Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus.

Clare Burn Aschner,Betsy C Herold,Carl Pierce,David M Knipe

doi:10.3390/vaccines8020277

Abstract

Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, dl5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and dl5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or dl5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 104 pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination.

Highlights

Herpes simplex virus 1 and 2 (HSV-1 and Herpes simplex viruses (HSV)-2) are prevalent human pathogens
These results demonstrate that antibody-dependent cellular cytotoxicity (ADCC) provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination
The enormous global health burden of these two related viruses has resulted in extensive vaccine development efforts, which have primarily focused on the generation of neutralizing antibodies targeting the viral envelope glycoprotein D as the correlate of immune protection

Summary

Introduction

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are prevalent human pathogens. HSV-1 infects approximately 67% of the population by 49 years of age and is the primary cause of oral and ocular disease, a leading cause of infectious corneal blindness and fatal infectious encephalitis and has emerged as the Vaccines 2020, 8, 277; doi:10.3390/vaccines8020277 www.mdpi.com/journal/vaccinesVaccines 2020, 8, 277 more common cause of genital disease in the developed world [1,2,3,4]. The enormous global health burden of these two related viruses has resulted in extensive vaccine development efforts, which have primarily focused on the generation of neutralizing antibodies (nAbs) targeting the viral envelope glycoprotein D (gD) as the correlate of immune protection. One such vaccine was a recombinant gD-2 protein vaccine formulated with a proprietary aluminum hydroxide (alum) and monophosphoryl lipid A adjuvant, gD2−AS04 (GlaxoSmithKline, Brentford, UK). The vaccine was administered intramuscularly at 0, 1 and 6 months Another vaccine that has recently completed Phase I clinical trials is a replication-defective HSV-2 strain deleted in two genes involved in viral replication (UL5 and UL29), designated dl (HSV529, Sanofi Pasteur, Lyon, France) [7]. Only a subset of participants elicited significant CD4 and even fewer CD8 T cell responses [7]

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Discussion

Conclusion