Author ORCID Identifier

https://orcid.org/0000-0001-8288-787X

Date of Award

Spring 3-14-2025

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Margaret E. Ackerman

Second Advisor

David A. Leib

Abstract

No efficacious vaccine exists for herpes simplex virus and the global burden of disease remains high. Antibodies can serve as potent therapeutics to protect high risk populations such as neonates. Although rare, neonatal HSV (nHSV) infections can result in significant mortality and lifelong neurological morbidity even with antiviral therapy. While HSV-specific maternally derived antibodies significantly reduce the risk of neonatal disease in humans, the mechanisms by which they mediate protection have yet to be described. Using a mouse model of neonatal HSV (nHSV) infections we aimed to determine the mechanisms of antibody-mediated protection using monoclonal antibodies (mAbs) targeting two of the major surface glycoproteins involved in viral entry, glycoproteins D and B (gD, gB).

Direct administration of HSV-specific mAbs to neonatal mice protected them from HSV-1 and HSV-2-mediated mortality. mAbs against gD required both viral neutralization and Fc effector functions for broad and potent protection against HSV-1. For protection against HSV-2, however, Fc function alone, and not neutralization was required for these gD-specific mAbs. In contrast to gD-specific mAbs, mAbs targeting gB required effector functions for protection against HSV-1 in neonatal mice. Viral neutralization, while contributing to protection, was not the dominant mechanism of protection in this model. mAb Fc- and IgG subclass engineering also demonstrated that rendering IgG Fc insensitive to viral immune evasion by HSV gE/gI improved mAb efficacy in vitro and in vivo. This engineering strategy improved mAbs targeting both gD and gB, demonstrating the broad applicability to improve mAb therapeutics against HSV infections. In sum, these studies suggest the particular importance of effector functions in mediating protection against HSV infection in neonatal mice and that Ab-engineering represents a promising path forward to improve mAb-mediated protection.

Original Citation

Slein MD, Ackerman ME, Leib DA. Maternal antibodies to neurovirulent pathogens in fetal tissues. Annual Reviews of Virology. Volume 12. In Press

Slein MD, Backes IM, Garland CR, Kelkar NS, Leib DA, Ackerman ME. Effector functions are required for broad and potent protection of neonatal mice with antibodies targeting HSV glycoprotein D. Cell Reports Medicine. February 20, 2024. https://doi.org/10.1016/j.xcrm.2024.101417

Slein MD, Backes IM, Kelkar NS, Garland CR, Khanwalkar US, Sholukh AM, Johnston CM, Leib DA, Ackerman ME. Improving antibody-mediated protection against HSV infections by eliminating interactions with the viral Fc receptor gE/gI. bioRxiv 2024.11.20.624598; doi: https://doi.org/10.1101/2024.11.20.624598

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