Zika Read online

  When it was all over, they were able to say that their mystery virus wasn’t yellow fever, dengue, West Nile, Eastern or Western or Japanese or St. Louis encephalitis, louping ill, Canfield B, Ilheus, lymphocytic choriomeningitis, Bunyamwera, Semliki Forest, Ntaya, or Bwamba fever.

  It was “hitherto unrecorded,” they said, and therefore a new discovery. They named it Zika.

  But for the next 60 years, until 2007, it was barely heard of. In all that time, only 14 active human infections were described.

  The first was described in 1952, by British health authorities investigating an outbreak of jaundice in the Afikpo Division of eastern Nigeria, which was then a British colony.

  It was in “an African female aged 10 years.” She was brought to a clinic because she had fever and headache. She was not jaundiced, but she had a fever of 100.8 degrees.

  The two other patients in the study were men, aged 24 and 30. Both had antibodies to Zika but not the virus; only the girl had something in her blood that made mice sick.

  By an abbreviated version of the mouse tests done in the first paper, it was shown that she did not have yellow fever, West Nile, Bunyamwera, Bwamba, Ntaya, Mengo, and so on—and that she did have Zika.

  The author of the paper describing the first human Zika infection was Francis N. Macnamara, acting director of the Virus Research Institute of Yaba, Nigeria. A lot of top-notch research in tropical medicine during the colonial period was done by British, French, and Belgian scientists, much of it to keep African workforces alive and the troops of the colonizing power healthy. Dr. Macnamara’s institute was the foundation for the Nigerian Institute of Medical Research, which is in the Yaba district of Lagos, the country’s financial capital. Macnamara noted that the young girl’s blood “contained numerous malaria parasites” but reassured readers that “in tropical Africa, infection with more than one pathogen is the rule rather than the exception” and that his tests were not confounded by the presence of malaria.

  The 10-year-old female was reported to be “completely recovered six weeks later.” So neither the Zika nor the malaria was fatal. That is not surprising; even today, kids in malarial regions of rural Africa who live past their fifth birthday have usually had malaria so many times that they are largely immune. It normally gives them just a debilitating fever.

  Dr. Macnamara’s paper was partially off base. He was investigating a big outbreak of jaundice, so its chief concern was whether or not Zika causes jaundice. (It generally doesn’t—the poor girl was caught up by accident in an investigation of what was probably a completely different disease.)

  But the paper contained a couple of very interesting asides.

  One notes that the strain found in Nigeria “became adapted to mice more readily” than the original strain found in Uganda. Macnamara speculated that this was due to the fact that the Uganda strain was found in a forest, “whereas the Nigerian strain was probably well-adapted to man.”

  The paper also mentions, just in passing, a set of blood tests that the Yaba institute did on residents of the town of Uburu. Of the 84 residents tested, 50 had antibodies to Zika virus.

  The first deliberate infection of a human with Zika was reported in 1956. It was in a human volunteer described as “a 34-year-old European male who was resident in Nigeria for a period of 4½ months prior to inoculation and had not contracted any known infection during that time.” In other words, it was a new researcher at Dr. Macnamara’s laboratory, William G. C. Bearcroft, who decided to infect himself.

  After marking the spot on his left arm with an indelible pencil, he injected a “6th mouse brain passage material of the Eastern Nigeria strain of Zika virus (Macnamara, 1954) which had been preserved in sealed ampoules in the dessicated state at a temperature of –50 degrees C. for a period of 2 years.”

  He got a mild headache, a low fever—and no jaundice. He also let Aedes aegypti mosquitoes feed on him and then later on mice, hoping they would transmit the virus. Many of the mosquitoes died for unknown reasons, and none of the mice got the virus.

  There is a long history in medicine of researchers testing things on themselves. Modern ethics boards frown on the practice, but some important discoveries have been made that way. In this case, Dr. Bearcroft didn’t learn very much other than that Zika probably did not cause jaundice.

  Jaundice—caused by the buildup of bilirubin, indicating liver damage—was important since it was the classic sign of yellow fever, a dangerous disease. Reporting that a patient has jaundice (from jaune, French for “yellow”) literally means that his skin and the whites of his eyes have turned yellowish.

  In 1964, another researcher, this time a 28-year-old European male who had been in Africa only two and a half months, argued that the girl and Bearcroft had probably never had Zika, but rather Spondweni, a related virus. He claimed he was the first person to be able to scientifically describe the symptoms of Zika, because he had just had it. He was David I. H. Simpson. Simpson was a student of Dr. George W. A. Dick’s when he taught microbiology at the Royal Victoria Hospital in Belfast, Northern Ireland. Dick encouraged him to work abroad, and he moved to the East African Virus Research Institute in Entebbe, Uganda (which was a later name of the Rockefeller Foundation’s Yellow Fever Institute). Simpson said he contracted Zika in the course of his work with the virus at the Entebbe lab, which he had just joined.

  Interestingly, he was the only one to develop the most characteristic sign of Zika: “a diffuse pink maculopapular rash” on his torso, face, and upper arms that lasted for five days, finally spreading all over his body. He called the disease “mild.”

  After that flurry of interest, the virus appears only sporadically in medical history before 2007. Between 1960 and 1983, cases were detected in the Central African Republic, Gabon, Senegal, Ivory Coast, Cameroon, and Sierra Leone. At some point—perhaps in the 1960s, perhaps earlier—it moved to Asia. It was identified in Malaysia in 1969 and in Pakistan and Indonesia as early as 1977.

  Ultimately, a strain began to cross the Pacific. (Later genetic sequencing determined that it most closely resembled a 2010 sample from Cambodia, but so little sampling was done back then that there is no guarantee it started in that country. There is much more air traffic between the South Pacific and other places, like Indonesia.)

  Why wasn’t it studied more?

  And why didn’t it cause outbreaks of microcephaly during that time?

  The first question has several answers.

  Zika wasn’t studied because it was rarely even diagnosed. Its symptoms resembled those of other, more serious diseases, notably dengue. Those diseases were often circulating in the same country, so a doctor seeing a rash and fever would probably shrug and say, “It’s dengue, but mild. You’re lucky.” There was no point in sending a sample away—and nowhere to send it to. No lab routinely did Zika tests. Modern labs need “primers” for their PCR machines, a thermal cycler for amplifying DNA. The primers are short sequences of half the DNA “ladder” that match the other halves being run through the machine. For routine tests, primers are for sale in many forms. For extremely obscure viruses, a lab would have to create its own.

  Moreover, Zika was never considered important. Everyone thought it didn’t kill people or even hospitalize them. The scant medical literature on it described it as mild in humans. It also didn’t harm any valuable farm animals like chickens, cattle, pigs, or even camels.

  In the hunt for research funding, a virologist specializing in Zika would struggle to get grants, while those studying bird flus would see the dollars roll in because of the threat to the poultry industry and, later, the possibility that avian flu would kill millions of people. (The panic of a decade ago about avian flu is over. The threat is not.) That is a serious disincentive, and there are many orphan viruses that are known about, but not studied.

  And as the early papers showed, Zika was hard to study because there was no reliabl
e animal model. Small, docile, fast-reproducing creatures like mice, rats, gerbils, and rabbits are ideal, but they don’t always cooperate. The best model for human flu, oddly enough, turns out to be ferrets; human flus reliably make them lose weight, become lethargic, and sometimes die. But live ferrets—big furry weasels—are fast, fierce, and famous for a vicious bite.

  Monkeys get Zika, but don’t reliably fall ill from it. And monkeys have enormous drawbacks as animal models: they are expensive, they take lots of care and feeding, they bite, they throw feces, and they are smart enough to notice a missing or open lock and escape. They are also adored by animal-rights activists, who may conduct raids to free them. Moreover, monkeys caught in the wild may have unpredictable diseases that infect other primates, including humans. In 1989, a batch of crab-eating macaques shipped from the Philippines to Reston, Virginia, turned out to have a relative of the Ebola virus that jumped from monkey to monkey in the animal house and was also caught by a handler who cut himself working with them. Luckily for everyone in the lab—and possibly for everyone in the United States—that viral relative was not lethal to humans. The outbreak was ended by killing all the monkeys, sterilizing the building, and then demolishing it. It is now known as Reston virus.

  Haddow, Kitchen, and Dick had developed a mouse model through cumbersome “serial passage” through many mice. “Passaging” is a common technique in virology. For example, the “spines” of human flu vaccines were made by passaging human flu viruses through many generations of fetal chicks. When viruses are adapted to growing in chicks, they no longer reproduce easily in humans—and they can be grown in chicken eggs. Every year, millions of fertilized chicken eggs are used to grow flu vaccine. One crucial question for vaccine makers each year is whether they will have enough roosters to fertilize the eggs. Aging but still spry cocks destined to end up on supermarket shelves as ground-poultry products get temporary reprieves each year because they are on call to perform a vital task for the vaccine industry.

  But a virus that emerges at the end of a long series of mouse passages and attacks mouse nerve cells is no longer exactly the same as the virus that infects monkeys and humans. Scientists can only hope that any discoveries they make—any drugs that kill it off in those mice, for example—will work in humans, too.

  Only this year (2016) did scientists come up with easy mouse models for Zika. Nowadays there are dozens of strains of genetically altered mice for sale—mice that routinely develop the symptoms of Parkinson’s, multiple sclerosis, or Alzheimer’s, for instance. They are variants of the first “knockout mice.” Different genes in their DNA have been “knocked out,” or silenced.

  In March 2016, researchers at the University of Texas Medical Branch in Galveston announced that they had found a set of off-the-shelf mice known as AG129, which lack the genes to mount an interferon-based immune reaction, would succumb to Zika. Notably, the virus killed fetal mice but not adults, which paralleled its effect on humans. It was found concentrated in their brains, as it was in human fetuses. It also concentrated in their testes, as it was suspected to do in adult men. That made it a good model, although others were likely to be found, the researchers admitted.

  As to why it circulated for decades without causing microcephaly, we can only guess.

  In Africa, the answer is easy. It no doubt circulated there for centuries. The blood tests from Uburu showed that of 84 residents tested, 60 percent had had the virus. Children in most of Africa get thousands of mosquito bites as they grow up. If only a few of those bites had Zika in them instead of malaria, they would get it, recover, and be immune. If most girls, like the 10-year-old in the Afikpo Division, became immune before their child-bearing years began, they would never pass it to their babies.

  Why it never caused microcephaly in Asia is still a puzzle.

  There’s no certainty about how long it circulated there. It also remains unknown whether there were other factors, like a previous bout of dengue, that predispose some women to more dangerous infections.

  Another possible answer is that it did cause microcephaly—but that no one noticed. There have always been microcephalic children in Asia, as there are everywhere else, because the condition has many causes. Some degree of it occurs in between 1 in 5,000 and 1 in 10,000 births. Mothers can get infected during pregnancy for the first time with Toxoplasma gondii (a bacterium found in cat feces, which is why pregnant women are told to avoid cat litter boxes), with cytomegalovirus, herpes, or syphilis. It can also result from fetal alcohol syndrome, from drug abuse, from exposure to some industrial or agricultural poisons, or from severe malnourishment in the mother. And it can be caused by genes, like those that cause Down syndrome.

  A likely explanation may be that there were clusters over the decades, but they were blamed on rubella—German measles. In unvaccinated populations, rubella epidemics wax and wane. The virus blows through a population, infecting everyone, causing damage but creating herd immunity, and then disappears for a decade or more. It can’t return until enough new victims have been born to sustain a new epidemic. That’s why, in the prevaccine era, highly infectious diseases were called childhood diseases. Most teenagers and adults had already had them. But sometimes the gaps between epidemics were long enough that many young women entered their child-bearing years unprotected, as occurred in the United States in 1964, a year that saw a lot of birth defects.

  Until the huge efforts to vaccinate the world’s poorest children emerged in the last 15 years—thanks largely to the Bill and Melinda Gates Foundation and the generosity of American and European taxpayers—epidemics of childhood diseases like rubella and measles were far more routine in poor countries than they are now.

  Zika can hit anyone, but it is more likely to hit poor people, who live in slums with open gutters and piles of rain-collecting garbage where mosquitos breed. Poor people are also more likely to be exposed to other causes of microcephaly: not being vaccinated against rubella, living where feral cats roam, being poisoned by industrial chemicals in shantytowns that spring up near factories, suffering from severe malnourishment.

  In addition, poor people are less likely to give birth in hospitals. Home birth is a strong tradition in much of Asia. Even today, in India, Bangladesh, Pakistan, and elsewhere, many women are under family pressures to give birth at home with a traditional attendant. Going to a hospital may be seen by their grandparents as bowing to a foreign, Western medical tradition. And it costs money. Even in “free” public hospitals, doctors and nurses live on meager salaries, and their pharmacies are often empty. It’s not uncommon in poor countries to see a row of tiny pharmacy stalls outside the gates of big hospitals. They have the drugs that the hospital does not. A nurse knows what a patient needs, goes out to buy it, and charges the patient. So a young girl in Bangladesh may be pressed to both stand up for her culture and save the family money by giving birth on a floor mat.

  Microcephalic babies born at home are never counted. Without intensive care, some die quickly. Some that do live may just be hidden in the house out of shame—fear that they mean someone in the family angered the gods, for example. Brazil’s cluster was noticed because it took place in hospital wards. South America’s largest country, Brazil still has an emerging economy. It has some first-class hospitals, and even the poorest, most traditional families have heard that the outcomes for mothers and babies are better there than they are giving birth on the floor at home. So they go.

  At some point—no one is sure exactly when or where—Zika broke out of Asia. It would spend the next few years leapfrogging from island to island across the South Pacific like the Marines in World War II, but in reverse.

  3

  On the Move

  THE FIRST TIME Zika was noticed outside of Africa and Asia was in 2007, when Thane Hancock, a family physician working for the Yap Department of Health Services, sent an email to the CDC in Atlanta asking for help. Yap is one of the Caroline Islands in the west
ern Pacific, and about 500 Yap islanders, Hancock said, had come down with something that resembled mild dengue, but didn’t come up positive on the dengue test kits the island had on hand.

  Yap had a mere 7,000 inhabitants, so 500 cases constituted a big outbreak.

  Yap is part of the Federated States of Micronesia. In World War II, a Japanese bomber group and about 6,000 troops were based on it, and the U.S. Navy bombed it repeatedly. With Japan’s surrender, the United States seized the islands. They became independent in 1986, but signed a Compact of Free Association with the United States. They are not a territory like Puerto Rico or Guam, but still loosely attached, so when they needed help, they turned to the CDC.

  The email arrived in late May and was forwarded to the Epidemic Intelligence Service. The EIS is the CDC’s elite division of disease detectives, and competition to get into each year’s class of 75 trainees is stiff. Its symbol is a globe with a shoe sole superimposed on it, and the sole is worn through, like a detective’s who will stop at nothing. The service investigates about 100 outbreaks a year—everything from E. coli killing fast-food customers in the Midwest to rashes on an island half a world away.

  On June 13, Lieutenant Colonel (Dr.) Mark Duffy, an Air Force epidemiologist assigned to the division of vector-borne infectious diseases, and Dr. Tai-Ho Chen, a medical officer in the EIS Field Assignments branch, arrived on Yap. They immediately started seeing patients in the island’s five clinics and sent samples to the agency’s arbovirus laboratory in Fort Collins, Colorado.

  Dengue kept looking like the most likely explanation, Dr. Duffy said later, until the results came back on June 22. It was something new for the Pacific, and something that had never been seen causing a big outbreak before: Zika virus.