title: Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.
abstract: Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonistsin vivoIn mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses.IMPORTANCEMillions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptomatic infection have exhibited T cell responses against specific HSV-2 antigens not observed in symptomatic individuals. We describe for the first time the immunogenicity profile in animal models of UL40, a novel HSV-2 T cell antigen that has been correlated with asymptomatic HSV-2 disease. Additionally, vaccine candidates adjuvanted by a robust formulation of the CpG oligonucleotide delivered in emulsion were superior to unadjuvanted or MPL-alum-adjuvanted formulations at eliciting a robust cell-mediated immune response and blocking the establishment of a latent viral reservoir in the guinea pig challenge model of HSV-2 infection.
authors.affiliation: Vaccine Platform Group, MedImmune, Gaithersburg, Maryland, USA henselm@medimmune.com dereksloan@yahoo.com.
authors.forename: Michael T
authors.identifier: http://orcid.org/0000-0003-3324-8566
authors.initials: MT
authors.lastname: Hensel
authors.affiliation: Vaccine Platform Group, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
authors.affiliation: Vaccine Protein Biochemistry Group, Medimmune, Mountain View, California, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Dorwart
authors.affiliation: Applied Immunology and Microbiology Group, MedImmune, Mountain View, California, USA.
authors.forename: Darren S
authors.initials: DS
authors.lastname: Heeke
authors.affiliation: Applied Immunology and Microbiology Group, MedImmune, Mountain View, California, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Rao
authors.affiliation: Translational Biology Group, MedImmune, Mountain View, California, USA.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Tummala
authors.affiliation: Statistical Sciences, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Cohen
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Roselyn J
authors.initials: RJ
authors.lastname: Eisenberg
authors.affiliation: Translational Biology Group, MedImmune, Mountain View, California, USA henselm@medimmune.com dereksloan@yahoo.com.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood* / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006168:Guinea Pigs; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000502:physiology; D007111:Immunity, Cellular / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology; D017735:Virus Latency / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D006023:Glycoproteins; D022301:Herpes Simplex Virus Vaccines; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D022223:Vaccines, Subunit; D014759:Viral Envelope Proteins
keywords: T cells; adjuvants; herpes simplex virus; immunization; latent infection; neutralizing antibodies