Zika infection in pregnancy can cause birth defects, but a fall in cases means risks may not be understood. Credit: Mauricio Lima/NYT/eyevine

Studies of thousands of pregnant women that were set up to probe the link between Zika and birth defects may not provide definitive answers because of a sharp drop in the number of new cases, researchers have warned. The unexpected development is making the disease harder to study, and threatens to hamper trials of experimental vaccines that might protect pregnant women in future outbreaks.

“We’re seeing few, if any, cases, particularly in southern Brazil, which we thought might be the next big area to be hit this year,” says Oliver Brady, an epidemiologist at the London School of Hygiene and Tropical Medicine.

Seventy countries have reported mosquito-borne Zika virus transmission since 2015, with the most intense epidemics sweeping South America and the Caribbean. Phylogenetic research suggests that the virus first entered Brazil in late 2013 or early 2014 (see http://dx.doi.org/10.1038/nature22495), although it was not detected until mid-2015. The virus has been linked with a range of birth defects, including microcephaly, in the fetuses and newborns of women infected during pregnancy — a pattern of abnormalities known as congenital Zika syndrome. But reliable data on the absolute risks are lacking, and gathering such information is one of the objectives of the affected studies.

The two largest studies each intend to recruit 10,000 or more pregnant women. The Zika in Infants and Pregnancy (ZIP) study was launched last June by the US National Institutes of Health (NIH) and the Fundação Oswaldo Cruz-Fiocruz (Fiocruz), a national scientific agency in Brazil, and has so far recruited almost 3,000 women. The other study is just beginning to recruit. It is being carried out by the ZIKAlliance, a multidisciplinary consortium of 53 research centres that launched in December with €12 million ($13.5 million) from the European Union. Both trials are taking place across multiple sites in South America and the Caribbean.

Credit: Source: PAHO/WHO

But with the drop in new cases (see ‘Decline and fall’), the ZIKAlliance is now reconsidering its plan. “We are going to be pragmatic, we are going to try, but if there are not enough infected cases, then there is little point,” says the consortium’s scientific coordinator Xavier de Lamballerie, a virologist at Aix-Marseille University and French national biomedical agency INSERM.

The ZIKAlliance intends to capture what cases it can at its sites, and is considering focusing resources in sites where Zika has been rarer, such as Bolivia, where future flare-ups might be more likely. “We will track cases there where they are,” he says, “It’s a race against the clock.”

The ZIP study is similarly faced with low numbers of Zika cases, says Anthony Fauci, director of the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). “That’s good for the population — if making it more difficult to get reasonable data for the study,” he says. The low level of cases will also affect field trials of experimental vaccines, he adds. One such trial, the NIH VRC 705 phase II trial, began in March and aims to enrol at least 2,490 volunteers in 7 countries in the Americas.

But Fauci says that capturing enough data in an outbreak, where numbers of cases fluctuate from place to place and over time, and, at times, dry up altogether, is always an issue. “That’s just a risk you accept,” he says. “Sometimes a study that you think would take two years, winds up taking four or five years. But ultimately we hope that we can get some meaningful data.”

Epidemiologists say that they are unsure why the number of cases of the mosquito-borne disease has declined so steeply, and whether it will spike again in some region in South America or elsewhere. Often, the disease causes no symptoms, so most cases go undetected; it’s possible that the rapid spread of the disease in the Americas has meant it has burnt itself out because enough people have become immune to the virus.

Large-scale trials inevitably take time to organize. But delays incurred in obtaining ethical and other approvals in the trials’ host countries have slowed the process further, as have a lack of clear rules for matters such as the shipping and ownership of samples.

It’s unlikely that Zika infection will disappear completely, however, says Fauci. “One doesn’t know what is going to happen with the Zika situation and whether or not there will be flare-ups in one country more than another,” he says. Spreading trial sites across different countries helps, he notes. “We try to build into the system enough flexibility, where you can assign slots depending on where the outbreak activity is.”

Researchers are still hopeful that despite lower than expected disease activity, the trials could produce useful results. Learning from other disease outbreaks such as Ebola, the main research agencies and groups involved in combating Zika last year agreed on common methodologies and designs for the latest studies. This means that the raw data from ZIP and the ZIKAlliance’s study, as well as from other cohort studies, can be pooled to increase the sample size.

“It’s the first time that we have achieved such a degree of harmonization of research protocols at an international level,” de Lamballerie says.