Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis.

Maria Luisa Visciano,Betsy C Herold,Carl Pierce,Richard Hunte,Aakash Mahant Mahant

doi:10.3390/v13071284

Abstract

Herpes simplex virus (HSV) prevention is a global health priority but, despite decades of research, there is no effective vaccine. Prior efforts focused on generating glycoprotein D (gD) neutralizing antibodies, but clinical trial outcomes were disappointing. The deletion of gD yields a single-cycle candidate vaccine (∆gD-2) that elicits high titer polyantigenic non-gD antibodies that exhibit little complement-independent neutralization but mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Active or passive immunization with ΔgD-2 completely protects mice from lethal disease and latency following challenge with clinical isolates of either serotype. The current studies evaluated the role of complement in vaccine-elicited protection. The immune serum from the ΔgD-2 vaccinated mice exhibited significantly greater C1q binding compared to the serum from the gD protein vaccinated mice with infected cell lysates from either serotype as capture antigens. The C1q-binding antibodies recognized glycoprotein B. This resulted in significantly greater antibody-mediated complement-dependent cytolysis and neutralization. Notably, complete protection was preserved when the ΔgD-2 immune serum was passively transferred into C1q knockout mice, suggesting that ADCC and ADCP are sufficient in mice. We speculate that the polyfunctional responses elicited by ΔgD-2 may prove more effective in preventing HSV, compared to the more restrictive responses elicited by adjuvanted gD protein vaccines.

Highlights

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are large DNA viruses that establish lifelong infection with periods of latency interspersed with episodes of asymptomatic or clinical reactivation
C1q binds to antibodies that are bound to viral particles or virally infected cells to promote activation of the complement cascade leading to complement-dependent cytolysis (CDC), opsonization and phagocytosis and/or complement-dependent neutralization
To determine if antibodies elicited in response to ∆glycoprotein D (gD)-2 or recombinant gD-2 (rgD-2)/Alum-MPL vaccination in mice exhibiting complement binding activity, a C1q sandwich binding ELISA was performed with immune serum (n = 10 mice per group)

Summary

Introduction

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are large DNA viruses that establish lifelong infection with periods of latency interspersed with episodes of asymptomatic or clinical reactivation. HSV-1 primarily causes oral mucocutaneous lesions, ocular disease and sporadic encephalitis, whereas both cause genital and neonatal infections. While HSV-2 dominates globally, HSV-1 is emerging as the more common cause of genital and neonatal disease in developed countries [1,2]. Immunocompromised hosts are at risk of more severe and prolonged symptoms with each of these syndromes and are at greater risk of viral dissemination. HSV-2, in particular, is a major cofactor fueling the HIV epidemic and is associated with an increased risk of HIV transmission and acquisition [3,4]. There are an estimated 3.7 billion people under the age of 50 years infected with HSV-1 and 491 million people between the ages of 15–49 years seropositive for HSV-2 [1,2], but despite the enormous health burden and the years of research in the field, there is no licensed HSV vaccine [5]

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