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Infectious diseases

Antibody neutralizes Zika in preclinical trials

A superpotent immunoglobulin M antibody stopped the virus in animal tests

Drawing shows IgM antibodies (in blue) binding to the Zika virus (orange spheres)

Alexander Stewart / NIAID-NIH

A study led by a team from the US National Institute of Allergy and Infectious Diseases (NIAID) and Cornell University that included the participation of colleagues from the Federal University of Espírito Santo (UFES) identified a potential ally in the quest to prevent and treat infection by the Zika virus. The group conducted tests on rodents of an immunoglobulin M (IgM) antibody isolated from a pregnant Brazilian woman who was infected by the virus in 2015 but did not transmit it to her baby. The antibody was found to neutralize the virus so effectively that the microorganism even became undetectable in the animals’ blood.

In another experiment, rodents were given a lethal dose of the virus. All those treated with the IgM antibody survived, while the rest of the group died. The results of the study were published in the scientific journal Cell in early December. In newborns who inherit the virus in the womb from their infected mother, the pathogen can cause Congenital Zika Syndrome (CZS). The condition is caused by damage to the central nervous system and can hinder a child’s development and independence to varying degrees. Babies born with CZS are 14 times more likely to die in the early years of their life than those without the syndrome (see Pesquisa FAPESP issue no. 316). One of the most serious problems associated with CZS is microcephaly, when the child’s head is smaller than expected for their age.

The researchers were surprised by the IgM antibody’s effectiveness against the Zika virus in initial trials. “We usually don’t even look at these antibodies in this type of study. Sometimes, we even discard them,” explains American pediatrician Sallie Permar from Weill Cornell Medicine, one of the coordinators of the study, in an interview with Pesquisa FAPESP. “This is because they have a very short lifespan.” Only about 10% of the immune system’s defense cells are IgM antibodies. They are the first response produced by the organism as soon as an infection occurs. Other types of antibodies then become dominant in the fight against the invading pathogen.

“We produce IgM in large quantities and very easily, but its effectiveness is not necessarily high,” says Maurício Nogueira, a virologist from the São José do Rio Preto School of Medicine (FAMERP) who was not involved in the study. “Over time, the body starts to manufacture immunoglobulin G, also known as IgG, which is part of the long-term immune response. These antibodies are smaller and more refined than IgM and typically produce a more specific response to infections.” About 80% of the immunoglobulins in the human immune system are IgG.

The antibody was isolated from a pregnant woman infected by the virus that did not transmit the pathogen to her baby

The first hint of IgM’s potential against the Zika virus dates back to the 2015–2016 outbreak of the disease in Brazil, at which time infectious disease specialist Reynaldo Dietze from UFES, one of the coauthors of the article, began recruiting pregnant women infected with Zika for a clinical study. Dietze had been collaborating with Permar’s team for quite some time. The objective was to monitor pregnant women with Zika who went on to have babies with and without CZS.

The team analyzed the blood plasma of 10 infected women, with samples collected between 8 and 406 days after the onset of symptoms. All of them, according to the authors, had high levels of antibodies against the virus when they gave birth. But one woman’s antibodies were still active more than a year after infection, which is extremely rare. The fact that she was producing immune cells for such a long time caught the researchers’ attention. “We then saw that they were IgM antibodies,” says Permar. “It was a new situation that didn’t make sense based on what the books say.” The patient had a prolonged infection, but her baby was born healthy.

After making this unexpected discovery, the scientists decided to study the antibody’s potential effectiveness against the virus in rodents. While the preliminary results are encouraging, an IgM-based Zika treatment or vaccine is not yet on the horizon. “Intensifying an antibody in the lab and showing that it provokes a significant response is the first stage of a long process,” says Nogueira. “It takes time to determine whether it will have an effect on people or open a therapeutic window that will allow us to develop a treatment.”

Permar agrees. “But the time to develop a vaccine for Zika is now,” says the pediatrician from Weill Cornell Medicine. “When the next outbreak occurs, we need the tools ready and available to contain the virus.” According to the researcher, the IgM antibody could be used both to produce a vaccine and to develop treatment. One of the challenges facing future studies is to design a safe protocol that would allow the inclusion of pregnant women, who are most vulnerable to the effects of the virus, in the initial phases of any tests. In the next stage of the preclinical studies, which will be carried out on animals, the Cornell team aims to identify any beneficial effects of IgM antibodies in pregnant rodents.

Scientific article
SINGH, T. et al. A zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization. Cell. vol. 185, no. 25. dec. 8, 2022.