T cell inducing vaccine against cytomegalovirus immediate early 1 (IE1) protein provides high level cross strain protection against congenital CMV

Abstract

Human cytomegalovirus (HCMV) is a leading cause of congenital disease resulting in cognitive impairment and deafness in newborns. Multiple strains of HCMV enable re-infection and convalescent immunity does not protect against risk of congenital CMV (cCMV). Consequently, a cross strain protective CMV vaccine is a high priority. The guinea pig is the only small animal model for cCMV and species specific guinea pig cytomegalovirus (GPCMV) encodes homolog HCMV viral proteins making it suitable for vaccine studies. Neutralizing antibodies against viral entry glycoprotein complexes and cell free virus are insufficient for complete protection because highly cell associated virus enables evasion. CMV T-cell antigens are important in HCMV convalescent immunity and potentially in reducing the risk of cCMV. Immediate early protein IE1 is essential to HCMV and a T-cell target in humans. In this study, a recombinant defective adenovirus encoding GPCMV IE1 (AdIE1) was evaluated in a preclinical vaccine study. AdIE1 vaccinated animals evoked a T-cell response in a guinea pig IFNγ ELISPOT assay to IE1 (GP123). Vaccinated animals exhibited protection against subcutaneous challenge by GPCMV prototype strain (22122) with viral load substantially reduced compared to the unvaccinated control group and previous Ad based vaccine study against viral pp65 tegument protein. In a vaccine study against cCMV, dams were challenged mid-pregnancy with dual wild type virus strains (22122 and clinical strain TAMYC). At birth, pups were evaluated for viral load in target organs. AdIE1 vaccine had high efficacy against cCMV with GPCMV pup transmission reduced from 92% in the litters of the unvaccinated control group of dams to 23% in the vaccine group resulting in an absence of virus or statistically significant reduction in viral load in pup organs. Overall, IE1 is a more protective T-cell antigen than previously studied pp65 providing cross strain immunity against cCMV in this preclinical model.