Zika

by Donald G. McNeil

  On April 14, 2016, I wrote another article, entitled “Health Officials Split Over Advice on Pregnancy in Zika Areas.”

  By this time, outside experts were even more aghast at the CDC’s reluctance.

  “It’s a no-brainer,” said Peter Hotez, dean of the Baylor tropical medicine school. “They should say, ‘Don’t get pregnant—watch TV for six months and you won’t have a badly hurt baby.’”

  Houston had just had a flood and was swamped in water. He published an op-ed piece in the Times saying how dangerous the summer was likely to be. CBS News interviewed him, and he took the camera crew around a poor neighborhood, showing them old tires full of water that were mosquito havens.

  He told me that he had specifically said during the interview that women in Houston should consider not getting pregnant. CBS decided not to use the statement. He had said the same thing when PBS NewsHour interviewed him on April 18, and PBS did use it.

  As of this writing, the CDC and the WHO are unmoved. Dr. Aylward acknowledged that the WHO was having its own internal debate—“theoretically, many have thought it may work”—but it was not going to issue official advice. There were too many unknowns, he said, including how long to wait. In a country of 200 million like Brazil, the epidemic would not necessarily fade away as it had on islands, and the risk period was now the whole pregnancy, not just one trimester.

  PAHO was leaning more toward nodding approvingly as individual member countries suggested it. Dr. Marcos Espinal, who was running that agency’s response, said he “did not have a problem with waiting three to six months,” as Colombia had suggested. “But I do have a problem with two years,” as El Salvador had, he said. “You’re changing a whole generation.”

  It could be argued that thousands of children with birth defects could change a whole generation to an even greater extent.

  12

  The Future

  WHAT NOW?

  No one knows for sure. The epidemic is still emerging. Predicting how viruses will behave is a fool’s errand. Predicting people is worse.

  But some things are clear:

  Zika is very much on the move. Transmission is increasing in Central America and the Caribbean, and will keep doing so at least until the fall. The disease is now headed for its first summer in the United States, where no one has immunity.

  That doesn’t mean an explosion is inevitable. The CDC expects “limited clusters” anywhere in Florida or in parts of Alabama, Louisiana, Mississippi, and Texas close to the Gulf of Mexico. Hawaii is also considered vulnerable. That has been the national experience thus far with dengue and chikungunya, which are carried by the same mosquitoes. There have been pockets of cases in Key West and Martin County in Florida, in Brownsville, Texas, and on several Hawaiian islands.

  But the outbreaks stayed small because most Americans, even in poor neighborhoods, have screened windows and air-conditioning. From a mosquito’s standpoint, we live in nearly impregnable castles. American children don’t usually get dozens of bites each night as poor children in Brazilian slums do, so the mosquitoes can’t spin up a viral whirlwind by transferring it frantically from neighbor to neighbor.

  The other reason earlier outbreaks never spread was that the authorities sprang into action fast. In 2009, it took only three dengue cases in Key West for the Florida Keys Mosquito Control District to roll out its helicopters and truck sprayers, to send teams down the island’s streets with pesticide foggers and backpack tanks that shot larvicide into pools of water, to disperse other teams that went house to house asking residents to check their birdbaths and gutters, chlorinate their pools, and drop larvae-killing pellets into everything that collected rainwater. It was an impressive effort; although the outbreak ultimately lasted two years, it was held to ninety known cases. Even more impressive: the first case was in faraway Rochester, New York, in a woman who kept going back to her doctor saying, “I don’t feel right,” even after the doctor had diagnosed and treated her problem as a urinary tract infection. Eventually, on her third visit, the doctor consulted an infectious disease specialist, who suggested a dengue test because she had visited Key West—even though dengue had not been seen in Florida since 1934.

  However, Zika is different. Many dengue victims and 80 percent of all chikungunya victims see doctors quickly because they have high fever, headaches, and joint pain. Outbreaks are spotted early.

  But 80 percent of all Zika cases are silent, and many symptomatic ones are mild. People often ignore early signs for days and call a doctor only when they look in a mirror and see bright red bloodshot eyes and a chest covered with a rash.

  As a result, outbreaks may spread widely before anyone calls the mosquito teams. The more that happens, the thinner the teams get stretched.

  Zika’s spread may end up more closely resembling West Nile’s. That virus also has silent cases. It’s unlike Zika in that it’s carried by Culex mosquitoes, which live all over the country. Also, it must simultaneously circulate in birds, whose hotter blood amplifies the virus enough for new mosquitoes to pick it up and infect humans. Nonetheless, despite helicopter spray flights and plenty of scary public service announcements when it arrived, it proved unstoppable. It entered the United States in New York City in 1999 and made its way slowly but steadily west for six years. All that held it up was winter. It moved a few states west each summer, then had to wait for the birds and mosquitoes to come back. It didn’t really infest the Pacific Northwest until 2005.

  West Nile is now endemic in the United States. It circulates every summer. About 2,000 cases are diagnosed each year, and about 100 persons die of it; the typical victim is a man over 65. Occasionally, there are sudden outbreaks, like one in 2012 that killed 69 people in Dallas–Fort Worth, pushing that year’s death toll to a record 286.

  Even if something like that happens with Zika, there will probably never be a huge surge of microcephaly in the continental United States. If West Nile caused brain damage in 1 in 1,000 cases, then 2 babies would be harmed each year. (One-in-1,000 odds is a very crude estimate from Brazil, where it was estimated that 1.3 million infections occurred in 2015, and the country has had more than 1,400 confirmed cases of microcephaly. But cases are still being confirmed and infection numbers in Brazil are still growing, so the ratio could change.)

  But there is no guarantee that Zika will follow that pattern. There are too many uncertainties. How far Aedes aegypti will range this summer will depend on how hot and wet the weather gets. Aedes albopictus mosquitoes will range farther, since they tolerate lower temperatures, but whether they will aggressively spread Zika is still unknown.

  If the virus is ever going to hit hard, this summer will be its best opportunity, since virtually no one is immune. If it persists and becomes endemic like West Nile, each summer’s outbreaks will be limited by the growing portion of the population that is immune.

  On the other hand, if it does that, it will never completely go away. Even if many women choose to hold off getting pregnant this summer, that can’t last forever, so they will eventually be at risk. Their best hope will be a vaccine.

  Dr. Stanley A. Plotkin, inventor of a rubella vaccine, predicted in January that making a Zika one would be relatively easy. Vaccines against other flaviviruses, including yellow fever and Japanese encephalitis, already exist. So it should be possible to take the “spines” of those vaccines, he said, and just attach Zika antigens, the proteins that provoke the immune system to make the right antibodies.

  A majority of Americans—55 percent—polled by the University of Pennsylvania’s Annenberg Public Policy Center in May said they would be likely to get a vaccine if there was one.

  At least 18 private and public research labs are working on vaccines, from the Butantan Institute in Brazil to Bharat Biotech in India to a partnership of South Korea’s GeneOne Life Science with Philadelphia’s Inovio Pharmaceuticals. Some are producing “killed” versions and
some “live, attenuated” ones. In the former, the virus is grown in cells, killed with heat or a chemical like formalin, and purified. In the latter, the human virus is weakened by one of several methods. It can be passaged through monkey cells or chick embryos or something else nonhuman; it can be forced to grow in nonhuman conditions such as low temperatures, or a piece of its genome can be snipped out or silenced. Once injected into a human, it reproduces for a while, but slowly, until the immune system dispatches it. Live vaccines provoke the strongest immune responses, but are also the riskiest, because they do grow and, in very rare cases, mutate into something threatening. They are not usually used in pregnant women or immune-compromised patients.

  The National Institutes of Health has three vaccines in the works, said Dr. Anthony S. Fauci, who oversees them. One is a killed vaccine, one is a live attenuated, and one—the farthest along—is a new technology called a DNA vaccine. In that one, bits of the Zika virus’s genes are spliced into a plasmid, a small ring of DNA that can break into cells the way a virus does. Once inside, it generates “virus-like particles,” which have enough pieces of the Zika virus for the immune system to react to, but aren’t whole virus and so can’t cause disease. The live attenuated one is a “chimera,” so named after the mythical beast with three heads: lion, goat, and snake. The scientists took an already-weakened dengue vaccine virus, snipped out the genes coding for the viral shell, and inserted those genes from the Zika virus into their place.

  As of this writing, the DNA vaccine is supposed to move into the human-testing phase by September, and the two others are to follow within about six months after that.

  That doesn’t mean any vaccine will be ready soon. The most optimistic scenario Dr. Fauci predicts is two years, if everything goes right. Most experts expect three to five. Pessimists say twenty to never.

  Testing proceeds in stages. Phase I is safety testing to make sure no completely unexpected side effect shows up. In this case, it will probably be in about 80 healthy adult volunteers from the area around NIH headquarters in Bethesda, Maryland. They’ll be watched for three months.

  By January, if that goes well, testing will move to a country with active Zika transmission and perhaps 2,000 or so volunteers will be recruited, initially just healthy adults. How long it takes to see whether a significant difference emerges in the number of infections between those who got the vaccine and those who got placebos will depend, Dr. Fauci said, on how intense the transmission is. In a raging epidemic, it could appear in months. In one that has faded, it could take years.

  Meanwhile, safety testing will begin on children, the elderly, and perhaps even pregnant women. Those involve tougher ethical decisions. Normally, pregnant women are the absolutely last group any vaccine or drug maker agrees to experiment on. If it harms babies—and some experimental vaccines, notably an HIV one, have actually increased infection rates—the moral guilt is a bottomless pit. Not to mention the lawsuits. But pregnant women are the whole reason for making a Zika vaccine. Most likely a killed vaccine will be tested in them, Dr. Fauci said, but live ones will not.

  If the epidemic has completely died out everywhere—which seems extremely unlikely—then the last options are “viral challenges” and “monkey models.”

  In a “challenge,” some healthy volunteers who have been vaccinated and then tested to be sure they have antibodies will be deliberately injected with Zika to see whether it protects them. It can probably be done ethically because it’s usually a mild disease. (I say “probably” because an ethics board will have to weigh the Guillain-Barré risk.) Ebola vaccines aren’t challenge-tested because Ebola kills. Malaria vaccines, however, are—because there is a cure for malaria. If the vaccine flops, you can still rescue your volunteers.

  Because of modern PCR testing, scientists can now use monkeys, whereas scientists in 1947 could not. Even if all monkeys remain visibly healthy throughout testing, if the virus builds to high levels in the blood of unvaccinated ones after a challenge but does not in vaccinated ones, it works.

  However, some experts, like Michael T. Osterholm, who runs the University of Minnesota’s Center for Infectious Disease Research and Policy, harbor doubts that there will ever be a vaccine—because of Guillain-Barré. Some vaccines, in rare cases, also trigger it. If it is a side effect in the range of 1 in 4,000, as French Polynesia’s outbreak suggested, many thousands of volunteers must be recruited to make sure the vaccine clearly does it less often than the disease. Even a random Guillain-Barré case or two from any cause will scramble the testing statistics.

  There are other ways to fight a virus, of course.

  The most practical solution would be a treatment, or even a cure. But to hunt for a cure, you must know exactly how a virus does its damage, and science is only beginning to figure that out for Zika by trying to re-create every stage of the infection process in mice. The placenta is a series of semipermeable barriers between the mother’s blood and the baby’s, and it’s not clear how the virus breaches those barriers, but a new study found 1,000 times as much virus in fetal mouse placenta as in the maternal blood. It is also not known exactly how the virus attacks the growing brain, but more than one recent study has suggested that it targets radial glial cells and may break into them through a surface receptor known as AXL. Radial glial cells appear very early in the brain-formation process and resemble snakes that have swallowed prey; they are long and stretched very thin but with a bump in the middle where their nuclei are. Their long, thin tentacles connect layers of the brain, with “feet” at one end and hairlike cilia at the other. They are believed to be the scaffolding that guides into place other cells, like astrocytes and neurons, that will ultimately form the brain, so any injury to them is devastating. AXL receptors are common on radial glial cells, and they are also thought to be the means through which Zika enters skin cells—which suggests that there may actually be a common thread to two very different Zika symptoms: skin rash and fetal brain damage. But the science is very new and nothing is yet certain.

  But even if the mechanism is figured out, there is no guarantee that a cure can be found. There are many antibiotics that kill bacteria, and many chemotherapeutics that fight cancer. Unfortunately, relatively few drugs kill viruses.

  A tumor is just a regular human cell that has gone haywire and is growing far faster than it should. Many drugs kill human cells; the trick is finding drugs that kill fast-growing ones while sparing healthy ones. Bacteria are practically animals: they ingest molecules, they make proteins, they move, they even catch viral infections. They have many processes that can be interrupted.

  Viruses, on the other hand, are just shells containing bits of RNA or DNA that hijack cell machinery. Hepatitis C is one of the few viral infections that drugs can actually cure; for those patients, antivirals like Harvoni are miracle drugs. Some drugs merely slow viral replication down, as Tamiflu does influenza or Atripla does HIV.

  There is no proven cure for flaviviruses like Zika. In virology journals, many papers describe flavivirus “inhibitors” that work in cell cultures. Most are obscure chemicals that turned up when whole libraries of chemical compounds were screened. One paper published in 2012 was intriguing; it said ivermectin was highly potent against yellow fever and somewhat effective against Japanese encephalitis. William C. Campbell and Satoshi Omura won half of the 2015 Nobel Prize in Physiology or Medicine for inventing ivermectin, and it is the cornerstone of campaigns against worm diseases like river blindness in Africa. It is well-known to American pet owners; it’s the active ingredient in Heartgard for dogs. (It was also the drug Brian Foy was investigating in Senegal.)

  Other papers say various hepatitis C drugs work against Zika in the lab, as well as chloroquine, an antimalaria drug discovered in 1934, and amodiaquine, a newer antimalarial. The last two are both known to be safe for pregnant women. Many drugs may have potential, but none have been approved yet.

  In theory, another route wo
uld be monoclonal antibodies. During the 2014 Ebola epidemic, much fuss was made over ZMapp, a cocktail of three cloned antibodies that had completely protected monkeys in tests. By the time the outbreak ended, however, it had been given to only seven people, two of whom died. Its maker said supplies had run out.

  Antibodies are expensive to manufacture in bulk. ZMapp was produced from a chimera of mouse and human genes, then grown in tobacco plants, extracted, and purified in tiny amounts. Scientists spent many years developing it. Work on Zika would have to start from scratch.

  Immunoglobulin—antibodies derived the old-fashioned way, from human blood—has been used to treat Zika-related Guillain-Barré.

  It has been used occasionally in pregnant women with Rh-negative blood and histories of multiple miscarriages, to protect the fetus. But it carries other risks and is cumbersome to get and administer, so no one has yet suggested a role for it in pregnant women.

  CDC guidelines for doctors treating pregnant women with confirmed Zika are heartbreakingly simple. Doctors should offer “supportive care,” like headache and fever relief, and ultrasounds and MRIs every three to four weeks. That—and encouragement to hope for the best—is all they have.

  When microcephaly began making news in January 2016, doctors said it usually could not be detected before the third trimester, about the 28th week of pregnancy, which put women under tremendous time pressure while they struggled with an agonizing decision over whether to terminate. That time has been reduced—there are cases where fetal brain abnormalities were picked up as early as week 19. But it is not predictable, and no one knows how soon after an infection damage will appear.

  Because no one in this hemisphere is immune, PAHO has predicted that the virus will reach every country except Canada and mainland Chile. In the South Pacific, it is still spreading to new island groups, such as American Samoa and Fiji, causing intense outbreaks. It also reached the Cape Verde Islands, which lie in the Atlantic between Brazil and Africa and are Portuguese-speaking; the virus is the same as the one in Brazil. It has even gone as far as the Maldives in the Indian Ocean.