Limited cross strain CMV protection by a bivalent (gB/pp65) vaccine is based on an impaired gB antibody response and evasion of pp65 cell mediated immunity

Congenital CMV (cCMV) is a leading cause of hearing loss and cognitive impairment in newborns and a vaccine is a high priority. The guinea pig with species-specific guinea pig cytomegalovirus (GPCMV) is the only small animal model for cCMV. Prior GPCMV vaccine studies have focused on prototype strain 22122 and not evaluated cross-strain protection, an important vaccine benchmark. The essential viral entry gB glycoprotein is an immunodominant antibody target and considered a corner stone of a CMV vaccine. Trimeric gB antigen induces potent neutralizing antibody titers but a clinical strain of GPCMV (TAMYC) is highly cell-associated limiting gB antibody cross-strain protection. In HCMV and GPCMV tegument protein pp65 is a major T cell antigen and important for convalescent immunity. A defective adenovirus (Ad) vaccine strategy encoding GPCMV gB and pp65 (AdgB+AdGP83) was evaluated for cross-strain protection. Vaccinated animals induced a cell-mediated response via IFNγ ELISPOT assay against pp65 peptides conserved between strains. Additionally, the combined vaccine produced similar anti-gB and prefusion gB titers to historical sera from a standalone trimeric gB vaccine (AdgB). However, antibody response to gB(AD-1) oligomerization domain was impaired in the combined vaccine compared to historical AdgB vaccine sera which resulted in reduced neutralizing titer that were more similar to naturally convalescent GPCMV infected animals. In a pathogenicity study, vaccinated animals had partial protection against clinical TAMYC GPCMV strain challenge (SQ) compared to non-vaccinated control group. However, the vaccine failed to prevent viremia or virus dissemination to target organs, including the salivary glands, a notable limitation. Potentially, TAMYC virus evades T cell response against pp65 by dramatically reducing levels of pp65 expression compared to prototype 22122 strain. Overall, results indicate that a combination vaccine offers limited cross-strain protection despite prior success of separate pp65 or gB vaccines against GPCMV (22122 strain) and conservation of antigens between strains.