Harnessing in-tissue antibodies for therapeutic HSV control

About This Grant

PROJECT SUMMARY/ABSTRACT Herpes simplex virus types 1 and 2 (HSV-1/2) are major human viral pathogens that cause one of the most common, debilitating, stigmatized and lifelong infections of humankind with more than 143 million new infections every year and affecting more than 4 billion people around the world and more than 100 million Americans. While current antiviral therapies significantly reduce lesion burden they fail to eliminate subclinical shedding, mitigate chronic mucosal inflammation, or prevent neonatal herpes. Antiviral-resistant HSV strains create a significant burden for immunocompromised. Therefore, there is a medical need to develop better therapies for HSV-2. This study is based on our recent discovery of tissue-based antibody-secreting cells (ASCs) that can be found in genital skin up to 4 months after HSV lesion healing. These ASCs secrete antibodies that are highly potent against HSV and therefore can represent a critical component of tissue-restricted immune mechanism of HSV control. The potency and epitope diversity of the monoclonal antibodies we have identified is greater than those previously tested in humans. This provides both spatial and functional data that warrant assessment of these tissue-derived antibodies as potential novel in vivo therapeutics for HSV-2 prevention and functional cure. Recent advances in creating antibodies with extended half-life that can be given every 4 to 6 months and enhanced effector functions render clinical use of such antibodies feasible and add to the medical importance of long-acting functionally active human monoclonal antibodies. This proposal is dedicated to the comprehensive preclinical evaluation of human monoclonal antibodies isolated from skin-based ASCs to establish the link between their in vitro activity and in vivo efficacy in mouse and guinea pig models of HSV-2 infection and reactivation. Using advances in antibody engineering, we aim to develop long-acting immunotherapeutics capable of reducing viral shedding, preventing primary infection, and suppressing recurrent reactivation. These findings will not only inform HSV-2 immunotherapy but also provide critical insights for herpes vaccine development.