Nucleoside-modified mRNA Encoding HSV-2 Glycoproteins C, D, E Prevents Clinical and Subclinical Genital Herpes

Abstract

The goals of a genital herpes vaccine are to prevent painful genital lesions and reduce or eliminate subclinical infection that risks transmission to partners and newborns. We evaluated a trivalent glycoprotein vaccine containing herpes simplex virus type 2 (HSV-2) entry molecule glycoprotein D (gD2) and two immune evasion molecules, glycoprotein C (gC2) that binds complement C3b, and glycoprotein E (gE2) that blocks IgG Fc activities. The trivalent vaccine was administered either as baculovirus proteins with CpG and alum, or the identical amino acids were expressed using nucleoside-modified mRNA in lipid nanoparticles. Both formulations completely prevented genital lesions in mice and guinea pigs. Differences emerged when evaluating subclinical infection. The trivalent protein vaccine prevented dorsal root ganglia infection and day 2 and 4 vaginal cultures were negative in 23/30 (73%) mice compared with 63/64 (98%) in the mRNA group (P=0.0012). In guinea pigs, 5/10 (50%) animals in the trivalent subunit protein group had vaginal shedding of HSV-2 DNA on 19/210 (9%) days compared with 2/10 (20%) animals in the mRNA group that shed HSV-2 DNA on 5/210 (2%) days (P=0.0052). Immunology assays were performed in mice. The trivalent mRNA vaccine was superior to trivalent proteins in stimulating serum and vaginal ELISA IgG antibodies, serum neutralizing antibodies, antibodies that bind to crucial gD2 epitopes involved in entry and cell-to-cell spread, CD4 ⁺ T cell responses, and T follicular helper and germinal center B cell responses. The trivalent nucleoside-modified mRNA-LNP vaccine is a promising candidate for human trials.

One Sentence Summary:

Improved efficacy using mRNA for a herpes vaccine