WO2015134368A2 - Recombinant herpes simplex virus 2 (hsv-2) vaccine vectors - Google Patents

Recombinant herpes simplex virus 2 (hsv-2) vaccine vectors Download PDF

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Publication number
WO2015134368A2
WO2015134368A2 PCT/US2015/018272 US2015018272W WO2015134368A2 WO 2015134368 A2 WO2015134368 A2 WO 2015134368A2 US 2015018272 W US2015018272 W US 2015018272W WO 2015134368 A2 WO2015134368 A2 WO 2015134368A2
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Prior art keywords
hsv
glycoprotein
recombinant
infection
subject
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English (en)
French (fr)
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WO2015134368A3 (en
Inventor
William Jacobs
Pablo A. GONZALEZ MUNOZ
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 to EP15758673.6A priority Critical patent/EP3113801B1/en
Priority to CA2942166A priority patent/CA2942166A1/en
Priority to AU2015225499A priority patent/AU2015225499B2/en
Priority to CN201911344961.3A priority patent/CN110938604B/zh
Priority to CN201580022222.6A priority patent/CN106456805B/zh
Priority to EP20195405.4A priority patent/EP3943106A1/en
Priority to JP2016555659A priority patent/JP6652497B2/ja
Application filed by Albert Einstein College of Medicine filed Critical Albert Einstein College of Medicine
Publication of WO2015134368A2 publication Critical patent/WO2015134368A2/en
Publication of WO2015134368A3 publication Critical patent/WO2015134368A3/en
Priority to US15/015,322 priority patent/US9999665B2/en
Anticipated expiration legal-status Critical
Priority to US15/455,495 priority patent/US10076568B2/en
Priority to US15/995,471 priority patent/US10391165B2/en
Priority to US16/238,933 priority patent/US10918712B2/en
Priority to US16/526,056 priority patent/US10751411B2/en
Priority to US17/420,529 priority patent/US20220088185A1/en
Priority to AU2020217310A priority patent/AU2020217310B2/en
Priority to US16/995,926 priority patent/US10980874B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
    • C07K16/087—Herpes simplex virus
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    • A61K2039/525—Virus
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
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    • C12N2710/16011—Herpesviridae
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    • 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
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    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16641—Use of virus, viral particle or viral elements as a vector
    • C12N2710/16643—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
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    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
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    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16671—Demonstrated in vivo effect

Definitions

  • Herpes simplex virus 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.
  • HSV-2 herpes simplex virus-2
  • L3 ⁇ 4 an HSV-2 glycoprotein D-encoding gene
  • 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 virus 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 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 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.
  • 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
  • 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-1, HSV-2 or co-infection in a subject is also provided.
  • HSV-2 herpes simplex virus-2
  • a vaccine composition comprising a virus 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 virus 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 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 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 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.
  • a method of vaccinating a subject for HSV-2 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 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 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 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
  • 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 is also provided.
  • 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 Severe combined immunodeficiency mice inoculated with up to 10 7 plaque-forming units (pfu) of HSV-2 AgD-/+ virus do not manifest signs of disease after high dose intravaginal or subcutaneous inoculation. In contrast SCID mice inoculated with wild-type virus at a 1,000-fold lower viral dose (10 4 pfu) succumb to disease. 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 LD 90 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 (A) and death (B), AgD-/+-immunized mice displayed significantly less pathology.
  • A weight loss
  • B death
  • 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 virus could be recovered from AgD-/+- immunized mice in Day 4 vaginal washes or Day 5 vaginal tissue and DRG. (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001).
  • 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- ⁇ 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 ⁇ 0.01; ***p ⁇ 0.001).
  • 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 herpes simplex virus-2
  • the HSV-2 glycoprotein D comprises the amino acid sequence set forth in SEQ ID NO: 1 :
  • 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: PMC 109494) "The Genome Sequence of Herpes Simplex Virus Type 2" for HSV-2 genome and Use gene, hereby incorporated by reference in its entirety).
  • 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 Use gene.
  • the virus 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 Use gene.
  • an isolated cell comprising therein a recombinant HSV-2 genome which does not comprise an HSV-2 Use gene.
  • 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 or HSV-2 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 or HSV-2 glycoprotein D gene, or is a nucleic acid having a sequence identical to a HSV-1 or HSV-2 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 virus 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 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 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 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.
  • 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.
  • 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 11 ⁇ 2 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 virus, Pig corona respiratory virus, a rabies virus, a Lassa virus, a bunyavirus, a CMV, or a filovirus.
  • the glycoprotein is an HIV gpl20.
  • the filovirus is an ebola virus.
  • the virus 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 virus, a rabies virus, a Lassa virus, a bunyavirus, a CMV, or a filovirus.
  • the glycoprotein is an HIV gpl20.
  • the filovirus is an ebola virus.
  • the virus 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 virus 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 virus as described herein, or a virion as described herein.
  • the vaccine composition comprises an immunological adjuvant.
  • composition comprising a virus as described herein, or a virion as described herein, wherein the genome of the virus 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 serum 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.
  • Also provided is a method of eliciting an immune response 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 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 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.
  • Also provided is a method of vaccinating a subject for HSV-2 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 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 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 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 virus, 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 herpes simplex virus-2
  • 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 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.
  • the subject is a mammalian subject.
  • the mammalian subject is a human subject.
  • 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+ gD ⁇ /+ 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
  • the transgene is a M. tuberculosis biofilm-encoding gene. In an embodiment, the transgene is an HIV gpl20-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 virus and is a Lassa virus, a human immunodeficiency virus, an RSV, an enterovirus, an influenza virus, a parainfluenza virus, pig corona respiratory virus, a lyssavirus, a bunyavirus, or a filovirus.
  • 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 gpl20-encoding gene.
  • the subject is a human.
  • the subject has not yet been infected with HSV- 1 , HSV-2 or co-infection.
  • 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 /+ 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-1 promoter). Indeed, HSV-2 AgD particles isolated from non-complementing cells do not infect epithelial (Fig. 1) or neuronal cells (SK-N-SH, not shown).
  • Fig. 1 Fig. 1
  • SK-N-SH neuronal cells
  • a phenotypically complemented virus (AgD-/+) is obtained, which is fully capable of infecting cells that are common targets for wild-type HSV-2.
  • AgD-/+ no infectious particles or viral plaques (pfu) are produced from these cells and the virus fails to spread from infected to uninfected cells, reflecting the requirement for gD in these processes; thus it is an abortive infection.
  • 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 subcutaneous ly 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 virus (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 serum 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- ⁇ production by these cells.
  • Immunization with AgD-/+ increased the IFN- ⁇ 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 LD 90 (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 LD 90 (5xl0 5 pfu/mouse, data not shown). This protection was associated with significantly reduced epithelial disease scores (Fig.
  • HSV-2-AgD "/+sD 1 was found to confer protection in C57BL/6 and Balb/C to vaginal challenge with virulent HSV-2.
  • intravaginal HSV-2 challenged AgD "/+sD 1 immunized mice had no detectable HSV-2 in vaginal or neural tissue at 5 days post-challenge.
  • HSV-2 AgD-/+gD-l sc. sc. antibodies were found to recognize numerous HSV-2 proteins (both gD and gB) unlike HSV-2 morbid-bound mice. Serum antibodies from vaccinated animals showed neutralization of HSV-1 and HSV-2 in vitro.
  • eerum from AgD-/+gD-l 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 virus type 2
  • Infection risk increases with age and because the virus 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 perinataly 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 heterogenity 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 virus 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 virus. Immunization (subcutaneous prime followed by a single boost administered either subcutaneous ly or intravaginally) was 100% protective against intravaginal challenge with virulent HSV-2.
  • HSV-2 AgD /+ Robust humoral and cellular immunity was elicited by HSV-2 AgD /+ and it was concluded that Us6 (gD-2) is required for productive infection in vivo.
  • Us6 gD-2
  • This live attenuated viral strain will provide sterilizing immunity against HSV. Also passive serum or serum product transfer can be employed.
  • 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
  • Yamaguchi, S., et al A method for producing transgenic cells using a multi- integrase system on a human artificial chromosome vector. PLoS One, 2011. 6(2): p. el7267.
  • Bxbl integrase as the best of fifteen candidate serine recombinases for the integration of DNA into the human genome.

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