A vaccine to prevent infection from dengue — a mosquito-borne disease that kills 20,000 people a year — is poised to roll out in Indonesia next year. But the jab is stirring debate: some researchers say that important safety concerns have been overlooked.
The vaccine, developed by the pharmaceutical company Takeda, headquartered in Tokyo, is particularly significant because it is the first for people who have not been exposed to dengue, which infects up to 400 million people a year. The Indonesian drug regulator approved use of the vaccine without testing for previous exposure in August. Europe’s drug regulator is also considering approving the vaccine without testing.
The only other approved vaccine, Dengvaxia, developed by Sanofi in Paris, can be given only to people who have already been infected. In individuals with no history of infection, Dengvaxia increases the risk of severe disease, including hemorrhagic fever, which might be caused by a rare but serious condition called antibody-dependent enhancement (ADE), in which vaccination induces antibodies that make a subsequent infection worse.
It is the possibility of ADE that is fuelling concerns about the new vaccine among some scientists, who say that this cannot be ruled out on the basis of clinical-trial data gathered so far. “I was really disappointed and surprised that the Indonesian government approved” the vaccine without restrictions, says Aravinda de Silva, a virologist at the University of North Carolina at Chapel Hill who has collaborated with Takeda and other dengue-vaccine developers.
A Takeda spokesperson says that clinical-trial data has been collected from more than 28,000 people over 4.5 years, which is in line with World Health Organization recommendations. The data show that the vaccine called Qdenga is safe, regardless of past dengue exposure, the spokesperson says. And the European Medicines Agency says there is no clear evidence of a higher risk of severe disease in people who have not been infected previously .
Other researchers say Qdenga will help to reduce the growing burden of dengue. The virus is endemic in more than 100 countries, predominantly in Asia. With no treatments and limited ways to control the spread of mosquitoes, vaccines are desperately needed. “I support the licensure of the vaccine in Indonesia,” says Tedjo Sasmono, a virologist at the Eijkman Research Center for Molecular Biology in Jakarta. Indonesia has one of the world’s highest numbers of dengue infections each year.
Dengue has four distinct ‘serotypes’ (DENV-1, DENV-2, DENV-3 and DENV-4) and protection from any two of them is needed to reduce the chance of serious disease. After a second infection, or vaccination followed by a breakthrough infection, people are typically protected against all four.
Qdenga is a two-dose inactivated-virus vaccine that uses DENV-2 as a backbone. Genes for key proteins from the other three serotypes are engineered into this backbone.
In 2019, Takeda published the results2 of a trial across 8 countries, conducted in roughly 19,000 children aged between 4 and 16. One year after immunization, the vaccine had an efficacy of 80% against symptomatic dengue, and 95% against hospitalization. In a press release posted in June this year, Takeda reported that 4.5 years after immunization, the efficacy had dropped to 61% for symptomatic infection and 84% for hospitalization.
Indonesia’s drug regulator has approved the vaccine for people aged between 6 and 45. Dropping testing for past dengue exposure makes the vaccine more practical and easier to roll out, says Eggi Arguni, a paediatrician at Gadjah Mada University in Yogyakarta, Indonesia. And approving Qdenga for six-year-olds will make vaccination available to younger children; in Indonesia, Dengvaxia is licensed for use only in people aged nine or older, she says. More than half of children in Indonesia have been exposed to dengue at least once by the age of six, which reduces any potential risk of ADE triggered by the new vaccine, says Arguni.
In mid-October, a committee at the European Medicines Agency recommended that the vaccine be approved for people aged four and older in Europe and dengue-endemic countries outside the European Union. The European Commission has yet to announce its decision.
Lessons from the past
But some researchers are worried about the vaccine being approved for everyone, given what is known so far. Studies suggest that after dengue infection, the immune system is hyped up enough to protect against a second infection with any serotype for one to two years — a phenomenon that is mimicked by vaccines, says de Silva. But after that period, people are protected only from the serotype to which they were first exposed, and are at increased risk of ADE when infected with other serotypes. A vaccine that does not protect against all four serotypes in people who have never been infected could induce a similar phenomenon, says Leah Katzelnick, an epidemiologist at the US National Institutes of Health in Bethesda, Maryland.
That’s probably what happened with Dengvaxia. Clinical trials suggested the vaccine was safe before it was rolled out across the Philippines in 2016, but scientists raised concerns after they reviewed the data on hospitalizations in young kids1. In further analysis and modelling of clinical-trial data collected up to five years after immunization, Sanofi found that the vaccine almost doubled the risk of previously infection-naive children aged between 2 and 16 being hospitalized, some of whom developed severe disease, including dengue hemorrhagic fever3. The increased risk might have been due to ADE, but that has not been confirmed definitively.
The episode caused a huge backlash in the Philippines against vaccines in general, says Katzelnick. “Not being cautious on this has negative ramifications beyond just dengue.”
So far, no cases of ADE have been reported in clinical trials of Qdenga. But some scientists who have reviewed the clinical data say the jab could increase the risk of the condition in people who have not previously been infected, because it does not seem to protect against all four serotypes.
Data described in a paper published online in October last year4 show that vaccinated individuals without previous infection were still protected against DENV-2 in the third year after their jab, but had limited to no protection against DENV-1 or DENV-3. There were not enough cases of infection with DENV-4 to determine whether the vaccine offered protection against that serotype in people who had never previously been infected.
The data only provides evidence for the vaccine having lasting protecting against one serotype, says de Silva, which means it’s possible that a breakthrough infection with serotypes 1, 3 or 4 could cause ADE.
Researchers are also concerned because, according to the trial data, vaccinated individuals who had never had dengue before their jab but were infected with DENV-3 two years afterwards were more likely to end up in hospital than were people who had not been vaccinated. The case numbers are small, and not statistically significant, but they are “very strongly in the wrong direction”, says Katzelnick. It will be important to see whether these numbers rise over time, she says. “These observations are warning signs,” says de Silva — they suggest that the vaccine could be acting like a DENV-2 infection, and therefore increasing the risk of hospitalization in previously naive people infected with DENV-3.
This is a concern because DENV-3 is widespread in many areas, including parts of Indonesia, says Alejandro Marín López, a viral vaccinologist at Yale University in New Haven, Connecticut.
The vaccine should be tested in more people without previous infections before it is rolled out to large populations, says Scott Halstead, a retired virologist and vaccinologist formerly at the Uniformed Services University of the Health Sciences in Bethesda.
Adequate safety data
The EMA told Nature their committee recommended Qdenga on the basis of more than four years of data on safety and efficacy. They say that this accumulated data shows efficacy against DENV-1 and DENV-2, even in people without previous infections. Together, DENV-1 and DENV-2 are responsible for most of the dengue burden globally, and efficacy against those serotypes “outweights any remaining uncertainty on lack of efficacy”, against DENV-3 and DENV-4, says the EMA.
Indonesia’s drug regulator did not respond to requests for comment.
Choo Beng Goh, head of medical affairs at Takeda Asia Pacific, told Nature that the company had identified no important safety risks in long-term analyses of the vaccine. The World Health Organization recommends obtaining three to five years’ worth of follow-up data after dengue vaccination to assess safety and efficacy accurately. This is consistent with Takeda’s phase III trial in children, Goh says.
He agrees that in people who have not previously been exposed to dengue, long-term vaccine data showed no efficacy against DENV-3 and there were not enough data to assess efficacy against DENV-4. But he says there was no evidence of ADE associated with the vaccine, and overall — when looking at data combining all four serotypes — the vaccine demonstrated efficacy in infection-naive individuals. Goh says the company plans to continue collecting data during Qdenga’s rollout in Indonesia.
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