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How to make a Zika virus vaccine, in 4 not-so-easy steps

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Brian Resnick is Vox’s science and health editor, and is the co-creator of Unexplainable, Vox's podcast about unanswered questions in science. Previously, Brian was a reporter at Vox and at National Journal.

The basic idea behind vaccines is simple: Expose people to a non-dangerous form of a virus, and their bodies' immune systems will bolster their defenses, protecting them from future encounters with the virus.

But in practice, developing a new vaccine can be tricky. Sometimes a vaccine that works in animals shows no effect in humans. Sometimes a vaccine that appears safe in initial trials can produce unforeseen side effects later on. "There’s always surprises in the vaccine field," says Philip K. Russell, a retired US Army medical researcher who helped develop vaccines for hepatitis and meningitis.

These "surprises" make vaccine development a slow, painstaking process. "As a general rule it takes 20 years to make a vaccine," says Paul Offit, chair of vaccinology at the University of Pennsylvania's Perelman School of Medicine.

This slowness has become a problem amid the current Zika epidemic, as the virus has exploded across the Americas since arriving in Brazil, probably around 2013. No Zika vaccines have been approved yet — and what vaccines are in development have not yet made it to human trials. Nobody thought Zika was a high enough priority to warrant making a vaccine for it," says Peter J. Hotez, dean of the National School of Tropical Medicine at the Baylor College of Medicine. "It was always the last slide on a PowerPoint presentation about arboviruses."

Now that the virus has been linked to birth defects, however, developing a Zika vaccine has become a worldwide priority. So here's what it takes to develop one (or to develop a vaccine for any virus).

Step 1: Figure out which part of the virus provokes an immune response

An electron micrograph of yellow fever virus.
Photo By BSIP/UIG Via Getty Images

Every virus comes with an outer protein coat. By scanning this coat like a barcode, our body's immune systems are able to identify viruses and then call for the creation of antibodies to destroy them.

The key to vaccine research is to identify which particular protein — or proteins — on that coat set off those immune system alarms. That way, researchers can create serums that mimic the virus without actually causing infection.

With Zika, we have a head start here. "We’re at an advantage because Zika is what is called a flavivirus — it is the same category of virus that is yellow fever, dengue and West Nile," Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told me in February. "You would anticipate — and with good historical reasons — the kinds of approaches that would be applicable to one flavivirus would be applicable to another."

We already have an approved vaccine for yellow fever. And vaccines for West Nile and dengue have reached clinical trials. These vaccines, Fauci says, can serve as the template for Zika vaccine development.

In March, scientists at Purdue University announced they had completed a map of Zika's protein structure, paving the way for further insights for vaccine development.

Step 2: Create a serum that delivers that protein into a human

A macrophage. This immune system cell gobbles up foreign invaders.

Once the key proteins have been identified, scientists need to find a way to get those proteins safely into the human body. Here, they have several different possible strategies, each with pros and cons:

1) Inject dead viruses into the body. This is the method Jonas Salk pioneered when he created the first vaccine for polio in the 1950. The basic concept remains the same today. Researchers grow dangerous live viruses, and then kill them. The inactivation process usually involves heat or chemicals, and researchers take care not to destroy the proteins that provoke the immune response.

This is the simplest and safest method, because these dead viruses cannot cause infection. The downside, however, is that this method tends to produce the weakest level of immune response. Furthermore, the immune response from inactivated viruses is more likely to weaken over time, and requires booster doses.

2) Inject pieces of viruses. If scientists can identify the genes that code for the protein, they can isolate that gene and then grow large amounts of the protein. Those bits of protein — which cannot replicate or cause infection — can be injected. The hepatitis B vaccine works this way.

3) Attenuate viruses. These are viruses that have been genetically altered so they no longer cause disease. This is the method used in the oral polio vaccine that has all but eradicated polio. This method produces a strong immune response but can carry greater risk. The polio vaccine, for instance, can in some cases revert back into a virulent strain.

(And because a Zika vaccine campaign would ideally target pregnant women, this method will probably prove too risky. Pregnant women, says Hotez, "are the highest bar there is from a safety point of view. That’s what’s really going to slow down the clinical development of a Zika vaccine.")

4) Create Frankenstein viruses. This is when the outer protein coat of a virus is put on the backbone of a harmless virus. "You create a new virus called a chimera," Russell says. He speculates the outer shell of the Zika virus could fit nicely on the backbone of the yellow fever vaccine that's already in use.

5) Inject people with bits of viral DNA. DNA-based vaccines are the latest frontier in vaccine science. Instead of injecting a virus or a viral protein into a person, these vaccines just contain the bits of DNA that code for the proteins. The vaccinated person's own cells then produce the protein, which sets off an immune response.

NAID's Fauci says this method is the most likely way we'll develop a Zika vaccine. Already, his scientists have altered a DNA vaccine for West Nile to produce Zika proteins. "By the middle of the summer, we’ll have enough to start a phase I trial to determine safety and whether it induces an appropriate immune response," he told me in February. By March, he announced that phase I safety trials on humans will begin this summer or fall.

(Keep in mind, though, that none of these methods are guaranteed to work. One of the reasons that we haven't developed an HIV vaccine is that all of these methods have so far failed.)

Step 3: Test, test, test, test. And then test some more.

An illustration of a dengue virus infection.

This is the main reason vaccine production takes so long. The vaccine has to be proven absolutely safe and effective, and that takes several steps.

After a serum is created, it's first tested in animals to show that it's safe and produces the right antibodies. "And that takes weeks and months," Russell says.

When the vaccine clears the animal tests, it can start in human trials. Phase I is to test for safety. Researchers will also test the recipients' blood, making sure the vaccine provokes the right immune response.

In phase II, the recipient pool is widened, and researchers look to see if the vaccine prevents infection in the real world. Here, researchers want to find the most effective dose. In phase III, the trial moves to a large scale, where the researchers will obtain the statistical power to say how effective the vaccine is.

If the vaccine appears to be safe and effective, the FDA will review the evidence and decide whether to license the vaccine for wide-scale use. This process can take months or years. But when there's an urgent need, it can be accelerated.

Step 4: Manufacture and dispense the vaccine

Alex Wong/Getty Images

Even once a vaccine is approved by the FDA, manufacturing presents another hurdle. "We have to develop assays and tests to prove the vaccine is the same every time you make it," Russell says. This can take six months.

All considered, the researchers I spoke to agree that in the best-case scenario, it will be a few years before a Zika vaccine makes it to production.

"I do not think we’re going to have a Zika vaccine in time for this current epidemic," Hotez says. "It will have marched all the way through Latin America, the Caribbean, the Gulf coast of the United States. You might be able to have a vaccine in time to stop it spreading across the Atlantic."

Researchers were actually more prepared to respond to the Ebola epidemic in 2013. Vaccines that had made it through animal trials were already sitting on shelves. With Zika, we're much closer to square one.

According to Fauci, in the best case, Phase I trials for a Zika vaccine "will likely end by the end of 2016, and if looks good, if it looks safe, we can do an accelerated trial of a Phase II and III as we get into 2017. By all standards of vaccine development, that’s rocket speed."

Correction: This post initially stated Peter J. Hotez is the dean of the National School of Tropical Medicine at Baylor University. He holds that position at the Baylor College of Medicine. The institutions are unaffiliated.