In the wake of the World Health Organization’s announcement Monday that Zika virus constitutes a public health emergency, research groups and public agencies are mobilizing to tackle the emerging infection and its suspected links to a devastating form of a birth defect known as microcephaly.
WHO officials emphasized the lack of a working vaccine, the absence of a reliable blood test for the virus and the dearth of natural immunity in the Western Hemisphere. Their recommended first steps are to control the disease’s vector, the mosquito known as Aedes aegypti, and for at-risk women to take precautions to avoid mosquito bites.
The sudden appearance of the virus in the Americas — and the seemingly new tie to the birth defect where infants’ brains don’t fully develop during pregnancy — underscore the huge gaps in our knowledge about the disease, said Fred Hutchinson Cancer Research Center virologist Dr. Trevor Bedford.
Any infection carries its own set of mysteries. But the Zika outbreak is frustratingly puzzling, even for a relatively new disease, Bedford said.
“At the moment it seems like there are a huge number of questions, more so than I’m even used to in these situations, [that is], emerging viral diseases,” he said.
To that end, we asked Bedford and other infectious disease experts at the Hutch to point out what we still don’t know about Zika — and how research groups may start to plug those holes in the effort to halt the virus’ spread.
Here are some of the burning questions they’ve identified:
It may seem like an obvious question, but we have no good idea how many people in the Americas have contracted Zika in the current outbreak. That’s due to two issues that muddy the waters: About four out of five people infected with Zika won’t even know they’re sick, and there are no reliable, rapid blood tests to look for the virus’s presence.
The standard type of blood test doesn’t work well because Zika is so similar to its viral cousin, dengue, Bedford said. The tests can’t distinguish between Zika infection and a past dengue infection, and because the two are spread by the same kind of mosquito, dengue is very common in the same parts of the world where Zika is now appearing.
What we do know: WHO officials have estimated there were between 500,000 to 1.5 million Zika infections in Brazil in 2015, with an additional 3 million to 4 million cases that could sweep the Americas in 2016, but admit those numbers are uncertain. Their estimates for 2015 and 2016 are based on models of how dengue spread, but it’s still not clear whether Zika will follow the same trajectory, Bedford said.
We don’t know much about how the virus spreads, Bedford said. We know it’s transmitted by mosquitos that have bitten other infected people, but researchers don’t yet know how many new infections each infected person causes. Virologists use this measure to understand the contagion of a given disease — and how difficult a resulting epidemic would be to control.
Bedford’s expertise is in modeling how viruses circle the world based on their genomic sequences, from which he and others in the field can extrapolate how the viruses likely evolved from a common ancestor.
“You can do a whole lot if you have viral sequences,” he said. “Even a hundred viruses sampled from different locales” would help solve many of these outstanding questions, such as when, exactly, the virus first arrived in the Americas.
What we do know: Based on just a handful of viral sequences from around the world, virologists at the University of Edinburgh and the University of Oxford have made initial estimates of how and when Zika may have made its way from Africa, where it originated, to South America. Although this work can be improved with more data points, it matches a previous hypothesis that Zika first arrived in Brazil during the 2014 World Cup.
Some are worried that another major sporting event slated to be held in Brazil, the 2016 Summer Olympics, could kick off an even bigger wave of global Zika transmission. That same 100 or so viral sequences can also tell us how quickly the virus will spread in the future, Bedford said, and could help pinpoint whether the virus will likely still be raging in South America by August.
Zika is likely spreading so quickly in the Americas because people in the Western Hemisphere don’t have a natural immunity to the virus that those in Africa do, Bedford said. So it’s possible that once enough herd immunity is established in this hemisphere, the epidemic will die down of its own accord. But we don’t know when that will happen, Bedford said.
“How fast that epidemic will sweep through [the population] and crash depends upon a number of these important epidemiological parameters,” he said. “I don’t think we have a very good idea at all about those parameters at the moment.”
What we do know: Right now, it’s summer in Brazil, meaning better breeding grounds for the A. aegypti mosquito. The Olympics will take place in August — winter in Brazil — which could lower the insect population, but it’s not clear yet whether the change in seasons will be enough to suppress the virus’s spread.
There’s been a spike in microcephaly cases reported in Brazil since Zika arrived, but it’s not yet proven that the virus causes those birth defects — nor if a pregnant woman is infected, how likely it is that her baby would have microcephaly. The WHO’s director general, Dr. Margaret Chan, said Monday that studies to understand the potential link would begin in the next two weeks.
To get at the answer to these questions, researchers need to conduct prospective studies, said Fred Hutch biostatistician and epidemiologist Dr. Betz Halloran.
“You follow women before they get pregnant and then if they get pregnant, see what happens,” she said. Halloran is hoping to start such a study in the U.S. Virgin Islands, where the first confirmed case of Zika infection was recently reported.
What we do know: Although it’s not clear how many are true cases of microcephaly, more than 4,000 cases of the birth defect have been reported in Brazil since October. “People are very tentative about saying it’s causal, but it’s highly likely [Zika is] associated with these birth defects,” Halloran said.
There’s another curious wrinkle to the Zika story — pregnant women may be the most susceptible to the disease’s damaging effects, but vaccination during pregnancy is often a challenging unknown, even with currently available vaccines.
Zika is “really quite unique” in that aspect, said Dr. Jim Kublin, Fred Hutch vaccine expert and executive director of the HIV Vaccine Trials Network. Kublin said he doesn’t know of any other vaccine that was first targeted at pregnant women, although it’s also possible that by vaccinating enough of the general public, pregnant women could avoid risk of Zika through herd immunity.
“That’s usually the last target population that we think about in a vaccine development plan because of the potential toxic effects [to the fetus],” he said.
It’s also not yet clear whether any amount of Zika during pregnancy could trigger birth defects, or if a certain amount of the virus will tip the scales, Kublin said. That knowledge could inform the type of vaccine designed.
“It’s a huge challenge to try to understand whether or not a vaccine focused on this virus could prevent these catastrophic results of microcephaly,” he said.
What we do know: Dr. Tony Fauci, head of the National Institute for Allergy and Infectious Diseases, has said that Zika vaccines could enter early clinical trials within the year, and could be based on existing vaccines to dengue or West Nile virus. But even if the early trials go well, it could be several more years before a Zika vaccine is publicly available, Fauci said.
Kublin pointed to the swift development of a likely effective Ebola vaccine in 2015 following the outbreak in West Africa. “It really was a remarkable feat,” he said. “Hopefully we’ll see something similar here.”
The 2014 Ebola outbreak underscored not only knowledge gaps, but organization and resource gaps in the world’s responses to new epidemics, Halloran said. She’s part of the WHO’s “R&D blueprint for action to prevent epidemics,” a group of experts and officials that is laying the foundation for responses to future emerging infections.
“The idea for the committee is to be working on diseases that haven’t necessarily hit the road yet — and to be prepared,” Halloran said.
The group is coordinating everything from protocols for new studies to funding sources for research into new epidemics to agreements with countries’ governments to share data with the WHO. But even this panel of experts can’t perfectly predict the future: Zika wasn’t originally on their list of top priority diseases, announced in December, although “it is now,” Halloran said.
The committee is planning to wrap up its preparations later this year and could even help jumpstart vaccine development for some of the top priority pathogens, which could save critical time.
“In some cases, if you pick the disease and you actually pick the right one, and you could prepare a vaccine, it could save years,” Halloran said.
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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.