Zika (17 page)

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 would 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.

The initial worries that it would circle the globe, however, seem to be getting more remote each day. Europe and most of northern Asia don't have
Aedes aegypti
. The worry was that the Cambodian-Polynesian-American strain of Zika would be so different from earlier Asian and African strains that they would not be protective. But surveillance has been conducted since January and, while sporadic Zika cases have been found in Thailand and other Southeast Asian countries, they weren't part of big outbreaks. Only wide serosurveys will tell whether herd immunity from endemic transmission is high all over Africa and Asia, but the lack of intense outbreaks—particularly in Senegal, which is closely connected to the Cape Verde Islands—suggests it is.

In U.S. territories such as Puerto Rico and the Virgin Islands, the epidemic is expected to grow in intensity all summer. Guillain-Barré and other autoimmune diseases like ITP are already on the rise, and on May 13, 2016, Puerto Rico's health department announced that a woman on the island lost a baby that turned out to be microcephalic. Puerto Rico has 3.5 million people, and Dr. Johnny Rullán, the island's former health secretary and now the governor's special assistant for the epidemic, conservatively estimated that every 10,000 circulating infections would trigger one autoimmune reaction, so there could be 350. (French Polynesia's experience would suggest there will be more like 850.)

Ultimately, hundreds or thousands of Guillain-Barré victims needing mechanical ventilation might put a far greater strain on the hemisphere's hospitals than neonates needing intensive care, especially if women decide on their own to hold off pregnancies.

Some doctors in the United States, especially in mosquito-prone areas, are privately suggesting that to patients, and more are saying so publicly. Dr. Edward Goodman, chief epidemiologist at Texas Health Presbyterian, the Dallas hospital made famous two years ago because two of its nurses caught Ebola while caring for a patient, went on television to suggest that women in Dallas consider delaying pregnancy.

At the Zika summit in Atlanta, Dr. Ana Ríus said women in Puerto Rico seemed to be taking her advice: the birthrate was dropping, and the island was on track to have only 28,000 babies in 2016, some 8 percent fewer than in 2015.

Americans' knowledge of the disease is getting more sophisticated, according to the Annenberg Center, which has been doing polls about Zika since February 2016. Early on, half of all Americans worried it would come to their neighborhoods, many thought all mosquitoes had it, and 42 percent thought it was usually fatal. By April, a majority answered that infants and pregnant women are most at risk.

Terrible consequences may
not
come to pass. In the continental United States, Zika may be contained, or may spread far more slowly than anyone fears. Many women may successfully protect themselves through birth control, moving out of danger zones if they can, or minimizing bites.

There certainly will not be the overwhelming flood of microcephalic neonates in American hospitals that there was in Brazil. It will probably not be as bad anywhere else in the hemisphere. Brazil was caught utterly by surprise when thousands of its babies were at or near term. Now many countries' medical establishments are on the alert, doctors are ordering ultrasounds, and many women may choose to terminate. Some will be able to do so legally; some may find another way.