In the United States, cytomegalovirus (CMV) is the most common congenital infection, with an estimated 1 in 200 cases, and is the leading cause of birth defects. Disease manifestations in newborns congenitally infected with CMV include hearing and vision loss, developmental and motor delay, and microcephaly. A safe and effective maternal CMV vaccine that can reduce risk of congenital infections is not yet available for clinical use.
Not all CMV-infected moms congenitally transmit the virus, suggesting that Mother Nature has ways to protect against infection. Mining immune responses for clues in CMV-infected moms who do not transmit the virus congenitally to their babies may inform protective responses needed to develop an effective vaccine.
In an elegant study that used a case-control matched cohort of CMV-infected transmitting and non-transmitting dyads (moms and babies), Semmes et al. unraveled the intricacies of maternal antibody responses that are predictive of reduced congenital CMV transmission. At first glance, maternal antibody binding responses in transmitting moms were higher against several CMV envelope proteins compared with non-transmitting moms. Yet at a fine detail, and once maternal antibodies were probed for their antiviral functions, an immune-correlates-of-protection analysis revealed that the properties of maternal antibodies matter most. Antibodies with evolved avidity to the virus envelope proteins were highly predictive of reduced congenital CMV infection. The authors also demonstrated that, in CMV-infected non-transmitting moms, antibodies with the ability to mediate antibody-dependent cellular phagocytosis (ADCP)—through activating Fcγ receptors—are predictive of reduced risk of congenital CMV infection. Thus, quality, not quantity, of maternal antibodies against CMV matter, and decoding the antiviral activities of these antibodies informs precise antibody responses that a vaccine needs to elicit. Because the biology of CMV involves a cycle between free virus, cell-to-cell transmission, and a latent cycle, it is intriguing that maternal antibody responses with high avidity and a strong antiviral effector function mediated via Fcγ receptors expressed on phagocytic cells are key for protection.
This immune-correlates-of-protection study against congenital CMV infection begins to lay the groundwork of key benchmarks that may be useful in assessing CMV vaccines for their ability to protect against congenital transmission. Given the high rates of congenital CMV throughout the world and the devastating impacts on our youngest, the urgency to develop a safe and effective CMV vaccine cannot be any higher.