Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models

Awasthi, Sita; Knox, James J; Desmond, Angela; Alameh, Mohamad-Gabriel; Gaudette, Brian T; Lubinski, John M; Naughton, Alexis; Hook, Lauren M; Egan, Kevin P; Tam, Ying K; Pardi, Norbert; Allman, David; Luning Prak, Eline T; Cancro, Michael P; Weissman, Drew; Cohen, Gary H; Friedman, Harvey M

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing antibody titers were higher at one month and declined far less by eight months in mRNA- than protein-immunized animals. Both vaccines protected against death and genital lesions when infected one month after immunization; however, protection was more durable in the mRNA than protein group when infected after eight months, an interval representing >15% of the animal's lifespan. Serum and vaginal neutralizing antibody titers correlated with protection against infection as measured by genital lesions and vaginal virus titers two days post infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times post immunization that persisted for up to one year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.