In Utero Human Cytomegalovirus Infection Is Associated With Increased Levels of Putatively Protective Maternal Antibodies in Nonprimary Infection: Evidence for Boosting but Not Protection.

Abstract

Although primary maternal cytomegalovirus infections are associated with higher risk of in utero transmission, most fetal infections worldwide result from nonprimary maternal infections. Antibodies directed at glycoprotein B (gB) and the gH/gL/pUL128-130-131 pentamer can neutralize virus, and higher levels of antibody directed at several particular pentamer epitopes defined by monoclonal antibodies (mAbs) are associated with reduced risk of fetal cytomegalovirus (CMV) transmission during primary maternal infection. This had not been explored in maternal nonprimary infection. In a setting where most maternal CMV infections are nonprimary, 42 mothers of infants with congenital CMV infections (transmitters) were compared to 75 CMV-seropositive mothers whose infants were CMV-uninfected (nontransmitters). Control infants were matched by sex, maternal human immunodeficiency virus (HIV) status, and gestational age. We measured the ability of maternal antibodies to block 3 key pentameric epitopes: one in the gH subunit, another straddling UL130/UL131, and the third straddling gH/gL/UL128/UL130. We tested if levels of antibodies directed at these epitopes were higher in nontransmitters compared to transmitters. Levels of all 3 putatively protective pentamer-directed antibodies were significantly higher in transmitters compared to nontransmitters. In contrast, antibodies targeting an epitope on gB were not different. Total antibody specific for pentamer and for gB were also higher in transmitters. We found no evidence that higher levels of any CMV-specific antibodies were associated with reduced risk of congenital CMV infection in nonprimary maternal infection. Instead, we found higher maternal antibody targeting epitopes on CMV pentamer in transmitters than nontransmitters, providing evidence for antibody boosting but not protection.