A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
Masayuki Kuraoka, … , Garnett Kelsoe, Betsy C. Herold
Masayuki Kuraoka, … , Garnett Kelsoe, Betsy C. Herold
Published December 1, 2022
Citation Information: J Clin Invest. 2023;133(3):e161968. https://doi.org/10.1172/JCI161968.
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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 1

Isolation and characterization of B cells specific for HSV-2.

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Isolation and characterization of B cells specific for HSV-2. HSV-specif...
HSV-specific BCRs were isolated from GC B cells in inguinal lymph nodes, memory B cells in spleens, and plasmacytes in BM of mice after ΔgD-2 vaccinations. Single GC and memory B cells were introduced into Nojima cultures, while single plasmacytes were subjected to a single-cell RT-PCR method. (A) Representative flow diagrams for GC B cells (left), memory B cells (middle), and plasmacytes (right). GC and memory B cells were pre-gated on B220+CD138– cells and B220+ cells, respectively. (B) The reactivity of culture supernatant IgGs against HSV-2(G) infected (HSV+) and uninfected (HSV–) Vero cell lysates was assessed by ELISA. Representative ELISA screening for single GC B cell cultures is shown. Each dot represents a single B cell (n = 672). Gray dots on the HSV+ column represent samples that also bound HSV– lysates. The dotted line indicates a reactivity threshold determined as mean + 6SD of B cell–negative, mock-cultured culture supernatants. (C) Distributions of VH gene segment use by HSV-specific GC B cells (top, n = 61) and memory B cells (bottom, n = 15). (D) Distributions of VH mutation frequency for HSV-specific GC B cells (n = 61) and memory B cells (n = 15). Each dot represents an individual B cell. Horizontal bars indicate mean. **P < 0.01 by Mann-Whitney U test.