Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and 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), 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.

An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection

“…An HSV-2 mRNA vaccine protects against HSV-1 genital infection and day four cultures [26]. In Fig 1, we reported that some mice immunized with the mRNA vaccine had positive day two cultures (16/29 mice) and day four cultures (4/29 mice) when infected with HSV-1 at 2×10 6 PFU.…”

“…Our vaccine for preventing HSV-2 genital infection consists of three HSV-2 glycoproteins, gC2, gD2, and gE2 that are expressed on the virion envelope and at the surface of infected cells and thus potentially accessible to antibodies that block their functions. Antibodies to gD2 block virus entry, antibodies to gC2 neutralize virus and block C3b binding, while antibodies to gE2 block cell-to-cell spread and immune evasion [25][26][27].…”

“…One platform expresses the antigens in baculovirus and administers purified proteins with CpG oligonucleotides and aluminum hydroxide (alum) as adjuvants [25]. The other platform expresses the same immunogens as nucleoside-modified mRNA in lipid nanoparticles (LNP) [26]. The mRNA molecule is modified to improve stability and prevent innate immune sensors from inhibiting translation [28].…”

“…Nucleoside-modified mRNA-LNP stimulates potent T follicular helper cell and germinal B cell responses that result in high titer and durable antibody responses [29]. The HSV-2 trivalent nucleoside-modified mRNA-LNP (mRNA) vaccine outperformed the trivalent protein-CpG/alum (protein) vaccine in producing higher titers of neutralizing antibodies and antibodies that block gC2 and gE2 immune evasion activities, and in protecting mice and guinea pigs against intravaginal HSV-2 infection [26].…”

“…We previously reported that immunization with the HSV-2 trivalent protein vaccine protects against HSV-1 genital lesions and recurrent HSV-1 genital shedding after intravaginal infection of guinea pigs [31]. Since performing those guinea pigs studies, we determined that the HSV-2 mRNA vaccine version outperforms the protein vaccine in preventing HSV-2 genital infection [26]. The goals of the current study were: 1) to determine whether the HSV-2 mRNA vaccine outperforms the protein vaccine in protecting against HSV-1 genital infection; and 2) to evaluate whether the HSV-2 mRNA vaccine protects as well against HSV-1 as against HSV-2 genital infection.…”