W

hen a leading vaccine manufacturer announced earlier this month that it was pulling out of the race to develop a vaccine against the Zika virus, it effectively shelved what was widely considered to be one of front-running candidates. Along with the dramatic drop in the number of new cases of Zika in recent months, does this signal that the threat has now passed, or does it mean we are now no closer to a vaccine should a resurgence of the disease eventually occur?

Neither, in fact. When Zika does start to spread again, which seems likely, the loss of this one vaccine is unfortunate, particularly because it is from a major manufacturer. But there are numerous other Zika vaccine candidates currently in the works.

While it’s not entirely clear what lies behind Sanofi Pasteur’s decision, it is worrisome, suggesting that a deeper problem is at play and highlighting one of the biggest challenges in vaccine development.

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Even after the Zika outbreak was declared to be an international emergency, attracting global attention and more than $1 billion in funding to halt its spread, it is still not clear whether there will be a viable market for a vaccine, once one is eventually approved. This may sound crazy, given that there have now been more than 220,000 confirmed cases of Zika infection in the Americas alone — with many more suspected. More than 80 countries and territories have been affected by Zika. But when it comes to infectious disease, as we saw with Ebola, just because an outbreak occurs doesn’t necessarily mean a vaccine market will follow.

Before the Ebola epidemic broke out in West Africa in 2014, only a few hundred cases occurred every few years. Outbreaks typically happened only in rural parts of some of the poorest parts of Africa, in countries that could ill afford to pay a price for a vaccine that was high enough to allow manufacturers to recoup the billion-dollar investments it can typically take to bring a vaccine to market.

Because of this, several existing candidate Ebola vaccines sat on the shelf for more than a decade. It took a major outbreak, thousands of deaths, global panic, and hundreds of millions of dollars in funding from the U.S. Biomedical Advanced Research and Development Authority and National Institutes of Health; the Wellcome Trust; Norway; Gavi, the organization that I head; and others to eventually drive a vaccine through the final stages of development.

Things have changed since then. In the aftermath of the Ebola outbreak, the Coalition for Epidemic Preparedness and Innovation, a partnership of public, private, philanthropic, and civil organizations, was created. The aim was to prevent a repeat of this kind of entirely avoidable epidemic by funding the development of vaccines for diseases that have the potential to cause epidemics, but no hope of a market.

It is a very different story with Zika. Rather than preying only on impoverished African villages, this virus has also pervaded dozens of relatively wealthy countries, whose governments and citizens could certainly afford to pay for a vaccine. Does this imply that a healthy market awaits any vaccine that successfully runs the gauntlet of getting regulatory approval?

Perhaps surprisingly, no. The reality is that we still don’t know much about the epidemiology of the virus, for example, or why it has appeared to stop spreading. Although that’s good news for people living in infected areas — particularly pregnant women — understanding why this has happened has huge implications for how future infections might spread and how a vaccine might be deployed.

One possible explanation is that the virus has been spread to almost the entire population in areas of South and Central America. If almost everyone in a region becomes infected with Zika and develops a natural immunity to it, that could create a wall of herd immunity, which would prevent the spread of the disease, at least for now.

If this is the case, then carrying out mass vaccination campaigns in the countries most affected may not be the best vaccination strategy. Instead, it may be more appropriate to focus on other areas that have so far largely been unaffected but where the Aedes species mosquito, which transmits the Zika virus, is endemic. The irony is that the sharp decline in Zika cases will only serve to complicate clinical trials, because it becomes more difficult to test the effectiveness of a vaccine if the disease isn’t spreading.

Another complication for vaccine development concerns emerging evidence of a possible interplay between the Zika virus and its close cousin, the dengue virus. In theory, people infected with Zika may experience more severe reactions if they have previously been infected with dengue. This sort of cross-reactivity is not uncommon with viruses like Zika, and would help explain the initial and sudden explosion of Zika in Brazil last year. Cross-infection may also hold clues to why the Zika virus can have such devastating complications on babies before birth. If cross-infection does play such roles, then it may be necessary to preferentially vaccinate in areas where dengue is common.

We currently have more questions than answers about Zika. In time, we may find that the dip in the number of infections is only temporary, and that Zika will continue to spread wildly, consistently causing disease. In that case, a strategy of widespread vaccination is the right approach.

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But we may also see the number of Zika infections subside, only to resurface once a new generation of uninfected hosts is born and grows up with no natural immunity — say once every 15 years.

It’s still too early to tell, but the uncertainty about Zika makes the development of a vaccine decidedly riskier for manufacturers.

Because of this, it is essential that we try to remove some of the uncertainty by continuing research in the epidemiology of the virus. We must also draw up strategies that cover all the bases, including a plan of action for a possible market failure for a Zika vaccine. If it does come to that, one option would be to call upon the Coalition for Epidemic Preparedness and Innovation to provide incentives to stimulate vaccine development, while Gavi looks at ways to work with manufacturers to assure access to the vaccine for developing countries.

Regardless of how many vaccines are in development, until we figure this out we may find that none of them will make it to the market.

Seth Berkley, M.D., is the CEO of Gavi, the Vaccine Alliance.

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