For pregnant women, Zika virus infections are incredibly worrisome due to the virus’ ability to cause a wide range of fetal abnormalities, with microcephaly occurring in around 5% of live births by Zika-infected mothers. But, the underlying cause of the congenital abnormalities has remained unknown. Now, an international team of researchers has linked the risk of microcephaly to features of maternal antibodies, pointing a direction for future studies into why a Zika infection results in birth defects in some babies but not others.

“Why some Zika virus-infected pregnant women deliver apparently healthy newborns while others have babies with microcephaly is unknown,” says Davide F. Robbiani, MD, PhD, a research associate professor at the Rockefeller University and first author on the paper. This question came to the forefront of researchers’ priorities after the widespread Zika outbreak in Brazil in 2015–2016.

The study, published today in the Journal of Experimental Medicine in a paper titled, “Risk of Zika microcephaly correlates with features of maternal antibodies” suggests that the risk of developing microcephaly depends on the types of antibody produced by pregnant mothers in response to Zika infection.

Factors that have been proposed to increase the risk of microcephaly vary from gestational age, comorbidities, socioeconomic status, genetic factors, and previous exposure to viruses that are similar to Zika, such as dengue virus or West Nile virus.

Through the collaboration with researchers and physicians in Brazil, Robbiani and colleagues analyzed blood samples collected during the 2015–2016 outbreak from Zika-infected mothers who had given birth to either healthy or microcephalic children.

A previous exposure to structurally related flaviviruses can result in antibodies that cross-react with Zika virus. These antibodies, the authors write, “can cross-neutralize or cross-enhance Zika virus infection” and “have been suggested to facilitate vertical transmission” from mother to fetus. However, through a series of laboratory tests, the researchers saw no significant differences in the activity of antibodies produced against dengue or other Zika-related viruses. Therefore, they suggest that having pre-existing antibodies to Dengue virus is not associated with increased risk of Zika-related microcephaly.

However, when Robbiani and colleagues analyzed the activity of antibodies produced against Zika virus, they saw several differences in the antibodies produced by the mothers of babies with microcephaly. Antibodies from these mothers were actually more effective at neutralizing the Zika virus than the antibodies produced by mothers of healthy newborns. Surprisingly, however, these antibodies also showed an enhanced ability to boost the entry of Zika virus into human cells grown in the laboratory.

The authors write that “infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers.”

The researchers confirmed their findings in macaques infected with the Zika virus. Pregnant monkeys that produced antibodies capable of enhancing the entry of Zika virus into cells were more at risk of giving birth to babies suffering from Zika-induced brain damage.

“Though our results only show a correlation at this point, they suggest that antibodies may be implicated in Zika fetal disease,” Robbiani says. “Antibodies may exist that, instead of protecting, enhance the risk of Zika microcephaly, so the next step will be to figure out which antibodies are responsible for this, and how they promote fetal damage. This has significant implications for vaccine development; a safe Zika vaccine would have to selectively elicit antibodies that are protective, while avoiding those that potentially enhance the risk of microcephaly.”

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