A dengue vaccine is ready to be introduced, but safety concerns remain

A dengue vaccine is ready to be introduced, but safety concerns remain

A dengue vaccine is ready to be introduced, but safety concerns remain

A dengue vaccine is ready to be introduced, but safety concerns remain

Mosquito nets are currently one of the main ways to prevent the spread of dengue fever.Credit: Erik DeCastro/Reuters

A vaccine to prevent dengue – a mosquito-borne disease that kills 20,000 people a year – is set to be launched in Indonesia next year. But the sting is sparking debate: Some researchers say important safety concerns have been overlooked.

The vaccine, called Qdenga, developed by the Tokyo-based pharmaceutical company Takeda, is particularly significant because it is the first for people who have not been exposed to dengue fever. The virus infects up to 400 million people a year. Indonesia’s drug regulator approved the use of the vaccine without testing for prior exposure in August. The European medicines regulator is also considering approving the vaccine without testing.

The only other approved vaccine, Dengvaxia, developed by Sanofi in Paris, can only be given to people who are already infected. In people without a history of infection, Dengvaxia increases the risk of severe illness, including hemorrhagic fever, which can be caused by a rare but serious condition called antibody-dependent enhancement (ADE), in which vaccination produces antibodies that worsen subsequent infection. .

It is the possibility of ADEs that is fueling concern about the new vaccine among some scientists, who say it cannot be ruled out based on clinical trial data collected 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 worked with Takeda and other dengue vaccine makers.

A Takeda spokesman says clinical trial data was collected from more than 28,000 people over 4.5 years, which is in line with World Health Organization recommendations. The data show that Qdenga is safe, regardless of previous exposure to dengue fever, the spokesperson said. And the European Medicines Agency says there is no clear evidence of a higher risk of severe disease in people who have not been previously infected.

Other researchers say Qdenga will help reduce the growing burden of dengue fever. The virus is endemic in more than 100 countries, mostly in Asia. With no treatment and limited ways to control the spread of mosquitoes, vaccines are desperately needed. “I support the licensing 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 largest dengue infections each year.

First approval

Dengue has four different ‘serotypes’ (DENV-1, DENV-2, DENV-3 and DENV-4) and protection against any two of these is required to reduce the chance of serious disease. After a second infection, or vaccination followed by a breakthrough infection, people are usually 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 have been engineered into this backbone.

In 2019, Takeda announced the results2 trials in 8 countries, conducted on approximately 19,000 children aged between 4 and 16 years. One year after immunization, the vaccine was 80% effective against symptomatic dengue and 95% effective against hospitalization. In a press release published in June of this year, Takeda reported that 4.5 years after immunization, the effectiveness 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 years. Forgoing testing for previous dengue exposure makes the vaccine more convenient and easier to administer, says Eggi Arguni, a pediatrician at Gadjah Mada University in Yogyakarta, Indonesia. And approving Qdeng for six-year-olds will make vaccination available to younger children; in Indonesia, Dengvaxia is only licensed for use in people nine years of age 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 the potential risk of ADEs caused by the new vaccine, Arguni says.

In mid-October, a committee at the European Medicines Agency recommended that the vaccine be approved for people four years of age 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 concerned that the vaccine will be approved for everyone, given what is known so far. Studies suggest that after a dengue infection, the immune system is sufficiently boosted to protect against another infection with any serotype for one to two years — a phenomenon mimicked by vaccines, de Silva says. 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 cause 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 showed the vaccine was safe before it was introduced in the Philippines in 2016, but scientists raised concerns after reviewing data on hospitalizations of young children.1. In further analysis and modeling of clinical trial data collected up to five years after immunization, Sanofi found that the vaccine nearly doubled the risk of hospitalization in uninfected children aged 2 to 16, some of whom developed severe illness, including dengue. hemorrhagic fever3. The increased risk may have been due to ADEs, but this has not been definitively confirmed.

The episode sparked a huge backlash in the Philippines against vaccines in general, Katzelnick says. “Being careless about this has negative consequences beyond dengue.”

To date, no cases of ADE have been reported in Qdenga clinical trials. But some scientists who reviewed the clinical data say the jab could increase the risk of disease in people who haven’t been infected before, because it doesn’t appear to protect against all four serotypes.

The data was described in an article published online last October4 show that vaccinees without previous infection were still protected against DENV-2 in the third year after vaccination, but were limited to no protection against DENV-1 or DENV-3. There were not enough cases of DENV-4 infection to determine whether the vaccine offers protection against that serotype in people who have never been infected before.

The data only provide evidence that the vaccine has sustained protection against one serotype, de Silva says, meaning it’s possible that a breakthrough infection with serotypes 1, 3 or 4 could cause ADE.

Hospital data

The researchers are also concerned because, according to the trial data, vaccinated people who had never had dengue before the sting but were infected with DENV-3 two years later were more likely to end up in the hospital than unvaccinated people. 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 if those numbers grow over time, she says. “These observations are warning signs,” says de Silva—they suggest that the vaccine may act like a DENV-2 infection, and therefore increase the risk of hospitalization in previously naive people infected with DENV-3.

This is concerning because DENV-3 is widespread in many areas, including parts of Indonesia, says Alejandro Marin Lopez, a viral vaccinologist at Yale University in New Haven, Connecticut.

The vaccine would need to be tested in more people without previous infections before it is introduced to the general population, said Scott Halstead, a retired virologist and vaccinologist formerly at the Uniformed Services University of the Health Sciences in Bethesda.

Adequate safety data

EMA said Nature their committee recommended Qdenga based on more than four years of safety and efficacy data. They say these accumulated data show efficacy against DENV-1 and DENV-2, even in people without previous infections. Together, DENV-1 and DENV-2 are responsible for the majority of the dengue burden globally, and efficacy against those serotypes “outweighs any remaining uncertainty regarding the lack of efficacy,” against DENV-3 and DENV-4, the EMA said.

Indonesia’s drug regulator did not respond to requests for comment.

Choo Beng Goh, Head of Medical Affairs at Takeda Asia Pacific, said Nature that the company did not identify important safety risks in long-term analyzes of the vaccine. The World Health Organization recommends obtaining three to five years’ worth of data after dengue vaccination to accurately assess safety and efficacy. This is consistent with Takeda’s Phase III trial in children, says Goh.

He agrees that in people not previously exposed to dengue, long-term vaccine data have not shown efficacy against DENV-3, and there was insufficient data to assess efficacy against DENV-4. But he says there was no evidence of vaccine-related ADEs, and overall — when looking at data combining all four serotypes — the vaccine showed efficacy in uninfected individuals. Goh says the company plans to continue collecting data during Qdeng’s rollout in Indonesia.

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