Maternal Antibodies Can Protect Infants from Cytomegalovirus

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Antibodies that summon virus-engulfing white blood cells may play an important role in protecting infants from potentially serious congenital infection with HCMV.

HCMV is thought to infect most individuals in developed countries and virtually all people in developing countries. While most infections go unnoticed, HCMV is thought to subtly promote multiple human ailments, from cancers to heart disease. Moreover, a weak immune system from HIV, immunosuppressive drugs, or being very old or young, can trigger HCMV spread and potentially fatal illness.

Pediatricians at Weill Cornell School of Medicine (New York, NY, USA) and their colleagues examined antibodies in the blood of 81 mothers infected with HCMV, comparing the properties of the antibodies in mothers who had transmitted versus hadn’t transmitted HCMV to their infants. To identify protective antibody responses, they measured HCMV-specific IgG binding and anti-viral functions in paired maternal and cord blood sera from HCMV seropositive transmitting (n=41) and non-transmitting (n=40) mother-infant dyads identified via a large USA-based public cord blood bank.

A binding antibody multiplex assay (BAMA) was used to quantify HCMV glycoprotein-specific IgG binding and avidity. Fc receptor (FcR) binding by HCMV glycoprotein-specific IgG was done using FcR binding by HCMV glycoprotein 500 specific IgG and was measured using a modified BAMA. HCMV neutralization was measured by high-throughput fluorescence bioimaging. Whole virion HCMV antibody-dependent cellular phagocytosis (ADCP) was measured on a LSRII flow cytometer (BD Biosciences, San Jose, CA, USA).

The investigators reported that a key finding was that women in the non-transmission group tended to show higher levels of the white blood cell-summoning mechanism, known as antibody-dependent cellular phagocytosis, against HCMV. They found that high avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. They also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes.

Sallie R. Permar, MD, a Professor of Pediatric Infectious Diseases and senior author of the study, said, “These findings certainly have implications for the types of immune responses HCMV vaccines should be targeting. For fighting against HCMV, which is so good at evading the immune system, we have to go beyond the simple concept of neutralizing antibodies to consider antibodies that work in other ways.”

The authors concluded that eliciting HCMV-specific IgG that engages FcγRI/FcγRIIA and mediates non-neutralizing Fc effector functions such as ADCP may be an important immune response in the prevention of congenital HCMV transmission and a promising new approach for HCMV vaccinology. The study was published on June 28, 2022 in the Journal of Clinical Investigation.

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