In a study published in the journal Cell on November 18, a team led by scientists at Weill Cornell Medicine, and the National Institutes of Health (NIH) have isolated an uncommon and ultrapotent antibody that can neutralize the pathogenic zika virus at early stages of infection during pregnancy in preclinical models.

Zika virus infected mothers pass the pathogen on to the unborn fetus, causing neurodevelopmental deficits such as abnormally small heads (microcephaly) in up to 14% infants. Protection against such dire possibilities clinically termed “congenital zika syndrome” can be provided through neutralizing antibodies such as the one discovered this study. At present, there are no approved vaccines against zika.

Sallie Permar
Sallie Permar, MD, PhD, is the Nancy C. Paduano Professor in Pediatrics and chair of pediatrics at Weill Cornell Medicine and pediatrician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center and NewYork-Presbyterian Komansky Children’s Hospital [Weill Cornell]
Sallie Permar, MD, PhD, a professor of pediatrics at Weill Cornell Medicine and Mattia Bonsignori, MD, MS, chief of the translational immunobiology unit of the laboratory of infectious diseases at NIAID (National Institute of Allergy and Infectious Diseases) are the senior authors of the study.

“The important thing is that we’ve got to be ready for another outbreak of Zika,” said Permar. “Pregnant people are the exact population that needs vaccines or immunotherapies for zika. It’s crucial to get anti-zika vaccines and therapies that are safe in pregnancy rolled out as soon as there is evidence of an outbreak.”

The IgM antibody identified by Permar and her team has the potential to help fill that gap. Unlike the common two-pronged IgG that comprises nearly three quarters of the total antibody in our serum, IgM a five-pronged antibody comprises only a tenth of our entire stock of serum antibody and can bind ten antigens at once. It is the largest type of antibody known. Due to its unusual structure IgM is capable of modes of antigen recognition that are not available to IgG.

“There are two potential ways it could be used,” said Permar. “To quickly reduce levels of zika in the blood of pregnant people who have become infected, or as a preventative measure given to those at risk of contracting the virus during an outbreak.”

The investigators isolated the pentameric IgM from a zika virus-infected pregnant woman whose child was born without congenital zika syndrome. Through in vitro and in vivo studies in mice, the researchers demonstrated the antibody’s high level of potency in neutralizing the virus, such that even miniscule levels of the antibody provide protection against the pathogen. Mice injected with the antibody were not only protected from otherwise lethal infections, but the virus was suppressed to the level that it could no longer be detected in their blood.

The zika virus is transmitted by infected Aedes aegypti mosquitoes. Although the pathogen causes mild illness in adults, it can cause severe birth defects, including abnormally small heads and brain damage in unborn fetuses through maternal infections.

DH1017.IgM neutralizes the zika virus during pregnancy in mice models. [Adapted from Singh T., et al, Cell, 2022]
Co-authors Reynaldo Dietze, MD, DSc, professor at Global Health and Tropical Medicine and the Federal University of Espίrito Santo, and Camila Giuberti, PhD, also a scientist at the Federal University of Espίrito Santo, collected blood samples from zika-infected pregnant women in Brazil, during the zika outbreak that started in 2015.

They noted one of these pregnant women gave birth to an apparently healthy baby even after detectable levels of zika in her blood for nearly two months. Lead author of the study Tulika Singh, PhD, a former graduate student at Permar’s lab, found that the patient’s B lymphocytes produced an IgM antibody with a potent ability to prevent viral particles from invading cells.

This surprised the investigators because the antibody (DH1017.IgM) belonged to a category that is typically weaker, immature and produced early in an infection. However, in this instance its ultra potency is attributable to it being an IgM antibody. In structural analyses conducted by the team, they found that DH1017.IgM could bind the zika virus with multiple arms, simultaneously. IgM antibodies might be especially effective against zika virus, the authors suggested.

In ongoing translational studies, the team is testing the safety and efficacy of DH1017.IgM in preventing maternal-to-fetal transmission in additional preclinical models.

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