Human Cytomegalovirus Findings Key for Vaccine Development

Researchers in New York have discovered that antibodies that summon virus-engulfing white blood cells may play an important role in protecting infants from potentially serious congenital infection with human cytomegalovirus (HCMV).

In the most comprehensive analysis of HCMV to date, teams at Weill Cornell Medicine and NewYork-Presbyterian 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. 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.

“These findings certainly have implications for the types of immune responses HCMV vaccines should be targeting,” said senior author Dr. Sallie Permar, the Nancy C. Paduano Professor in Pediatrics and Chair of Pediatrics at Weill Cornell Medicine and Pediatrician-in-Chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and NewYork-Presbyterian Komansky Children’s Hospital.

HCMV and related viruses in the herpesvirus family are believed to have been infecting humans and other mammals for at least tens of millions of years. During that time, these viruses have developed myriad tools and strategies to evade their hosts’ immune defenses and establish long-term infections. 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.

HCMV sustains itself in the human population in part by mother-to-child transmission during pregnancy. These congenital HCMV infections can cause stillbirth, hearing loss, brain development abnormalities and other conditions in young children; and preventing them is a major public health goal. But conventional vaccine and antibody-based therapy strategies have so far proven ineffective against congenital HCMV infection—underscoring the need to understand how the immune system can fight this virus effectively.

“Currently when a mom does have acute CMV infection, or is known to have an infected fetus, we have nothing to offer in terms of vaccines or immunotherapies,” Dr. Permar said.

One remarkable finding concerned “neutralizing antibodies.” These are antibodies that bind to vulnerable sites on the virus and thereby directly disrupt the virus’s ability to infect cells, reproduce and spread in standard lab dish tests. Normally, vaccines against a virus aim to elicit neutralizing antibodies; prior, unsuccessful HCMV vaccines have done this too. But Dr. Permar and colleagues found that higher levels of HCMV-neutralizing antibodies in maternal blood were not associated with a lower risk of mother-child transmission.

They did find evidence, though, that mothers who didn’t pass on the virus had higher levels of antibody-dependent cellular phagocytosis. That suggests that this indirect mode of antibody immunity, in which antibody proteins use their “tail” sections, called Fc regions, to summon virus-gobbling macrophages and other white blood cells, is one that HCMV is not as adept at escaping.

“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,” Dr. Permar said. The results will certainly guide HCMV vaccine efforts with new-found speed in wake of the SARS-CoV-2 vaccine success. Dr. Permar and colleagues are currently applying these findings in work with the vaccine company Moderna, which is developing a candidate HCMV vaccine using the versatile mRNA platform.

The study was published recently in the Journal of Clinical Investigation.