For nearly 70 years, scientists have known of the existence of an obscure mosquito-borne virus that has gradually spread from its birthplace in Africa to the Indian subcontinent, East Asia and even some far-flung islands in the Pacific.
But few of those infected got sick, and most of those who did suffered no more than a mild fever and a rash. And so it wasn't until Zika exploded with previously unseen speed and severity across Brazil and the rest of South America in 2015 that the world — and researchers — began to pay the virus much heed.
Now, as evidence mounts that Zika can cause a host of grim birth defects, and as transmission of the virus by mosquitoes extends across the U.S. territory of Puerto Rico and into South Florida, scientists are in a race to crack the code of an organism and an epidemic that, in spite of numerous and rapid advances, remains largely mysterious.
The World Health Organization, which declared Zika an international health emergency in February, says response to the massive outbreaks has been hindered by "a severe lack" of research and a shortage of funding to look into some basic questions raised by its progress.
Medical and public-health researchers across the world are belatedly seeking answers to these critical questions: They don't know why some people get sick and others don't, or how many of those infected are vulnerable to Guillain-Barré syndrome, a rare immunological disorder associated with Zika infection that can cause paralysis or death. They don't know how Zika may affect infants or small children, though studies in Brazil have linked it to babies born with abnormally small heads. They don't know precisely how long the virus persists in a human host and in bodily fluids such as semen and urine, or how long immunity to Zika lasts after an infected person develops antibodies.
Evidence from other related flaviviruses — a group that includes dengue and West Nile — suggests that immunity should be long-lasting, maybe even lifelong, but no one's sure yet. Knowing they're immune could erase worry about future infection for women in Zika zones who got the virus and seek to get pregnant later.
Limited tools to fight
The dearth of definitive data on Zika leaves public health officials in Miami-Dade, the only place in the United States where mosquitoes are known to be infecting people with the virus, with limited tools to combat its spread and little in the way of advice or hard information for a public increasingly nervous — and at times confused — about the risks posed by the outbreak.
(The first locally transmitted case of Zika virus was confirmed in Pinellas County on Aug. 23. However, the state does not believe mosquitoes are actively spreading Zika in the county. That won't be known for certain until the state's investigation is complete.)
Though intensive spraying of insecticides has failed to eradicate the Aedes aegypti mosquitoes that transmit dengue in other countries, for instance, officials have to rely on it to knock back the same mosquito in Miami and Miami Beach, the confirmed places where it has been infecting people with Zika.
That may prove effective in curbing this outbreak in the short run, scientists say. But they also say it's not a long-term solution to what they believe could well become a recurring problem for Miami now that it has been established that active transmission is possible here. That's something researchers weren't sure could even happen.
"It's to some extent the only thing you can do," said Justin Lessler, a professor of public health at Johns Hopkins University in Baltimore, referring to the insecticide spraying and advice to residents to use repellent and cover up when they go out.
Lessler, co-author of two recent articles on the Zika epidemic in Latin America and the global threat the virus poses, published in the journal Science, says more research is needed if health authorities are to be better prepared for the next Zika outbreak — which he and other scientists say could readily happen. No one thinks a full-scale epidemic is in the offing locally, but no one should dismiss the risks posed by the outbreak, either, he said.
"This is almost certainly the tip of a larger iceberg. It's potentially the biggest outbreak of Aedes-borne vector disease in decades," Lessler said. "That has to give us pause. This virus has been surprising in many ways."
What about a vaccine?
Like others, Lessler said the best hope for an effective response lies in development of a vaccine. But anyone counting on that to stem the ongoing outbreaks is sure to be disappointed, scientists warn. Though 18 versions are in some stage of development under the guidance of the National Institutes of Health, the agency began testing a vaccine only this month. Any vaccine would not be ready before 2018. By then, they say, Zika epidemics in the hemisphere will likely be on the wane if not burned out.
Medical researchers also have little in the way of an explanation or response to the most alarming discovery about Zika in the course of the epidemic in Brazil — that it can cause microcephaly, or abnormally small heads and brain damage, in fetuses borne by some infected women. Scientists don't yet know why that happens, or how many exposed women are at risk, and there is no treatment. They also puzzle over why Zika spread so rapidly across Brazil, or why the country has reported an alarmingly high incidence of microcephaly when other affected countries have not.
Hypothetical explanations for the force of the Brazilian epidemic range from mutations in Zika-carrying mosquitoes, or the higher temperatures and rains generated by the El Niño weather phenomenon that promoted mosquito breeding and faster incubation of the virus, to differences in how local surveillance programs report cases of microcephaly. Another speculative explanation for its force in Brazil and Puerto Rico: that exposure to the virus that causes dengue in previous epidemics in both places made people more susceptible to Zika.
But all those possibilities are so far untested.
Whether the Puerto Rico epidemic leads to a burst of birth defects may help tell whether Brazil's reported incidence is an anomaly. Only one case linked to local transmission has been detected on the island so far, but that's because the epidemic started relatively recently, with the first confirmed case at the end of December. That means fetuses carried by women exposed in their first trimester — when the chances of developing microcephaly and other brain defects are highest — will not yet have reached full term. If the rate of incidence reported in Brazil carries over to Puerto Rico, U.S. public health experts predict there will be as many as 270 Zika-related microcephaly cases on the island.
One of Zika's biggest surprises, some researchers say: Until confirmation came last month that Aedes aegypti mosquitoes were transmitting the virus in Miami-Dade, some scientists doubted that could happen. Some believed that conditions were not conducive to local transmission given South Florida's first-world sanitation, the prevalence of air conditioning, far lower population densities than in urban areas in Latin America and a subtropical climate that puts the region at the far edge of the geographical range for the mosquito.
One thing scientists now think they do know: According to projections issued last week by an international team of scientists from the University of Florida and several other research institutions, the outbreak in Florida may spread to some other Southern states but is likely to remain contained to small clusters and fade out by winter, when cooler temperatures will significantly reduce mosquito populations.
"Once it cools down a bit, it's hard to maintain these transmission cycles even if mosquitoes are still there," said Ira Longini, a professor of biostatistics at UF and one of the study's designers.
Small flare-ups expected
Scientists doubt the virus will become permanently established in South Florida's human or mosquito populations, though sporadic outbreaks may well occur in the future as travelers continue to bring Zika in from Latin America and the Caribbean, including Haiti — as has occurred with other viral diseases carried by the same mosquitoes.
"My guess is there would be small flare-ups as introductions happen or a small chain of transmission develops," Lessler said.
Lessler said the frequency of future Zika outbreaks in the southern United States may thus depend to a large degree on what happens with Zika in Brazil, the biggest single source of tourism to Miami-Dade, in other Latin American countries and in Puerto Rico, where a financial crisis has sent tens of thousands of residents to settle in Florida, mostly around Orlando.
The nearly sure bet, based on the typical course of viral epidemics, is that those large outbreaks will wane over the next year or two as more people are exposed and much of the population develops immunity, depriving the virus of enough fresh hosts to sustain its spread. The number of new cases being reported in Brazil and neighboring countries, in fact, has already begun to drop, said Derek A. T. Cummings, a professor of biology at UF and co-author of the Science article on the virus' global threat.
Zika and the island of Yap
Because of the same natural phenomenon, known as "herd immunity," Zika has disappeared from the Micronesian island of Yap, which hosted the world's first large outbreak in 2007, and in the archipelago of French Polynesia, which experienced an epidemic of the virus in 2013 and 2014 and was the first place where Zika was linked to Guillain-Barré.
"That's to be expected with these outbreaks of pathogens in places that have not experienced them in the past," Cummings said. "You get large, explosive outbreaks, and they burn through their fuel as people develop immunity. If it declines in the Americas, we will see it less and less frequently here."
The French Polynesian variant of Zika did not disappear from the world, however. It reappeared in Brazil, probably carried in a traveler's bloodstream, triggering that country's epidemic as the virus raced through a population with no immunity.
Even as Zika immunity spreads in Brazil, there's a danger that stems from its famously dense tropical forests and jungles. The Zika virus could retreat to what scientists call a "sylvatic reservoir" in which infected forest-dwelling primates harbor the virus, ready to fuel future epidemics by passing on Zika through mosquitoes back to new human generations lacking immunity. That's similar to what scientists say accounts for the sporadic outbreak of other, more lethal diseases such as Ebola, which can be harbored by bats.
"After this initial wave there could be a long lull of years or even decades," Lessler said. "But it's possible it sticks around and comes back from time to time."
But figuring out if that can indeed happen with Zika in Brazil — as well as answering other fundamental puzzles posed by the virus — will likely require researchers to go back to the beginning, to determining how it emerged and became established in Africa, and how prevalent it remains among people on the continent, Lessler said. Some of the things the scientists don't know about Zika in Africa: Whether there are sylvatic reservoirs in the continent, why there have been no large-scale outbreaks, and whether one could still occur there.
A rhesus monkey in Uganda
The Zika virus was first identified in the blood of a rhesus monkey at a research institute in Uganda in 1947 and was subsequently found in Aedes africanus mosquitoes, according to articles published by Science and WHO. The first case of human infection was confirmed in Nigeria in 1954.
A WHO timeline says that between the 1960s and 1980s, Zika spread from Africa to Asia but produced no large outbreaks until the 2007 outbreak in Micronesia. Some researchers suggest that frequent exposure to the virus in Africa and Asia produced widespread immunity, lessening its impact. Outbreaks may have simply been missed because so many of those infected show no symptoms, and because the symptoms of those who do get sick can be confused with those of people with mild cases of dengue and chikungunya.
Evidence in this period also emerged that Zika can be spread through sexual contact, something now confirmed.
In early 2015, Brazilian authorities notified WHO of 7,000 cases of an illness featuring skin rashes in northeastern states, and authorities confirmed the cause as Zika later that year. By then the virus had spread to 12 Brazilian states, and numerous cases of related Guillain-Barré were being reported as well. By October, Brazilian authorities were reporting an associated rise in the incidence of microcephaly, as the virus began popping up in neighboring Colombia and Suriname. By end of 2015, the first locally transmitted case in Puerto Rico was confirmed.
Another badly needed tool that's now lacking, he said: a simple and fast test to determine whether someone has Zika antibodies. Right now, doctors can determine whether someone is carrying the virus, but researchers believe it doesn't linger longer than 24 days in most infected people. That means it would be hard to determine whether someone had Zika after the fact.
But the easy detection of antibodies will be essential to conducting surveys to determine how many people actually have been infected in an outbreak, a critical clue in understanding how far and fast Zika can spread, and what the risk to people will be in future waves of infection, Lessler said.
In the meantime, he and UF's Cummings urge people in declared Zika zones in Wynwood and South Beach to heed health officials' advice and avoid complacency. While the chances of developing the worst effects, such as Guillain-Barré or microcephaly, most likely remain small, the risks are real.
People might just have to get used to routinely using insect repellent, wearing long sleeves at times when mosquitoes bite, or avoiding places where they do entirely, whether in readiness for the next Zika wave, maybe as soon as next year — or something else.
"We can see this sort of thing is happening with increasing frequency," Cummings said, citing previous outbreaks of travel-related mosquito-borne diseases in South Florida. "What Zika portends is that, because of increases in global travel between areas harboring viruses that we don't have here, we're going to see more and more of these viruses. There are other flaviviruses that are circulating in Asia and Africa that could be the next Zika.
"We need to be prepared."
Contact Andres Viglucci at [email protected]