Replication-Deficient Whole-Virus Vaccines Against Cytomegalovirus Induce Protective Immunity in a Guinea Pig Congenital Infection Model

Abstract

Vaccines are needed to prevent congenital cytomegalovirus (CMV) infections. This study used the guinea pig cytomegalovirus (GPCMV) model to examine replication-deficient whole-virus vaccines against maternal viremia and congenital infection. Two recombinant GPCMVs, GP51-DD and GP52-DD, were engineered with destabilization domains fused to essential viral late proteins GP51 and GP52. These viruses, predicted to replicate in the presence of the synthetic ligand Shield-1 but not in its absence, were evaluated for Shield-1-dependence in vitro and for safety, immunogenicity, and efficacy in a pregnancy/challenge model. GP52-DD was profoundly Shield-1-dependent, producing no detectable infectious progeny in its absence. In contrast, the replication of GP51-DD was delayed in the absence of Shield-1, but the virus reached similar peak titers with or without the compound. GPCMV-seronegative guinea pigs received two subcutaneous injections of placebo (sham-immunized), GP51-DD, GP52-DD, or wild-type GPCMV (WT-GPCMV). DNAemia post-vaccination was detected in only one of 14 dams in each of the GP51-DD- and GP52-DD-immunized groups compared to 10/10 control animals immunized with WT-GPCMV, confirming the recombinant viruses were attenuated. GPCMV-specific antibody responses were similar in all three vaccinated groups. When immunized dams were bred and challenged with virulent GPCMV, DNAemia was detected in all sham-immunized controls and in 44% of GP52-DD-immunized dams (at significantly reduced levels) but was absent in dams immunized with GP51-DD or WT-GPCMV. Notably, immunization with GP52-DD, GP51-DD, or WT-GPCMV significantly reduced congenital GPCMV transmission (protective efficacies of 89%, 94%, and 100%, respectively). Thus, the replication-deficient GP52-DD vaccine was attenuated and protected against intrauterine GPCMV transmission. ImportanceCongenital cytomegalovirus (CMV) infections could be prevented by a vaccine, but most of the vaccine designs that have advanced to clinical trials have been subunit vaccines. These viral envelope glycoprotein-targeting designs have not yielded an effective vaccine that provides durable immunity. A vaccine that confers immune responses to a broader repertoire of viral immunogens, such as vaccines based on the whole virus, could enhance protection. However, there are concerns about the safety of live attenuated CMV vaccines. Using the guinea pig/guinea pig cytomegalovirus model of congenital infection, this study demonstrates that two replication-deficient whole virus vaccines are attenuated in animals while also being highly immunogenic, providing protective immunity against maternal viremia and fetal infection at levels similar to that conferred by a wild-type virus.