Bivalent HSV mRNA vaccine shows protection in mice and an immune contribution from IFN-I
HSV vaccine limitations and multi-antigen design
In a mouse study comparing herpes simplex virus (HSV) vaccine candidates, the gD2-gE1 combination showed promising results in some antibody and T-cell responses and in suppressing viral DNA in ganglia. The experiments also provided evidence that type I interferon (IFN-I) signaling contributes in part to this candidate’s enhanced immune responses. However, the findings should not be interpreted as demonstrating complete prevention of infection or preventive efficacy in humans.
HSV-1 and HSV-2 cause oral and genital infections, but according to the paper, no preventive or therapeutic vaccines have been approved. Viral immune evasion and the need to protect against both serotypes are major challenges in vaccine development.
The researchers designed three mRNA vaccines expressing either the single antigen gD2 or the bivalent antigen combinations gD2-gC1 and gD2-gE1. HSV-2-derived gD2 was paired with HSV-1-derived gC1 or gE1. This approach aims to target gD, which is involved in viral entry, together with gC or gE, which are involved in immune evasion. The mRNA was delivered in lipid nanoparticles (LNPs).
Comparison of immune responses and protection after challenge
BALB/c mice received two intramuscular injections, on days 0 and 14. The monovalent candidate contained 10 µg of gD2 mRNA, while each bivalent candidate contained 10 µg of mRNA per antigen, for a total of 20 µg. All three candidates elicited antibody and T-cell responses.
Binding antibody levels were similar across candidates. Six weeks after the first dose, the gD2-gE1 group had higher HSV-1 neutralizing antibody levels than the other candidate groups, but there was no significant difference among candidates in HSV-2 neutralizing antibodies at the same time point. Neutralizing antibodies against both serotypes remained detectable at week 14, and antigen-stimulated T-cell responses were strongest overall in the gD2-gE1 group.
In experiments conducted four weeks after the additional dose, 10 mice per group were challenged intravaginally with HSV-1 or HSV-2. All mice in the three vaccine groups survived the 14-day observation period. The HSV-1 control group had a 14-day survival rate of 40%, while all mice in the HSV-2 control group were reported to have died by day 13. Vaccinated groups had lower vaginal viral loads and no vaginal lesions. These survival results alone cannot establish that gD2-gE1 provided better protection than the other candidates.
Differences also appeared in ganglion analyses. At 28 days after challenge, HSV-2 DNA was not detected in the dorsal root ganglia of the gD2-gE1 group, whereas it was detected in two mice in each of the other two vaccine groups. This finding suggests the potential to suppress nervous system infection. Failure to detect DNA in that tissue at that time point should not be interpreted as complete elimination of latent infection.
The role of IFN-I and questions for further validation
Analysis of draining lymph nodes 24 hours after vaccination showed a stronger IFN-I response in the gD2-gE1 group than in the other candidate groups. Mice deficient in IFNAR1, a component of the IFN-I receptor, subsequently showed lower antibody responses and some lower CD4-positive T-cell responses than normal mice receiving the same vaccine. These results support a partial contribution of IFN-I signaling to enhanced adaptive immunity. However, they do not directly demonstrate, through challenge experiments in deficient mice, that protection against infection itself depends on IFN-I.
The bivalent candidates involved higher mRNA and LNP doses than the monovalent candidate, so differences between the formulations cannot be attributed solely to the antigen combinations. The specific mechanism by which the gE1 combination elicits stronger IFN-I responses remains unknown. Mice also do not reproduce natural HSV reactivation and recurrence, so validation in other animal models is needed. Human safety, preventive efficacy, and the timing of entry into clinical trials were outside the scope of this study’s findings.
Source: Original article in npj Vaccines, DOI: 10.1038/s41541-026-01450-8.
Herpes simplex virus (HSV) types 1 and 2 cause widespread oral or genital infections, but no prophylactic or therapeutic HSV vaccine has been approved to date. In this study, we developed three mRNA vaccine candidates expressing key viral glycoproteins: monovalent gD2, bivalent gD2-gC1, and bivalent gD2-gE1. We assessed their immunogenicity and protective efficacy in a murine model. All candidates elicited robust humoral and cellular immunity and provided significant protection against intravaginal HSV challenge. Notably, the gD2-gE1 vaccine induced markedly stronger immune responses. Mechanistically, its superior immunoprotective efficacy was associated with the stronger IFN‑I response, which thereby enhanced the adaptive immune response. Collectively, our findings provide a scientific rationale and valuable insights for the future development of HSV vaccines.
This study provides preclinical evidence to guide antigen combinations and follow-up evaluation measures for HSV preventive vaccines. For example, testing the gD2-gE1 candidate in another animal model that allows assessment of recurrence could support a development strategy that tracks viral shedding, ganglion viral DNA, and recurrence alongside survival and lesions. Comparisons controlling for differences in total mRNA and LNP doses between monovalent and bivalent candidates could also help distinguish the contribution of the antigen combination. IFN-I responses may serve as a research measure for optimizing candidates, but it is too early to conclude that enhancing these responses would make a vaccine safer and more effective in humans.