WO2020142677A1 - Transfert passif d'immunité au moyen de vecteurs de vaccin du virus de l'herpès simplex 2 (hsv -2) recombinant - Google Patents

Transfert passif d'immunité au moyen de vecteurs de vaccin du virus de l'herpès simplex 2 (hsv -2) recombinant Download PDF

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WO2020142677A1
WO2020142677A1 PCT/US2020/012170 US2020012170W WO2020142677A1 WO 2020142677 A1 WO2020142677 A1 WO 2020142677A1 US 2020012170 W US2020012170 W US 2020012170W WO 2020142677 A1 WO2020142677 A1 WO 2020142677A1
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hsv
glycoprotein
subject
infection
mice
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Betsy Herold
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Albert Einstein College of Medicine
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Albert Einstein College of Medicine
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Priority claimed from US16/238,933 external-priority patent/US10918712B2/en
Priority to JP2021539019A priority Critical patent/JP2022517322A/ja
Priority to KR1020217024471A priority patent/KR102686042B1/ko
Priority to CA3124523A priority patent/CA3124523A1/fr
Priority to AU2020204688A priority patent/AU2020204688A1/en
Priority to KR1020247023560A priority patent/KR20240116556A/ko
Application filed by Albert Einstein College of Medicine filed Critical Albert Einstein College of Medicine
Priority to EP20702946.3A priority patent/EP3906052A1/fr
Priority to CN202080018414.0A priority patent/CN113727728A/zh
Priority to IL284448A priority patent/IL284448B2/en
Priority to US17/420,529 priority patent/US20220088185A1/en
Publication of WO2020142677A1 publication Critical patent/WO2020142677A1/fr
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Priority to JP2023176398A priority patent/JP2024016032A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/245—Herpetoviridae, e.g. herpes simplex virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5254—Virus avirulent or attenuated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/844—Liver
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/884—Vaccine for a specifically defined cancer prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/892—Reproductive system [uterus, ovaries, cervix, testes]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • Herpes simplex vims types 1 and 2 persist as significant health problems globally, disproportionally impacting developing countries and poor communities around the world and fueling the HIV epidemic. Vaccines are urgently needed for these infections as currently there is no effective vaccine for HSV-1, HSV-2 or HIV.
  • HSV-1 is the primary cause of infectious blindness
  • HSV-2 is the primary cause of genital ulcers globally, although HSV-1 is now more commonly identified in association with genital tract disease in developed countries.
  • Genital herpes is a recurrent, lifelong disease that can stigmatize and psychologically impacts those affected.
  • HSV-2 gD subunit gD-2 gD subunit
  • the present invention addresses this need for new and improved HSV-1 and HSV-2 vaccines.
  • a method is provided of eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection, comprising effectuating passive transfer to the first subject of an amount of a product from a pregnant female immunized with HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus-1 (HSV- 1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, wherein the product comprises antibodies induced thereby, effective to elicit an immune response against an HSV-2 and/or HSV-1 infection in the first subject, wherein the first subject is a fetus or neonate.
  • HSV-1 herpes simplex virus-1
  • a method is provided of inhibiting a perinatal HSV-1 and/or HSV-2 infection in a neonate comprising administering to a female pregnant with a fetus which will become the neonate an amount of an HSV-1 and/or HSV-2 glycoprotein D-encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus- 1 (HSV-1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, effective to inhibit a perinatal HSV-1 and/or HSV-2 infection in a neonate.
  • HSV-1 herpes simplex virus- 1
  • a method in inhibiting HSV-1 and/or HSV-2 viral dissemination from a mother to her neonate comprising administering to the mother an amount of an HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus- 1 (HSV-1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, effective to inhibit HSV-1 and/or HSV-2 viral dissemination from a mother to her neonate.
  • HSV-1 herpes simplex virus- 1
  • HSV-2 herpes simplex virus-2
  • U s e an HSV-2 glycoprotein D-encoding gene
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene (U s e) in the genome thereof.
  • An isolated cell comprising therein a recombinant HSV-2 genome as described herein or a recombinant HSV-1 gene as described herein, wherein the cell is not present in a human being.
  • a vaccine composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein.
  • composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein, wherein the genome of the vims or virion comprises at least a deletion of a second gene, wherein the second gene is necessary for HSV-2 viral replication or virulence.
  • a pharmaceutical composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein, and a pharmaceutically acceptable carrier.
  • Also provided is a method of eliciting an immune response in a subject comprising administering to the subject an amount of (i) the recombinant HSV-2 vims as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to elicit an immune response in a subject.
  • Also provided is a method of treating an HSV-1, HSV-2 or HSV-1 and HSV-2 co-infection in a subject or treating a disease caused by an HSV-1, HSV-2 or co-infection in a subject comprising administering to the subject an amount of (i) the recombinant HSV-2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-1, HSV-2 or co- infection or treat a disease caused by an HSV-1, HSV-2 or co-infection in a subject.
  • Also provided is a method of vaccinating a subject for HSV-1, HSV-2 or co- infection comprising administering to the subject an amount of (i) the recombinant HSV-2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for HSV-1, HSV-2 or co-infection.
  • Also provided is a method of immunizing a subject against HSV-1, HSV-2 or co-infection comprising administering to the subject an amount of (i) the recombinant HSV- 2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against HSV-1, HSV-2 or co-infection.
  • the amount of recombinant HSV-2 is an amount of pfu of recombinant HSV-2 effective to achieve the stated aim.
  • a method of producing a virion of a recombinant herpes simplex virus-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising a HSV-1 or HSV-2 glycoprotein D on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding a HSV-1 or HSV-2 glycoprotein D with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a HSV-2 virion produced by the cells.
  • HSV-2 herpes simplex virus-2
  • a recombinant nucleic acid having the same sequence as a genome of a wild-type HSV-2 except that the recombinant nucleic acid does not comprise a sequence encoding an HSV-2 glycoprotein D.
  • HSV-2 herpes simplex virus-2
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-1, HSV-2 or co-infection in a subject.
  • HSV-2 herpes simplex virus-2
  • a virion of an isolated, recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof.
  • a vaccine composition comprising a vims as described herein, or a virion as described herein.
  • composition comprising a virus as described herein, or a virion as described herein, wherein the genome of the vims or virion comprises at least a deletion of a second gene, wherein the second gene is necessary for HSV-2 viral replication.
  • composition comprising a virus as described herein, or a virion as described herein, and a pharmaceutically acceptable carrier.
  • Also provided is a method of eliciting an immune response in a subject comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to elicit an immune response in a subject.
  • Also provided is a method of treating an HSV-2 infection in a subject or treating a disease caused by an HSV-2 infection in a subject comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-2 infection or treat a disease caused by an HSV-2 infection in a subject.
  • a method of vaccinating a subject for HSV-2 infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for HSV-2.
  • Also provided is a method of immunizing a subject against HSV-2 infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against HSV-2.
  • a method of producing a virion of a recombinant herpes simplex virus-2 (HSV-2), having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising an HSV-1 glycoprotein D on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding a HSV-1 glycoprotein D with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a recombinant HSV-2 virion comprising an HSV-1 glycoprotein D on a lipid bilayer thereof produced by the cell.
  • HSV-2 herpes simplex virus-2
  • a method of producing a virion of a recombinant herpes simplex virus-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising a non-HSV-2 surface glycoprotein on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding the non-HSV-2 surface glycoprotein with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a recombinant HSV-2 virion comprising a non-HSV-2 surface glycoprotein on a lipid bilayer thereof produced by the cell.
  • HSV-2 herpes simplex virus-2
  • a recombinant nucleic acid having the same sequence as a genome of a HSV-2 except that the sequence does not comprise a sequence encoding an HSV-2 glycoprotein D.
  • HSV-2 herpes simplex virus-2
  • HSV-2 herpes simplex virus-2
  • HSV-2 herpes simplex virus-2
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-1 infection in a subject.
  • a virion of an isolated, recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-2 infection in a subject.
  • Also provided is a method of treating an HSV-1 infection, or HSV-1 and HSV-2 co-infection, in a subject, or treating a disease caused by an HSV-2 infection or HSV-1 and HSV-2 co-infection in a subject comprising administering to the subject an amount of (i) a virus as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-2 infection or treat a disease caused by an HSV-2 infection in a subject or an amount effective to treat an HSV-1 and HSV-2 co-infection or treat a disease caused by an HSV-1 and HSV-2 co-infection in a subject.
  • Also provided is a method of vaccinating a subject for an HSV-1 infection, or HSV-1 and HSV-2 co-infection comprising administering to the subject an amount of (i) a virus as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for an HSV-1 infection, or HSV-1 and HSV-2 co-infection.
  • Also provided is a method of immunizing a subject against an HSV-1 infection, or HSV-1 and HSV-2 co-infection comprising administering to the subject an amount of (i) a virus as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against an HSV-1 infection, or HSV-1 and HSV-2 co-infection.
  • HSV-2 herpes simplex virus-2
  • HSV-2 herpes simplex virus-2
  • Also provided is a method of inducing antibody dependent cell mediated cytotoxicity (ADCC) against an antigenic target in a subject comprising administering to the subject an isolated, recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and further comprising a heterogenous antigen on a lipid bilayer thereof in an amount effective to induce antibody dependent cell mediated cytotoxicity (ADCC) against an antigenic target.
  • HSV-2 herpes simplex virus-2
  • HSV-2 AgD initiates an abortive infection: HSV-2 AgD-/+ only replicates successfully in cells that provide gD in trans (e.g. VD60 [40, 41]), but not in cells such as Vero cells (ATCC CCL-81, Green monkey kidney) or CaSki (ATCC CRL-1550, Homo sapiens, cervix) that do not encode Us6.
  • Vero cells ATCC CCL-81, Green monkey kidney
  • CaSki ATCC CRL-1550, Homo sapiens, cervix
  • Non-complemented HSV-2 AgD (AgD-/- obtained from Vero cells) cannot infect cells such as Vero and CaSki, which do not encode Use-
  • Fig. 2A-C A.
  • SCID mice inoculated with up to 10 7 plaque-forming units (pfu) of HSV-2 AgD-/+ vims do not manifest signs of disease after high dose intravaginal or subcutaneous inoculation.
  • Survival curves are shown in A, epithelial scores (scale of 0 to 5) for evidence of erythema, edema, or genital ulcers in B and neurological scores (scale of 0 to 5) for evidence of neuronal infection in C.
  • Fig. 3A-C Immunization with HSV-2 AgD-/+ virus elicits anti-HSV-2 antibodies. While sc. -sc. immunization elicits significant levels of both systemic and mucosal (vaginal washes) anti-HSV-2 antibodies, sc.-i.vag. immunization with HSV-2 AgD-/+ elicits lower levels of systemic anti-HSV-2 antibodies and no increase in antibody levels in vaginal washes. Anti-HSV-2 antibody levels in serum are shown in A and anti- HSV-2 antibody levels in vaginal washes are shown in B.
  • mice immunized with AgD-/+ display neutralizing anti-HSV-2 antibodies in the serum after challenge with virulent HSV- 2.
  • the neutralizing capacity of the antibodies elicited by AgD-/+ immunization is shown in C. (* p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001).
  • Fig. 4A-C A: CD8+ gBT-I T cell counts in spleens of C57B1/6 mice transferred with Tg T cells, then primed and boosted with HSV-2 AgD-/+ or VD60 lysate (Control).
  • B Percentage of gBT-I memory T cells in spleens of vaccinated or Control mice.
  • C 14 days after boost, splenocytes were isolated and re-stimulated in vitro with gB498-505 peptide and analyzed 6 hr later for cytokine production by intracellular cytokine staining and flow cytometry. (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001).
  • Fig. 5A-F Immunization with HSV-2 AgD-/+ (10 6 pfu/mouse) protects mice from a lethal HSV-2 challenge. Mice were primed subcutaneously and boosted 3-weeks apart either sc. or i.vag. and then challenged 3-weeks after boost intravaginally with an LD90 of virulent wild-type HSV-2(4674). While Control (immunized with the VD60 cell lysate) mice succumbed to disease, as manifested by significant weight loss (5 A) and death (5B), AgD-/+-immunized mice displayed significantly less pathology.
  • AgD- /+-immunized mice showed less epithelial disease (C) and neurological pathology (D) after lethal challenge. Additionally, AgD-/+-vaccinated mice displayed significantly less viral loads in vaginal washes (E), vaginal tissue and dorsal root ganglia (DRG) (F) after intravaginal challenge with a lethal dose of virulent HSV-2 compared to mice immunized with VD60 cell lysate as a Control. No infectious vims could be recovered from AgD-/+- i minimized mice in Day 4 vaginal washes or Day 5 vaginal tissue and DRG. (*p ⁇ 0.05; **p ⁇
  • Fig. 6A-C Mice immunized with HSV-2 AgD-/+ secrete less inflammatory cytokines in vaginal washes after challenge with virulent HSV-2. Mice immunized with HSV-2 AgD-/+ secrete less TNF-a, IL-6 and IL-Ib in vaginal washes than mice immunized with VD60 lysate and challenged with virulent HSV-2. Differences in inflammatory cytokine expression are observed at different time-points after challenge. (*p ⁇ 0.05; **p ⁇
  • Fig. 7A-D Immunization with HSV-2 AgD-/+ recruits T cells to the infection site and associated LNs.
  • Mice immunized sc. -sc. with AgD-/+ displayed increased percentages of activated anti-HSV-2 gBT-I CD8+ (A) and CD4+ T cells (B) in sacral lymph nodes (LNs) after challenge with virulent HSV-2.
  • LNs were extracted and incubated 6 h with UV-inactivated AgD-/- and then stained with antibodies for flow cytometry analysis. Mice immunized sc.-i.vag.
  • HSV-2 ⁇ gD-2 provides complete protection against disease following intravaginal or skin challenge with vaccine doses as low as 5xl0 4 PFU.
  • C57BL/6 mice were primed and then 21 days later boosted subcutaneously (sc) with either 5xl0 4 PFU, 5xl0 5 PFU, 5xl0 6 PFU of HSV-2 ⁇ gD-2 or VD60 lysates (control).
  • Serum was assessed for HSV-2 antibodies before (PreBleed), day 7 post prime, and day 7 post boost via ELISA (line represents mean). *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ⁇ gD-2 vaccinated groups vs. control-vaccinated group via two-way ANOVA. Kaplan Meier analysis was used for survival curves.
  • Fig 9A-9D Mice vaccinated with HSV-2 AgD-2 are protected against clinical isolates of HSV-1 and HSV-2.
  • FIG. 10A-10D Vims is rapidly cleared and no latent vims is detected in HSV-2 ⁇ gD-2 immunized mice following challenge with clinical isolates.
  • the presence of replicating or latent HSV in DRG tissue obtained from AgD-2 vaccinated (day 14 post challenge) or control vaccinated (time of euthanasia) mice by plaque assay (10B) and qRT-PCR (IOC), respectively (n 5 mice/group). Latency was further evaluated by co-culturing Vero cells with DRG isolated from AgD-2 and control immunized mice that were challenged with an LD90 of HSV-2 SD90 at day 5 post-challenge (10D).
  • FIG 11A-11D HSV-2 IgG2 specific antibodies are rapidly recruited into the skin of HSV-2 AgD-2 vaccinated mice following viral challenge.
  • 11 A Mice were immunized with AgD-2 or VD60 cell lysates (Control) and subsequently challenged with HSV- l(B 3 xl.l) and HSV-2(SD90) clinical isolates on the skin.
  • HSV-2 left
  • HSV-1 right
  • HSV-specific antibodies in the skin
  • pools of skin homogenates were serially diluted and assayed in the HSV-2 ELISA (6 mice per pool and results are mean ⁇ SD obtained from duplicates) (11B).
  • the ratio of anti-HSV-2 IgG sub-isotypes in the day 2 post-challenge skin homogenate pool was determined using sub-isotype specific secondary antibodies (11C).
  • Antibody-dependent-cellular-phagocytosis (ADCP) activity (left panel) of serum from HSV-2 ⁇ gD-2 or control vaccinated mice 7 days post-boost was quantified using THP-1 monocytic cell line and beads coated with HSV-2 viral cellular lysates (v) or cellular lysates (c).
  • IFN-g levels (right panel) were measured in the supernatants 8 hr post THP-1 and Ab/bead incubation (11D).
  • the %ADCP is calculated as percent of cells positive for beads multiplied by the MFI of positive cells divided by 10 6 (left panel). (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001, HSV-2 AgD-2 vs. control-vaccinated group, student’ s t-test)
  • Fig 12A-12H Adaptive and innate immune cells are recruited to infected skin by day 5 post-challenge in HSV-2 AgD-2 vaccinated mice. Skin sections from mice immunized with AgD-2 or VD60 lysates (control) and then challenged with LD90 of SD90 or Bx 3 l.l or unvaccinated mock-infected controls were stained for CD3 + (T cells) (12A), B220 + (B cells) (12B) or Ibal + (pan macrophage) (12C); representative immunohistochemistry images following challenge with HSV-l(B 3 xl.l) or HSV-2(SD90) are shown.
  • CD3 + (12D), B220 + (12E), and Ibal + (12F) cells were enumerated by counting 3 random fields per mouse (5 mice per group). Skin sections were also stained for CD4 + (12G) and CD8 + (12H) by immunofluorescence and the percentage positive cells quantified. Each symbol is the average of the 2 fields for individual mouse and the line represents mean; the dashed line represents counts from unvaccinated, mock-infected mice (3 fields averaging for 1 mouse) (*p ⁇ 0.05, AgD-2- vs. control-vaccinated group by student’s t-test).
  • Control but not AgD-2 vaccinated mice have persistent neutrophil infiltration in skin biopsies.
  • Skin sections of unimmunized mock-infected mice or mice immunized with HSV-2 AgD-2 or VD60 lysates (control) and infected with HSV-l(B 3 xl.l) virus were harvested on Day 5 post-challenge and stained for neutrophils using Ly6G (red). Nuclei are stained blue with DAPI.
  • FIG. 14A-14F Mice immunized with AgD-2 have decreased inflammatory cytokines and chemokines in the skin compared to control immunized mice by day 5 post challenge.
  • Biopsies of skin from mice immunized with AgD-2 or VD60 lysates (Control) at day 2 or day 5 post-challenge (or unimmunized, uninfected controls) were homogenized and evaluated for TNF (14A), IL-Ib (14B), IL-6 (14C), CXCL9 (14D), CXCL10 (IP-10) (14E), and IL-33 (14F) (n 6 animals/group, line represents mean, dashed line represents counts from unimmunized, mock infected animals).
  • FIG. 15A-15C Maternal immunization with AgD-2 protects neonates; age dependent response. Graphs illustrate percent survival versus days. Significant protection against HSV-1 and HSV-2 was observed in 7 (15A) and 14-day (15B) old pups bom to AgD-2 vaccinated dams, but protection was reduced when pups were challenged on day 1 of life (15C).
  • FIG. 16A-16D Protection correlates with transfer of HSV-specific FcyRIV- Activating Antibodies. 7 day old pups born to either AgD-2 or VD60 (control) vaccinated dams were challenged intranasally with 10 5 pfu of HSV-1 or HSV-2, and serum was collected from pups at time of sacrifice or day 14-post challenge and assessed as follows: 16A: HSV-1 (closed symbols) or HSV-2 (open symbols) specific IgG quantified by ELISA at 1:1000 dilution; 16B: IgG subtypes of the HSV- 1-specific or HSV-2-specific antibodies demonstrate that AgD-2 induces both IgGl and IgG2 with slightly predominance of IgG2; 16C: Neutralizing antibody titers demonstrate little or no complement-independent neutralization by AgD-2 immune serum (1:5 dilution); and 16D: FcyRIV-activating antibody titers.
  • Fig. 17 AgD-2 maternal vaccination reduces amount of HSV viral DNA detected in trigeminal ganglia, the site of latency. Neonatal mice bom to vaccinated mothers have reduced log # of copies of HSV based on qPCR in their trigeminal ganglia (which is the site of latency with intranasal infection).
  • Fig. 18A-18D AgD-2 maternal vaccination reduced dissemination to vital organs (lung, liver, brain, kidney).
  • Fig. 19A-19B Transplacental and breastmilk acquired Abs provide optimal protection in the murine model.
  • Pups bom to AgD-2 or VD60 (control) immunized dams were switched at birth and nursed by the opposite dam and then challenged with HSV-1 (19A) or HSV-2 (19B) on Day 7 or Day 14 of life.
  • Pups bom to a AgD-2 vaccinated mother were significantly protected if nursed by that dam but lost protection if nursed by a VD60- immunized mother.
  • pups born to a VD60-immunized mom were also significantly protected from viral challenge on Day 7 or Day 14 if nursed by a AgD-2 vaccinated dam.
  • Fig. 20 Optimal protection against latency via transplacental and breastmilk acquired Abs.
  • Fig. 21A-21B Protection is correlated with Ab levels present in the neonate’s serum at time of challenge.
  • Fig. 22A-22D Convalescent immune serum from mice infected with a sublethal dose of HSV failed to protect pups from subsequent viral challenge.
  • a method is provided of eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection, comprising effectuating passive transfer to the first subject of an amount of a product from a pregnant female immunized with HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof an wherein said HSV-2 is phenotypically complemented with a herpes simplex virus-1 (HSV- 1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, wherein the product comprises antibodies induced thereby, effective to elicit an immune response against an HSV-2 and/or HSV-1 infection in the first subject, wherein the first subject is a fetus or neonate.
  • HSV-1 herpes simplex virus-1
  • the product comprises serum of the pregnant female.
  • the product comprises breast milk of the pregnant female.
  • the first subject is a fetus.
  • the first subject is a neonate.
  • the first subject is born from a second subject.
  • the pregnant female is pregnant with the fetus.
  • the first subject and the pregnant female are human.
  • the product comprises antibodies elicited by immunization of the pregnant female with the HSV-2 having the deletion.
  • the product comprises FcyRIV-acti vating antibodies.
  • the product comprises IgGl and IgG2 antibodies.
  • the product comprises anti-HSV-1 IgG or anti-HSV-2 IgG.
  • the method elicits an immune response in the first subject against an HSV-2.
  • the method elicits an immune response in the first subject against an HSV-1.
  • the product further comprises an immunological adjuvant.
  • the product further comprises an HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus-1 (HSV-1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D.
  • HSV-1 herpes simplex virus-1
  • a method is provided of inhibiting a perinatal HSV-1 and/or HSV-2 infection in a neonate comprising administering to a female pregnant with a fetus which will become the neonate an amount of an HSV-2 having a deletion of the entire HSV-2 glycoprotein D- encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus- 1 (HSV-1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, effective to inhibit a perinatal HSV-1 and/or HSV-2 infection in a neonate.
  • HSV-1 herpes simplex virus- 1
  • a method is provided of inhibiting HSV-1 and/or HSV-2 viral dissemination from a mother to her neonate comprising administering to the mother an amount of an HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof and wherein said HSV-2 is phenotypically complemented with a herpes simplex virus-1 (HSV-1) glycoprotein D, effective to inhibit HSV-1 and/or HSV-2 viral dissemination from a mother to her neonate.
  • HSV-1 herpes simplex virus-1
  • the mother is pregnant with a fetus which will become the neonate.
  • the HSV-1 infection and/or HSV-1 viral dissemination is inhibited.
  • the HSV-2 infection and/or HSV-2 viral dissemination is inhibited.
  • an immune response is elicited against HSV-1.
  • an immune response is elicited against HSV-2.
  • the complementing cell is a VD60 cell.
  • the pregnant female, the mother or the second subject is seronegative for HSV-1, seronegative for HSV-2, or seronegative for both HSV-1 and HSV-2.
  • the pregnant female or the mother is subcutaneously administered the HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof.
  • the pregnant female or the mother is administered a subcutaneous boost does of the HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof after an initial subcutaneous administration of the HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene.
  • HSV-2 herpes simplex virus-2
  • the HSV-2 glycoprotein D comprises the amino acid sequence set forth in SEQ ID NO: l :
  • the isolated, recombinant HSV-2 further comprises a herpes simplex virus-1 (HSV-1) glycoprotein D on a lipid bilayer thereof.
  • HSV-1 herpes simplex virus-1
  • the HSV-1 glycoprotein D comprises the amino acid sequence set forth in SEQ ID NO:2:
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • HSV-2 Use gene For example, see Dolan et al. J Virol. 1998 March; 72(3): 2010-2021. (PMCID: PMC109494) “The Genome Sequence of Herpes Simplex Virus Type 2” for HSV-2 genome and Use gene, hereby incorporated by reference in its entirety).
  • the HSV-2 in which the HSV-2 glycoprotein D-encoding gene is deleted is an HSV-2 having a genome (prior to the deletion) as set forth in one of the following Genbank listed sequences: HSV-2(G) (KU310668), HSV-2(4674) (KU310667), B3xl.l (KU310657), B3xl.2 (KU310658), B3xl.3 (KU310659), B3xl.4 (KU310660), B3xl.5 (KU310661), B3x2.1 (KU310662), B3x2.2 (KU310663), B3x2.3 (KU310664), B3x2.4 (KU310665), B3x2.5 (KU310666).
  • Genbank listed sequences HSV-2(G) (KU310668), HSV-2(4674) (KU310667), B3xl.l (KU310657), B3xl.2 (KU310658), B3xl.3 (KU310659), B3x
  • the virion further comprises an HSV-1 glycoprotein D on a lipid bilayer thereof.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • the vims further comprises an HSV-1 on a lipid bilayer thereof.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • An isolated cell comprising therein a recombinant HSV-2 genome which does not comprise an HSV-2 Use gene.
  • the recombinant HSV-2 genome is recombinant by virtue of having had a HSV-2 glycoprotein D gene deleted therefrom.
  • the cell is a complementing cell which provides expressed HSV 1 or 2 glycoprotein not encoded for by the recombinant HSV-2 genome.
  • the complementing cell comprises a heterologous nucleic acid encoding a HSV-1 glycoprotein D.
  • the cell expresses HSV-1 glycoprotein D on a membrane thereof.
  • the HSV-1 glycoprotein D is encoded by the heterologous nucleic acid, which heterologous nucleic acid is a HSV-1 glycoprotein D gene, or is a nucleic acid having a sequence identical to a HSV-1 glycoprotein D gene.
  • a vaccine composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein.
  • the vaccine comprises an immunological adjuvant.
  • the vaccine does not comprise an immunological adjuvant.
  • compositions or pharmaceutical compositions described herein comprising a recombinant HSV-2 the HSV-2 is live.
  • composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein, wherein the genome of the vims or virion comprises at least a deletion of a second gene, wherein the second gene is necessary for HSV-2 viral replication or virulence.
  • a pharmaceutical composition comprising the recombinant HSV-2 virus as described herein, or the virion as described herein, and a pharmaceutically acceptable carrier.
  • the composition or pharmaceutical composition or vaccine is formulated so that it is suitable for subcutaneous administration to a human subject. In an embodiment, the composition or pharmaceutical composition or vaccine is formulated so that it is suitable for intravaginal administration to a human subject. In an embodiment, the composition or pharmaceutical composition or vaccine is formulated so that it is suitable for intra-muscular, intra-nasal, or mucosal administration to a human subject.
  • Also provided is a method of eliciting an immune response in a subject comprising administering to the subject an amount of (i) the recombinant HSV-2 vims as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to elicit an immune response in a subject.
  • Also provided is a method of treating an HSV-2 infection in a subject or treating a disease caused by an HSV-1, HSV-2 or co-infection in a subject comprising administering to the subject an amount of (i) the recombinant HSV-2 vims as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-1, HSV-2 or co-infection or treat a disease caused by an HSV-1, HSV-2 or co-infection in a subject.
  • the methods comprise treating an HSV-1 or HSV-2 pathology caused by an HSV-1, HSV-2 or co-infection.
  • the disease caused by an HSV-1, HSV-2 or co-infection is a genital ulcer.
  • the disease caused by an HSV-1, HSV-2 or co-infection is herpes, oral herpes, herpes whitlow, genital herpes, eczema herpeticum, herpes gladiatorum, HSV keratitis, HSV retinitis, HSV encephalitis or HSV meningitis.
  • treating, or vaccinating for, an HSV-1, HSV-2 or co-infection i.e. infection with both HSV-1 and HSV-2
  • co-infection i.e. infection with both HSV-1 and HSV-2
  • separate, individual, embodiments of treating an HSV-1 infection, treating an HSV-2 infection, treating a co-infection, vaccinating against an HSV-1 infection, vaccinating against an HSV-2 infection, and vaccinating against a co-infection are each provided.
  • Also provided is a method of vaccinating a subject for HSV-1, HSV-2 or co- infection comprising administering to the subject an amount of (i) the recombinant HSV-2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for HSV-1, HSV-2 or co-infection.
  • Also provided is a method of immunizing a subject against HSV-1, HSV-2 or co-infection comprising administering to the subject an amount of (i) the recombinant HSV- 2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against HSV-1, HSV-2 or co-infection.
  • the subject is administered a subcutaneous or intravaginal priming dose and is administered a second dose subcutaneously or intravaginally.
  • the subject is administered as many subcutaneous or intravaginal priming doses to elicit anti-HSV antibodies and T cells.
  • a method of producing a virion of a recombinant herpes simplex virus-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising an HSV-1 or HSV-2 glycoprotein D on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding a HSV-1 or HSV-2 glycoprotein D with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a HSV-2 virion produced by the cell.
  • HSV-2 herpes simplex virus-2
  • the cell expresses HSV-1 or HSV-2 glycoprotein D on a membrane thereof.
  • a recombinant nucleic acid having the same sequence as a genome of a wild-type HSV-2 except that the recombinant nucleic acid does not comprise a sequence encoding an HSV-2 glycoprotein D.
  • the recombinant nucleic acid is a DNA.
  • the recombinant nucleic acid is an RNA.
  • HSV-2 herpes simplex virus-2
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-1, HSV-2 or co-infection in a subject.
  • the isolated, recombinant HSV-2 further comprises a herpes simplex virus-1 (HSV-1) or herpes simplex virus-2 (HSV-2) glycoprotein D on a lipid bilayer thereof.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • virion of an isolated, recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-1, HSV-2 or co-infection in a subject.
  • the virion further comprises an HSV-1 or HSV-2 glycoprotein D on a lipid bilayer thereof.
  • the HSV- 2 glycoprotein D-encoding gene is an HSV-2 Us 6 gene.
  • the HSV-1, HSV-2 or co- infection causes a genital ulcer.
  • HSV-2 herpes simplex virus-2
  • the isolated, recombinant HSV-2 further comprises a surface glycoprotein on a lipid bilayer thereof which is a herpes simplex virus- 1 (HSV-1) glycoprotein D.
  • the isolated, recombinant HSV-2 further comprises a non-HSV-2 viral surface glycoprotein on a lipid bilayer thereof.
  • the isolated, recombinant HSV-2 further comprises a bacterial surface glycoprotein on a lipid bilayer thereof.
  • the isolated, recombinant HSV-2 further comprises a parasitic surface glycoprotein on a lipid bilayer thereof, wherein the parasite is a parasite of a mammal.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 US6 gene.
  • the surface glycoprotein is encoded by a transgene that has been inserted into the genome of the recombinant HSV-2.
  • the surface glycoprotein is present on a lipid bilayer thereof by way of infecting a cell with a recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene, wherein the cell is or has been transfected to express the surface glycoprotein on a cell membrane thereof, and wherein the recombinant HSV-2 comprising the surface glycoprotein present on a lipid bilayer is produced from the cell.
  • the viral glycoprotein is from a HIV, an enterovirus, a RSV, an influenza virus, a parainfluenza vims, Pig corona respiratory vims, a rabies vims, a Lassa vims, a bunyavirus, a CMV, or a filovirus.
  • the glycoprotein is an HIV gpl20.
  • the filovims is an ebola virus.
  • the vims is HIV, a M. tuberculosis, a chlamydia, Mycobacterium ulcerans, M. marinum, M. leprae, M. absenscens, Neisseria gonnorhea, or a Treponeme.
  • the Treponeme is Treponeme palidum.
  • the virion of the isolated, recombinant HSV-2 further comprises a surface glycoprotein on a lipid bilayer thereof which is a herpes simplex virus- 1 (HSV-1) glycoprotein D.
  • the virion of the isolated, recombinant HSV-2 further comprises a non-HSV-2 viral surface glycoprotein on a lipid bilayer thereof.
  • the virion of the isolated, recombinant HSV-2 further comprises a bacterial surface glycoprotein on a lipid bilayer thereof.
  • the virion of the isolated, recombinant HSV-2 further comprises a parasitic surface glycoprotein on a lipid bilayer thereof, wherein the parasite is a parasite of a mammal.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • the surface glycoprotein is encoded by a transgene that has been inserted into the genome of the recombinant HSV-2 of the virion.
  • the surface glycoprotein is present on a lipid bilayer thereof by way of infecting a cell with a recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene, wherein the cell is or has been transfected to express the surface glycoprotein on a cell membrane thereof, and wherein the recombinant HSV-2 comprising the surface glycoprotein present on a lipid bilayer is produced from the cell.
  • the virion has been recovered from such.
  • the viral glycoprotein is from a HIV, an enterovirus, a RSV, an influenza virus, a parainfluenza virus, Pig corona respiratory vims, a rabies virus, a Lassa virus, a bunyavirus, a CMV, or a filovirus.
  • the glycoprotein is an HIV gpl20.
  • the filovirus is an ebola vims.
  • the vims is HIV, a M. tuberculosis, a chlamydia, Mycobacterium ulcerans, M. marinum, M. leprae, M. absenscens, Neisseria gonnorhea, or a Treponeme.
  • the Treponeme is Treponeme palidum.
  • an isolated cell comprising therein a vims as described herein or a virion as described herein, wherein the cell is not present in a human being.
  • the cell comprises a heterologous nucleic acid encoding a HSV-1 glycoprotein D.
  • the cell expresses HSV-1 glycoprotein D on a membrane thereof.
  • the HSV-1 glycoprotein D is encoded by the heterologous nucleic acid, which heterologous nucleic acid is a HSV-1 glycoprotein D gene, or is a nucleic acid having a sequence identical to a HSV-1 glycoprotein D gene.
  • a vaccine composition comprising a vims as described herein, or a virion as described herein.
  • the vaccine composition comprises an immunological adjuvant.
  • compositions comprising a virus as described herein, or a virion as described herein, wherein the genome of the vims or virion comprises at least a deletion of a second gene, wherein the second gene is necessary for HSV-2 viral replication.
  • the composition comprises semm from, or is derived from serum from, a mammal into which the virus or virion has been previously introduced so as to elicit an immune response.
  • composition comprising a virus as described herein, or a virion as described herein, and a pharmaceutically acceptable carrier.
  • a method of eliciting an immune response in a subject comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to elicit an immune response in a subject.
  • Also provided is a method of treating an HSV-2 infection in a subject or treating a disease caused by an HSV-2 infection in a subject comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-2 infection or treat a disease caused by an HSV-2 infection in a subject.
  • a method of vaccinating a subject for HSV-2 infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for HSV-2.
  • Also provided is a method of immunizing a subject against HSV-2 infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against HSV-2.
  • HSV-2 and HSV-1 diseases are known in the art, and are also described herein. Both treatment and prevention of HSV-2 and HSV-1 diseases are each separately encompassed. Also treatment or prevention of a HSV-2 and HSV-1 co-infection are covered. Prevention is understood to mean amelioration of the extent of development of the relevant disease or infection in a subject treated with the vims, virion, vaccine or compositions described herein, as compared to an untreated subject.
  • a method of producing a virion of a recombinant herpes simplex virus-2 (HSV-2), having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising an HSV-1 glycoprotein D on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding a HSV-1 glycoprotein D with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a recombinant HSV-2 virion comprising an HSV-1 glycoprotein D on a lipid bilayer thereof produced by the cell.
  • HSV-2 herpes simplex virus-2
  • a method of producing a virion of a recombinant herpes simplex virus-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and comprising a non-HSV-2 surface glycoprotein on a lipid bilayer thereof, comprising infecting a cell comprising a heterologous nucleic acid encoding the non-HSV-2 surface glycoprotein with a recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof under conditions permitting replication of the recombinant herpes simplex virus-2 (HSV-2) and recovering a recombinant HSV-2 virion comprising a non-HSV-2 surface glycoprotein on a lipid bilayer thereof produced by the cell.
  • HSV-2 herpes simplex virus-2
  • a recombinant nucleic acid having the same sequence as a genome of a HSV-2 except that the sequence does not comprise a sequence encoding an HSV-2 glycoprotein D.
  • HSV-2 herpes simplex virus-2
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-2 infection in a subject.
  • HSV-2 herpes simplex virus-2
  • HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-1 infection in a subject.
  • a virion of an isolated, recombinant HSV-2 having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof for treating or preventing an HSV-2 infection in a subject.
  • Also provided is a method of treating an HSV-1 infection, or HSV-1 and HSV-2 co-infection, in a subject, or treating a disease caused by an HSV-2 infection or HSV-1 and HSV-2 co-infection in a subject comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-2 infection or treat a disease caused by an HSV-2 infection in a subject or an amount effective to treat an HSV-1 and HSV-2 co-infection or treat a disease caused by an HSV-1 and HSV-2 co-infection in a subject.
  • a method of vaccinating a subject for an HSV-1 infection, or HSV-1 and HSV-2 co-infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to vaccinate a subject for an HSV-1 infection, or HSV-1 and HSV-2 co-infection.
  • Also provided is a method of immunizing a subject against an HSV-1 infection, or HSV-1 and HSV-2 co-infection comprising administering to the subject an amount of (i) a vims as described herein; (ii) a virion as described herein, (iii) a vaccine as described herein; (iv) a composition as described herein; or (v) a pharmaceutical composition as described herein, in an amount effective to immunize a subject against an HSV-1 infection, or HSV-1 and HSV-2 co-infection.
  • the subject is a mammalian subject.
  • the mammalian subject is a human subject.
  • a method is provided of eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection, comprising passive transfer to the subject of an amount of a product from a second subject immunized with HSV-2 having a deletion of the entire HSV-2 glycoprotein D-encoding gene in the genome thereof an wherein said HSV-2 is phenotypically complemented with a herpes simplex virus- 1 (HSV-1) glycoprotein D by propagating said HSV-2 in a complementing cell expressing said HSV-1 glycoprotein D, wherein the product comprises the HSV-2 or the antibodies or immune factors induced thereby, effective to elicit an immune response against the HSV-2 and/or HSV-1 infection.
  • HSV-1 herpes simplex virus- 1
  • the product comprises serum of the second subject.
  • the second subject is a pregnant female.
  • the first subject is a fetus or neonate.
  • the second subject is pregnant with the first subject.
  • the product comprises antibodies elicited by immunization of the second subject with the HSV-2.
  • HSV-2 herpes simplex virus-2
  • the heterogenous antigen is a protein, peptide, polypeptide or glycoprotein.
  • the heterogenous antigen heterogenous antigen with respect to HSV-2 but is an antigen found on or in the relevant“pathogen.”
  • Pathogens, viral and bacterial are described herein.
  • the pathogen is a bacterial pathogen of a mammal or a viral pathogen of a mammal.
  • the antigen or the transgene encoding the pathogen is not actually taken or physically removed from the pathogen, but nevertheless has the same sequence as the pathogen antigen or encoding nucleic acid sequence.
  • the isolated, recombinant HSV-2 comprises a heterogenous antigen of a pathogen on a lipid bilayer thereof.
  • the pathogen is bacterial or viral.
  • the pathogen is a parasite of a mammal.
  • the HSV-2 glycoprotein D-encoding gene is an HSV-2 Use gene.
  • the isolated, recombinant HSV-2, the heterogenous antigen is encoded by a transgene that has been inserted into the genome of the recombinant HSV-2.
  • Also provided is a method of inducing antibody dependent cell mediated cytotoxicity (ADCC) against an antigenic target in a subject comprising administering to the subject an isolated, recombinant herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene in the genome thereof and further comprising a heterogenous antigen on a lipid bilayer thereof in an amount effective to induce antibody dependent cell mediated cytotoxicity (ADCC) against an antigenic target.
  • HSV-2 herpes simplex virus-2
  • Recombinant HSV-2 AgD l+ expressing the appropriate transgenes will selectively induce antibodies and cellular immune responses that protect against skin or mucosal infections by pathogens.
  • the heterogenous antigen is a surface antigen.
  • the transgene encodes an antigen from an HIV, a M. tuberculosis, a chlamydia, Mycobacterium ulcerans, M. marinum, M. leprae, M. absenscens, Neisseria gonnorhea, or a Treponeme.
  • the Treponeme is Treponeme palidum.
  • the transgene is a M. tuberculosis biofilm-encoding gene.
  • the transgene is an HIV gp 120-encoding gene.
  • the heterogenous antigen is a surface antigen of the antigenic target.
  • the heterogenous antigen is a parasite antigen.
  • the heterogenous antigen is a bacterial antigen or a viral antigen.
  • the antigenic target is a vims and is a Lassa vims, a human immunodeficiency vims, an RSV, an enterovims, an influenza vims, a parainfluenza virus, pig corona respiratory virus, a lyssavirus, a bunyavirus, or a filovims.
  • the antigenic target is a bacteria and is Mycobaterium tuberculosis, M. ulcerans, M. marinum, M. leprae, M. absenscens, Chlamydia trachomatis, Neisseria gonorrhoeae or Treponema pallidum.
  • the isolated, recombinant HSV-2 transgene is a M. tuberculosis biofilm-encoding gene or wherein the transgene is an HIV gp 120-encoding gene.
  • the subject is a human. In an embodiment of the methods described herein, the subject has not yet been infected with HSV-1, HSV-2 or co-infection. In an embodiment of the methods described herein, the subject has been infected with HSV-1, HSV-2 or co-infection.
  • a co-infection means a co-infection with HSV-1 and HSV-
  • gD gD
  • VD60 cells Vero cells expressing HSV-1 gD
  • Intravaginal challenge of wild-type or SCID mice with 10 7 pfu/mouse of the complemented gD-null virus revealed no virulence, whereas doses as low as 10 4 pfu/mouse of parental wild-type virus were 100% lethal.
  • immunization of mice with HSV-2 AgD ⁇ /+ yielded complete protection against intravaginal challenge with a clinical isolate of HSV-2.
  • HSV-2 AgD ⁇ /+ Robust humoral and cellular immunity elicited by HSV-2 AgD ⁇ /+ was measured and it is concluded that gD is required for productive infection in vivo and that an attenuated strain deleted in this essential glycoprotein elicits protective immunity against HSV-2.
  • HSV-2 AgD ⁇ /+ is a promising vaccine for prevention or treatment of genital herpes.
  • HSV-2 AgD-/+ Mechanisms and correlates of protection elicited by HSV-2 AgD-/+.
  • a gD-2 null virus was generated, and it was demonstrated that it is highly attenuated in both immunocompetent and immunocompromised mice and when tested as a vaccine candidate, induced a protective immune response against intravaginal challenge with HSV-2.
  • Subcutaneous immunizations with HSV-2 AgD-/+ will induce humoral and cellular immune responses that are required for protection against intravaginal challenge with both serotypes of HSV (HSV-2 and HSV-1).
  • HSV-2 AgD-/+ initiates an abortive infection: An HSV-2 strain that is deleted for Us6 was constructed to assess its contribution in in early signaling events occurring during cell infection [41].
  • This virus is incapable of infecting host cells, unless it is grown on a gD-complementing cell line (e.g. VD60 cells encoding gD-1 [40, 41]) that encodes Us6 under the control of its endogenous promoter (for example, in an embodiment, the gD-l promoter).
  • a gD-complementing cell line e.g. VD60 cells encoding gD-1 [40, 41]
  • HSV-2 AgD particles isolated from non-complementing cells do not infect epithelial (Fig. 1) or neuronal cells (SK-N-SH, not shown).
  • a phenotypically complemented vims (AgD-/+) is obtained, which is fully capable of infecting cells that are common targets for wild-type HSV-2.
  • HSV-2 AgD-/+ is safe in the murine infection model: AgD-/+ was evaluated for safety in vivo in wild-type and severe combined immunodeficiency (SCID) mice by inoculating high doses subcutaneously or intravaginally. Mice inoculated intravaginally with 10 7 pfu of AgD-/+ (titered on complementing cells) did not manifest any signs of virus- induced pathology throughout the experiments, whereas animals inoculated with 1,000-fold less wild-type vims (10 4 pfu) succumbed to HSV-2 disease and died starting Day 8 after inoculation (Fig. 2A).
  • HSV-2 AgD-/+ elicits systemic and mucosal antibodies to HSV-2: Mice inoculated and boosted subcutaneously (sc.-sc.) with AgD-/+ or inoculated subcutaneously and boosted intravaginally (sc.-i.vag.) with this candidate vaccine strain (10 6 pfu/mouse) elicited a humoral immune response to HSV-2 as evidenced by an increase in serum and vaginal washes anti-HSV-2 antibodies (Fig. 3A and 3B). The control animals were immunized with an uninfected VD60 cell lysate (referred to as Control).
  • the antibodies were measured by ELISA using infected cell lysates as the antigen (response to uninfected cell lysates subtracted as background). Noteworthy, the magnitude of the antibody response differs depending on the route of immunization. Indeed, s.c.-s.c. immunization elicited significantly more semm and vaginal wash antibodies to HSV-2 than s.c.-i.vag. immunization. This finding suggests that the vaginal wash antibodies likely represent transudate of IgG from the blood and suggest that sc. -sc. is a more appropriate route for eliciting high levels of systemic and local IgG antibodies to HSV-2.
  • HSV-2 AgD-/+ elicits HSV-2-specific T cell activation: gB498-505-specific transgenic CD8+ T cells (gBT-I) were transferred into C57BL/6 mice prior to vaccination. Vaccinated mice were inoculated with 10 6 pfu AgD-/+ or with VD60 cell lysates (Control). Spleens were harvested on Day 14 after the boost and quantified by flow cytometry using counting beads (CountBrightTM, Lifetechnologies) (Fig. 4A). At the same day, spleens were stained for memory surface markers and analyzed by flow cytometry (Fig. 4B).
  • splenocytes harvested the same day were re-stimulated in vitro for 6 hours with the agonist gB498-505-peptide and intracellular cytokine staining was performed to measure IFN-g production by these cells.
  • Immunization with AgD-/+ increased the IFN-g production in the vaccinated compared to control mice (Fig. 4C).
  • the response in control mice presumably reflects the persistence of the gBT-I T cells in naive mice after transfer.
  • Similar results were obtained using multiplex cytokine analyses for supernatants of splenocytes re-stimulated in vitro with gB498-505-peptide (not shown).
  • mice immunized with HSV-2 AgD-/+ are protected against intravaginal HSV-2 lethal challenge: Animals vaccinated with HSV-2 AgD-/+ either sc. -sc. or sc.-i.vag. suffer less body weight after intravaginal lethal dose challenges equivalent to LD90 (5xl0 4 pfu/mouse) and survive challenges, whereas mice immunized with the VD60 control lysate succumbed to disease by Day 10 (Fig. 5A and 5B). The vaccines also provided complete protection against 10 times the LD90 (5xl0 5 pfu/mouse, data not shown). This protection was associated with significantly reduced epithelial disease scores (Fig.
  • HSV-2-AgD /+gD 1 was found to confer protection in C57BL/6 and Balb/C to vaginal challenge with virulent HSV-2.
  • intravaginal HSV-2 challenged AgD /+gD 1 immunized mice had no detectable HSV-2 in vaginal or neural tissue at 5 days post-challenge.
  • HSV-2 ⁇ gD-/+gD- 1 sc. sc. antibodies were found to recognize numerous HSV-2 proteins (both gD and gB) unlike HSV-2 morbid-bound mice.
  • Seram antibodies from vaccinated animals showed neutralization of HSV-1 and HSV-2 in vitro.
  • serum from ⁇ gD-/+gD- 1 vaccinated mice elicited Antibody Dependent Cellular Cytotoxicity (ADCC) of HSV-2 infected cells in vitro.
  • ADCC Antibody Dependent Cellular Cytotoxicity
  • HSV-2 AgD-/+gD-l is attenuated and completely safe in wt and SCID mice.
  • Recombinant HSV-2 AgD-/+gD-l protected against lethal HSV-2 intravaginal and HSV-2/HSV-1 skin infection. Protection was observed in two different mouse strains. There was no detectable infection, and sterilizing immunity. Also observed was induction of HSV-2 specific CD8+ T cells and systemic and mucosal HSV Abs. IgG2a and IgG2b were the predominant anti-HSV isotype. Also observed was FcyRIII/II-dependent ADCC. Surprisingly, passive transfer of immune serum protects naive mice, and FcRn and FcyR knockout mice were not protected with immune sera.
  • HSV-2 herpes simplex vims type 2
  • Infection risk increases with age and because the vims establishes latency with frequent subclinical or clinical reactivation, the impact of infection is lifelong.
  • HSV-2 significantly increases the risk of acquiring and transmitting HIV [2-4].
  • the prevalence of HSV-2 varies among global regions, fluctuating from 8.4% for Japan up to 70% for sub-Saharan Africa, a region where HIV prevalence is epidemic [5, 6]. In the US the prevalence of HSV-2 is -16% and that of HSV-1 has declined to - 54%.
  • HSV-1 glycoprotein D subunit vaccine trial in which the majority of cases of genital herpes disease were caused by HSV-1 [7-9].
  • HSV-1 is associated with fewer recurrences and less genital tract viral shedding compared to HSV-2, both serotypes are transmitted perinatally and cause neonatal disease; neonatal disease is associated with high morbidity and mortality even with acyclovir treatment [10-12].
  • CD4 + and CD8 + T cells were identified surrounding neurons and, while there was heterogeneity in the viral proteins targeted, the tegument protein, virion protein 16 (VP 16), was recognized by multiple trigeminal ganglia T cells in the context of diverse HLA-A and -B alleles; these findings suggest that tegument proteins may be important immunogens [33].
  • cytotoxic T cells directed at tegument proteins were also identified in studies of humans latently infected with HSV-2 [34].
  • CD8 + T cells persist in genital skin and mucosa at the dermal-epidermal junction following HSV reactivation suggesting that they play a role in immune control [35]
  • HSV-2 virus genetically deleted for native HSV-2 gD.
  • the HSV-2 gD gene encodes an envelope glycoprotein essential for viral entry and cell-to-cell spread. Glycoprotein D also binds to tumor necrosis factor receptor superfamily member 14 (TNFRSF14), an immune-regulatory switch also known as herpesvirus entry mediator (HVEM). Because HVEM harbors docking sites for more than one ligand and signaling differs depending on whether these molecules bind to HVEM in cis or in trans, gD may have modulatory effects on immune cells [36, 37].
  • TNFRSF14 tumor necrosis factor receptor superfamily member 14
  • HVEM herpesvirus entry mediator
  • gD competes with the natural ligands for this receptor and modulates the cytokine response to the virus [38, 39].
  • the gD gene was replaced with a DNA fragment encoding the green fluorescent protein ( gfp ) and transformed complementing Vero cells expressing HSV-1 gD (VD60 cells [40]) (e.g. gD-1 under gD-1 promoter)with this construct were screened for homologous recombinant vims that formed green plaques.
  • the mutant virus replicates in the complementing Vero cell line to high titers (designated HSV-2 AgD ⁇ /+ when passaged on complementing cells), but is noninfectious in non-complementing cells (designated HSV-2 AgD when isolated from non-complementing cells).
  • This virus was purified and characterized in vitro [41].
  • Intravaginal or subcutaneous inoculation of immunocompetent or immunocompromised (SCID) mice revealed no virulence compared to the lethal infection caused by parental wild-type vims. Immunization (subcutaneous prime followed by a single boost administered either subcutaneously or intravaginally) was 100% protective against intravaginal challenge with virulent HSV-2.
  • HSV primarily infects genital or oral nucleated epidermal cells due to breaches in the skin or mucocutaneous layers in humans (75).
  • a skin scarification model was used for these studies, which displays viral kinetics and histopathology similar to humans (76).
  • mice were challenged either intravaginally or by skin scarification with an LD90 (5xl0 5 PFU) of HSV-2(4674), a previously described clinical isolate (77). All HSV-2 ⁇ gD-2 immunized mice survived (5/5 per group), whereas all of the control- vaccinated mice (immunized with VD60 cell lysate) succumbed to disease (Fig. 8 A, 8B). Although the mice vaccinated with the lowest dose (5xl0 4 ) showed mild epithelial disease, no signs of neurological disease were observed and all animals completely recovered by day 14 in both the vaginal and skin challenge models. HSV antibodies (measured by ELISA) were detected in the serum of all vaccinated mice one week after boost, but not prime, and the antibody titer increased with administration of higher vaccine doses (Fig. 8C).
  • mice immunized with ⁇ gD-2 are protected from high viral challenges of virulent HSV-1 and HSV-2 clinical isolates.
  • ⁇ gD-2 vaccine protects against diverse HSV-1 and HSV-2 strains.
  • five HSV-1 were obtained (denoted B3xl.l - B3xl.5) and five HSV-2 (denoted B3x2.1 - B3x2.5) clinical isolates from the Clinical Virology Lab at Montefiore located in the Bronx, NY as well as a South African HSV-2 clinical isolate (SD90).
  • the isolates were grown on Vero cells and were passaged no more than three times before sequencing and phenotyping.
  • Illumina sequencing showed that the strains exhibited substantial genetic diversity with pairwise distances as high as 6.3% between B3xl.5 and the other B3xl isolates and 5.0% between B3x2.2 and the other B3x2 isolates.
  • In vivo virulence of each clinical strain was compared to laboratory strains by challenging B alb/C mice using the skin scarification model with lxlO 5 PFU of the HSV-1 strains or 5xl0 4 PFU of HSV-2 strains.
  • the clinical isolates demonstrated a range of virulence with B 3x1.1, B3xl.3, B3x2.3, and SD90 inducing more rapid disease with the highest morbidity in naive mice. Similar results were observed in the vaginal challenge model with the same 4 isolates exhibiting the most virulent disease (not shown). Interestingly, no differences between the isolates were observed by in vitro single and multistep growth curves on Vero cells.
  • HSV-2 ⁇ gD-2 recruits HSV-2 specific IgG2 antibodies and immune cells into the skin following challenge: To characterize the immune response to the vaccine and viral challenge in the skin, biopsies were obtained 21 days post boost and 2 or 5 days-post challenge and processed for histology and/or homogenized and then evaluated for presence of HSV-specific Abs by ELISA using either an HSV-2(4674) or HSV-1(17) infected cell lysate as the antigen. The ⁇ gD-2 immunized mice had low levels of HSV-specific Abs detected in the skin post-boost, which rapidly increased as early as day 2 post-challenge (Fig. 11A).
  • Murine IgG2 antibodies bind FcyR (78).
  • ADCP antibody-dependent-cellular- phagocytosis
  • Serum from ⁇ gD-2 vaccinated mice obtained 1 week post-boost elicited higher HSV specific phagocytosis and induced greater IFN-g secretion compared to serum from control immunized mice or beads coated with cell lysates (Fig. 1 ID).
  • the T-cells were further characterized by staining for CD4 or CD8; there was a significant increase in the CD4+ population but not the CD8+ population in ⁇ gD-2 compared to control-immunized mice (p ⁇ 0.05) (Fig. 12F and 12G). Conversely, there was a decrease in Ibal+ monocyte/macrophage cells (Fig. 12C and 12H) and Ly6G+ neutrophils (Fig. 13) in ⁇ gD-2 compared to control immunized mice.
  • HSV-2 ⁇ gD-2 affords complete protection against a panel of genetically diverse HSV-1 and HSV-2 clinical isolates and prevents the establishment of latency.
  • Vaccine efficacy was confirmed in an optimized skin model, which is reflective of human primary disease.
  • the ⁇ gD-2 elicited high titer antibodies that were rapidly recruited into the skin resulting in clearance of virus by day 5 even following challenge with 100-times the LD90 of the most virulent strain, SD90.
  • HSV-2 ⁇ UL5/ ⁇ UL29 The protective effect of ⁇ gD-2 against a broad array of HSV-1 and HSV-2 clinical isolates differentiates it from other candidate vaccines such as HSV-2 ⁇ UL5/ ⁇ UL29, which failed to fully protect against the clinical isolate SD90, or gD subunit vaccines and others that have only been tested against one or two laboratory viral strains.
  • the broad protection afforded by ⁇ gD-2 likely reflects the unique nature of the immune response elicited.
  • the Abs induced were enriched for the IgG2 subtype (-80% of all HSV- specific IgG), had low level neutralizing activity (not shown), were rapidly recruited into the skin with titers reaching 1:24,000 in skin biopsies by day 2 post-challenge, and mediated Fc effector functions (78) including ADCP (shown here) and ADCC.
  • the antibody response to ⁇ gD-2 was dose-dependent, correlated with the rapidity of viral clearance as evidenced by disease scores and likely contributed to the vaccine’s ability to completely prevent the establishment of latency.
  • IL-33 was the only cytokine that trended higher in the skin from the ⁇ gD-2 immunized mice compared to controls.
  • the precise role of IL-33 is not known.
  • Prior studies have shown that rIL-33 administration enhanced skin wound healing in mice and was associated with activation of innate lymphoid cells and differentiation of monocytes into type 2 macrophages (81, 82).
  • Systemic administration of IL-33 to mice was associated with an increase in FcgR2b, which is linked to decreased inflammation (88). Possibly, the increase in IL-33 observed in the skin of ⁇ gD-2 vaccinated mice promoted wound healing and resolution of inflammation ⁇
  • Vero African green monkey kidney cell line; CCL-81; American Type Culture Collection (ATCC), Manassas, VA, USA) cells, VD60 cells [Vero cells encoding gD-1 under endogenous promoter (85)], and CaSki (human cervical epithelial cell line; CRL-1550; ATCC) were passaged in DMEM supplemented with 10% fetal bovine serum (FBS, Gemini Bio-Products, West Sacramento, CA).
  • FBS fetal bovine serum
  • THP-1 human monocyte cell line; TIB-202; ATCC
  • RPMI-1640 Life Technologies
  • HSV-2(G) ⁇ gD-2 and its propagation on VD60 cells has been previously described (95, 94). No variability in vaccine efficacy has been observed comparing 5 different viral preparations.
  • HSV-2(4674) (86) was propagated on CaSki cells.
  • Laboratory strains HSV-2(G) (87), HSV-2 (333-ZAG) (86) , HSV-1(17) (89), and HSV- 1(F) (87) were propagated on Vero cells.
  • South African isolate HSV-2(SD90) (97) was provided by David Knipe and propagated on Vero cells.
  • HSV-1 (B3xl.l through B3xl.5) and five HSV-2 (B3x2.1 through B3x2.5) de-identified clinical isolates were provided by the Clinical Virology Lab at Montefiore and passaged three times on Vero cells for a low-passage working stock.
  • In vitro growth curves Single-step and multi-step growth curves were performed as previously described (86). For single-step growth of each virus, Vero cells were infected with virus at a multiplicity of infection (moi) of 5 PFU/cell and supernatants and cells were collected every 4, 8, 16 and 24 hours (h) post- infection (pi) and stored at -80°C. For multi- step growth of each vims, Vero cells were infected at a moi of 0.01 PFU/cell and supernatants and cells were harvested every 12 h pi up to 72 hours. Infectious virus was measured by performing plaque assays with supernatants and lysed cells.
  • moi multiplicity of infection
  • pi post- infection
  • HSV DNA was prepared by infecting confluent Vero cells in a T150 flask with each of the B3x clinical isolates at an MOI of 10. Cells were harvested 16 hpi and washed twice with PBS. DNA was extracted using DNeasy® Blood and Tissue (Qiagen) following the manufacturer’s recommendations. DNA was quantitated by Qubit dsDNA hs assay (Life Technologies). Paired-end libraries were prepared by the Nextera XT DNA library preparation kit (Illumina) following the manufacturer’s instructions. Libraries were sequenced on an Illumina MiSeq Desktop Sequencer.
  • Viral genome sequences were assembled with the VirAmp pipeline (89) following removal of host sequence by alignment to the Macaca mulatta genome as a substitute for the incomplete Chlorocebus sabaeus (source of Vero cells) genome.
  • HSV-1 and HSV-2 genomes were annotated with Genome Annotation Transfer Utility on ViPR by comparison to HSV- 1(96) (GenBank accession no. JN555585.1) & HSV-2(HG52) (JN561323) prior to submission to GenBank.
  • GenBank numbers for the genome sequences are as follows: HSV-2(G) (KU310668), HSV-2(4674) (KU310667), B3xl.l (KU310657), B3xl.2 (KU310658), B3xl.3 (KU310659), B3xl.4 (KU310660), B3xl.5 (KU310661), B3x2.1 (KU310662), B3x2.2 (KU310663), B3x2.3 (KU310664), B3x2.4 (KU310665), B3x2.5 (KU310666).
  • mice were treated with 2.5 mg of medoxyprogesterone acetate (MPA; Sicor Pharmaceuticals, Irvine, CA) sc five days prior to challenge. Mice were then inoculated intravaginally with an LD90 (5xl0 5 pfu/mouse) of HSV-2 (4674) at 30 pl/mouse and scored for disease and monitored for survival for 14 days as previously described (21).
  • MPA medoxyprogesterone acetate
  • HSV-2 4674
  • mice were depilated on the right flank with Nair and allowed to rest for 24 hr.
  • mice were anesthetized with isoflurane (Isothesia, Henry-Schein), then abraded on the exposed skin with a disposable emory board for 20-25 strokes and subsequently challenged with lxlO 5 PFU HSV-1 or 5xl0 4 PFU HSV-2 strains for in vivo virulence studies or challenged with an LD90, lOxLDcio, or lOOxLDcio of select HSV strains (see Table 1) for vaccine efficacy studies.
  • isoflurane Isothesia, Henry-Schein
  • mice were monitored for 14 days and scored as follows: 1: primary lesion or erythema, 2: distant site zosteriform lesions, mild edema/erythema, 3: severe ulceration and edema, increased epidermal spread, 4: hind- limp paresis/paralysis and 5: death. Mice that were euthanized at a score of 4 were assigned a value of 5 on all subsequent days for statistical analyses.
  • HSV RT-qPCR DNA was extracted from weighed tissue samples using DNeasy® Blood and Tissue (Qiagen) following the manufacturer’s recommendations. Extracted DNA was then normalized to 10 ng of DNA per reaction and viral DNA quantified using real-time quantitative PCR (RT-qPCR, qPCR) using ABsolute qPCR ROX Mix (Thermo Scientific). Primers for HSV polymerase (UL30) were purchased from Integrated DNA Technologies (Cat#: 1179200494) and used to detect viral genomic DNA. Isolated HSV-2 viral DNA was calibrated for absolute copy amounts using QuantStudio® 3D Digital PCR (dPCR, ThermoFisher Scientific) and subsequently used as a standard curve to determine HSV viral genome copies. Samples that read 4 or less copy numbers were considered negative. Data are presented as log 10 HSV genomes per gram of DRG (dorsal root ganglia) tissue.
  • Skin biopsies were obtained from HSV-2 ⁇ gD-2 or VD60 lysates (control) immunized mice (-5-10 mm in diameter by mechanical excision) day 21 post-boost or day 2 and 5 post viral skin challenge. The tissue was weighed and homogenized in RNase/DNase free Lysing Matrix A tubes (MP Biomedicals, Santa Ana, CA) with serum-free DMEM at 6.0m/sec for three 30sec cycles in the FastPrep-24TM 5G (MP Biomedicals).
  • Anti-HSV antibodies were detected by ELISA as previously described using uninfected, HSV-1(96), or HSV-2(4674)-infected Vero cell lysates as the coating antigen (94).
  • Biotin anti-mouse Ig k or biotin anti-mouse IgA, IgM, IgGl, IgG2a, IgG2b, or IgG3 at 1 pg/ml (Becton Dickenson, San Diego) were used as secondary detection antibodies.
  • SpectraMax M5 series ELISA plate reader at an absorbance of 450 nm. The resulting absorbance was determined by subtracting values obtained for uninfected cell lysates to values obtained with infected cell lysates.
  • Total anti- HSV Ig is reported as the optical density (OD) at 450 nm normalized to relative tissue weight at a 1: 1000 dilution of tissue homogenate.
  • Anti-HSV IgG, IgA, IgM, or IgGl-3 are reported as the optical density (OD) at 450 nm at all dilutions except IgGl-3 which is reported only at a 1:100 dilution of skin homogenate.
  • IL-6 interleukin-6
  • IL-1 beta IL-1 beta
  • IL-33 tumor necrosis factor alpha
  • TNFa tumor necrosis factor alpha
  • MIG monokine induced by interferon- gamma
  • IP- 10, CXCL10 interferon-inducible cytokine
  • Antigen retrieval was performed in 10 mM sodium citrate buffer at pH 6.0, heated to 96°C, for 30 minutes. Endogenous peroxidase activity was blocked using 3% hydrogen peroxide in water.
  • the sections were stained by routine IHC methods, using SuperPicTureTM (ThermoFisher Scientific, Cat: 87-9673) against rabbit primary antibodies to anti-CD3 (Ready to use format, ThermoFisher Scientific, Cat: RM-9107-R7), anti-B220 (BD Biosciences Cat: 550286), or anti-Ibal (1:3000 dilution Wako Pure Chemical Industries, Richmond, VA) and then stained with diaminobenzidine as the final chromogen.
  • Slides were thoroughly washed and incubated with an goat anti-rat secondary antibody conjugated with either Alexa flour 555 or Alexa flour 488 (1:500 or 1:200, respectively) for 30 min at RT. Slides were washed and mounted with media containing DAPI (ProFong® Diamond Antifade Mountant with DAPI, ThermoFisher Scientific). Slides were imaged using a Nikon Eclipse Ti-U inverted light microscope at 20x magnification from apical layer (epidermal) to basal layer (striated muscle) at two different locations per sample.
  • DAPI ProFong® Diamond Antifade Mountant with DAPI
  • ADCP Antibody dependent cellular phagocytosis
  • Serum from immunized mice at 1 week post boost was heat-inactivated at 56°C for 30 min and diluted 1:5 in serum-free RPMI. 50m1 of diluted serum was added to wells that contained the HSV lysates or control cell lysates coated beads and incubated for 2 h at 37°C. 2xl0 4 cells/well THP-1 cells were added to each at a final volume of 200pl/well and incubated for 8 hr at 37°C at 5% CO2. Subsequently, IOOmI of supernatant was removed and stored at -20°C then resuspended with IOOmI 4% paraformaldehyde.
  • Virus detection in tissue Skin and dorsal root ganglia (DRG) were weighed and homogenized as described above. Supernatants of homogenized tissue were then overlaid on confluent Vero cell monolayers (2xl0 5 cells/well in a 48-well plate) for 1 h. Wells were washed with PBS and then with 199 medium (Gibco®) containing 1% heat- inactivated FBS, overlaid with 0.5% methylcellulose and incubated at 37°C for 48 h. Cells were fixed with 2% paraformaldehyde, stained with a crystal violet solution and the number of PFU quantified. Neuronal ex-vivo co-culture assays were performed as previously described (94).
  • Neonatal HSV infection worldwide, is about 14,000 cases/yr.
  • Primary maternal genital HSV accounts for 50-80% of neonatal cases. Perinatal transmission with either results in severe mortality and morbidity even with effective therapy. It is apparent that pre existing maternal antibodies can apparently provide some protection since the risk of perinatal HSV transmission decreases to 1-3% with recurrent maternal HSV disease.
  • preexist maternal antibodies can apparently provide some protection since the risk of perinatal HSV transmission decreases to 1-3% with recurrent maternal HSV disease.
  • mice and ethics statement Murine studies were approved by the Institutional Animal Care and Use Committee at Albert Einstein College of Medicine, Protocol #2016- 1205. C57BL/6 mice were purchased from Jackson Laboratory (JAX, Bar Harbor, ME).
  • Vero African green monkey kidney cell line; CCL-82; ATCC
  • HaCAT human keratinocytes, ATTC CLS 300493
  • VD60 cells Vero cells encoding gD-1 under its endogenous promoter
  • HSV-2 The clinical isolates, HSV-2 (4674) and HSV-1 (B3xl.l), and the laboratory strain, HSV-2 (333) ZAG, which expresses green fluorescence protein (GFP) under control of the CMV promoter inserted at an intergenic site within the virus were propagated on Vero cells.
  • HSV-2(G) ⁇ gD-2 was propagated on complementing gD-1 expressing VD60 cells and viral titers determined by plaque assays on VD60 and Vero cells in parallel; no plaques were detected on the non-complementing Vero control cells.
  • mice Female mice were vaccinated with 5 x 10 6 pfu of ⁇ gD-2 (grown on VD60 cells), uninfected control VD60 cell lysates, or 5pg of recombinant gD-2 protein combined with 150 pg of aluminum (Alum) (Imject Alum; Pierce Biotechnology, Rockland, IL) and 12.5 pg of monophosphoryl lipid A (MPL) (Invivogen, San Diego, CA) (rgD-2/ Alum- MPL). Vaccines were administered subcutaneously at 4 weeks of age (prime) and a 7 weeks (boost) in a final volume of 100 pl/mouse.
  • Alum aluminum
  • MPL monophosphoryl lipid A
  • qPCR quantitative polymerase chain reaction
  • HSV-specific total or isotype specific IgG were determined by a previously described enzyme-linked immunosorbent assay (ELISA) in serum or in breastmilk.
  • ELISA enzyme-linked immunosorbent assay
  • Breastmilk was collected from pregnant female mice on days 8-12 post-parturition by separating them from their offspring for at least 2 hours and administration of a single-dose of 2 IU/kg of oxytocin via intraperitoneal injection 5 minutes before milking. Droplets of milk were manually expressed and then pipetted into sterile Eppendorf tubes and frozen at -20°C until use.
  • ELISA plates were coated with Vero cell lysates harvested 24 h after infection with HSV-l(B3xl.l) or HSV-2(4674) at a multiplicity of Infection (MOI) of 0.1 pfu/cell or uninfected control lysates.
  • MOI multiplicity of Infection
  • Serial dilutions of serum were incubated with the coated plates overnight at 4°C and bound IgG, IgGl, IgG2, or IgG3 was quantified using specific biotin- labeled secondary Abs (BD Biosciences, San Jose, CA).
  • the anti-HSV IgG level was determined after subtracting optical densitometry (OD) values obtained for uninfected cell lysates.
  • the neutralization titer was defined as the highest heat-inactivated serum dilution to result in 50% reduction in the number of plaques relative to plaques formed in the absence of immune serum (-100 plaques per well). FcyRIV activation was determined using the m Fey IV ADCC Reporter Bioassay (Promega, Madison, WI) with HSV-2(4674) or HSV- l(B3xl.l)-infected Vero cells as the targets.
  • Antibody-Dependent Cell-Mediated Killing (ADCK) assay Effector immune cells were isolated from spleens and livers and pooled from 5-10 naive neonatal or 3-5 naive adult mice. Red blood cells were removed by lysis with ammonium-chloride- potassium (ACK) lysis buffer (Gibco, Grand Island, NY). Pooled cells were counted and resuspended in complete RPMI media. Target cells were HaCaT cells infected for 4 h at 37°C with a MOI of 1 pfu/cell of HSV-2 (333) ZAG, or as a control, uninfected HaCaT cells.
  • ACK ammonium-chloride- potassium
  • the targets were dissociated with CellStripper (Coming), resuspended at 10 7 cells/ml in DMEM and 2 x 10 5 cells (in IOOmI) were added to each well of a 96-well U bottom plate.
  • the targets were incubated with pooled heat- inactivated serum (1:5 dilution in DMEM) isolated from ⁇ gD-2 or VD60 control vaccinated adult mice for 15 minutes at room temperature.
  • the pooled effector cells were then added at an effector to target cell ratio of 10:1 for 1 hr.
  • the cultures were stained with Live/Dead Red fixable dye (Invitrogen) for 30 min, fixed with 5% paraformaldehyde in phosphate buffered saline (PBS) and resuspended in FACs buffer (2% heat-inactivated FBS in PBS).
  • the cells were analyzed by flow cytometry on an LSRII (Becton Dickinson) and the percentage of GFP-positive (HSV-2 infected) dead cells was determined using FlowJo analysis software.
  • FcyR expression Immune cells isolated as for the ADCK assay from spleens and livers of adult or neonatal mice were adjusted to 1x107 cells/mL in FACS Buffer and 100 pi of cell suspension was added to a 96-well round-bottom microtiter plate.
  • Cell populations were defined as follows: macrophages, CDl lbintF4/80hi; neutrophils, CDl lbhiF4/801oLy6GhiLy6Cint; monocytes, CDllbhiF4/801oLy6GintLy6Chi. Samples were read on LSRII flow cytometer (BD Biosciences) and data were analyzed using FlowJo analysis software. The percent of FcyR positive cells was calculated based on %FMO FITC positive-%FITC positive.
  • Maternal vaccination with ⁇ gD-2 protects 7-14 day old pups from HSV-1 or HSV-2 challenge: To determine if maternal vaccination could protect pups from HSV postnatally, adult female mice were vaccinated with two doses of ⁇ gD-2, rgD-2/Alum- MPL, or as a control, an uninfected VD60 cell lysate prior to mating, and their pups challenged intranasally with clinical isolates of HSV- lor HSV-2 at an -LD90 dose. Pups were initially challenged on day of life 7, which is presumed to correspond immunologically to a term human infant.
  • HSV binding ELISA
  • neutralizing and FcyRIV activating Ab levels were quantified in blood obtained from pups who were infected on Day 7 of life with HSV-1 or HSV-2 at time of euthanasia for disease (mean Day 6 post-challenge) or at the end of the experiment for pups who survived challenge (Day 14 post-challenge).
  • Vaccination with gD-2/Alum-MPL and ⁇ gD-2 elicited similar titers of HSV-1 or HSV-2 binding IgG Abs whereas, as expected, little or no HSV-specific IgG was detected in HSV-infected pups born to VD60 immunized mice (Figs. 16A, 16B). However, the functionality of the Abs differed. The Abs in serum of pups bom to dams immunized with gD-2/Alum-MPL were predominantly neutralizing (mean NT 1:25) (Fig. 16C) but did not activate the murine FcyRIV (Fig. 16D).
  • mice born to ⁇ gD-2-immunized dams displayed significant FcyRIV activation indicative of ADCC activity, but little or no neutralizing activity.
  • Optimal protection requires antibodies acquired from breastmilk: The difference in protection observed when pups were challenge on Day 1 of life compared to Day 7 or 14 suggests that transplacentally acquired antibodies alone are not sufficient and/or there are age-dependent differences in FcyR effector cell function(s).
  • mice born to ⁇ gD-2-immunized mothers were switched at birth and nursed by mothers who had been immunized with VD60 cell lysates (only transplacentally-acquired Abs) and, conversely, mice bom to VD60 control-immunized mothers were nursed by ⁇ gD-2- immunized mothers (only breastmilk- acquired Abs).
  • Positive controls were mice that were both born to and nursed by ⁇ gD-2-immunized mothers and negative controls were mice that were bom to and nursed by VD60 control lysate-immunized mothers.
  • the pups were then challenged intranasally on Days 7 or 14 of life and monitored for two weeks.
  • HSV-2(ZAG)(which expresses GFP)-infected HaCAT target cells were incubated with HSV-2(ZAG)(which expresses GFP)-infected HaCAT target cells in the presence of serum harvested from ⁇ gD-2 or VD60 immunized adult mice and the ability of the effector cells to kill the target cells was quantified. (Data not shown).
  • HSV infects 10 per 100,000 births with most cases occurring in Africa reflecting a high incidence of maternal HSV-2.
  • the highest overall prevalence may be in the Americas where a growing number of HSV-1 and HSV-2 seronegative women reach reproductive age thus rendering them at greater risk of acquiring primary genital infection with either serotype.
  • Suppressive acyclovir treatment for women with a history of frequent recurrences and/or Caesarean section if active lesions are detected at time of labor may reduce the risk of HSV but most perinatal transmission occurs in the setting of primary maternal HSV and in the absence of clinical lesions.
  • optimal prevention will require a vaccine that is effective against clinical isolates of both HSV-1 and HSV-2 and that generates IgG responses that efficiently cross the placenta.
  • the half-life of human IgG is much longer and infants, as fetuses, receive most of their maternal IgG transplacentally because of the relatively high levels of expression of the neonatal FcR in the syncytiotrophoblasts. Accordingly, the fetal protection (transplacental) in mouse under-represents the protection that is obtainable by the technique in fetal and neonatal humans.
  • Awasthi, S., et al., Immunization with a vaccine combining herpes simplex virus 2 (HSV-2) glycoprotein C (gC) and gD subunits improves the protection of dorsal root ganglia in mice and reduces the frequency of recurrent vaginal shedding of HSV-2 DNA in guinea pigs compared to immunization with gD alone. J Virol, 2011. 85(20): p. 10472-86. Manservigi, R., et al., Immunotherapeutic activity of a recombinant combined gB- gD-gE vaccine against recurrent HSV-2 infections in a guinea pig model. Vaccine, 2005. 23(7): p. 865-72.
  • Herpes simplex virus type 2 tegument proteins contain subdominant T-cell epitopes detectable in BALB/c mice after DNA immunization and infection. J Gen Virol, 2009. 90(Pt 5): p. 1153-63.
  • HSV-2 Herpes simplex virus 2
  • HSV Herpes simplex virus
  • Bxbl integrase as the best of fifteen candidate serine recombinases for the integration of DNA into the human genome.
  • Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease. Elife 4.

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Abstract

L'invention concerne des méthodes de transfert passif d'immunité au moyen de vecteurs de vaccin du virus de l'herpès simplex 2 (HSV -2) recombinant, des virions de ceux-ci, des compositions et des vaccins les comprenant.
PCT/US2020/012170 2014-03-03 2020-01-03 Transfert passif d'immunité au moyen de vecteurs de vaccin du virus de l'herpès simplex 2 (hsv -2) recombinant Ceased WO2020142677A1 (fr)

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CN202080018414.0A CN113727728A (zh) 2019-01-03 2020-01-03 使用重组单纯疱疹病毒2(hsv-2)疫苗载体的免疫的被动转移
CA3124523A CA3124523A1 (fr) 2019-01-03 2020-01-03 Transfert passif d'immunite au moyen de vecteurs de vaccin du virus de l'herpes simplex 2 (hsv -2) recombinant
AU2020204688A AU2020204688A1 (en) 2019-01-03 2020-01-03 Passive transfer of immunity using recombinant herpes simplex virus 2 (HSV-2) vaccine vectors
KR1020247023560A KR20240116556A (ko) 2019-01-03 2020-01-03 재조합 단순 헤르페스 바이러스 2 (hsv-2) 백신 벡터를 사용한 면역의 수동 전달
JP2021539019A JP2022517322A (ja) 2019-01-03 2020-01-03 組み換え単純ヘルペスウイルス２（ｈｓｖ－２）ワクチンベクターを使用する免疫の受動伝達
EP20702946.3A EP3906052A1 (fr) 2019-01-03 2020-01-03 Transfert passif d'immunité au moyen de vecteurs de vaccin du virus de l'herpès simplex 2 (hsv -2) recombinant
KR1020217024471A KR102686042B1 (ko) 2019-01-03 2020-01-03 재조합 단순 헤르페스 바이러스 2 (hsv-2) 백신 벡터를 사용한 면역의 수동 전달
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WO2023245159A1 (fr) * 2022-06-16 2023-12-21 Albert Einstein College Of Medicine Vecteurs du virus de l'herpès simplex 2 (hsv-2) recombinants et lignées de cellules vero transgéniques modifiées

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