Research ArticleVACCINES

Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes

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Science Immunology  20 Sep 2019:
Vol. 4, Issue 39, eaaw7083
DOI: 10.1126/sciimmunol.aaw7083

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Hinting at a herpes vaccine

Currently, a vaccine for genital herpes does not exist despite the prevalence of this sexually transmitted disease. Previous attempts to make vaccines against herpes simplex virus 2 (HSV-2) included trials with protein subunit vaccine candidates that delayed vaccine onset but were not protective. Awasthi et al. describe a vaccine candidate that is composed of nucleoside-modified mRNA in lipid nanoparticles that encodes the HSV-2 glycoproteins C, D, and E. This trivalent vaccine protected mice and guinea pigs from developing genital lesions and reduced viral shedding. Neutralizing antibody and CD4+ T cell responses were detected in immunized mice. These results suggest that an mRNA-based HSV-2 vaccine may have potential for further preclinical development.

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), which binds complement C3b, and glycoprotein E (gE2), which blocks immunoglobulin G (IgG) Fc activities. The trivalent vaccine was administered as baculovirus proteins with CpG and alum, or the identical amino acids were expressed using nucleoside-modified mRNA in lipid nanoparticles (LNPs). 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 of 30 (73%) mice compared with 63 of 64 (98%) in the mRNA group (P = 0.0012). In guinea pigs, 5 of 10 (50%) animals in the trivalent subunit protein group had vaginal shedding of HSV-2 DNA on 19 of 210 (9%) days compared with 2 of 10 (20%) animals in the mRNA group that shed HSV-2 DNA on 5 of 210 (2%) days (P = 0.0052). The trivalent mRNA vaccine was superior to trivalent proteins in stimulating ELISA IgG antibodies, 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.

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