A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
Masayuki Kuraoka, Clare Burn Aschner, Ian W. Windsor, Aakash Mahant Mahant, Scott J. Garforth, Susan Luozheng Kong, Jacqueline M. Achkar, Steven C. Almo, Garnett Kelsoe, Betsy C. Herold
Masayuki Kuraoka, Clare Burn Aschner, Ian W. Windsor, Aakash Mahant Mahant, Scott J. Garforth, Susan Luozheng Kong, Jacqueline M. Achkar, Steven C. Almo, Garnett Kelsoe, Betsy C. Herold
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Research Article Infectious disease

A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice

Abstract

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2–vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo–electron microscopic structure of the Fab–glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.

Authors

Masayuki Kuraoka, Clare Burn Aschner, Ian W. Windsor, Aakash Mahant Mahant, Scott J. Garforth, Susan Luozheng Kong, Jacqueline M. Achkar, Steven C. Almo, Garnett Kelsoe, Betsy C. Herold

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Figure 7

Mapping of binding sites for BMPC-23 and HSV010-13.

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Mapping of binding sites for BMPC-23 and HSV010-13. (A) Structures of HS...
(A) Structures of HSV-1 gB in the prefusion (6Z9M) and postfusion (2GUM) states were aligned on domain VI to illustrate the orientation of domain IV relative to the viral and host cell membranes. (B) Models built with cryo-EM densities for BMPC-23 and HSV010-13 were aligned, and a single Fab from each structure is shown. Densities were only of sufficient quality to build models of the Fv domains (Supplemental Figure 3). (C) Domain IV and Fv domains of BMPC-23 as well as a neutralizing mAb, 93k (6vni), which recognizes domain IV of the alphaherpesvirus varicella zoster virus, were extracted and aligned to domain IV of HSV-1 gB in the prefusion state. The side view is the same as in A, while the top view is rotated 90° with the top moving toward the reader. The prefusion gB is shown as a transparent surface, and the Fv-bound domain IV is shown as a cartoon. BMPC-23 and HSV010-13 are occluded from binding domain IV in the prefusion state, while the 93k epitope is accessible.