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 4

BMPC-23 protects against vaginal HSV-2 infection.

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BMPC-23 protects against vaginal HSV-2 infection. Medroxyprogesterone-pr...
Medroxyprogesterone-pretreated female mice (n = 5 per group) were treated i.p. with 250 or 500 μg of BMPC-23, 250 μg of 5E7, or 500 μg of immune serum obtained from control VD60 lysate–vaccinated mice 24 hours before vaginal inoculation with HSV-2(4674). Mice were scored daily for signs of disease using the following scale: 1, erythema at inoculation site; 2, hair loss, erythema, edema, urinary retention; 3, severe edema, hair loss, lesion formation, constipation and urinary retention, hind-limb paresis; 4, severe ulceration, hind-limb paralysis; and 5, death. (A) Bar graphs show disease scores for mice at each day. (B) Survival is compared with that of the VD60 control–treated mice by Gehan-Breslow-Wilcoxon test, ***P < 0.001.