encephalitis (VEE) virus, and chimeras derived from Alphavirus vectors such as the foregoing; herpes virus vectors, such as cytomegalovirus (CMV)- derived vectors; arena virus vectors, such as lymphocytic choriomeningitis virus (LCMV) vectors; measles virus vectors; vesicular stomatitis virus vectors; pseudorabies virus vectors; adeno-associated virus vectors; retrovirus vectors; lentivirus vectors; and viral-like particles. In other embodiments, the recombinant nucleic acid is in the form of a DNA plasmid.

[0099] Recombinant nucleic acids encoding a N N gE polypeptide of the present disclosure may be delivered naked, or in conjunction with a nucleic acid carrier (e.g. as detailed in the section entitled Nucleic Acid Carriers, below).

[0100] RNA

[0101] In one embodiment, the recombinant nucleic acid used in the method of the present disclosure is RNA encoding a N N gE polypeptide of the present disclosure, which may be translated in a cell (i.e. mRNA). RNA molecules can have various lengths but are typically 500-20,000 ribonucleotides long e.g. 1000-20,000, 1000-15,000, 1000-10,000, 1000-5000, 1000-3000, 1000-2500, 1000-2500 or 1000-2000 ribonucleotides long. The RNA can be non-self-replicating (also referred to as “conventional” RNA), or selfreplicating.

[0102] Generally, the RNA comprises a 5’ cap, such as a 7 ’-methylguanosine (a.k.a 7- methylguanosine / m7G / m7G), which may be added via enzymatic means or a non- enzymatic reaction. The RNA may have the following exemplary 5’ caps:

[0103] - a 7 ’-methylguanosine linked 5’-to-5’ to the 5’ first ribonucleotide by a triphosphate bridge (also referred to as “Cap O”);

[0104] - a 7 ’-methylguanosine linked 5’-to-5’ to the 5’ first ribonucleotide by a triphosphate bridge, and wherein the first 5’ ribonucleotide comprises a 2 ’-methylated ribose (2’-0-Me) (also referred to as “Cap 1”);

[0105] - a 7 ’-methylguanosine linked 5’-to-5’ to the 5’ first ribonucleotides by a triphosphate bridge, and wherein the first and second 5 ’ ribonucleotides comprise a 2’-methylated ribose (2’-0-Me) (also referred to as “Cap 2”);

[0106] - or a 7 ’-methylguanosine linked 5’-to-5’ to the 5’ first ribonucleotides by a triphosphate bridge, and wherein the first, second and third 5’ ribonucleotides comprise a 2 ’-methylated ribose (2’-0-Me).

[0107] Generally, the RNA comprises a 3’ poly-adenosine (“poly-A”) tail, e.g. comprising 10-700 A ribonucleotides. The poly-A tail may comprise at least two non-contiguous stretches of A ribonucleotides (also referred to as a “split poly-A tail”), or a (in particular, only one) contiguous stretch of A ribonucleotides. The total number of A ribonucleotides (“As”) in at least two non-contiguous stretches may be, for example, 10-700, such as 10-600, 10- 500, 20-500, 50-500, 70-500, 100-500, 20-400, 30-300, 40-200, 50-150, 70-120, 100-120, or, in particular, 100-120.

[0108] In some aspects the RNA comprises (in addition to any 5' cap structure) one or more modified ribonucleotides, i.e. ribonucleotides that are modified in structure relative to standard A, C, G or U ribonucleotides. In other embodiments, the RNA does not comprise modified ribonucleotides, i.e. the RNA contains standard A, C, G or U ribonucleotides only (except for any 5’ cap structure, if present). In embodiments wherein one or more modified ribonucleotides are used, exemplary modified ribonucleotides include: - modified cytosine, such as N4-acetyl-cytidine (ac4C), 5-methyl-cytidine (m5C), 5- halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl- pseudoisocytidine, 2-thio-cytidine (s2C), and 2-thio-5 -methyl -cytidine

[0109] - modified uridine, such as 1 -methyl -pseudouridine, 1 -ethyl -pseudouridine, 5- methoxy uridine, 2-thio uridine, 5-cyano uridine, 2'-0- methyl uridine and 4'-thio uridine.

[0110] - modified adenine, such as 7-deaza-adenine, 1-methyl- adenosine (mlA), 2-methyl- adenine (m2A), and N6-methyl-adenosine (m6A)

[0111] - modified guanine, such as inosine (I), 1-methyl -inosine, wyosine, methylwyosine, 7-deaza-guanosine, 7-cyano-7-deaza-guanosine, 7-aminomethyl-7-deaza- guanosine, 7-methyl -guanosine (m7G), 1-methyl -guanosine, 8-oxo-guanosine, and 7 -methyl- 8-oxo-guanosine .

[0112] In some embodiments, the percentage of standard As substituted with A-substitutable modified nucleotide (e.g. those above) is at least: 0.1%, 0.5%, 0.8%, 1%, 2%, 5%, 10%,

[0113] 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or at least 99.9%, or 100%. In some embodiments, the percentage of standard Cs substituted with cytosine-substitutable modified nucleotide (e.g. those above) is at least: 10%, 20%,

[0114] 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or at least

[0115] 99.9%, or 100%. In some embodiments, the percentage of standard Gs substituted with G- substitutable modified nucleotide (e.g. those above) is at least: 10%, 20%, 30%, 40%, 50%,

[0116] 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or at least 99.9%, or 100%. In some embodiments, the percentage of standard Us substituted with U-substitutable modified nucleotide (e.g. those above) is at least: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or at least 99.9%, or 100%.

[0117] In some embodiments, the RNA is codon-optimized. Codon optimization may provide an elevated GC content, relative to non-codon optimized RNA encoding the same protein(s). The GC content (the percentage of all ribonucleotides in the RNA which are G or C) of the RNA may be at least 10%, such as at least 20%, 30%, 35% or at least 40%. The GC content of the RNA may be 10-70%, such as 20-65%, 30-65% or 35-65%. The GC content of the RNA may be 30-70%, such as 40-70%, 45-70%, 50-70%, or 55-70%. Codon optimization may provide an elevated C content relative to non-codon optimized RNA encoding the same protein(s). The percentage of C-optimizable codons in the RNA which have been substituted, as a result of codon optimization, for a codon with greater C content (while encoding the same amino acid) may be least 30%, such as at least 40%, 50%, 55% or at least 60%. The percentage of C-optimizable codons in the RNA which have been substituted, as a result of codon optimization, for a codon with greater C content (while encoding the same amino acid) may be 30-80%, such as 40-90%, 45-90%, 50-80%, 55- 80% or 60-80%.

[0118] Generally, the RNA comprises a 5’ and / or a 3’ untranslated region (UTR), preferably both a 5’ and 3’ UTR; e.g. selected from the 5 ’and 3’ UTRs of RNA transcripts of the following genes (preferably the following human genes): beta-actin, albumin, ATP synthase beta subunit, fibroblast activation protein (“FAP”), H4 clustered histone 15 (“HIST2H4A”), glyceraldehyde-3-phosphate dehydrogenase, heat shock protein family A (Hsp70) member 8 gene, interleukin-2 gene (“IL-2”), and transferrin.

[0119] Generally, the RNA will comprise, in the 5’ to 3’ direction: 5’ Cap, 5’ UTR, open reading frame encoding at least N N gE polypeptide of the present disclosure, 3 ’UTR, and 3’ poly-A tail (in particular, the 5’ Caps; 5’ UTRs, 3 ’UTRs and 3’ poly-A tails as detailed above throughout this subsection).

[0120] Nucleic Acid Carriers

[0121] Nucleic acids (especially RNA) by themselves and unprotected, may be degraded by the subject’s nucleases and may require a carrier to facilitate target cell entry. Accordingly, in some embodiments the methods of the present disclosure include administering to a human subject a carrier comprising a recombinant nucleic acid (such as RNA) encoding a N7N gE polypeptide.

[0122] The carrier may be lipid-based (e.g. a lipid nanoparticle or cationic nanoemulsion), polymer-based (e.g. comprising polyamines, dendrimers and / or copolymers), peptide or protein-based (e.g. comprising protamine, a cationic cell-penetrating peptide, and / or an anionic peptide conjugated to a positively charged polymer), cell-based (e.g. antigen presenting cells, such as dendritic cells loaded with the recombinant nucleic acid), or virusbased (e.g. viral replicon particles). In particular embodiments, the carrier is non-virion, i.e. free or substantially free of viral capsid. In particular, lipid-based carriers provide a means to protect the recombinant nucleic acid (such as RNA), e.g. through encapsulation, and deliver it to target cells for protein expression. In certain embodiments, the lipid-based carrier is, or comprises, a cationic nano-emulsion (“CNE”). CNEs and methods for their preparation are described in, for example, in WO 2012 / 006380. With a CNE, the recombinant nucleic acid which encodes the N N gE polypeptide is complexed with a CNE particle, in particular comprising an oil core and a cationic lipid. The cationic lipid can interact with the negatively charged molecule, thereby anchoring the molecule to the emulsion particles. In a particular embodiment, a lipid-based carrier is a lipid inorganic nanoparticle (“LION”).

[0123] In a preferred embodiment, recombinant nucleic acids (such as RNA) are encapsulated in a lipid nanoparticle (LNP). Thus, in a preferred embodiment, the present disclosure also provides methods of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant nucleic acid encoding a N N gE polypeptide, wherein the recombinant nucleic acid is encapsulated in an LNP.

[0124] A plurality of such LNPs will be part of a composition (e.g. a pharmaceutical composition) comprising free and / or encapsulated nucleic acid (such as RNA), and in some embodiments the LNPs encapsulate at least: 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97.0%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or at least 100% of the total number of nucleic acid (such as RNA) molecules in the composition. At least 80% of the LNPs in the composition may be 20-200 nm, 40-190 nm, 60-180 nm or, in particular, 80-160 nm in diameter. In a particular embodiment, substantially all, or all, LNPs in the composition are 20-200 nm, 40-190 nm, 60-180 nm or, in particular, 80-160 nm in diameter.

[0125] The LNP can comprise multilamellar vesicles (MLV), small uniflagellar vesicles (SUV), or large unilamellar vesicles (LUV).

[0126] LNPs according to the present disclosure may be formed from a single lipid (e.g. a cationic lipid) or, in particular, from a mixture of lipids. In particular, the mixture comprises various classes of lipids, such as: (a) a mixture of cationic lipids and sterols,

[0127] (b) a mixture of cationic lipids and neutral lipids,

[0128] (c) a mixture of cationic lipids and polymer-conjugated lipids,

[0129] (d) a mixture of cationic lipids, sterols and polymer-conjugated lipids, or

[0130] (e) a mixture of cationic lipids, neutral lipids and polymer-conjugated lipids; or preferably:

[0131] (f) a mixture of cationic lipids, sterols and neutral lipids; or more preferably:

[0132] (g) a mixture of cationic lipids, neutral lipids, sterols and polymer-conjugated lipids. Further classes of lipids, such as anionic lipids, may also be present in a mixture of lipids. The cationic lipid may have a pKa of 5.0-10.0, 5.0-9.0, 5.0-8.5, preferably 5.0-8.0, 5.0-7.9, or 5.0-7.8, 5.0-7.7, or 5.0-7.6. The pKa of the cationic lipid is distinct to the pKa of the LNP as a whole (sometimes called “apparent pKa”).

[0133] The cationic lipid preferably comprises a tertiary or quaternary amine group, more preferably a tertiary amine group. Exemplary cationic lipids comprising tertiary amine groups include: l,2-dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2- dilinoleyoxy-3morpholinopropane (DLin-MA), l,2-dilinoleoyl-3 -dimethylaminopropane (DLinDAP), l,2-dilinoleylthio-3 -dimethylaminopropane (DLin-S-DMA), l-linoleoyl-2- linoleyloxy-3dimethylaminopropane (DLin-2-DMAP), l,2-dilinoleyloxy-3- trimethylaminopropane chloride salt (DLin-TMA.Cl), l,2-dilinoleoyl-3- trimethylaminopropane chloride salt (DLin-TAP.Cl), l,2-dilinoleyloxy-3-(N- methylpiperazinojpropane (DLin-MPZ), 3-(N,Ndilinoleylamino)-l,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-l,2-propanediol (DOAP), l,2-dilinoleyloxo-3-(2-N,N- dimethylaminojethoxypropane (DLin-EG-DMA), and 2,2-dilinoleyl-4- dimethylaminomethyl [ 1 ,3] -dioxolane (DLin-K-DMA), 2,2-dilinoleyl-4-(2- dimethylaminoethyl)[l,3]-dioxolane (DLin-KC2-DMA); dilinoleyl-methyl-4- dimethylaminobutyrate (DLin-MC3-DMA); or MC3 (see, e.g. US20100324120).

[0134] The lipids in the LNP may comprise (in mole %) 20-80, 25-75, 30-70, or 35-65%, preferably 30-60, 40-55 or 40-50% cationic lipid; such as about 40% (or 40%), about 42% (or 42%), about 44% (or 44%), about 46% (or 46%) or about 48% (or 48%) cationic lipid. The lipids in the LNP may comprise (in mole %) at least 20, 25 or at least 35%, or preferably at least 40% cationic lipid. The lipids in the LNP may comprise (in mole %) no more than 80, 70 or no more than 60% or preferably no more than 50% cationic lipid.

[0135] The molar ratio of protonatable nitrogen atoms in the LNP’s cationic lipids to phosphates in the nucleic acid, such as RNA (a.k.a “N:P” ratio), may be in the range of (including the endpoints) 1: 1-20: 1, 2: 1-10: 1, 3: 1-9: 1, or 4: 1-8: 1; preferably 4.5: 1-7.5: 1, 4.5: 1-6.5: 1 or 5.0: 1-6.5: 1.

[0136] The polymer-conjugated lipid is preferably a PEGylated lipid. In an LNP, the PEGs of such PEGylated lipids may have average molecular weight of 0.5-11.0 kDa; such as 0.5- 8.0, 0.8-8.0, 0.8-7.0, 0.8-6.0, 0.8-5.0, 0.8-4.0, 1.0-4.0 or 1.0-3.5 kDa, preferably 1.0-3.0, 1.2-2.8, 1.4-2.6, 1.5-2.5, 1.6-2.4, or 1.7-2.3 kDa, or more preferably 1.8-2.2, 1.9-2.1, about 2.0 (or 2.0 kDa). The average molecular weight of such PEGs may be expressed as the median molecular weight. In an LNP, the PEGs of such PEGylated lipids may have a weight average molecular weight of 0.5-11.0 kDa; such as 0.5-8.0, 0.8-8.0, 0.8-7.0, 0.8- 6.0, 0.8-5.0, 0.8-4.0, 1.0-4.0 or 1.0-3.5 kDa, preferably 1.0-3.0, 1.2-2.8, 1.4-2.6, 1.5-2.5, 1.6-2.4, or 1.7-2.3 kDa, or more preferably 1.8-2.2, 1.9-2.1, about 2.0 (or 2.0 kDa). Alternatively, in an LNP, the PEGs of such PEGylated lipids may have a number average molecular weight of 0.5-11.0 kDa; such as 0.5-8.0, 0.8-8.0, 0.8-7.0, 0.8-6.0, 0.8-5.0, 0.8- 4.0, 1.0-4.0 or 1.0-3.5 kDa, preferably 1.0-3.0, 1.2-2.8, 1.4-2.6, 1.5-2.5, 1.6-2.4, or 1.7-2.3 kDa, or more preferably 1.8-2.2, 1.9-2.1, about 2.0 (or 2.0 kDa). Alternatively, in an LNP, at least 80% of the PEGs of such PEGylated lipids may have molecular weight of 0.5-11.0 kDa; such as 0.5-8.0, 0.8-8.0, 0.8-7.0, 0.8-6.0, 0.8-5.0, 0.8-4.0, 1.0-4.0 or 1.0-3.5 kDa, preferably 1.0-3.0, 1.2-2.8, 1.4-2.6, 1.5-2.5, 1.6-2.4, or 1.7-2.3 kDa, or more preferably 1.8-2.2, 1.9-2.1, about 2.0, or 2.0 kDa.

[0137] Exemplary PEGylated lipids include 2- [(polyethylene glycol)-2000]-N,N- ditetradecylacetamide and l,2-dimyristoyl-rac-glycero-3 -methoxypolyethylene glycol- 2000, l,2-dimyristoyl-sn-glycero-2-phosphoethanolamine-N-[methoxy(polyethylene glycol)] and l,2-dimyristoyl-rac-glycerol-3 -methoxypolyethylene glycol. Preferably, the PEGylated lipid is 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide or 1,2- dimyristoyl-rac-glycero-3 -methoxypolyethylene gly col-2000. The lipids in the LNP may comprise (in mole %) 0. 1-8.0, 0.4-7.0, 0.6-6.0, 0.8-4.0 or 0.8- 3.5%, preferably 1.0-3.0% polymer-conjugated lipid (preferably PEGylated lipid); such as about 1.0 (or 1.0%), about 1.5% (or 1.5%), about 2.0% (or 2.0%) or about 2.5% (or 2.5%) polymer-conjugated lipid (preferably PEGylated lipid). The lipids in the LNP may comprise (in mole %) at least 0.1, 0.5 or at least 0.8%, or preferably at least 1% polymer- conjugated lipid (preferably PEGylated lipid). The lipids in the LNP may comprise (in mole %) no more than 8.0, 6.0 or 4.0% or preferably no more than 3.0% polymer- conjugated lipid (preferably PEGylated lipid).

[0138] Preferably, the neutral lipid is l,2-distearoyl-sn-glycero-3 -phosphocholine (DSPC) or 1,2- dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), although other neutral lipids available to the skilled person may also be used.

[0139] The lipids in the LNP may comprise (in mole %) 0-15.0, 0.1-15.0, 2.0-14.0, 5.0-13.0, 6.0- 12.0 or 7.0-11.0%, preferably 8.0-11.0% or 9.0-11.0% neutral lipid; such as about 9.4% (or 9.4%), about 9.6% (or 9.6%), about 9.8% (or 9.8%) or about 10.0% (or 10%) neutral lipid. The lipids in the LNP may comprise (in mole %) at least 0.1, 5.0 or at least 7.0%, or preferably at least 8.0% or at least 9.0% neutral lipid. The lipids in the LNP may comprise (in mole %) no more than 15.0, 13.0 or no more than 12.0%, or preferably no more than 11.0% neutral lipid.

[0140] Exemplary sterols include cholesterol, cholesterol sulfate, desmosterol, stigmasterol, lanosterol, 7-dehydrochole sterol, dihydrolanosterol, symosterol, lathosteriol, 14-demethyl- lanosterol, 8(9)-dehydrocholesterol, 8(14)-dehydrocholesterol, 14-demethyl-14- dehydrolanosterol (FF-MAS), diosgenin, dehydroepiandrosterone sulfate (DHEA sulfate), dehydroepiandrosterone, sitosterol, lanosterol-95, 4,4-dimethyl(d6)-cholest-8(9), 14-dien- 3p-ol (dihydro-FF-MAS-d6), 4,4-dimethyl(d6)-cholest-8(9)-en-3p-ol (dihydro T-MAS-d6), zymostenol, sitostanol, campestanol, camperstanol, 7-dehydrodesmosterol, pregnenolone, 4,4-dimethyl-cholest-8(9)-en-3p-ol (dihyrdro T-MAS), A5-avensterol, brassicasterol, dihydro FF-MAS, 24-methylene cholesterol, oxysterols, deuterated sterols, fluorinated sterols, sulfonated sterols, phosphorylated sterols, A-ring substituted sterols, cholest-5-ene- 3B,4B-diol, 5a-cholestan-3B-ol, 4-cholesten-3-one, cholesta-8(9),24-dien-3-one, cholesta- 8(9),24-dien-3-one, 2,2,3,4,4-pentadeuterio-5a-cholestan-3B-ol, cholesteryl phosphocholine, cholesteryl-d7 pentadecanoate, cholesteryl-d7 palmitate, B-ring substituted sterols, cholestanol, 5B,6B-epoxy-d7, 3B-hydroxy-5-cholestene-7-one, 6a- hydroxy-5a-cholestane, cholestanol, 5a,6a-epoxy, cholest-5-en-3B,7a-diol, cholest-5-en- 3B,7B-diol, cholestanol, 5a,6a-epoxy-d7, A5,7-cholesterol, cholesta-5,8(9)-dien-3B-ol, cholesta-5,8(14)-dien-3B-ol, 7a-hydroxy-4-cholesten-3-one, zymostenol-d7, zymostenol, 7-dehydrodesmosterol, 3b,5a-dihydroxy-cholestan-6-one, D-ring substituted sterols, 3B- hydroxy-5a-cholest-8(14)-en- 15-one, 3B-hydroxy-5a-cholestane- 15-one, 5a-cholest-8(14)- ene-3B,15a-diol, 5a-cholest-8(14)-ene-3B,15B,-diol, lanosterol-95, 5a-7,24-cholestadiene, 14-dehydro zymostenol, ergosta-5,7,9(l l),22-tetraen-3B-ol, cholest-5-ene-3B,25-diol, cholest-(25R)-5-ene-3B,27-diol, 24(R / S),25-epoxycholesterol, 24(S),25-epoxycholesterol, 24(R / S),25-epoxycholesterol-d6, cholest-5-ene-3B,22(S)-diol, cholest-5-ene-3B,22(R)-diol, cholest-5-ene-3B,24(S)-diol, cholest-5-ene-3B,24(R)-diol, 27-hydroxy-4-cholesten-3-one, campestanol, N,N-dimethyl-3B-hydroxycholenamide, 25,27-dihydroxycholesterol, N,N- dimethyl-3B-hydroxycholenamide, 25,27-dihydroxycholesterol, 5-cholestene-3p,20a-diol, 24S,25-epoxy-5a-cholest-8(9)-en-3p-ol, 24(S / R),25-epoxylanost-8(9)-en-3p-ol, 7-keto-27- hydroxy cholesterol, 7 a,27-dihydroxy-4-cholesten-3 -one, 7 a, 27-dihydroxy cholesterol, 7B,27-dihydroxy cholesterol, 5a,6B-dihydroxycholestanol, 7a, 25 -dihydroxy cholesterol, 7p,25-dihydroxycholesterol, 7a, 24(S)-dihydroxy cholesterol, 7a,24(S)-dihydroxy-4- cholesten-3 -one, 7 -keto-25 -hydroxy cholesterol, 7 a,24S,27-trihydroxycholesterol, dihydrotestosterone, testosterone, estrone, estrogen, estradiol, corticosterone, cortisol, or 24S,27-dihydroxycholesterol.

[0141] In some embodiments the recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide is administered in an amount effective to induce a N N gE immune response in the human subject. The N N gE immune response may be an antigen-specific B cell response which produces neutralizing antibodies to N N gE. The N N gE immune response may be an antigen-specific T cell response. The antigen-specific T cell response may comprise a CD4+ T cell response, such as a response involving CD4+ T cells expressing a plurality of cytokines, e.g. IFNgamma, TNFalpha and / or IL2. Alternatively, or additionally, the antigen-specific T cell response comprises a CD8+ T cell response, such as a response involving CD8+ T cells expressing a plurality of cytokines, e.g., IFNgamma, TNFalpha and / or IL2. In some embodiments, the recombinant nucleic acid encoding a N N gE polypeptide is administered in a “therapeutically effective amount” or “therapeutically effective dose”, meaning that the amount or dose administered elicits an immune response sufficient to produce a desired therapeutic effect, such as delaying the onset or progression of dementia or mild cognitive impairment. In certain aspects of the disclosed methods, the recombinant nucleic acid encoding the N N gE polypeptide is the only N N polypeptide administered to the subject. In certain aspects, the nucleic acid encoding the N N gE polypeptide is co-administered with a heterologous antigen to the subject, such as with a pneumococcal polysaccharide antigen, a SARS-CoV-2 antigen, an RSV antigen, or with a Mycobacterium tuberculosis antigen. “Heterologous antigen” as used herein refers to an antigen that is different from a the N N gE polypeptide encoded by the recombinant nucleic acid.

[0142] In some aspects, the method comprises administering to the human subject at least 1 microgram of the recombinant nucleic acid encoding the N N gE polypeptide per dose. In certain embodiments the recombinant nucleic acid is administered in an amount selected from about 1 micrograms to about 200 micrograms per dose, such as about 25, about 50, about 75, about 100, about 125, about 150, about 175 or about 200 micrograms per dose.

[0143] In some embodiments the method comprises administering at least one dose of the recombinant nucleic acid (e.g., RNA) encoding the N N gE polypeptide to the human subject, such as a single dose. In some aspects the recombinant nucleic acid (e.g. RNA) is administered as a first dose and a second dose wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose, such as one, two, three, four, five or six months after the first dose.

[0144] Methods of Delaying Progression

[0145] In one embodiment the present disclosure provides a method of delaying the progression of dementia in a human subject, comprising administering to the subject at least one dose of (i) a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or (ii) a recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide. In one aspect the subject has been diagnosed with dementia.

[0146] In another embodiment the present disclosure provides a method of delaying the progression of mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of (i) a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or (ii) a recombinant nucleic acid (such as RNA) encoding a VZV gE polypeptide. In one aspect the subject has been diagnosed with mild cognitive impairment.

[0147] In making a diagnosis of dementia or mild cognitive impairment, a health care provider may take into consideration many factors, including the subject’s medical history (including personal and family history, duration of symptoms, and medication history); a physical examination; a neurological evaluation (assessing , e.g., balance, sensory function, mental agility, reflexes, muscle strength, eye movement, speech, and coordination); results of cognitive and neuropsychological tests (assessing, e.g., memory, problem-solving skills, attention span, counting skills, and language abilities).

[0148] Cognitive and neuropsychological tests useful for diagnosing dementia and mild cognitive impairment include the Clinical Dementia Rating Scale (CDR), including the CDR global score and the CDR sum of box score (Lynch et al. Dement Geriatr Cogn Disord 2006; 21:40-43); the Mini-Mental State Examination (MMSE) (Folstein et al. J. Psychiatric Research 1975;12(3): 189-98; the Montreal Cognitive Assessment (MoCA) (Nasreddine et al. J Am Geriatr Soc. 2005 Apr;53(4):695-9); the Wechsler Adult Intelligence Scale (WAIS) (Hartman Appl Neuropsychol. 2009; 16(1): 85-7); the Wechsler Memory Scale (WMS) (Ryan et al, Appl Neuropsychol Adult. 2023 Jan 12: 1-8); the Benton Visual Retention Test (BVRT) (REF); the Rey Auditory Verbal Learning Test (Estevez-Gonzalez et al., Int J Geriatr Psychiatry. 2003 Nov;18(l 1): 1021-8); the Clock Drawing Test (CDT) (Park et al., J Adv Nurs. 2018 Dec;74(12):2742-2754); the Trail Making Test (TMT) (Bowie et al., Nat Protoc. 2006; l(5):2277-81) and the Preclinical Alzheimer’s Cognitive Composite (PACC and PACC5) (Papp et al., Alzheimers Dement (NY). 2017 Nov 10;3(4):668-677.

[0149] Other tools useful for diagnosing dementia and mild cognitive impairment include brain imaging, such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), Electroencephalography (EEG), Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) scans to identify neuropathologies such as strokes, tumors, brain atrophy, and detection of amyloid plaques, hyperphosphorylated tan, glucose hypometabolism, and abnormal cerebral blood flow. Diagnosis of dementia and mild cognitive impairment may also involve assessment of associated biomarkers. In some aspects the biomarkers are detected in peripheral fluids (e.g. blood, saliva, urine, and cerebrospinal fluid). Exemplary fluid biomarkers which are used in the diagnosis of dementia and mild cognitive impairment include amyloid beta (Abeta) proteins such as Abeta-42 and Abeta-40; tau proteins and phosphorylated tau (p- tau) proteins such as p-taul81 and p-tau217. Changes in specific ratios of fluid biomarkers are also useful for the diagnosis of dementia and mild cognitive impairment. For example, reduced ratio of the concentration of Abeta42 / Abeta40, as well as the elevated ratio of the concentrations of total tau (t-tau) / Abeta42 and p-taul81 / Abeta42, may be associated with dementia and mild cognitive impairment.

[0150] Diagnosis of dementia and mild cognitive impairment may also be based on the detection of genetic markers. For example, subjects who carry two copies of the AP0E4 variant of the apolipoprotein E gene have an increased risk of developing dementia by age 85.

[0151] In some embodiments, the methods of the present disclosure are useful for delaying the progression of dementia or mild cognitive impairment associated Alzheimer’s disease, vascular disease, Lewy body disease, Frontotemporal degeneration, Parkinson’s disease and / or dementia or mild cognitive impairment associated with more than one disease (Mixed dementia).

[0152] In some embodiments, the methods of the present disclosure are useful for delaying the progression of dementia or mild cognitive impairment for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 years from the date that the subject was last administered the N N gE polypeptide or the recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide.

[0153] The present disclosure demonstrates that HZ vaccination has a greater benefit in women than men with respect to reducing the risk of dementia and mild cognitive impairment (see Example 1). Accordingly, in preferred embodiments the human subject of the methods of the present disclosure is a woman. Methods of Delaying Onset

[0154] In one embodiment the present disclosure provides a method of delaying the onset of dementia in a human subject, comprising administering to the subject at least one dose of (i) a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or (ii) a recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide. In one aspect the subject is at risk of developing dementia.

[0155] In another embodiment the present disclosure provides a method of delaying the onset of mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of (i) a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or (ii) a recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide. In one aspect the subject is at risk of developing mild cognitive impairment.

[0156] The risk of dementia and mild cognitive impairment increases with age. For example, dementia associated with Alzheimer’s affects 1-3% of subjects aged 60-64, 3-12% of subjects aged 70-80, and 25-35% of subjects older than 85 years. Evans, JAMA. 1989 Nov 10;262(18):2551-6; Kukull and Bowen, Medical Clinics of North America Volume 86, Issue 3, May 2002, Pages 573-590. Accordingly, in one embodiment the human subject of the method of the present disclosure is at least 50 years old, such as at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, or at least 85 years old. In some embodiments, the human subject is about 50-59 years old, about 60-69 years old, about 70- 79 years old, about 80-89 years old, or about 90-99 years old. In preferred embodiments, the human subject is at least 65 years old, more preferably at least 70 years old. In one embodiment, the human subject is at least 80 years old. In one embodiment, the human subject is about 80-89 years old.

[0157] In one embodiment, the subject exhibits at least one risk factor for dementia or mild cognitive impairment. Known risk factors for dementia or mild cognitive impairment include cardiovascular disease, hypertension (high blood pressure), atherosclerosis, elevated LDL cholesterol, elevated plasma homocysteine, diabetes, obesity (Body Mass Index > 30), major depression, traumatic brain injury, stroke, tobacco use, alcohol use, family history of dementia or mild cognitive impairment, hearing loss, social isolation, low level of education in early life, and physical inactivity. In certain embodiments, the human subject is seropositive for Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV)-l. In some embodiments the human subject is positive for a genetic risk factor of dementia, such as a subject carrying one or two copies of the APOE4 allele of the apolipoprotein E gene. In some embodiments, the human subject of the methods of the present disclosure exhibits 2, 3, 4, 5 or more of the foregoing risk factors. A specific risk factor for dementia is a history of mild cognitive impairment. In some embodiments, the human subject of the methods of the present disclosure is at least 65 years old and exhibits at least one of the foregoing risk factors.

[0158] In some embodiments, the methods of the present disclosure are useful for delaying the onset of dementia or mild cognitive impairment associated Alzheimer’s disease, vascular disease, Lewy body disease, Frontotemporal degeneration, Parkinson’s disease and / or dementia or mild cognitive impairment associated with more than one disease (Mixed dementia).

[0159] In some embodiments, the methods of the present disclosure are useful to delay the onset of dementia or mild cognitive impairment for at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 years from the date that the subject was last administered the N N gE polypeptide or the recombinant nucleic acid (such as RNA) encoding a N N gE polypeptide.

[0160] The present disclosure demonstrates that HZ vaccination has a greater benefit in women than men with respect to reducing the risk of dementia and mild cognitive impairment (see Example 1). Accordingly, in preferred embodiments the human subject of the methods of the present disclosure is a woman.

[0161] The present disclosure is illustrated by the following exemplary clauses:

[0162] 1. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

[0163] 2. The method of Embodiment 1 further comprising administering to the subject an adjuvant. 3. The method of Embodiment 2 wherein the adjuvant comprises aluminum and / or a TLR9 agonist oligonucleotide.

[0164] 4. The method of Embodiment 2 wherein the adjuvant comprises a saponin.

[0165] 5. The method of Embodiment 4 wherein the saponin is QS-21.

[0166] 6. The method of any of Embodiments 4-5 wherein the adjuvant comprises a TLR4 agonist.

[0167] 7. The method of Embodiment 6 wherein the TLR-4 agonist is 3-O-desacyl-4’- Monophosphoryl Lipid A (3D-MPL).

[0168] 8. The method of any of Embodiments 2-7 wherein the adjuvant comprises liposomes.

[0169] 9. The method of Embodiment 8 wherein the liposomes comprise a sterol.

[0170] 10. The method of Embodiment 9 wherein the sterol is cholesterol.

[0171] 11. The method of any of Embodiments 8-10 wherein the liposomes comprise a neutral lipid, for example phosphatidylcholine, egg yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine.

[0172] 12. The method of any of the preceding Embodiments wherein the N N gE polypeptide is the only N N polypeptide administered to the subject.

[0173] 13. The method of any of the preceding Embodiments wherein the N N gE polypeptide is administered in an amount effective to induce a N N gE immune response in the subject.

[0174] 14. The method of any of the preceding Embodiments wherein the N N gE polypeptide is administered in an amount selected from about 10 micrograms to about 100 micrograms per dose. 15. The method of any of the preceding Embodiments comprising administering a first dose and a second dose of the N N gE polypeptide wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose.

[0175] 16. The method of any of the preceding Embodiments wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the recombinant N N gE polypeptide.

[0176] 17. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

[0177] 18. The method of Embodiment 17 wherein the recombinant nucleic acid is a recombinant vector.

[0178] 19. The method of any of Embodiments 17-18 wherein the recombinant nucleic acid is DNA.

[0179] 20. The method of any of Embodiments 17-18 wherein the recombinant nucleic acid is RNA.

[0180] 21. The method of Embodiment 20 wherein the RNA is non-replicating RNA or selfreplicating RNA.

[0181] 22. The method of any of Embodiments 20-21 wherein the RNA comprises at least one modified nucleotide.

[0182] 23. The method of Embodiment 22 wherein the RNA comprises at least one modified uridine.

[0183] 24. The method of Embodiment 23 wherein the modified uridine is Nl- methylpseudouridine . 25. The method of any of Embodiments 20-24 wherein the RNA is administered with a nucleic acid carrier.

[0184] 26. The method of Embodiment 25 wherein the nucleic acid carrier comprises lipid nanoparticles.

[0185] 27. The method of Embodiment 26 wherein the nucleic acid is encapsulated in the lipid nanoparticles.

[0186] 28. The method of any of Embodiments 17-27 where the recombinant nucleic acid is administered in an amount effective to induce a N N gE immune response in the subject.

[0187] 29. The method of any of Embodiments 17-28 wherein the N N gE polypeptide encoded by the recombinant nucleic acid is the only N7N polypeptide administered to the subject.

[0188] 30. The method of any of Embodiments 17-29 wherein the recombinant nucleic acid is administered in an amount effective to induce a N N gE immune response in the subject.

[0189] 31. The method of any of Embodiments 17-30 wherein the recombinant nucleic acid is administered in an amount selected from about 1 microgram to about 200 micrograms per dose.

[0190] 32. The method of any of Embodiments 17-31 comprising administering a first dose and a second dose of the recombinant nucleic acid wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose.

[0191] 33. The method of any of Embodiments 17-32 wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the recombinant nucleic acid encoding the N N gE polypeptide. 34. The method of any of the preceding Embodiments wherein the N7N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

[0192] 35. The method of any of the preceding Embodiments wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0193] 36. The method of any of the preceding Embodiments wherein the N N gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0194] 37. The method of any of the preceding Embodiments wherein the N N gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0195] 38. The method of any of the preceding Embodiments wherein the N N gE polypeptide comprises at least one amino acid substitution selected from I40T, D150N, A186V, and T496Y relative to SEQ ID NOs: 1-5 or 8.

[0196] 39. The method of any of the preceding Embodiments wherein the subject is at least 50 years old.

[0197] 40. The method of any of the preceding Embodiments wherein the subject is a woman.

[0198] 41. The method of any of the preceding Embodiments wherein the subject has been diagnosed with dementia or mild cognitive impairment.

[0199] 42. The method of any of the preceding Embodiments wherein the subject is at risk of dementia or mild cognitive impairment.

[0200] 43. The method of any of the preceding Embodiments wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment. 44. The method of any of the preceding Embodiments wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l.

[0201] 45. The method of Embodiment 39 wherein the subject is at least 65 years old.

[0202] 46. The method of any of the preceding Embodiments wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0203] 47. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such polypeptide, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

[0204] 48. The composition for use according to Embodiment 47, further comprising administering to the subject an adjuvant.

[0205] 49. The composition for use according to Embodiment 48, wherein the adjuvant comprises aluminum and / or a TLR9 agonist oligonucleotide.

[0206] 50. The composition for use according to Embodiment 48, wherein the adjuvant comprises a saponin.

[0207] 51. The composition for use according to Embodiment 50, wherein the saponin is QS-21.

[0208] 52. The composition for use according to any of Embodiments 50-51, wherein the adjuvant comprises a TLR4 agonist.

[0209] 53. The composition for use according to Embodiment 52 wherein the TLR-4 agonist is 3- O-desacyl-4’-Monophosphoryl Lipid A (3D-MPL).

[0210] 54. The composition for use according to any of Embodiments 48-53 wherein the adjuvant comprises liposomes.

[0211] 55. The composition for use according to Embodiment 54 wherein the liposomes comprise a sterol.

[0212] 56. The composition for use according to Embodiment 55 wherein the sterol is cholesterol.

[0213] 57. The composition for use according to any of Embodiments 54-56 wherein the liposomes comprise a neutral lipid, for example phosphatidylcholine, egg yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine .

[0214] 58. The recombinant N N gE polypeptide, or the composition for use according to any of Embodiments 47-57 wherein the N N gE polypeptide is the only N N polypeptide administered to the subject.

[0215] 59. The recombinant N N gE polypeptide, or the composition for use according to any of Embodiments 47-58 wherein the N N gE polypeptide is administered in an amount effective to induce a N N gE immune response in the subject.

[0216] 60. The recombinant N N gE polypeptide, or the composition for use according to any of Embodiments 47-59 wherein the N N gE polypeptide is administered in an amount selected from about 10 micrograms to about 100 micrograms per dose.

[0217] 61. The recombinant N N gE polypeptide, or the composition for use according to any of Embodiments 47-60 comprising administering a first dose and a second dose of the N N gE polypeptide wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose.

[0218] 62. The recombinant N N gE polypeptide, or the composition for use according to any of Embodiments 47-61 wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the recombinant N N gE polypeptide.

[0219] 63. A recombinant nucleic acid encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such recombinant nucleic acid, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

[0220] 64. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 63 wherein the recombinant nucleic acid is a recombinant vector. 65. The recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use according to any of Embodiments 63-64 wherein the recombinant nucleic acid is DNA

[0221] 66. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-64 wherein the recombinant nucleic acid is RNA.

[0222] 67. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 66 wherein the RNA is non-replicating RNA or selfreplicating RNA.

[0223] 68. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 66-67 wherein the RNA comprises at least one modified nucleotide.

[0224] 69. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 68 wherein the RNA comprises at least one modified uridine.

[0225] 70. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 69 wherein the modified uridine is N1 -methylpseudouridine

[0226] 71. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 66-70 wherein the RNA is administered with a nucleic acid carrier.

[0227] 72. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 71 wherein the nucleic acid carrier comprises lipid nanoparticles.

[0228] 73. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to Embodiment 72 wherein the nucleic acid is encapsulated in the lipid nanoparticles. 74. The recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use according to any of Embodiments 63-73 wherein the recombinant nucleic acid is administered in an amount effective to induce a N N gE immune response in the subject.

[0229] 75. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-74 wherein the N N gE polypeptide encoded by the recombinant nucleic acid is the only N N polypeptide administered to the subject.

[0230] 76. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-75 wherein the recombinant nucleic acid is administered in an amount effective to induce a N N gE immune response in the subject.

[0231] 77. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-76 wherein the recombinant nucleic acid is administered in an amount selected from about 1 microgram to about 200 micrograms per dose.

[0232] 78. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-77 comprising administering a first dose and a second dose of the recombinant nucleic acid wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose.

[0233] 79. The recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use according to any of Embodiments 63-78 wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the recombinant nucleic acid encoding the N N gE polypeptide.

[0234] 80. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-79 wherein the N N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain. 81. The recombinant N7N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-80 wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0235] 82. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-81 wherein the N N gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0236] 83. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-82 wherein the N N gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0237] 84. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-83 wherein the N N gE polypeptide comprises at least one amino acid substitution selected from MOT, D150N, A186V, and T496Y relative to SEQ ID NOs: 1-5 or 8.

[0238] 85. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-84 wherein the subject is at least 50 years old.

[0239] 86. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-85 wherein the subject is a woman. 87. The recombinant N7N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-86 wherein the subject has been diagnosed with dementia or mild cognitive impairment.

[0240] 88. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-87 wherein the subject is at risk of dementia or mild cognitive impairment.

[0241] 89. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-88 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment.

[0242] 90. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-89 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l.

[0243] 91. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to Embodiment 85 wherein the subject is at least 65 years old.

[0244] 92. The recombinant N N gE polypeptide, the composition comprising such polypeptide, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition comprising such recombinant nucleic acid, for use according to any of Embodiments 47-91 wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0245] 93. A method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide.

[0246] 94. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such polypeptide, for use in a method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide.

[0247] 95. The method of Embodiment 93 or the composition for use according to Embodiment 94 further comprising administering to the subject an adjuvant.

[0248] 96. The method or composition for use of Embodiment 95 wherein the adjuvant comprises aluminum or a TLR9 agonist oligonucleotide.

[0249] 97. The method or composition for use of Embodiment 95 wherein the adjuvant comprises a saponin.

[0250] 98. The method or composition for use of Embodiment 97 wherein the saponin is QS-21.

[0251] 99. The method or composition for use of any of Embodiments 97-98 wherein the adjuvant comprises a TLR4 agonist.

[0252] 100. The method or composition for use of Embodiment 99 wherein the TLR-4 agonist is 3-O-desacyl-4’-Monophosphoryl Lipid A (3D-MPL).

[0253] 101. The method or composition for use of any of Embodiments 95-100 wherein the adjuvant comprises liposomes.

[0254] 102. The method or composition for use of Embodiment 101 wherein the liposomes comprise a sterol.

[0255] 103. The method or composition for use of Embodiment 102 wherein the sterol is cholesterol.

[0256] 104. The method or composition for use of any of Embodiments 101-103 wherein the liposomes comprise a neutral lipid, for example phosphatidylcholine, egg yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine .

[0257] 105. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-104 wherein the NZN gE polypeptide is the only NZN polypeptide administered to the subject.

[0258] 106. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-105 wherein the NZN gE polypeptide is administered in an amount selected from about 10 micrograms to about 100 micrograms per dose.

[0259] 107. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-106 comprising administering a first dose and a second dose of the NZN gE polypeptide wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose.

[0260] 108. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-107 wherein the NZN gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

[0261] 109. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-108 wherein the NZN gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0262] 110. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-109 wherein the NZN gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0263] 111. The method, the recombinant NZN gE polypeptide or composition for use of any of Embodiments 93-110 wherein the NZN gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1. 112. The method, the recombinant N7N gE polypeptide or composition for use of any of Embodiments 93-111 wherein the N N gE polypeptide comprises at least one amino acid substitution selected from I40T, D150N, A186V, and T496Y corresponding to SEQ ID NO: 1.

[0264] 113. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-112 wherein the subject is seropositive for Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV)-l.

[0265] 114. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-113 wherein the subject is a woman.

[0266] 115. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-114 wherein the subject has been diagnosed with dementia or mild cognitive impairment.

[0267] 116. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-115 wherein the subject is at risk of dementia or mild cognitive impairment.

[0268] 117. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-116 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment.

[0269] 118. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-117 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l.

[0270] 119. The method, the recombinant N N gE polypeptide or composition for use of Embodiment 118 wherein the subject is at least 65 years old.

[0271] 120. The method, the recombinant N N gE polypeptide or composition for use of any of Embodiments 93-119 wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0272] 121. A method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of the recombinant nucleic acid encoding the recombinant N N gE polypeptide. 122. A recombinant nucleic acid encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such recombinant nucleic acid, for use in a method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of the recombinant nucleic acid encoding the recombinant N N gE polypeptide.

[0273] 123. The method of Embodiment 122, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use according to Embodiment 122 wherein the recombinant nucleic acid is a recombinant vector.

[0274] 124. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-123 wherein the recombinant nucleic acid is DNA.

[0275] 125. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-123 wherein the recombinant nucleic acid is RNA.

[0276] 126. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 125 wherein the RNA is non-replicating RNA or selfreplicating RNA.

[0277] 127. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 125-126 wherein the RNA comprises at least one modified nucleotide.

[0278] 128. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 127 wherein the RNA comprises at least one modified uridine. 129. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of Embodiment 128 wherein the modified uridine is Nl- methylpseudouridine .

[0279] 130. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 125-129 wherein the RNA is administered with a nucleic acid carrier.

[0280] 131. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 130 wherein the nucleic acid carrier comprises lipid nanoparticles.

[0281] 132. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 131 wherein the recombinant nucleic acid is encapsulated in the lipid nanoparticles.

[0282] 133. The method, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use of any of Embodiments 121-132 wherein the N N gE polypeptide encoded by the recombinant nucleic acid is the only N N polypeptide administered to the subject.

[0283] 134. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-133 wherein the recombinant nucleic acid is administered in an amount selected from about 1 microgram to about 200 micrograms per dose.

[0284] 135. The method, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use of any of Embodiments 121-134 comprising administering a first dose and a second dose of the recombinant nucleic acid wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose. 136. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of any of Embodiments 121-135 wherein the N N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

[0285] 137. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-136 wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0286] 138. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-137 wherein the N N gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0287] 139. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-138 wherein the N N gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0288] 140. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-139 wherein the N N gE polypeptide comprises at least one amino acid substitution selected from I40T, D150N, A186V, and T496Y corresponding to SEQ ID NO: 1.

[0289] 141. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-140 wherein the subject is seropositive for Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV)-l.

[0290] 142. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-141 wherein the subject is a woman.

[0291] 143. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-142 wherein the subject has been diagnosed with dementia or mild cognitive impairment. 144. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of any of Embodiments 121-143 wherein the subject is at risk of dementia or mild cognitive impairment.

[0292] 145. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-144 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment.

[0293] 146. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-145 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l. 147. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of Embodiment 146 wherein the subject is at least 65 years old.

[0294] 148. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 121-147 wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0295] 149. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising administering to the human subject at least one therapeutically effective dose of a vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier, such as a nucleic acid carrier.

[0296] 150. A vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier, such as a nucleic acid carrier, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising administering to the human subject at least one therapeutically effective dose of said vaccine.

[0297] 151. A method of treating a human subject at least 50 years old, comprising:

[0298] - administering to the human subject a first therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0299] - administering to the human subject a second therapeutically effective dose of a recombinant N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0300] 152. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide for use in a method of treating a human subject at least 50 years old, comprising:

[0301] - administering to the human subject a first therapeutically effective dose of the recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0302] - administering to the human subject a second therapeutically effective dose of the recombinant N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0303] 153. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-152 wherein the N N gE polypeptide is administered in an amount selected from about 10 micrograms to about 100 micrograms per dose.

[0304] 154. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-153 wherein the N N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

[0305] 155. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-154 wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0306] 156. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-155 wherein the N N gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0307] 157. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-156 wherein the N N gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0308] 158. The method, or the recombinant N N gE polypeptide or composition for use of any of Embodiments 151-157 wherein the N N gE polypeptide comprises at least one amino acid substitution selected from MOT, D150N, A186V, and T496Y corresponding to SEQ ID NO: 1.

[0309] 159. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-158 wherein the subject is seropositive for Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV)-l.

[0310] 160. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-159 wherein the subject is a woman.

[0311] 161. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-160 wherein the subject has been diagnosed with dementia or mild cognitive impairment.

[0312] 162. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-161 wherein the subject is at risk of dementia or mild cognitive impairment.

[0313] 163. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-162 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment.

[0314] 164. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-163 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l.

[0315] 165. The method, or the recombinant VZV gE polypeptide for use of Embodiment 164 wherein the subject is at least 65 years old.

[0316] 166. The method, or the recombinant N N gE polypeptide for use of any of Embodiments 151-165 wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0317] 167. A method of treating a human subject at least 50 years old, comprising:

[0318] - administering to the human subject a first therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0319] - administering to the human subject a second therapeutically effective dose of a recombinant nucleic acid encoding a N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose. 168. A recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide for use in a method of treating a human subject at least 50 years old, comprising:

[0320] - administering to the human subject a first therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0321] - administering to the human subject a second therapeutically effective dose of a recombinant nucleic acid encoding a N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0322] 169. The method of Embodiment 167, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use according to Embodiment 168 wherein the recombinant nucleic acid is a recombinant vector.

[0323] 170. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-169 wherein the recombinant nucleic acid is DNA.

[0324] 171. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-169 wherein the recombinant nucleic acid is RNA.

[0325] 172. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 171 wherein the RNA is non-replicating RNA or selfreplicating RNA.

[0326] 173. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 171-172 wherein the RNA comprises at least one modified nucleotide.

[0327] 174. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 173 wherein the RNA comprises at least one modified uridine. 175. The method, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use of Embodiment 174 wherein the modified uridine is N 1 - methylpseudouridine .

[0328] 176. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 171-174 wherein the RNA is administered with a nucleic acid carrier.

[0329] 177. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 176 wherein the nucleic acid carrier comprises lipid nanoparticles.

[0330] 178. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of Embodiment 177 wherein the recombinant nucleic acid is encapsulated in the lipid nanoparticles.

[0331] 179. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-178 wherein the N N gE polypeptide encoded by the recombinant nucleic acid is the only N N polypeptide administered to the subject.

[0332] 180. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-179 wherein the recombinant nucleic acid is administered in an amount selected from about 1 microgram to about 200 micrograms per dose.

[0333] 181. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-180 comprising administering a first dose and a second dose of the recombinant nucleic acid wherein the second dose is administered at least about one month after the first dose, for example from about one month to about six months after the first dose. 182. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of any of Embodiments 167-181 wherein the N N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

[0334] 183. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-182 wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

[0335] 184. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-183 wherein the N N gE polypeptide comprises at least one amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0336] 185. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-184 wherein the N N gE polypeptide comprises at least 2 amino acid substitutions at positions corresponding to residues 40, 150, 186, or 496 of SEQ ID NO: 1.

[0337] 186. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-185 wherein the N N gE polypeptide comprises at least one amino acid substitution selected from I40T, D150N, A186V, and T496Y corresponding to SEQ ID NO: 1.

[0338] 187. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-186 wherein the subject is seropositive for Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV)-l.

[0339] 188. The method, the recombinant nucleic acid encoding a VZV gE polypeptide, or the composition for use of any of Embodiments 167-187 wherein the subject is a woman.

[0340] 189. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-188 wherein the subject has been diagnosed with dementia or mild cognitive impairment. 190. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of any of Embodiments 167-189 wherein the subject is at risk of dementia or mild cognitive impairment.

[0341] 191. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-190 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment.

[0342] 192. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-191 wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l. 193. The method, the recombinant nucleic acid encoding a N7N gE polypeptide, or the composition for use of Embodiment 192 wherein the subject is at least 65 years old.

[0343] 194. The method, the recombinant nucleic acid encoding a N N gE polypeptide, or the composition for use of any of Embodiments 167-193 wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of: a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

[0344] 195. Use of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such polypeptide, for the manufacture of a medicament for delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

[0345] 196. Use of a recombinant nucleic acid encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such recombinant nucleic acid, for the manufacture of a medicament for delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

[0346] 197. Use of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such polypeptide, for the manufacture of a medicament for treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide 198. Use of a recombinant nucleic acid encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such recombinant nucleic acid, for the manufacture of a medicament for treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of the recombinant nucleic acid encoding the recombinant N N gE polypeptide.

[0347] 199. Use of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide for use in the manufacture of a medicament for treating a human subject at least 50 years old, comprising:

[0348] - administering to the human subject a first therapeutically effective dose of the recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0349] - administering to the human subject a second therapeutically effective dose of the recombinant N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0350] 200. Use of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide in the manufacture of a medicament for treating a human subject at least 50 years old, comprising:

[0351] - administering to the human subject a first therapeutically effective dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, and

[0352] - administering to the human subject a second therapeutically effective dose of a recombinant nucleic acid encoding a N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

[0353] 201. Use of a vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier, such as a nucleic acid carrier, in the manufacture of a medicament for delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising administering to the human subject at least one therapeutically effective dose of said vaccine.

[0354] EXAMPLES

[0355] Example 1: Retrospective study to evaluate dementia risk after herpes zoster immunization

[0356] The instant inventors designed and carried out a retrospective, observational, matched- cohort study with pairwise comparisons, using a large Electronic Health Records (EHR) database, to evaluate dementia risk after immunization with recombinant zoster vaccine (RZV, marketed under the brand name SHINGRIX) or live-attenuated zoster vaccine (ZVL, marketed under the brand name ZOSTAVAX). The study included two comparator cohorts: individuals immunized with 23 -valent pneumococcal polysaccharide vaccine (PPSV23), and individuals who had not received any herpes zoster (HZ) vaccine (the nonexposed [NE] cohort).

[0357] The primary objectives of this study were to compare cumulative hazards for dementia between the following matched cohorts:

[0358] RZV recipients versus ZVL recipients

[0359] RZV or ZVL recipients versus PPSV23 recipients

[0360] RZV or ZVL recipients versus NE individuals (not exposed to RZV or ZVL).

[0361] RZV recipients who received at least one dose of the vaccine (RZV cohort, or “RZV >1 dose”) were analyzed separately from RZV recipients who received at least 2 doses of the vaccine (RZV-2D cohort).

[0362] The results reported here show that immunization with either RZV or ZVL was associated with a lower risk of dementia compared to immunization with PPSV23 or lack of immunization against HZ. Surprisingly, the magnitude of benefit was higher for the RZV cohort than the ZVL cohort. This is the strongest evidence to date of such an association for RZV. The present findings thus indicate that HZ vaccination, especially with RZV, may convey clinical benefits to vaccinees extending beyond HZ prevention. 1. Methods

[0363] Population and follow-up

[0364] Anonymized individual data from the Optum Electronic Health Records (EHR) database (www[.]Optum[.]com), which comprises records of >100 million individuals from >2,000 hospitals and >5,000 clinics in the US, were used in this study.

[0365] Participants were included if they were aged >50 years, their health record was available in the Optum EHR, and the date of exposure (i.e., immunization with RZV, ZVL or PPSV23 or a confirmed HZ episode) was recorded. Individuals without a recorded RZV or ZVL vaccination were included in the respective NE cohorts if they had a recorded visit date within 3 months prior to or after the exposure date of the matched individuals. To ensure minimal data availability, only individuals with at least 25 recorded healthcare encounters were included in the NE and comparison cohorts.

[0366] Exclusion criteria were mainly related to data inconsistencies. We excluded participants without a documented birth year, with an immunization or dementia diagnosis date before birth or after death, with an immunization or diagnosis date before the 1stof October 2007 and with an invalid death status (i.e., participant marked as deceased but without a documented death date or participant marked as alive but with a death date entered). Individuals with a dementia diagnosis prior to the exposure date, with a recorded immunization before vaccine approval date, with more than 3 immunizations with the same vaccine or with a missing date of exposure were excluded as well.

[0367] The study period was defined as starting with year 2007 until 30 September 2023. Included individuals were followed up from the date of first recorded entry into Optum EHR until the last date of their records. Index date was defined as the date of first immunization with RZV, ZVL or PPSV23. For individuals with more than one immunization, the earliest date was taken as the index date. For individuals in the NE cohorts, the index date was randomly sampled from all documented visits that were approximately 3 months before or after the exposure date of a matched exposed individual. Only for primary comparisons between RZV and ZVL, the strictness in index date matching was reduced via injection of Gaussian noise to increase the pool of individuals available for matching. We also observed a short-term clustering of PPSV23 exposure and recorded dementia diagnosis, likely due to participants being vaccinated with PPSV23 soon after being diagnosed with dementia. However, a small fraction of diagnostic records was possibly delayed, resulting in some diagnoses being recorded after PPSV23 exposure. To avoid excluding these individuals (due to a dementia diagnosis preceding the exposure), the index date of PPSV23 exposure was artificially shifted to 10 days after the actual exposure for all except the temporal-shift sensitivity analysis. Since censoring was accounted for at modelling time, minimum observation periods were not defined, so as not to systematically exclude individuals with fewer health records.

[0368] Data normalization and stratification

[0369] Specific cohorts were selected based on their exposure to vaccination and cohort characteristics were compared pre- and post-matching.

[0370] Relevant outcomes were dementia and mild cognitive impairment (MCI), as defined by established International Classification of Disease (ICD) codes [See, e.g., Wilkinson, T. et al. Eur J Epidemiol 34, 557-565 (2019)]. Specifically, Dementia was diagnosed based on the presence of at least one ICD-9 (290.2, 290.3, 290.4, 291.2, 294.1, 331.0, 331.1, 331.2, 331.5) or ICD-10 (A81.0, FOO, F00.0, FOO.l, F00.2, F00.9, F01, F01.0, F01.1, F01.2, F01.3, F01.8, F01.9, F02, F02.0, F02.1, F02.2, F02.3, F02.4, F02.8, F03, F05.1, F10.6, G30, G30.0, G30.1, G30.8, G30.9, G31.0, G31.1, G31.8, 167.3) code. Mild Cognitive Impairment was diagnosed based on the presence of at least one ICD-9 (331.83) or ICD-10 (G31.84) code. Prescription of donepezil was not used to identify dementia cases because this medication is used off-label also for MCI. Incidence and risk of all-cause dementia were also analyzed in cohorts stratified by sex (male / female) and age (60-69 year-olds, 70-79 year-olds and 80-89 year-olds).

[0371] Machine Learning matching methodology

[0372] A Machine Learning (ML) methodology was used to optimize a propensity-score -matched cohort that included key confounders (demographic [age at exposure, year of exposure, sex, ethnicity, region], healthcare utilization [duration of records in years pre-exposure, median recorded number of visits per year, medication prescriptions, recorded number of elective adult immunizations against varicella, influenza, tuberculosis and diphtheria- tetanus-pertussis], index date timeframe [year of immunization], comorbidities [depression, diabetes, stroke, hypertension, body mass index, lifestyle factors [e.g., smoking, alcohol consumption]) to build comparable populations for each pairwise comparison. For comparisons between vaccinated individuals (i.e., immunization with RZV, ZVL or PPSV23), 394 covariates were used in matching. For comparison between vaccinated and NE cohorts, 395 covariates were used because only immunization with an HZ vaccine (but not PPSV23) needed to be removed from the matching covariates.

[0373] First, ML models were trained to distinguish between pre-matched individuals in each cohort based on the index date, and to reflect the differences (i.e., potential confounders) between the cohorts. Subsequently, new matched cohorts were formed by selecting a defined number (k) nearest neighbours with predicted case inclusion probabilities (propensity scores) that were within a defined threshold (a) into each cohort. After this matching step, the created cohorts were close to indistinguishable, meaning that the distribution of their characteristics was nearly identical, thus allowing for an unconfounded comparison between cohorts.

[0374] The 1: 1 propensity score matching (nearest-neighbour method) with caliper (0.05) was used in all instances [Abadie, A. & Imbens, G. W. Matching on the Estimated Propensity Score. Econometrica 84, 781-807 (2016)]. Extreme gradient boosting was used as the propensity score estimator. [See, e.g., Chen, T. & Guestrin, C. in Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining 785- 794 (Association for Computing Machinery, San Francisco, California, USA, 2016); Ke, G. et al. LightGBM: A Highly Efficient Gradient Boosting Decision Tree. (2017)].

[0375] Data analyses

[0376] For analyses of dementia and mild cognitive impairment (MCI) incidence after HZ vaccination, cumulative hazard functions (Nelson-Aalen) for each cohort were evaluated at 3 and 5 years post-exposure. Equivalence was determined via a chi-squared test (a=0.05) between the pairs of cohorts in terms of their cumulative hazard distributions at each evaluated time point. [See, e.g., Kim, J. H. Chi-Square Goodness-of-Fit Tests for Randomly Censored Data. The Annals of Statistics 21, 1621-1639 (1993)]. Missing covariates were imputed using the Multiple Imputation by Chained Equations method. [See, e.g. Gerry, S. et al. Early warning scores for detecting deterioration in adult hospital patients: systematic review and critical appraisal of methodology. BMJ 369, ml501, doi: 10.1136 / bmj.ml501 (2020)]. Sensitivity analyses

[0377] Several sensitivity analyses were conducted to diminish the effect of possible confounders on study results. If any potential residual confoundedness was identified in sensitivity analyses, the matching methodology was expanded to account for more observed confounders and proxies for potential unmeasured confounders until residual confounding was resolved or the study results were established to be uninterpretable. Any such reactive changes in matching covariates in response to identified presence of residual confounders were logged alongside the sensitivity analysis results to ensure end-to-end provenance.

[0378] Control groups by temporal shift

[0379] The dementia incidence was evaluated for the matched cohorts up to 1 year prior to index date, to confirm that the compared cohorts had comparable frequencies of dementia diagnoses prior to exposure. The rationale was that any significant differences in dementia incidence prior to the index date may point to presence of confounders not accounted for by matching.

[0380] Sensitivity to minimum observation time in database prior to exposure, long-term gaps in records and washout period

[0381] These analyses aimed to evaluate the frequency of large gaps (e.g., >1 year) in available records and the potential impact of such cases on the study results. Including only individuals with at least 1 year of available pre-exposure records decreased the likelihood of missing dementia diagnoses in the analyzed population. Additionally, we investigated whether the results were sensitive to including a washout period for diagnoses recorded relatively proximal (e.g., 12 months) in time after the exposure. The rationale behind this last approach was that any exposure would likely not have impacted the onset of dementia diagnosed within the first year post-exposure.

[0382] Coding sensitivity analyses

[0383] These were tests of different algorithms to improve coding for dementia. A higher- specificity algorithm used both a dementia-specific code and a documented prescription of dementia-specific medication for a positive dementia diagnosis. A higher-sensitivity algorithm used either the code or the prescription as a confirmation of dementia diagnosis. The higher-specificity algorithm was expected to detect fewer dementia cases but eliminate false positives, while the latter algorithm was expected to detect more dementia cases, but potentially including false positives.

[0384] 2. Results

[0385] Participant characteristics

[0386] Between 1 October 2007 and 30 September 2023, depending on the comparison, 553,538- 22,647,450 individuals were sampled for pre-matching RZV-2D (at least 2 doses), RZV (at least one dose), ZVL, PPSV23 and NE cohorts from the Optum Electronic Health Records (EHR) database. The cohorts were matched by correcting for 394-395 potential confounders (see Methods).

[0387] After correction, the matched cohorts in each comparison included: 45,851 (RZV-2D versus ZVL); 168,667 (RZV-2D versus PPSV23); 467,105 (RZV-2D vs NE); 53,244 (RZV vs ZVL), 227,708 (RZV vs PPSV23), 622,413 (RZV vs NE), 382,038 (ZVL vs PPSV23) and 939,954 (ZVL vs NE) individuals. Overall, the post-matching characteristics were well balanced between cohorts. The median age of vaccine (RZV-2D, RZV, ZVL and PPSV23) recipients and NE individuals was 63-65 years. Between 55.3% and 60.9% of participants were female, 80.9%-91.7% were Caucasian and most lived in the Midwestern (39.0%- 57.3%), Southern (11.3%-24.6%) and Northeastern (10.1%-24.0%) regions of the US. The most frequent underlying medical conditions were hypertension, falls / fractures and diabetes.

[0388] Despite ML-based matching, some discrete differences were still observed among matched cohorts. Compared to recipients of at least 2 RZV doses, lower proportions of ZVL recipients were Caucasian (82.3% vs 85.0%) and lived in the Midwest (39.6% vs 44.9%). Also, relatively fewer ZVL than RZV-2D recipients were diagnosed with medical conditions such as hypertension (44.6% versus 46.5%), falls / fractures (18.6% versus 21.6%) and diabetes (16.5% versus 18.1%). Relatively fewer ZVL than RZV-2D recipients were prescribed at least 1 of the 5 most important medications. The post-matching characteristics were more balanced between RZV-2D and PPSV23 recipients or individuals in the matched NE cohort. While relatively more Caucasian individuals were included in the RZV-2D than the NE cohort (86.5% vs 85.8%), comorbidity diagnoses (e.g., hypertension [65.3% vs 66.6%], depression [26.9% vs 28.3%]) and medication prescriptions (e.g., antihypertensives [35.8% vs 37.0%], antidepressants [38.6% vs 39.7%]) were relatively less frequent in RZV-2D recipients. Similar to the RZV-2D, higher proportions of individuals with comorbidities and with prescribed medications were observed in matched recipients of at least 1 RZV dose (RZV) versus ZVL and PPSV23 recipients. The described differences were not observed in the matched ZVL and NE cohorts.

[0389] Impact of vaccination on incidence and risk of dementia

[0390] In the matched cohorts, risk of all-cause dementia, defined as the first record under a validated ICD code, was lower in HZ vaccine recipients than PPSV23 vaccinees and NE individuals (FIG. 1A-E; FIG. 3A-C). RZV-2D recipients had a lower risk of all-cause dementia at both 3 and 5 years post-exposure compared to the PPSV23 cohort (relative risk [RR]: 0.76 [p<0.0001] and 0.80 [p<0.0005]) and the NE cohort (RR: 0.72 and 0.81 [p<0.0001 for both]). See FIGS. IB and 1C, respectively. Furthermore, the risk of being diagnosed with dementia was lower in RZV-2D and RZV recipients compared to matched ZVL recipients at 3 years post-exposure (RR: 0.73 [p<0.005] and 0.84 [p=0.0464]). At 5 years post-exposure, only RZV-2D recipients had a lower risk of dementia than ZVL recipients (RR: 0.77 [p<0.005]). See FIGS. 1A and 3A.

[0391] ZVL vaccination was associated with a significantly lower risk of dementia compared to PPSV23 vaccination (RR: 0.86 [p<0.0001] at 3 and 0.92 [p<0.0001] at 5 years) and no HZ vaccination (NE cohort) (RR: 0.63 [p<0.0001] at 3 and 0.67 [p<0.0001] at 5 years). See FIGS. ID and IE.

[0392] A different trend was observed when focusing on incidence of mild cognitive impairment (MCI). The risk of MCI was lower at 3 years post-exposure in RZV-2D and RZV recipients compared to NE individuals (RR: 0.75 [p<0.01] and 0.69 [pO.0001]). See FIGS. 2A-D and FIGS. 4A-B. However, no differences in the risk of MCI were observed between RZV-2D / RZV and PPSV23 recipients at any timepoint, or between RZV-2D / RZV recipients and NE individuals at the 5 -year follow-up points. ZVL recipients had a lower risk of MCI compared to both PPSV23 recipients and NE individuals at both 3 and 5 years post-exposure (FIG. 2C-D). Stratified results: Dementia type, sex and age

[0393] Risk of Alzheimer’s disease and vascular dementia was lower in RZV, but not ZVL, versus PPSV23 recipients at both 3 (RR: 0.81 [Alzheimer’s disease] and 0.77 [vascular dementia] [p<0.0001 for both]) and 5 years (RR: 0.86 [p<0.005] and 0.84 [p<0.05]) post-exposure (FIGS. 5A-B).

[0394] When analyzing the risk of all-cause dementia separately in vaccinated female and male individuals, immunization with RZV was associated with a significantly lower 3-year dementia risk compared to PPSV23 in both populations (FIG. 6A). The risk of dementia in ZVL versus PPSV23 recipients was lower in female but comparable in male individuals (FIG. 6B).

[0395] Finally, age-stratified analyses showed that the risk of dementia was similar among the 60- 69-year-old vaccinees (FIG. 7A), but RZV and ZVL recipients aged 70-79 (FIG. 7B) and 80-89 years (FIG. 7C) were at a significantly lower risk of developing dementia than the PPSV23 recipients of the same age at 3 years post-exposure.

[0396] Sensitivity analyses

[0397] The findings from primary analyses on the risk of dementia in HZ vaccine recipients were corroborated by several sensitivity analyses. The time-lag analysis, where the exposure dates were artificially shifted to 1 year prior to the actual exposure, showed that similar proportions of participants were diagnosed with dementia in the matched RZV or ZVL versus PPSV23 cohorts. However, relatively fewer RZV and ZVL recipients than NE participants developed dementia over this I -year period. It is thus likely that some residual confounding, not accounted for by ML-based matching, was present in RZV and ZVL versus NE comparisons. Next, when selecting only individuals with records available at least 1 year pre-exposure date, the RR of dementia in matched RZV or ZVL versus PPSV23 cohorts followed comparable trends as in the primary analysis. Similar results were observed if the start of follow-up was shifted to 1 year post-exposure date in each matched cohort. Although the statistical confidence was lower due to lower sample sizes, the findings from primary analyses were largely unaffected by introducing a > I -year preexposure observation period or shifting the follow-up period. Finally, the robustness of the described findings was assessed by using 2 different definitions of dementia: the first relying on dementia diagnosis or prescription of dementia medication (higher sensitivity) and the second, requiring both a dementia diagnosis and prescribed dementia-specific medication (higher specificity). The differences in the risk of dementia between RZV and PPSV23 recipients decreased after using the more specific definition of dementia (i.e., requiring both dementia diagnosis and prescribed dementiaspecific medication).

[0398] 3. Conclusions

[0399] This large-scale, ML-based matched-cohort study found that immunization with either RZV or ZVL was associated with a lower risk of dementia compared to immunization with PPSV23 or lack of immunization against HZ. Surprisingly, this study also demonstrated a higher magnitude effect of RZV on reducing risk of all-cause dementia at 3 and 5 years post- vaccination as compared to ZVL. The effect was larger in women, and in individuals aged 70 years and older. These data offer the first robust evidence that administration of RZV is associated with a reduced risk of dementia in adults aged >50 years.

[0400] SEQUENCE LISTING

[0401] Amino acid sequences writen in N-terminus to C-terminus direction. Nucleic acids writen in the 5’ to 3’ direction.

[0402] >SEQ ID NO : 1 Genbank Acces sion No . Q9J3M8

[0403] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPV NPGTSPLLRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAYRVDKS PYNQSMYYAGLPVDDFEDSE STDTEEEFGNAIGGSHGGSSYTVYI DKTR

[0404] >SEQ ID NO : 2 AEW88764 . 1 membrane glycoprotein E

[0405] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPV NPGTSPLIRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAYRVDKS PYNQSMYYAGLPVDDFEDSE STDTEEEFGNAIGGSHGGSSYTVYI DKSP

[0406] >SEQ ID NO : 3 Genbank Acces sion No . ABF21714

[0407] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHTDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPV NPGTSPLIRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAYRVDKS PYNQSMYYAGLPVDDFEDSE STDTEEEFGNAIGGSHGGSSYTVYI DKTR >SEQ ID NO : 4 Genbank Acces sion No . AAT07749

[0408] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHTDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVNQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPV NPGTSPLLRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAYRVDKS PYNQSMYYAGLPVDDFEDSE STDTEEEFGNAIGGSHGGSSYTVYI DKTR

[0409] >SEQ ID NO : 5 Genbank Acces sion No . AEW88980

[0410] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPMAGQPPATTKPKEITPV NPGTSPLIRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAYRVDKS PYNQSMYYAGLPVDDFEDSE STDTEEEFGNAIGGSHRGSSYTVYI DKSP

[0411] >SEQ ID NO : 6 Genbank Acces sion No . AQT34120

[0412] MFYEALKAELVYTRAVHGFRPRANCWLSDYI PRVACNMGTVNKPWGVLMGFGI ITGTLRITNPV RASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLEN AHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKG DLNPKPQGQRLIEVSVEENHPFTLRAPIQRI YGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTC FQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTE KQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFS LAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRV ASTVYQNCEHADNYTAYCLGI SHMEPSFGLI LHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVA YTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLI RYAAWTGGLAAWLLCLVI F LICTAKRMRVKAYRVDKSPYNQSMYYAGLPVDDFEDSESTDTEEEFGNAIGGSHGGSSYTVYIDKT R

[0413] >SEQ ID NO : 7 Genbank Acces sion No . ANS 12941

[0414] MFYEALKAELVYTRAVHGFRPRANCWLSDYI PRVACNMGTVNKPWGVLMGFGI ITGTLRITNPV

[0415] RASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLEN AHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKG DLNPKPQGQRLIEVSVEENHPFTLRVPIQRI YGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTC FQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTE KQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFS LAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRV ASTVYQNCEHADNYTAYCLGI SHMEPSFGLI LHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVA

[0416] YTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLI RYAAWTGGLAAWLLCLVI F LICTAKRMRVKAYRVDKSPYNQSMYYAGLPVDDFEDSESTDTEEEFGNAIGGSHGGSSYTVYIDKT R

[0417] > SEQ ID NO : 8 VZV gE Y569A

[0418] MGTVNKPWGVLMGFGI ITGTLRITNPVRASVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVN RGESSRKAYDHNSPYIWPRNDYDGFLENAHEHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGI HVI PTLNGDDRHKIVNVDQRQYGDVFKGDLNPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTE TWS FLPSLTCTGDAAPAIQHICLKHTTCFQDVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIV VNTSTLFDELELDPPEI EPGVLKVLRTEKQYLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTP AVTPQPRGAEFHMWNYHSHVFSVGDTFSLAMHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTC LYHPNAPQCLSHMNSGCTFTSPHLAQRVASTVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTT LKFVDTPESLSGLYVFWYFNGHVEAVAYTWSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPV NPGTSPLLRYAAWTGGLAAWLLCLVI FLICTAKRMRVKAARVDK

[0419] >SEQ ID NO : 9 signal sequence

[0420] MGTVNKPWGVLMGFGI ITGTLRITNPVRA

[0421] >SEQ ID NO : 10 s ignal sequence

[0422] MFYEALKAELVYTRAVHGFRPRANCWLSDYI PRVACNMGTVNKPWGVLMGFGI ITGTLRITNPV RA

[0423] >SEQ ID NO : 11 human immunoglobulin Fc polypeptide

[0424] EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDG

[0425] VEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQ

[0426] VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK

[0427] >SEQ ID NO : 12 VZV gE Ectodomain of Q9J3M8 . 1 (WT1 )

[0428] SVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0429] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKGDL

[0430] NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ

[0431] DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ

[0432] YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS

[0433] TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0434] WSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLLRYAAWTGGLA

[0435] >SEQ ID NO : 13 VZV gE Ectodomain

[0436] SVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0437] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVNQRQYGDVFKGDL NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0438] WSYVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLIRYAAWTGGLA

[0439] >SEQ ID NO : 14 VZV gE Ectodomain of ABF21714

[0440] SVLRYDDFHTDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0441] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKGDL NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0442] WSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLIRYAAWTGGLA

[0443] >SEQ ID NO : 15 VZV gE Ectodomain of AAT07749

[0444] SVLRYDDFHTDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0445] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVNQRQYGDVFKGDL NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0446] WSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLLRYAAWTGGLA

[0447] >SEQ ID NO : 16 VZV gE Ectodomain of AEW88980

[0448] SVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0449] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKGDL

[0450] NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ

[0451] DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ

[0452] YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS

[0453] TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0454] WSTVDHFVNAIEERGFPPMAGQPPATTKPKEITPVNPGTSPLIRYAAWTGGLA

[0455] >SEQ ID NO : 17 VZV gE Ectodomain of AQT34120

[0456] SVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0457] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKGDL NPKPQGQRLIEVSVEENHPFTLRAPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0458] WSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLIRYAAWTGGLA

[0459] >SEQ ID NO : 18 VZV gE Ectodomain of ANS 12941

[0460] SVLRYDDFHIDEDKLDTNSVYEPYYHSDHAESSWVNRGESSRKAYDHNSPYIWPRNDYDGFLENAH

[0461] EHHGVYNQGRGIDSGERLMQPTQMSAQEDLGDDTGIHVI PTLNGDDRHKIVNVDQRQYGDVFKGDL NPKPQGQRLIEVSVEENHPFTLRVPIQRIYGVRYTETWSFLPSLTCTGDAAPAIQHICLKHTTCFQ DVWDVDCAENTKEDQLAEI SYRFQGKKEADQPWIWNTSTLFDELELDPPEIEPGVLKVLRTEKQ YLGVYIWNMRGSDGTSTYATFLVTWKGDEKTRNPTPAVTPQPRGAEFHMWNYHSHVFSVGDTFSLA MHLQYKIHEAPFDLLLEWLYVPIDPTCQPMRLYSTCLYHPNAPQCLSHMNSGCTFTSPHLAQRVAS TVYQNCEHADNYTAYCLGI SHMEPSFGLILHDGGTTLKFVDTPESLSGLYVFWYFNGHVEAVAYT

[0462] WSTVDHFVNAIEERGFPPTAGQPPATTKPKEITPVNPGTSPLIRYAAWTGGLA

[0463] >SEQ ID NO : 19 CpG adj uvant

[0464] AACGTTCGAG

[0465] >SEQ ID NO : 20 CpG adj uvant

[0466] T GACT GT GAAC GT T C GAGAT GA

Claims

CLAIMS1. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

2. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such polypeptide, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

3. The method of Claim 1, the recombinant polypeptide or the composition for use of Claim 2 further comprising administering to the subject an adjuvant.

4. The method, the recombinant polypeptide or the composition for use of Claim 3 wherein the adjuvant comprises aluminum and / or a TLR9 agonist oligonucleotide.

5. The method, the recombinant polypeptide or the composition for use of Claim 3 wherein the adjuvant comprises a saponin, optionally wherein the saponin is QS-21.

6. The method, the recombinant polypeptide or the composition for use of Claim 5 wherein the adjuvant comprises a TLR4 agonist, optionally wherein the TLR-4 agonist is 3-O-desacyl-4’-Monophosphoryl Lipid A (3D-MPL).

7. The method, the recombinant polypeptide or the composition for use of any of Claims 3-6 wherein the adjuvant comprises liposomes, optionally wherein the liposomes comprise a sterol, and optionally wherein the sterol is cholesterol.

8. The method, the recombinant polypeptide or the composition for use of Claim 7 wherein the liposomes comprise a neutral lipid, for example phosphatidylcholine, egg yolk phosphatidylcholine, dioleoyl phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine .

9. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide.

10. A recombinant nucleic acid encoding a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, or a composition comprising such recombinant nucleic acid, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject, comprising administering to the subject at least one dose of the N N gE polypeptide.

11. The method of Claim 9, the recombinant nucleic acid or the composition for use of Claim 10 wherein the recombinant nucleic acid is a recombinant vector, optionally wherein the recombinant nucleic acid is DNA or RNA.

12. The method, the recombinant nucleic acid or the composition for use of Claim 11 wherein the recombinant nucleic acid is RNA and the RNA is non-replicating RNA or selfreplicating RNA.

13. The method, the recombinant nucleic acid or the composition for use of any of Claims 11-12 wherein the recombinant nucleic acid is RNA and the RNA comprises at least one modified nucleotide, optionally wherein the RNA comprises at least one modified uridine, and optionally wherein the modified uridine is N1 -methylpseudouridine.

14. The method, the recombinant nucleic acid or the composition for use of any of Claims 11-13 wherein the recombinant nucleic acid is RNA and the RNA is administered with a nucleic acid carrier, optionally wherein the nucleic acid carrier comprises lipid nanoparticles, and optionally wherein the nucleic acid is encapsulated in the lipid nanoparticles.

15. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding Claims wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in thehuman subject following administration of the recombinant N7N gE polypeptide or of the recombinant nucleic acid encoding the N N gE polypeptide.

16. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the N N gE polypeptide is truncated to remove the transmembrane domain and / or intravirion domain.

17. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the N N gE polypeptide comprises an amino sequence at least 90% identical, optionally at least 98% identical, to SEQ ID NOs: 1-8 or 12-18.

18. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the N N gE polypeptide comprises at least one, optionally at least 2 amino acid substitution at a position corresponding to at least one of residues 40, 150, 186, or 496 of SEQ ID NO: 1.

19. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the N N gE polypeptide comprises at least one amino acid substitution selected from I40T, D150N, A186V, and T496Y relative to SEQ ID NOs: 1-5 or 8.

20. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the subject is at least 50 years old, optionally wherein the subject is at least 65 years old.

21. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the subject is a woman.

22. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the subject has been diagnosed with dementia or mild cognitive impairment.

23. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the subject is at risk of dementia or mild cognitive impairment.

24. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the subject exhibits at least one risk factor for dementia or mild cognitive impairment, optionally wherein the at least one risk factor is selected from the group consisting of: a) a genetic risk factor, such as carrying at least one copy of the APO4E allele, b) mild cognitive impairment, c) cardiovascular disease, d) hypertension, e) atherosclerosis, f) elevated LDL cholesterol, g) elevated plasma homocysteine, h) diabetes, i) obesity (Body Mass Index > 30), j) major depression, k) traumatic brain injury, l) stroke, m) tobacco use, n) alcohol use, o) family history of dementia or mild cognitive impairment, p) hearing loss, q) social isolation, r) low level of education in early life, s) physical inactivity, t) seropositive for Varicella Zoster Virus (VZV), and u) seropositive for Herpes Simplex Virus (HSV)-l.

25. The method, the recombinant polypeptide or composition for use, or the recombinant nucleic acid or composition for use of any of the preceding claims wherein the dementia or mild cognitive impairment is associated with a condition selected from the group consisting of:a) Alzheimer’s disease, b) Vascular disease, c) Lewy body disease, d) Frontotemporal degeneration, e) Parkinson’s disease, and f) Huntington’s disease.

26. A method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or of a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide or of recombinant nucleic acid encoding a N N gE polypeptide.

27. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, a composition comprising such polypeptide, a recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or a composition comprising such nucleic acid, for use in a method of treating a human subject at least 50 years old, comprising administering to the human subject a therapeutically effective dose of recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or of recombinant nucleic acid encoding a Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide, wherein the onset or progression of dementia or mild cognitive impairment is delayed for at least 3 years in the human subject following administration of the therapeutically effective dose of recombinant N N gE polypeptide or of recombinant nucleic acid encoding a N N gE polypeptide.

28. A method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising administering to the human subject at least one therapeutically effective dose of a vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier, such as a nucleic acid earner.

29. A vaccine comprising a recombinant means for inducing an immune response to Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide and an adjuvant or a carrier, such as a nucleic acid carrier, for use in a method of delaying the onset or progression of dementia or mild cognitive impairment in a human subject at least 50 years old, comprising administering to the human subject at least one therapeutically effective dose of said vaccine.

30. A method of treating a human subject at least 50 years old, comprising:- administering to the human subject a first therapeutically effective dose of a recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or of a recombinant nucleic acid encoding N N gE polypeptide, and- administering to the human subject a second therapeutically effective dose of a recombinant N N gE polypeptide or of a recombinant nucleic acid encoding N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

31. A recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or a recombinant nucleic acid encoding N N gE polypeptide for use in a method of treating a human subject at least 50 years old, comprising:- administering to the human subject a first therapeutically effective dose of the recombinant Varicella Zoster Virus glycoprotein E (VZV gE) polypeptide or of the recombinant nucleic acid encoding N N gE polypeptide, and optionally- administering to the human subject a second therapeutically effective dose of the recombinant N N gE polypeptide or of the recombinant nucleic acid encoding N N gE polypeptide, wherein the second therapeutically effective dose is administered at least 5 years after the first therapeutically effective dose.

Images