Maternal Antibodies to Primary CMV Infection Link to Fetal Transmission

BACKGROUND Human cytomegalovirus (HCMV) is the leading global infectious cause of birth defects. Despite its prevalence as a cause of life-long disabilities, there are no licensed vaccines to prevent congenital CMV (cCMV), and correlates of protection remain poorly understood. To address this, we identified humoral immune responses to primary HCMV infection during early pregnancy associated with odds of vertical transmission. METHODS Maternal plasma was collected from a trial that screened >200,000 and enrolled 399 pregnant women serologically diagnosed with primary HCMV infection prior to randomization for hyperimmunoglobulin or placebo therapy (NCT01376778), where 78 transmitted cCMV. Plasma IgG, IgM, and IgA binding to HCMV antigens, neutralization, antibody-dependent cellular phagocytosis, and inhibition of cell-associated viral spread were measured and related to transmission outcome. RESULTS In a case-control conditional logistic regression, IgM binding to HCMV entry glycoproteins was associated with increased odds of cCMV, identifying potential biomarkers of congenital infection. In contrast, IgG binding to UL16, UL141, prefusion-like gB, gB antigenic domains (AD) 4+5, and gH/gL were associated with decreased odds of cCMV. Surprisingly, IgG binding to the immunodominant gB AD-1 region, pp150, and cell-associated gB were associated with increased odds of cCMV. A LASSO regression model selected IgG responses against UL16 and gB AD-4+5 as associated with decreased odds of transmission, suggesting their potential importance as vaccine targets. CONCLUSION UL16 and domain specificity of gB-specific IgG responses differentially impact cCMV odds following acute infection, emphasizing the importance of rational antigen selection and gB conformation for HCMV vaccine design to eliminate cCMV.