The Key Role of FcR Activating Antibodies in Generating “Sterilizing” Immunity Against Herpes Simplex Virus

This webinar highlights recent studies demonstrating the central role of FcR functions in vaccine-mediated protection against HSV-1 and HSV-2 infection, challenging the existing paradigm that high titer neutralizing antibodies are required.

Summary

HSV-1 and HSV-2 are significant global health problems, disproportionately impacting developing countries and fueling the HIV epidemic. HSV-2 vaccine efforts have been dominated by the presumption that neutralizing antibodies (Abs) to the envelope glycoprotein D (gD) alone or in combination with other glycoproteins would be protective. The rationale for this approach emanated from observations that gD-2 neutralizing Abs are elicited in response to natural infection and provide variable protection in animal models. However, the clinical trial outcomes have been uniformly disappointing. These findings highlight the need for novel vaccine strategies that elicit different types of immune responses that are more protective and more predictive preclinical models of vaccine efficacy and correlates of immune protection.

In collaboration with William R. Jacobs, we developed a candidate vaccine that presents a completely different paradigm. Rather than focusing on gD as the primary immunogen, we generated a live-attenuated vaccine strain by deleting the gD-2 gene, which is essential for HSV entry and cell-to-cell spread. We found that this vaccine candidate (HSV-2ΔgD) induces robust cellular and humoral immunity following prime-boost vaccination providing complete protection from subsequent intravaginal or skin challenge with diverse clinical isolates of HSV-1 and HSV-2. Furthermore, vaccine-induced immunity prevents the establishment of latency. Notably the HSV-2ΔgD-induced antibodies passively protect mice even if administered several days post-challenge. The vaccine elicits high titer FcR activating Abs that have little or no neutralizing activity in vitro, but elicit antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent phagocytosis. Together these findings highlight the central role of FcR functions in mediating protection, challenging the existing paradigm that high titer neutralizing anti-gD Abs are required.


Speaker

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Professor Betsy Herold, MD
Professor, Department of Pediatrics (Infectious Diseases) and Microbiology Immunology
Albert Einstein College of Medicine, NY

Betsy C. Herold, M.D. is Professor of Pediatrics and Microbiology-Immunology, Vice Chair for Research in the Department of Pediatrics, and Division Chief, Pediatric Infectious Diseases at Albert Einstein College of Medicine and the Children’s Hospital at Montefiore in the Bronx, NY. Dr. Herold is also the Director of the Translational Prevention Research Center at Einstein. She graduated from the University of Pennsylvania Medical School, completed a residency in pediatrics, clinical fellowship in pediatric infectious diseases, and postdoctoral fellowship in herpes virology at Northwestern University. She leads a translational research program focused on understanding HSV entry and pathogenesis to develop safe and effective antiviral therapies. Her lab has found a key role for calcium signaling in facilitating HSV infection, shed light on molecular mechanisms linking HSV and HIV, and promoted the development of intravaginal rings to deliver drugs to protect women from HSV and HIV.

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