Complete cross strain protection against congenital cytomegalovirus infection requires a vaccine encoding key antibody (gB) and T-cell (immediate early 1 protein) viral antigens
Year: 2025
Type: article
Abstract: Background: Cytomegalovirus is a leading cause of congenital disease, and multiple strains enable congenital CMV (cCMV) from both primary and non-primary infections. Therefore, a cross-strain protective cCMV vaccine is a high priority. Guinea pigs are the only small animal model for cCMV and guinea pig cytomegalovirus (GPCMV) encodes functional homolog proteins, including cell entry gB glycoprotein and non-structural immediate early 1 protein (IE1), which are essential for lytic infection. A gB vaccine antibody response fails to provide horizontal protection against highly cell-associated clinical GPCMV strain TAMYC compared to prototype strain 22122. Previously, a recombinant defective adenovirus (Ad) vaccine encoding IE1, a T cell antigen, provided high-level cCMV protection. In this study, we hypothesized that a combined Ad-based strategy encoding trimeric gB complex and IE1 (AdgB + AdIE1) could improve cross-strain protection against cCMV compared to a gB vaccine (AdgB). Methods: A preconception vaccine study was conducted to evaluate the immune response and ability of vaccines to provide cross-strain protection against cCMV. Seronegative female animals were assigned to three vaccine groups: Group 1 (AdgB), Group 2 (AdgB + AdIE1), and Group 3 (no vaccine). Animals were vaccinated following a previously defined protocol, and antibody ELISAs were used to evaluate the gB immune response (AD1, prefusion gB, and wild-type gB). Additionally, an IFNγ-ELISPOT assay was used to evaluate the IE1 T-cell response. During the second trimester, dams were challenged with GPCMV (22122 and TAMYC co-infection), and pregnancy proceeded to term. Viral loads in pup target organs (liver, lung, spleen, brain), blood, and placenta were evaluated. Results: Vaccinated dams elicited a higher gB neutralizing antibody response than that of experimentally infected convalescent animals. Antibodies recognized homolog AD1 gB domain as well as prefusion gB with a response surpassing that in GPCMV-infected convalescent animals. Group 2 dams also elicited a T cell response to IE1. Evaluation of viral load in pups demonstrated that the AdgB + AdIE1 vaccine reduced GPCMV transmission to below detectable limits compared to 91.7% in the unvaccinated group. In contrast, AdgB reduced cCMV transmission to 12% in the pups. Conclusion: Complete cross-strain cCMV protection is a significant milestone in this model and is achieved by the inclusion of an antibody response to trimeric gB and T-cell response to IE1. Importantly, gB and IE1 responses can synergize and increase protection against cCMV, unlike prior approaches with gB and pp65 tegument proteins.
Source: Frontiers in Immunology
Institutions: Texas A&M Health Science Center, Texas A&M University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funders: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Robert Koch Institut, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4415418985