In the Magazine Tech & Science

How a Small Team of Doctors Convinced the World to Stop Ignoring Zika

03_11_Zika_02
Mothers and their infants, all born with microcephaly, gather for a group photo during the two-month birthday celebration of Juan Pedro, second baby from right, at the Altino Ventura Foundation, a treatment center that provides free health care, in Recife, Brazil, February 4. With a proven link to Zika, researchers fear an unimaginable potential that the likely deadly disease could become as widespread as the common cold. Felipe Dana/AP

UPDATED | Saturday, February 13, 2016, was D-Day in Brazil, the launch of the most important battle yet in the war against Aedes aegypti, the mosquito that transmits the viruses that cause yellow fever, dengue, chikungunya and, most pressing today, Zika. Armed with insecticides and leaflets, and accompanied by thousands of soldiers, the Brazilian government—including President Dilma Rousseff and almost all the ministers—took to the streets to convince people to do everything they could to rid their homes of the mosquito. The country needed to do in a few months what it has not been able to accomplish in the 30-plus years since the first case of dengue, a potentially lethal, flu-like illness, was registered in Brazil in 1981: close ranks against the vector.

Aedes aegypti is endemic in Brazil—the blood-sucking insect is found in almost all of the more than 5,000 counties in the country. This one species of mosquito is responsible for Brazil’s annual epidemic of dengue that kills hundreds and sometimes thousands of people. Brazilians have learned to live with dengue, but in the first months of 2015 infectious disease experts began to see what they believed was a new mosquito-borne illness. It tended to cause flu-like symptoms, a light fever and a pinkish rash that disappeared in a day or two. Most local health care workers were treating it as though it were dengue. But when Dr. Kleber Luz, an infectious disease expert based in Natal, the capital of the state of Rio Grande do Norte, looked at the symptoms patients were presenting with, he quickly suspected it was not dengue. He called up a colleague, Dr. Carlos Brito, a researcher at the Osvaldo Cruz Foundation (Fiocruz) in Pernambuco, one of Brazil’s most prominent infectious disease institutions. Its specialty: arboviruses, the viruses transmitted by mosquitoes, ticks or other arthropods, including dengue, yellow fever and West Nile. “We collected more than 500 samples, and we insisted that it was not dengue, that it was something urgent and new,” says Luz. After ruling out other options, the two experts concluded it had to be Zika.

Zika has been known for decades in Africa and parts of Asia, but it had never spread in South America, so the doctors’ conclusion was met with distrust. The Ministry of Health was contacted, but the Brazilian government wasn’t convinced. Whatever was going around had no dangerous symptoms or long-lasting effects, and people weren’t dying. So the government chose not to implement mandatory reporting for the infection, and when the summer of 2015 ended, so did any worries about Zika. “There was enormous resistance to the idea that it could be Zika. Health authorities did not believe Zika would come to Brazil,” says Luz. “They underestimate the speed diseases spread around the world these days.” Frustrated, the doctors decided to form their own group to study the virus.

 

The first signs that Brazil was facing a terrifying wave of birth defects came in August 2015, when neuropediatrician Vanessa van der Linden was called in for a consultation in Recife. A woman had just given birth to twin boys; one had a severe case of congenital microcephaly, which results in an abnormally small head that compromises cognitive function. The doctors could not find a cause for it. “It was a private hospital, so I could investigate all the possible causes and do different kinds of tests,” says van der Linden. “But nothing showed up, Something was not right there, but I could not find what it was.” At the time, it seemed to be an extraordinary occurrence—after all, it was only one baby, a rare case.

But two weeks later, during her regular rounds, van der Linden found three more babies with microcephaly. And in the next week, two more. “I called my mother, who is also a neuropediatrician, and she had seven cases. It could not be a coincidence,” says van der Linden. In just two weeks, the doctor encountered more than 15 cases of microcephaly, more than would normally be found in a whole year. At one point, van der Linden says, “we had three cases in one night, when we would normally pass through four months without a single case. We had to investigate.”

Van der Linden was the first doctor to raise the alarm. She reached out to the Pernambuco Health Department. The authorities there searched the local hospitals and concluded that van der Linden was right: The registered cases of microcephaly were much higher than the year before, and none seemed to be due to the more common causes of the illness, such as rubella, cytomegalovirus, toxoplasmosis, HIV or parvovirus. The Ministry of Health in Brasília was informed. Its response was to call in a team of one: Carlos Brito.

Brito started simply. He asked questions, interviewed dozens of mothers, some as young as 14, who had recently given birth to babies with microcephaly so severe that the infants had constant seizures. “It was a very painful and distressing time,” says Brito. “What could we say to them if we did not know exactly what was happening? We had to find an answer, and fast.”

After a few days of research, the doctor developed a theory: The microcephaly could be caused by the Zika virus. Brito had the evidence. The mothers were of all different ages, were not using similar medications and, perhaps most important, they came from very different places. “The dispersal was too extensive,” says Brito. “It could not be an outbreak caused by a disease transmitted by saliva, such as rubella, or a sudden decline in immunity that would allow the spread of cytomegalovirus. It needed a vector.” Every mother tested negative for the common causes of the illness, and every one had experienced the Zika symptoms of a rash and a fever during their first trimester, which coincided exactly with the early 2015 Zika outbreak.

 

The fear of being right quarreled in Brito’s mind with the fear of being wrong. If it was Zika, there was the unimaginable potential that microcephaly could become as widespread as the common cold. Aedes aegypti is in every city in every part of Brazil, and for 30 years the country had tried—and failed—to control the pest. But if Brito was wrong, he could cause a panic and further delay the research needed to unearth the true cause of the microcephaly outburst.

Brito called his colleague, Luz, to find out if he was seeing the same pattern in Rio Grande do Norte, where the first cases of Zika had been registered the previous year. “In 12 hours, we found 11 cases,” says Luz. “And the time of the pregnancy could be traced to the beginning of the Zika outbreak.” Still, the doctors could not find proof that the virus had infected any of the babies. Symptoms of Zika normally disappear after one or two days. The virus leaves no trace in the body except antibodies, the unique proteins organisms produce to fight an infectious disease, and at the time there was no test that could find the presence of the antibodies in blood samples from either mother or baby.

When news began to spread that there might be a link between Zika and microcephaly, scientists through Brazil searched for signs in affected newborns. In Pernambuco, for example, the scientists at Fiocruz were applying a method called polymerase chain reaction to amplify traces of viral DNA in the hopes of locating Zika DNA remnants in the affected babies, but without success.

The hunt was fruitless until a month later. Dr. Adriana Melo was treating two pregnant women with unborn babies who, in the womb, appeared to have abnormally small heads. Both fetuses also had stunted cerebellums (a part of the brain that controls the muscles, hearing and eyesight), not usually a symptom connected to congenital microcephaly. “In 17 years as a doctor, I had never seen anything like that,” says Melo. “A few days later, I received a [text] in a researcher's group about the suspected link between microcephaly and Zika. And then it hit home: It was the only possible explanation.”

Melo reached out to colleagues in search of a way to test the two women for Zika, but none of the private laboratories she typically used had the tools necessary. “I did not have any contacts at the Ministry of Health and did not know the public ones that were beginning to research Zika. It took almost two months to find a way,” Melo says. Eventually, a friend mentioned a researcher at Fiocruz. “On the day of my birthday [November 5], she called me,” says Melo. “We talked for two hours, trying to figure a way to send amniotic liquid to Rio de Janeiro while my guests celebrated [my birthday] for me.”

When the results came back, Melo’s suspicions were confirmed: There were traces of Zika virus in the amniotic fluid. For the first time, the virus was found in contact with malformed newborns. “This was what we needed to confirm the link between the microcephaly and Zika,” says Brito. The Ministry of Health, however, considered the connection “very likely” but not confirmed. Two weeks later, on November 28, another Brazilian research foundation confirmed that their scientists had found the virus in the brain of a stillborn baby. The Brazilian Ministry of Health released a statement that day saying Zika was the cause of the microcephaly outbreak.

It took another six weeks for the World Health Organization to issue a worldwide alert, despite the pleas of the Brazilian government, which had already declared a national health emergency. In February 2016, the WHO convened an emergency committee of independent experts to assess the severity of the Zika outbreak. According to a WHO spokesperson, "this was four days after French Polynesia notified WHO of a retrospective investigation that detected a 20-fold increase in Guillain-Barre syndrome during the 2013-2014 Zika outbreak there." In consultation with the committee, WHO decreed a global health emergency. After weeks of sleepless nights, Brito—the father of three young women—could finally breathe; the world had opened its eyes to the medical crisis that was first uncovered three months ago by a small group of doctors in northeast Brazil.

Public health officials across the Americas are now working feverishly to devise some solution to Zika. There are the research projects that sound halfway between science and fiction, like releasing into the wild lab-made versions of Aedes aegypti that have been genetically modified to quickly render entire populations sterile, or using bacteria that live in the mosquito’s gut as a sort of Trojan horse to deliver molecules that could shut off the insect’s ability to reproduce. There are the Hail Mary proposals, like bringing back DDT, a powerfully effective neurotoxic insecticide that has widely fallen out of favor since Rachel Carson’s 1962 book, Silent Spring, revealed it caused environmental havoc.

Then there are the more mundane answers, like providing citizens with the basic knowledge and tools (environmentally friendly insecticide) they need to avoid infection and recognize Zika if it arrives in their home. Another simple solution is to bring better family planning options, like birth control and legalized abortion, to parts of South America where women with unwanted pregnancies have no legal recourse. Giving women more control over their reproduction, many say, would alleviate the real concern: the heightened risk that an infected woman would give birth to a child stricken with microcephaly.

Speaking of prophylactics—perhaps the real panacea would be a vaccine, distributed to every citizen of every troubled country. And it could be on its way; the U.S. National Institute of Allergy and Infectious Diseases, for one, is ramping up its efforts, focusing on adapting a West Nile virus vaccine that was recently successful in Phase I trials. Butantã, a Brazilian public lab, is in the last phase of a trial for a dengue vaccine in a partnership with NIH and they believe their protocol could be used to develop a vaccine for Zika. Fiocruz is working with a consortium of European labs to develop a vaccine as well. Big Pharma is looking into it too; Sanofi Pasteur, for example, has launched an initiative to leverage the work it has done with a recently approved dengue vaccine to quickly develop one for Zika. Quickly, though, is a relative term here. Realistically, a vaccine could take millions of dollars and several years to design, test and distribute.

So far, there have been 3,893 suspected and 508 confirmed cases of microcephaly in Brazil; in 41 of these, the link to Zika infection has been verified. On February 19, the WHO announced that a group of researchers from the U.S. Centers for Disease Control and Prevention and a Brazilian biotechnology company in the northeastern states of Bahia and Paraíba had found evidence of the Zika virus in autopsies conducted on infants with microcephaly, further solidifying the connection between the two health issues. Nevertheless, conspiracy theories abound in Brazil about the “true” cause of the microcephaly outbreak, ranging from expired vaccines to the use of larvicides or transgenic mosquitoes. These are fed by the fact that other countries, such as Colombia, have found the presence of Zika but no microcephaly.

“We do not have all the answers yet, of course. It is an ongoing investigation,” says Luz. “Perhaps the virus had a mutation before coming to Brazil? What we cannot do is to wait months to be 100 percent sure. We have to do something now.”

This story has been updated to clarify that the WHO was responsible for convening an emergency committee in February 2016 to assess the severity of the Zika outbreak.