Replication-deficient whole-virus vaccines against cytomegalovirus induce protective immunity in a guinea pig congenital infection model

Vaccines are needed to prevent congenital human cytomegalovirus (HCMV) infections. This study used the guinea pig cytomegalovirus (GPCMV) model to examine replication-deficient whole-virus vaccines for protection against maternal viremia and congenital CMV infection. Two recombinant GPCMVs, GP51-DD and GP52-DD, were engineered with destabilization domains fused to the 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 the GPCMV 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 reached similar peak titers with or without the compound. GPCMV-seronegative guinea pigs received two subcutaneous injections of phosphate-buffered saline, GP51-DD, GP52-DD, or wild-type GPCMV (WT-GPCMV). DNAemia attributable to vaccination was noted in 10/10 (100%) of WT-GPCMV-immunized animals but in only 10/28 animals (36%) immunized with DD vaccines (P < 0.001). GPCMV-specific ELISA and interferon-gamma ELISpot responses were similar in all vaccinated groups. When immunized animals were bred and challenged during pregnancy 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. Immunization with GP52-DD, GP51-DD, or WT-GPCMV significantly reduced congenital GPCMV transmission compared to placebo (protective efficacies of 89, 94, and 100%, respectively). Thus, replication-impaired GP51-DD and replication-deficient GP52-DD vaccines were comparable to WT-GPCMV in immunogenicity and protective efficacy.