When it comes to infectious diseases, the mosquitos are winning. In the last year, health officials reported a spike in dengue and have recorded infections even in nontropical areas, where the disease typically did not spread. Malaria is resurging in parts of North and South America, Africa, and Asia. Even Anthony Fauci, the former director of the National Institute of Allergy and Infectious Diseases, contracted a nasty case of West Nile from a mosquito in his backyard in DC.

Some of the increase can be explained by mosquitos thriving in new places thanks to changes in temperature and rainfall. Mosquitoes and the pathogens they carry are also developing resistance to the pesticides and drugs previously used to eliminate them.

The US government and other global health donors have invested billions to develop new vaccines and medicines for mosquito-borne diseases such as dengue, malaria, and chikungunya. One virus, though, that has faded into the background still has no vaccine and no cure: Zika.

In 2015, the Zika virus — which had previously rarely infected humans — suddenly spread rapidly, leading to more than a million cases over two years. Even worse, scientists observed a horrifying phenomenon: A small fraction of infected pregnant women gave birth to children with what became known as congenital Zika syndrome, characterized by severe birth defects such as hearing and vision loss, feeding problems, and microcephaly, a neurological condition in which babies have abnormally small heads. In Brazil, which was hardest hit by the epidemic, more than 3,500 babies were born with Zika-related birth defects.

Fortunately, the number of Zika infections worldwide declined rapidly toward the end of 2016, albeit for reasons still largely unknown. A leading theory is that the virus spread so fast that communities developed herd immunity. Or perhaps mosquito control efforts, like spraying pesticides and encouraging communities to eliminate sources of standing water, wiped out the virus’s transmission route. The continental US has not recorded any cases since 2018 and US territories have not since 2019.

Unfortunately, as Zika cases declined, so did global funding and interest in Zika. Public health officials and, more importantly, donors and policymakers turned toward other priorities, including the coming Covid-19 pandemic. No Zika vaccine ever came to fruition.

Despite the decline in attention, Zika is still spreading in many countries. In the first half of 2023, health officials recorded about 27,000 Zika infections in the Americas, with Brazil the most affected country with more than 2,700 cases. Thousands of babies are still being born with preventable disabilities.

“With a safe and effective Zika vaccine, we could eliminate the possibility of congenital Zika syndrome, and I think that would have a huge impact,” said Anna Durbin, a professor of international health and global disease epidemiology and control at Johns Hopkins University. “Even if there are few cases of congenital Zika syndrome, just the emotional, financial effect of that is huge.”

Scientists and global health experts warn that Zika, alongside other mosquito-borne infectious diseases, could make a broader resurgence. The first step to defeating pandemics is, of course, prevention, and a Zika vaccine is vital to that goal.

But major hurdles stand in the way. Private pharmaceutical companies aren’t willing to invest in vaccine development because so few people are getting infected now — and those who are getting infected largely live in relatively poor countries. Researchers say governments aren’t investing sufficient public funds in vaccine development. And it is almost impossible to run a traditional clinical trial for the few vaccines hastily developed during the 2015 outbreak.

In the early months of 2015, doctors in Brazil noticed a sudden surge of patients with an odd skin rash. They alerted the World Health Organization (WHO) that an unknown infectious disease might be emerging. Within a few months, scientists identified the cause of the outbreak: Zika, a virus first discovered in the Zika forest of Uganda in 1947 that is spread by certain types of mosquitoes.

At first, there was little cause for concern. Since the 1960s, the virus has caused only sporadic infections in Africa and Asia, and then later in the Americas. Moreover, Zika doesn’t cause symptoms in about 80 percent of people who are infected, while others typically experience only minor illness characterized by a low-grade fever, skin rash, and conjunctivitis. By March 2015, of the 7,000 or so people who had developed the skin rash in Brazil, no one had died.

But then in September, Brazilian doctors began noticing a troubling new pattern. Somewhere between 2 percent and 6 percent of babies born to women who had Zika had small, misshaped brains, a condition called microcephaly. Other babies were missing key brain structures or had other malformations. Clinicians called it congenital Zika syndrome.

To make matters worse, the virus was spreading rapidly beyond the borders of Brazil. In December, the Pan American Health Organization declared the Zika outbreak an international health emergency. The WHO followed suit in February the next year. By the end of 2016, 48 countries and territories across North and South America were reporting cases.

Funding for the outbreak response surged. The US government alone put up $1.1 billion to support activities such as surveillance, education, mosquito control, and vaccine research. Various research groups, mostly in the US, the UK, and South Korea, developed some 40 vaccine candidates. A handful of those vaccines underwent small phase 1 and 2 clinical trials and seemed promising, Dan Barouch, a professor of immunology at Harvard Medical School, recalled.

Then suddenly the outbreak subsided. Countries went from reporting thousands of cases every few months in 2016 to only a few, sporadic cases in 2017.

This was, obviously, a good thing. Unfortunately, though, once a disease poses a minimal threat to high-income countries, where most research and development takes place, progress toward developing effective vaccines and medicines tends to stall. Governments, scientists, and pharmaceutical companies transition funding and attention to the next health emergency, leaving low-income countries in the global South to fend for themselves.

But the rapid rise and fall of the Zika outbreak posed another challenge. Two years into the outbreak, when candidate vaccines were ready for real-world testing, there were no longer enough susceptible people for a phase 3 clinical trial.

Why Zika vaccine development has stalled

Before a regulatory body such as the US Food and Drug Administration can approve a new vaccine, it generally must be proven safe and effective in a large phase 3 clinical trial. A few thousand people are vaccinated and then observed to measure the dose’s effectiveness once some of those people contract the disease. So researchers need a large pool of people willing to be in a trial and who may also be exposed to the disease.

During the first year or so of the 2016-2017 Zika outbreak, there would have been more than enough people for such a trial. But researchers first had to complete smaller phase 1 and 2 trials, which primarily focus on safety. By the time some vaccines were ready for phase 3 trials, the outbreak was too small to provide sufficient subjects.

Even today, whenever Zika sporadically pops up around the world, there are typically only a few hundred cases at a given time, and researchers can’t pinpoint where and when cases will arise. They still can’t start up a trial, Durbin explained.

There are alternative pathways to getting a vaccine approved that don’t require phase 3 clinical trials. According to Durbin, drug developers don’t want to cover those costs because they are unlikely to recoup them, given how few people are getting Zika now.

A lack of government funding for vaccine research and development is compounding this problem. Government funding for various diseases comes in waves with the outbreaks, first for Ebola then for Zika, and then for Covid-19.

On the bright side, if another large-scale Zika outbreak were to occur, scientists already have a handful of vaccine candidates that are ready for larger clinical trials. Scientists and vaccine manufacturers would still need to make enough vaccines for a large trial and receive approval from authorities and ethics review boards in whichever countries the trials take place.

Even though transmission is much lower than in 2015 and 2016, Durbin says there is still an urgent need for a vaccine.

“Women who were living in Brazil during that outbreak were terrified if they were pregnant, absolutely terrified of what would happen to their babies,” she said. “It would provide tremendous peace of mind.”

The peace of mind of mothers in the global South, however, isn’t enough to move large drug companies.