Human cytomegalovirus (CMV) is the most common infectious cause of infant brain damage and posttransplant complications worldwide. Despite the high global burden of disease,
vaccine development to prevent
infection remains hampered by challenges in generating protective immunity. The most efficacious CMV
vaccine candidate tested to date is a soluble
glycoprotein B (gB)
subunit vaccine with
MF59 adjuvant (gB/
MF59), which achieved 50% protection in multiple historical phase 2 clinical trials. The
vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/
MF59 vaccine. We found that gB/
MF59 immunization elicited distinct CMV-specific
immunoglobulin G (
IgG)-binding profiles and
IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees. Using penalized multiple logistic regression analysis, we determined that protection against primary CMV
infection in both cohorts was associated with serum
IgG binding to gB present on a cell surface but not binding to the soluble
vaccine antigen, suggesting that
IgG binding to cell-associated gB is an immune correlate of
vaccine efficacy. Supporting this, we identified gB-specific
monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity. Our results highlight the importance of the native, cell-associated gB conformation in future CMV
vaccine design.