2651. Protection Against Human Cytomegalovirus Acquisition Is Associated with IgG Binding to Cell-Associated CMV glycoprotein B in Two Historical gB/MF59 Vaccine Cohorts

Abstract

BackgroundHuman cytomegalovirus (CMV) is the most common congenital infection worldwide. A CMV glycoprotein B (gB) subunit vaccine with MF59 adjuvant achieved ~50% protection in phase II clinical trials in postpartum and adolescent women. Interestingly, postpartum vaccinees showed poor virus neutralization but robust antibody-dependent cellular phagocytosis (ADCP). In this study, we performed a combined humoral immune correlate of risk analysis in vaccinees to define vaccine-elicited immune responses associated with protection and targets for vaccine candidate immunogenicity.MethodsgB/MF59 vaccinees who became infected and those who remained uninfected were 2:1 matched on race and number of vaccine doses. This study included 42 women from the adolescent (14 infected, 28 uninfected) and 33 from the postpartum cohorts (11 infected, 22 uninfected). IgG binding to whole gB, gB-neutralizing epitopes, FCRs, and whole virions were assessed by standard or multiplex ELISA. IgG binding to gB mRNA-transfected HEK293Ts was measured by flow cytometry. Neutralization of Towne, TB40/E, and AD169-repaired-GFP strains were measured in MRC-5, BJ5Ta, and/or ARPE-19 cells. Phagocytosis was assessed by THP-1 uptake of fluorescently conjugated TB40/E and AD169-repaired-GFP virions. Multiple linear regression controlling for cohort was performed for the combined log-transformed group data (apriori significance cut-off of P < 0.05, Benjamin–Hochberg FDR < 0.2).ResultsVaccine-elicited antibodies in adolescent and postpartum cohorts exhibited similar magnitude IgG binding to soluble HCMV gB protein, gB-neutralizing domains, and gB-transfected cells. Autologous Towne strain neutralization was observed in both cohorts, but heterologous strain neutralization was observed only in adolescent vaccinees (P = 0.001). Both cohorts exhibited robust phagocytosis of HCMV virions. Regression analyses revealed that risk of HCMV acquisition in vaccinees was associated with magnitude IgG binding to gB-transfected cells (P = 0.006, FDR = 0.15), not neutralization or phagocytosis responses.ConclusionProtection against primary HCMV infection was significantly associated with vaccine-elicited IgG binding to gB-transfected cells, suggesting the importance of a native, cell-associated gB conformation in future vaccine candidates.Disclosures All authors: No reported disclosures.