Glycoprotein G enables HSV-2 neuroinvasion and provides protection as a glycosylated vaccine antigen

Könighofer, E.; Gustafsson, C.; Gudmundsdotter, L.; Migorodskaya, E.; Nilsson, J.; Ekblad, M.; Adamiak, B.; Jennische, E.; Lange, S.; Trybala, E.; Görander, S.; Bergström, T.; Liljeqvist, J.-A.; Norden, R.

doi:10.64898/2026.02.25.706656

bioRxiv · 10.64898/2026.02.25.706656

Glycoprotein G enables HSV-2 neuroinvasion and provides protection as a glycosylated vaccine antigen

Könighofer, E.·Gustafsson, C.·Gudmundsdotter, L.·Migorodskaya, E.·Nilsson, J.·Ekblad, M.·Adamiak, B.·Jennische, E.·Lange, S.·Trybala, E.·Görander, S.·Bergström, T.·Liljeqvist, J.-A.·Norden, R.

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Abstract

The function of glycoprotein G (gG-2) of herpes simplex virus 2 (HSV-2) during genital infection is unknown. gG-2 is cleaved into a secreted variant (sgG-2) and a membrane associated variant (mgG-2). This work delineates the glycan profile of mgG-2, and demonstrates that mgG-2 is strongly immunogenic, eliciting glycan dependent humoral and Th1-polarized CD4+ T cell responses in a mouse vaccination model. The N- and O-glycosylation of mgG-2 is important to achieve full protection against HSV-2 infection as immunization with deglycosylated mgG-2 resulted in poor CD4+ T cell activation and viral spread to dorsal root ganglia and spinal cord. Furthermore, an mgG-2 negative HSV-2 mutant virus failed to spread to the dorsal root ganglia and the central nervous system of genitally infected mice, despite viral replication in vaginal cells. Our data demonstrate that mgG-2 is important for HSV-2 propagation and that adaptive immune responses targeting the glycosylated protein can prevent neuronal infection, identifying mgG-2 as a promising vaccine candidate.

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Könighofer, E., Gustafsson, C., Gudmundsdotter, L., Migorodskaya, E., Nilsson, J., Ekblad, M., Adamiak, B., Jennische, E., Lange, S., Trybala, E., Görander, S., Bergström, T., Liljeqvist, J.-A., Norden, R.. 2026-02-25. Glycoprotein G enables HSV-2 neuroinvasion and provides protection as a glycosylated vaccine antigen. https://doi.org/10.64898/2026.02.25.706656

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