A decade after the first releases of Wolbachia-infected mosquitoes in Brazil, researchers from the Fiocruz institute study the bacteria's frequency in the local mosquito population.
Outbreaks of dengue are killing thousands of people in South America each year and getting worse. Brazil hopes to turn the tide with a home-grown vaccine and an army of mosquitoes infected with Wolbachia bacteria.
Last month, a parade of vehicles wound its way through three cities in Brazil, releasing clouds of mosquitoes into the air. The insects all carry a secret weapon — a bacterium called Wolbachia that lowers the odds that the mosquitoes can transmit the dreaded dengue virus to humans.
These infected mosquitoes are the latest weapon in Brazil's fight against dengue, which infects millions of people in the country each year and can be fatal. A biofactory that opened in the town of Curitiba in July can produce 100 million mosquito eggs per week — making it the largest such facility in the world. The company that runs it, Wolbito do Brasil, aims to protect about 14 million Brazilians per year through its Wolbachia -infected mosquitoes.
That will come as welcome news for the Brazilian health officials battling the rapidly growing threat of dengue . In 2024, the country experienced its worst outbreak yet: with 6.6 million probable cases and more than 6,300 related deaths. This year's outbreak, although less severe, is also one of the highest on record, with 1.6 million probable cases so far (see ‘Dangerous outbreaks'). And the problem is spreading. Argentina, Colombia and Peru also experienced record-breaking outbreaks in 2024 and have seen a sustained increase in cases in recent years. Across Latin America and the Caribbean, deaths from dengue last year totalled more than 8,400 and the global figure reached more than 12,000 — the highest ever recorded for this disease.
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SOURCE: Brazilian Ministry of Health. Image courtesy of Nature.
As outbreaks grow larger and the crisis becomes more urgent, the Wolbachia method isn't Brazil's only bet. A locally produced dengue vaccine is now awaiting approval by the country's drug-regulatory agency, and its health ministry expects to start administering tens of millions of doses by next year.
These twin advances offer some hope to other countries — in the region and beyond. Driven by forces such as climate change, mosquito adaptation, globalized trade and movements of people, dengue is becoming a crisis worldwide, with an estimated 3.9 billion people at risk of infection. As Brazil rolls out its armies of infected mosquitoes and a vaccine in the coming year, the rest of the world will be watching closely.
The local approach
Currently, there is one main dengue vaccine in use around the world: Qdenga, licensed by the Japanese pharmaceutical company Takeda. The vaccine has been approved in many countries, including Brazil, which was the first nation to include it in its public-health system.
However, Qdenga's roll-out in Brazil is limited. The country bought nine million doses of the two-dose vaccine this year: enough to vaccinate 4.5 million of its population of more than 210 million. So far, Qdenga has been administered to children between the ages of 10 and 14, one of the groups most likely to end up in hospital after contracting dengue, together with older people. Its safety and efficacy have not yet been tested in adults aged over 60.
The main reasons for such a limited roll-out in Brazil are availability and cost. Even though Brazil secured Qdenga from Takeda at one of the cheapest prices in the world —around US$19 per dose — the cost is still high compared with other vaccines. And even in the most optimistic scenario, the maximum number of doses Takeda could provide by 2028 is 50 million — enough to vaccinate 25 million people. What's more, for people who have not had dengue before, clinical trials did not show Qdenga to be effective against all four variants — or serotypes — of the dengue virus.
Brazil is trying to address all of those limitations with its one-dose vaccine candidate, developed at the Butantan Institute, a public biomedical research centre in São Paulo. “Having local production capacity gives us independence on decisions — how many doses we need, and at what speed to vaccinate,” says Esper Kallás, Butantan's director. “You can practise prices that are more suitable and absorbable by a public-health system such as Brazil's.”
Butantan is also optimistic that its vaccine will be effective against all four forms of dengue. Severe disease usually occurs when a person is infected by a different serotype to their first infection. That means that a successful vaccine needs to generate antibodies for all four serotypes without triggering severe reactions, which makes it a difficult vaccine to develop. “It was indeed a challenge, as each serotype behaves differently,” says Neuza Frazatti Gallina, manager of the viral vaccine development laboratory at Butantan.
The vaccine's development began at the US National Institutes of Health in the late 1990s, where scientists transformed dengue viruses they had isolated from patients into weakened vaccine strains that could trigger the production of protective antibodies without causing disease. In 2009, Butantan extended that research by working to solve the challenges of combining the four strains into a vaccine.
After testing 30 formulations, Butantan arrived at one that proved highly effective in preventing infections, according to the preliminary results of a phase III trial involving more than 16,000 volunteers in Brazil. The study reported that two years after vaccinations, the formulation was 89% effective in preventing infections in people who had previously been infected with dengue, and 74% effective in those with no previous exposure
“It was a well-designed trial,” says Annelies Wilder-Smith, who is team lead for vaccine development at the World Health Organization (WHO). But she says one limitation of the trial is that it was conducted in a single country, and therefore runs a risk that all four serotypes were not circulating at the time.
In fact, serotypes 3 and 4 were not prevalent during the data-collection period of the clinical trial, although they are now circulating in Brazil. Butantan researchers suggest that the vaccine will be effective against serotypes 3 and 4, pointing to data from a phase II trial in 300 adults that showed participants produced neutralizing antibodies to each of the serotypes. That study evaluated safety and immunological response in the short term, rather than looking at the vaccine's long-term efficacy in preventing infections. The full results of the Brazilian phase III trial — which will provide data on long-term effectiveness — are not yet public and are undergoing peer review.
The vaccine is already moving through the country's regulatory process. And although there's still no certainty about when Anvisa, Brazil's regulatory agency, will approve the vaccine, the government is counting on it. In February, President Luiz Inácio Lula da Silva announced that, starting in 2026, the Ministry of Health would be buying 60 million doses annually.
To meet that demand, Butantan is now producing the vaccine at its São Paulo facility. On its lush campus, an entire building is dedicated to churning out doses.
Regarding the vaccine's approval, “We are very confident,” says Kallás. “We also anticipate that there is a very prominent need to have this product in the arms of people. So we hit the road running and started producing vaccines late last year.”
Although Butantan's production efforts will focus initially on meeting Brazil's need for millions of doses, Kallás expects that the vaccine could reach other countries. Butantan has been discussing with its development partner — the pharmaceutical giant Merck — and the Pan American Health Organization (PAHO) how to make the vaccine accessible to other countries. The logical first step, he says, would be to roll it out through PAHO to Latin America and the Caribbean, and then to other regions.
In the meantime, Merck is developing a potential vaccine for Asia with an almost identical formulation, which builds on the knowledge that Butantan has developed. In a statement, the drug firm said that Butantan is “sharing clinical data and other learnings”. In June, Merck started enrolling participants for its own phase III trial. “All the data, experiences and insights they have collected with the Butantan vaccine will be helpful,” says Wilder-Smith.
Infecting mosquitoes
While Butantan awaits news about the vaccine's approval, the Wolbachia method to control dengue is gaining momentum. The World Mosquito Program (WMP) — a non-profit group of companies owned by Monash University in Melbourne, Australia, where the strategy was developed — has operations in 14 countries, including Vietnam, Indonesia, Mexico and Colombia, but Brazil leads the way in terms of the scale of its expansion.
The method's arrival in the Americas is tied to Brazilian researcher Luciano Moreira, now the chief executive of Wolbito do Brazil. Wolbachia is naturally present in around 50% of insects, but not in the mosquito species Aedes aegypti , which is the main transmitter of dengue and many other viruses.
Researchers knew that Wolbachia shortened the lifespan of mosquitoes and expected that this effect could help to prevent dengue infections. But experiments run by Moreira and his colleagues in 2009 in Australia found that it also reduced the mosquitoes' viral loads and capacity to transmit some viruses . “Other labs at the same time found the same, showing that this was universal,” he says. Moreira and others then switched their approach from shortening the lives of mosquitoes to blocking virus transmission.
The goal of infecting mosquitoes with Wolbachia is to replace existing populations of the insects. When infected males mate with uninfected females, no offspring are produced. Infected females can reproduce successfully with both infected and uninfected males and pass the bacteria to their offspring. Over time, that means local mosquito populations develop high frequencies of Wolbachia infection, which should in turn reduce the rates of dengue transmission to humans.
In 2012, Moreira led the process to start a collaboration between the WMP and Brazil's Oswaldo Cruz Foundation (Fiocruz), a federally funded scientific institute where he was a researcher, to import Wolbachia -infected mosquito eggs from Australia. In Rio de Janeiro, Moreira and his research group bred those mosquitoes with local ones to create the first generation of Brazilian Wolbachia -infected A. aegypti
The first releases took place in 2014 and 2015 in Tubiacanga, a small neighbourhood of Rio de Janeiro, and in Niterói, a city of roughly 500,000 people in Rio de Janeiro state. The pilot projects continued expanding in Niterói and to other cities. By 2019, 70% of Niterói's population lived in areas where Wolbachia mosquitoes had been distributed. And the first assessment of the method's effectiveness showed encouraging results. Researchers reported in 2021 that there was a 69% reduction in infections in Niterói associated with releases of Wolbachia mosquitoes compared with a control area that had no releases . A follow-up study was conducted after further distributions in 2022 and 2023 in urban areas that had not been covered previously. Results from that study — which have not yet been peer reviewed — found an even greater reduction of almost 89% in probable cases, compared with the ten-year period before any mosquitoes were released.
In 2022, Anvisa approved the method as a control strategy, and the Ministry of Health funded efforts to expand the releases to 11 sites across the country. With three sites already starting releases and three more planning to do so in the next few months, Brazil needs more Wolbachia -infected mosquitoes.
The demand will be met by Wolbito do Brasil, which emerged from a partnership between the WMP and the Paraná Institute of Molecular Biology, which is affiliated with Fiocruz. It opened the biofactory in Curitiba “to expand production capacity, reach more cities and deliver these mosquitoes nationwide”, says implementation manager Gabriel Sylvestre. For the Wolbachia strategy, this expansion marks a transition from research to full-scale implementation.
It took more than a decade of studies to reach this point. The strongest evidence of Wolbachia 's effectiveness so far has come from a randomized controlled trial in Yogyakarta, Indonesia . The study compared geographical clusters and showed that establishing Wolbachia in A. aegypti mosquitoes reduced the incidence of confirmed symptomatic dengue cases by 77%.
Researchers are now conducting the first randomized controlled trial of the strategy in Brazil. According to Katie Anders, a dengue researcher at Monash University and former director of impact assessment at the WMP, if it shows results similar to those in Yogyakarta, the Brazilian trial might be the final step before the WHO issues a formal recommendation for the use of Wolbachia to help countries control dengue. “I think it will open the door to them having confidence and unlock the pathways for policy adoption,” she says.
For many countries, Wolbachia might be the quickest option to start preventing dengue, rather than waiting until a vaccine is adopted by public-health systems. In Malaysia, for example, the Qdenga vaccine is authorized and available in private health facilities. But according to paediatrician Zulkifli Ismail, a member of the Asia Dengue Voice and Action Group, its adoption into Malaysia's public-health system could take several years. Instead, he says, “The government is actually investing a lot of money in the Wolbachia project, which seems to be very effective in areas where it's been implemented.”
“It's now time for Wolbachia to really scale up,” says Wilder-Smith.
But, as Brazil is showing by moving forward with both Wolbachia and a vaccine, she says the dual strategy makes a lot of sense. “Invest in both,” says Wilder-Smith. “And it's a long-term investment, because dengue will not go away. It will just get worse.”
Nature
doi: https://doi.org/10.1038/d41586-025-02918-8
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