Prefusion-specific glycoprotein B human antibodies protect against neonatal HSV-2 infection

ABSTRACT Herpes simplex virus (HSV) causes severe neonatal infections and long-term neurological issues, with antivirals offering limited efficacy and no approved vaccines. Viral entry requires glycoprotein B (gB) for membrane fusion, yet no human antibodies to the prefusion form of gB have been identified, and antibodies targeting vulnerable epitopes are limited. We used prefusion-stabilized HSV-2 gB and LIBRA-seq technology to analyze B cells from seropositive and healthy donors, discovering four prefusion-specific human antibodies binding unique gB epitopes as determined by cryo-EM. Antibodies 5-18 and 3-6 showed strong cross-neutralization against HSV-1 and HSV-2, offering protection in a neonatal mouse model. These findings highlight the molecular and structural determinants of HSV-2 prefusion gB recognition by human antibodies and demonstrate the translational potential of prefusion-specific gB antibodies. Competing Interest Statement P.A., J.K., N.N.M., D.A.L., M.E.A., J.S.M., and I.S.G. are listed as inventors on patents filed describing the antibodies discovered here. I.S.G. is listed as an inventor on patent applications for the LIBRA-seq technology. J.S.M. is listed as an inventor on a patent application describing prefusion-stabilized HSV-2 gB proteins. I.S.G. is a co-founder of AbSeek Bio. I.S.G. has served as a consultant for Sanofi. The Georgiev laboratory at VUMC has received unrelated funding from Merck and Takeda Pharmaceuticals. The Ackerman laboratory at Dartmouth has received unrelated funding from Be Bio and Moderna. Footnotes Formatting updates were included for this version; minor changes.