Racing Zika: For Every Short Cut, There’s An Open Question

Xconomy National — 

[Updated 3/15/16, 7:16pm; corrected 3/16/16, 7:00pm. See below.] In the Luganda language, zika means “overgrown.” It’s also the name of the Ugandan forest where, in the mid-20th century, researchers discovered the now-notorious virus. Dense forest is an appropriate and vivid image for the latest global health threat. So much about the virus and its effects are new to us, obscured from view, but researchers are slashing away at the undergrowth to reach shafts of light.

The virus is spread by the bite of the Aedes mosquito, and possibly person to person through sex. From what we know so far, the danger to most adults is at worst like a mild case of flu. But in pregnant women, Zika seems to be invading the fetus’s brain and causing microcephaly, an abnormally small head due to stunted brain growth. The links between microcephaly and Zika are not ironclad but looking stronger by the week. Infection during the first trimester of pregnancy seems to contribute to the risk.

There is also growing evidence of a link between Zika infection and Guillain-Barré syndrome, a rare autoimmune condition that attacks the nervous system and, on occasion, can be life threatening.

Zika’s more sinister threat first drew notice from health officials in 2013, with an outbreak in French Polynesia. But few resources have been brought to bear until recently. For example, The National Institutes of Health until this year had spent nothing on Zika research, while budgeting about $97 million annually for work on its Flavivirus relatives such as dengue, West Nile, yellow fever, and Japanese encephalitis, said Anthony Fauci, the National Institute of Allergy and Infectious Disease (NIAID) director, in a January press briefing.

But the current outbreak, which started in Brazil in 2015, has coincided with more than 4,000 cases of microcephaly, well beyond the typical rate, and has spread northward through the Americas and the Caribbean. The scramble is on. Drugs, vaccines, and other interventions need to be developed and tested. NIAID has jumpstarted several programs using previous work on related viruses and says it is “possible” that a vaccine could be tested in humans before the end of 2016.

But products could be years away, which is cold comfort to people in harm’s way, unsure whether to forestall pregnancy—as some of their governments have recommended. (That is, if women even have that luxury. As the Economist recently noted, in many places where Zika infection has spread, so has debate over birth control and abortion policies.)

Recent weeks have brought developments that could accelerate progress toward a solution, although, as we’ll see, breakthroughs in such a new area of biological exploration inevitably come with risks that could blunt the momentum just as quickly.

Let’s start with a possible breakthrough in drug development. In a paper published last month, scientists at Adimab, in the distinctly un-tropical clime of Lebanon, NH, said they found powerful antibodies in a vial of blood from an Ebola survivor.

Those antibodies could potentially help people fight off Ebola infection. Led by senior scientist Laura Walker, the team said it did in six weeks what usually takes a year, found from 10 to 35 times as many antibodies as other similar experiments would find, Walker says.

Now they’re doing the same experiment with Zika. They have begun the work with blood samples drawn from three people in Brazil who were infected 14 months ago.

“This platform is applicable theoretically to any virus, as long as you have a blood sample from one or more patients with an antibody response,” says Walker.

With Ebola, they found 349 antibodies that the survivor’s immune system had produced to fight off the infection. Further testing at the U.S. Army Medical Research Institute of Infectious Diseases narrowed the field to a dozen or more super-potent antibodies, about 5 percent of the total from the sample. (It turns out not all antibodies in an immune response are created equal. A few are far more effective at stopping, or “neutralizing” an intruder–and those are the ones drug developers want to identify, clone, and perhaps modify as the basis of a medicine.)

Adimab has uploaded the sequences of the 349 antibodies into a public database. Anyone can work on them, and Walker and Adimab CEO Tillman Gerngross say  parties already are moving the handful of super-potent ones into the drug development process. They won’t say who, but say they have been contacted with technical questions.

If Adimab produces similar promising results with its Zika work—which is no guarantee—it won’t throw the work into the public domain this time. “We’re privately owned, we have shareholder responsibility, we can’t just go off and do stuff for free for others,” says Gerngross.

The aim this time would be to license the antibodies to a drug developer to create a treatment for those already infected with Zika.

“Laura’s team has demonstrated that within six weeks they can isolate antibodies that are highly neutralizing,” says Gerngross. “If you want to put in place a rapid response system [to emerging viral threats], there’s no more excuses.” [Due to an editing error, this quote previously misstated the amount of time taken to isolate antibodies.]

To be clear, once a developer has a handful of powerful, promising antibodies, the “rapid response” gives way to traditional development timelines and procedures. Drug makers have to modify the antibodies, test them in animals, get their manufacturing in place, and check several other boxes. In the gravest emergencies, certain strictures can be circumvented. In the 2014 Ebola outbreak in West Africa, at least seven infected people received the drug ZMapp, made by Mapp Biopharmaceutical of San Diego, even though it had never gone through a day of human testing.

As NIAID and many other groups have announced, several Zika vaccine programs are also underway. Vaccine and drug development are very different processes, but vaccine makers are also looking for short cuts and head starts. One of the world’s biggest, Sanofi, has already commercialized vaccines against dengue (Dengvaxia), yellow fever (VF-VAX) and Japanese encephalitis (Imojev), all Flaviviruses. It announced in February it would start on a Zika vaccine. Nicholas Jackson, head of global research at the Sanofi Pasteur vaccine group, told Fortune this month that Sanofi plans to use the same “backbone” from its other vaccines, which could help assuage safety questions.

I asked for further explanation of what Sanofi has learned from its other Flavivirus projects to move its Zika vaccine quickly. Spokeswoman Susan Watkins kept the descriptions vague: “Our available vaccine technology… and established Flavivirus collaborative network are strong assets with the capacity to potentially accelerate our R&D efforts to find a vaccine against Zika.” She also said Sanofi hopes to start clinical testing in the second half of 2017. [Update: Watkins wrote back to point out that Sanofi has used this process successfully before. It built its Japanese encephalitis and dengue vaccines on a “backbone” taken from its yellow fever vaccine, replacing key yellow fever genes with corresponding genes from the other viruses.]

One private company with a more ambitious timeline is PaxVax, of Redwood City, CA. The company, with funding from private equity and public health groups, has a typhoid vaccine on the market that it acquired two years ago and could see FDA approval of its cholera vaccine in June.

For Zika, the company’s starting point is an empty shell of the virus with no genetic material, forming so-called “virus-like particles” that resemble the virus’s structure but cannot cause an infection.

PaxVax is basing the work on its previously undisclosed development of a dengue vaccine, not as a product but as a “proof of concept” to show that the company’s VLP technology can simulate a Flavivirus. The Zika vaccine uses techniques from that project, says CEO Nima Farzan, and could be ready for human trials before the end of 2016 if regulators allow.

Before a drug or vaccine can come to market, there are formidable scientific and regulatory hurdles. While the family ties between Zika, dengue, and other Flaviviruses could provide clues and stepping stones, they could also end up as a hindrance. Could a person’s previous dengue infection make a Zika infection worse? Nothing has been proven, but researchers are suspicious that Zika became a big threat only when it emerged in a region where dengue is common. “It’s a huge concern,” says Krystal Fontaine, a virologist who specializes in dengue at the Gladstone Institutes of San Francisco. “There was a surge in dengue infections in 2015 in Brazil, the same year Zika infections began skyrocketing.”

Clinicians and researchers also need a better diagnostic test for Zika. The most accurate method catches bits of the viral genome in a blood sample while a person is infected. But there’s only a one-week window before the virus clears from the infected person’s blood. Because of that and relatively mild symptoms, Zika infection in adults likely passes unnoticed.

After the infection is gone, other blood tests can find antibodies, but it’s unclear if those antibodies were generated against Zika or another Flavivirus—a condition called cross-reactivity. “For good epidemiological studies, it’s important to make it clear that you’re not measuring something else, especially in these [co-infection] areas,” says Melanie Ott, who runs the Gladstone lab where Fontaine works.

A more accurate, detailed count of infected people would also help answer other questions, says epidemiologist Justin Lesser of the Johns Hopkins Bloomberg School of Public Health, such as, “What is the risk of microcephaly per infected pregnancy? And, is something different happening with Zika in the Americas than elsewhere in the world, or is what we are seeing only the result of an especially large number of infections?”

Ott says other unknowns about Zika—for example, does it linger in saliva and semen longer than it does in blood?—make for more questions than answers when it comes to planning a vaccine. “I would think [a vaccine] would be geared toward young women and girls but what we know about Zika is just evolving. We don’t know whether it’s hiding somewhere in people, or if there’s recurrence if you’ve been infected by another strain, which is the dengue problem,” she says. “We don’t know what to expect.”

Among Ott’s first experiments with Zika, samples of which only arrived in her lab last month, will be ones centered on tiny lipid, or fat, droplets that are like storage depots inside cells. Flaviviruses dengue and hepatitis C (a more distant relative) exploit those droplets in different ways when they invade cells. If Zika also uses those droplets in some fashion, “perhaps there’s a niche to exploit,” Ott muses.

Beyond the biological mysteries of Zika, there’s another hurdle: Who should get a vaccine, if and when one is produced? Pregnant women are, to date, the highest risk group. But testing any experimental medicine—let alone a new vaccine against an ill-understood viral foe—in pregnant women is extremely difficult. (In the emergency rush to develop and test vaccines during the most recent Ebola outbreak, Johnson & Johnson’s Janssen division vaccinated 1,200 people across 10 different studies. But it has not yet vaccinated pregnant women, according to a spokesman.)

“The issue is getting it to women of child bearing age who may become pregnant,” says Adam Urato, a specialist in maternal-fetal medicine who sees patients at the Tufts University School of Medicine near Boston. “That’s the time to think about vaccinating people. From my standpoint you can’t put anything into a pregnant woman and say there’s no risk.”

While some companies and researchers are plotting attacks on the Zika virus, others want to kill mosquitoes. An all-out pesticide assault would be impractical, expensive, and potentially more toxic than the Zika infection itself. Aedes thrives in urban areas and can breed in a few drops of standing water.

Enter the genetically modified mosquito. One version has been tested in Brazil, Malaysia, and Grand Cayman—and won regulatory approval in Brazil—and just got tentative FDA approval for a field trial in Florida’s Key West. The mosquito engineers at Oxitec, a British division of Germantown, MD-based Intrexon (NYSE: XON), release genetically altered males into the wild. They mate with wild females, and the offspring are born with a self-destruction gene that kills them before adulthood.

The idea is to reduce populations by at least 90 percent, as Oxitec says it has done in other field tests. The current 50 percent threshold that the Florida Keys Mosquito Control District says it achieves with pesticides is not considered enough to halt the spread of diseases spread by Aedes.

FDA released Friday its assessment of the planned test. It would not have negative impacts on people, animals, or the local ecosystem, the agency said, based mainly on Oxitec’s own report, which was also posted on the FDA site Friday. (Note: Link downloads a very large PDF file.)

FDA is giving the public one month to comment before Oxitec can move ahead with the test, which was originally conceived to fight the spread of dengue—as were the tests in Brazil and elsewhere—after a outbreak in Key West infected at least 88 people in 2009 and 2010. As the outbreak subsided, local officials got cold feet, however, and delayed the project. But the rapid spread of Zika via the same mosquito has rekindled the project.

Oxitec says its mosquito won’t mutate out of control, passing new traits from generation to generation upon its release, because of the built-in self-destruction. (In fact, there’s a recurrent cash flow for the company in the technology; long-term abatement projects would need intermittent releases of new genetically modified mosquitoes.)

The uncertainty here is at least two-fold: Will the altered mosquitoes actually bring down the Aedes population and halt the spread of disease without unintended consequences? And will Oxitec actually get the chance to find out? A petition to stop the Florida Keys project has gathered more than 160,000 signatures to date.

The next month of public comments should be lively, to say the least, based on the back and forth from a December 2014 public meeting.

Not just in the Florida Keys, but everywhere Zika is spreading, emotions are running high. “The big thing we need, number one, is more information,” says Urato.

The science is moving fast. As the Gladstone’s Ott says, “It should be a very interesting next one or two years.”