As a physician specializing in pediatric infectious diseases, Sallie Permar, MD, PhD, felt compelled to be part of the research effort when Zika came on the radar in 2015. Having treated children born with cytomegalovirus—a congenital virus that causes defects and disabilities similar to those caused by Zika, including neurological problems and vision and hearing loss—she understood the urgency. “There will be a generation of children [affected by Zika],” said Permar, an associate professor of pediatrics at Duke University School of Medicine “This is not just something we’re going to have for a few years that will go away. These children are going to live their whole lives with congenital Zika virus syndrome.”
Initially, Permar was “somewhat hesitant” because she hadn’t previously worked with vector-borne viruses. But she was able to translate her expertise in mother-to-child transmission of HIV and cytomegalovirus into Zika vaccine research. She joined forces with David O’Connor, PhD, a researcher at the University of Wisconsin School of Medicine and Public Health, who had learned about Zika’s connection to microcephaly while working in Brazil in October 2015. When he returned to Wisconsin and began thinking about research, he encountered the same problem as Permar: he knew nothing about Zika.
“I realized that studying Zika would require a different combination of skill sets than [what was needed for] the other viruses I study,” said O’Connor, a professor of pathology and laboratory medicine at Wisconsin. “I have a lot of HIV expertise and a wide collaborative network of people who have complimentary expertise, but we knew nothing about congenital viruses or infections that affect pregnancies. We didn’t have any experience with viruses that are transmitted by mosquitos.”
New research territory
Permar and O’Connor were not outliers in their lack of knowledge. The research community knew little about Zika before it made international headlines in 2015.
Like Permar, Karin Nielsen, MD, MPH, a clinical professor of pediatric infectious diseases at the David Geffen School of Medicine at UCLA, looked to her earlier work on mother-to-child HIV transmission and other congenital infections and made comparisons to Zika. “There were some parallels from what we know about similar infections and viruses that have similar patterns, so we were not starting from absolutely no information at all.” Still, she added, “Zika is different.”
In collaboration with a team of Brazilian researchers, Nielsen followed a cohort of pregnant women in Brazil who had been infected with Zika. In March 2016, Nielsen and her colleagues published a study in the New England Journal of Medicine that was among the first to document the devastating effects of Zika on infants. The research suggested that nearly one-third of children born to women infected with the virus will have complications ranging from microcephaly and brain calcifications to changes in the central nervous system.
“We were very surprised when we first looked at the data. Zika seems to affect pregnancy in any trimester. There seems to be a pattern where there is an increased number of fetal deaths, of stillbirths. Microcephaly is the tip of the iceberg,” Nielsen said. “These children will have other problems, primarily in the central nervous system, which might not be perceptible at birth. There is hearing loss, visual deficits. We will have to monitor exposed children for developmental milestones and so forth.” She added that a follow-up to the March study is expected to publish in the next few months.
The National Institutes of Health (NIH) will be able to answer some of these questions with the Zika in Infants and Pregnancy (ZIP) study, which launched in June. A collaboration with Fiocruz, a research organization linked to the Brazilian Ministry of Health, the study will track up to 10,000 pregnant women in Zika-endemic countries. Women will be followed beginning in their first trimester, and children will be followed for one year after birth.
“This is not just something we’re going to have for a few years that will go away. These children are going to live their whole lives with congenital Zika virus syndrome.”
Sallie Permar, MD, PhD
Duke University School of Medicine
As scientists continue to learn more about Zika, new questions have surfaced. “In some situations, we’re missing a lot of information and then we are able to fill it in. But [with Zika], we’re finding even more questions as we learn more,” said Catherine Y. Spong, MD, deputy director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
With the intent of accelerating Zika findings, in February 2016, NIH announced an expedited review process for Zika-related research. NIH aims to complete the review and funding process within 10 to 16 weeks. “This is a much faster way to turn around ideas and better understand the impact of Zika virus, the diagnostics, and the basic sciences,” Spong said. As of early November, NICHD had awarded three grants. Sixteen have been awarded across all NIH institutes.
The search for a vaccine
Researchers agree that Zika vaccine research must be a priority going forward. “I think the only way to really stop the Zika outbreak is to develop an efficient vaccine,” Nielsen said, adding that she is “hopeful and optimistic” a vaccine will become a reality.
According to Permar, the “silver lining” for Zika vaccine researchers is that HIV vaccine research over the past 30 years established infrastructure and trained scientists who “were able to be mobilized very quickly for preclinical testing of Zika vaccine candidates.”
In early August, the National Institute of Allergy and Infectious Diseases (NIAID) launched a Phase 1 clinical trial of a Zika vaccine candidate in humans. In addition, NIAID announced a new Phase 1 trial had started at Walter Reed Army Institute of Research in early November, with four additional trials expected to launch in the coming months.
Still, a vaccine could take several years, Permar said. “‘Very quickly’ might mean ‘in a few years’ for a clinical product, but the [Zika vaccine] is on a completely different trajectory than HIV vaccine development because it seems biologically easier to induce the types of antibodies that are going to block infections.”
According to Spong, studying the mode of Zika transmission and effective diagnostics will continue to be critical. “One of the biggest challenges we have faced to date has been the diagnostics. Trying to understand who has Zika, especially in a country that has other flaviviruses [has been difficult],” she said. “The diagnostics are being worked on quite aggressively. That has been one of the most difficult challenges.”
Researchers collaborate, share data
Before Zika research was in high gear, O’Connor confronted the task of determining how to share data with other scientists participating in the research who were scattered across two continents. Recognizing their study would be among the first with data related to Zika, O’Connor did what might once have been unthinkable in the academic research community: He made research results open access, posting real-time data online for anyone to view.
“We thought that perhaps there would be a small number of scientists who would be starting similar types of projects who might get wind of [the research],” O’Connor said. “Within a week or two, it sort of took on a life of its own, in part because it was like a scientific serial. People were tuning in to see what would happen next.”
In a July 2016 Viewpoint in JAMA Pediatrics, O’Connor and colleague Esper G. Kallas, MD, PhD, of the University São Paulo Medical School, São Paulo, Brazil, wrote that sharing real-time data with other investigators “could avoid unnecessary redundancy” and “accelerate the pace of discovery.” The piece also reported that users in 98 countries viewed the data.
It “seemed like a new frontier,” Permar said. “There is a lot that can be done by breaking down barriers through things like open publishing. With these major challenges that are going to continue to come up in infectious diseases, we need to not compete with each other.”
While O’Connor acknowledged that sharing real-time data might not work for all researchers, he believes it presents an opportunity when something like a Zika epidemic arises, when information is lacking. “Our job as scientists and researchers is to discover and disseminate information as quickly as we can. Our opportunities to do that are going to grow,” he said. It was especially “gratifying,” when he learned his work had “motivated others who are generating similar work … with Zika to consider dipping their toes in the water.”