the Two people died recently in Brazil During the dengue vaccination drive, which led to the suspension of vaccination on June 8, it was a crucial wake-up call for India. This is because Brazil’s dengue vaccine, Butantan-DV, is very similar, if not identical, to India’s soon-to-be-launched dengue vaccine, DengiAll.
The Brazilian and Indian vaccines took several years to manufacture. Both consist of live but weakened (attenuated) versions of dengue viruses (DENVs). Both vaccines are said to be quadrivalent because each vaccine is actually a physical mixture of four live, weakened DENVs.
In fact, DENVs come in four versions, or serotypes: called DENV-1, -2, -3, and -4. All four serotypes are known to be circulating in Brazil and India. Each DENV serotype has an outer envelope decorated with specialized envelope proteins, called E proteins – similar to the spike protein of coronaviruses. Although the four DENV serotypes are very similar, their E proteins are different enough to warrant immunization against each of the four serotypes.
Antibody-based enhancement
When attenuated DENV is used in a vaccine, it will induce several types of antibodies that can be grouped into two categories: type-specific antibodies and cross-reactive antibodies. Type-specific antibodies, which are often made in small quantities, are specific for unique regions of the E protein for a particular serotype. That is, type-specific antibodies recognize only one specific serotype and are superior at preventing infection by that serotype alone.
Cross-reactive antibodies, on the other hand, are usually synthesized in large quantities and are specific for similar regions in the E proteins of all four serotypes. That is, they can recognize any of the four serotypes and prevent infection, provided they are present at sufficiently high levels. When their levels fall, cross-reactive antibodies not only fail to prevent new DENV infections, they enhance them, leading to a severe and fatal form of dengue.
This phenomenon is called antibody-dependent enhancement (ADE). The potential risk of ADE during dengue vaccination is considered a serious adverse event. If not treated it can lead to death.
In the dengue vaccination campaign in Brazil, two people died out of 42 vaccine recipients who developed serious side effects, and one of them was forced to receive intensive care. These side effects included severe abdominal pain, persistent vomiting, and bleeding, none of which were detected in phase III clinical trials. These signs are alarmingly reminiscent of viral hemorrhagic fevers such as dengue in its acute form. Medical researchers should consider whether this may be due to ADE.
They should also clarify whether DengiAll will exhibit a similar risk when launched in India.
Problems with Dengvaxia
Both Butantan-DV and DengiAll build on the efforts of scientists at the US National Institutes of Health (NIH). Over many years, they attenuated each DENV serotype separately to make monovalent vaccines, evaluated each one for its ability to stimulate an immune response without causing disease, and finally mixed all four monovalent vaccine viruses to produce quadrivalent vaccines. Two of them, called TV003 and TV005, and their monovalent vaccine viruses have been licensed to the Butantan Institute in Brazil and Panacea Biotec in India, among others, for further development.
Butantan-DV is not the first dengue vaccine linked to such events. Just over a decade ago, Sanofi Pasteur developed the first quadrivalent dengue vaccine to be licensed. It differs from NIH’s TV003 and TV005 in that the four weakened serotypes were hybrid viruses, each coated on its surface with the E protein of one of the DENV serotypes (plus another protein).
This shot, called Dengvaxia, has been given to more than 8,000 children in the Philippines, a dengue-endemic country like Brazil and India. Serious adverse events occurred three years after vaccination. Another study revealed that Dengvaxia acts like a monovalent vaccine, eliciting antibodies to only one serotype, DENV-4. This means that mixing four live but weakened viruses to create a quadrivalent vaccine does not automatically guarantee quadrivalent immunity. Why? There is no clear answer yet.
Taken together, the severe adverse events associated with Butantan-DV raise many questions. Is butantan-DV tetravalent really functional? Is there a possibility of viral interference that harms its functions? Could ADE be the reason behind the potentially fatal outcomes in two cases?
Gap in phase 3 trials
These questions are made more difficult by a gap in vaccine efficacy data collected in Phase 3 trials. Reports issued in January 2024, November 2024, and March 2026 indicated that the effectiveness of Butantan-DV against DENV-3 and DENV-4 was unknown because these serotypes were not prevalent in Brazil at the time of the trials.
Panacea Biotec DengiAll Phase III trials, in collaboration with the Indian Council of Medical Research, You have completed your registration The goal is to reach 10,335 health volunteers in January this year. The trial began in August 2024; Participants will be followed for two years after vaccination. Once all the data is collected and analysed, the researchers (along with the company) will approach the Indian Drug Regulatory Authority to obtain market approval.
There is little reason to deny that DengiAll may not face the potentially fatal problems that arose with Butantan-DV. However, India can do a few things proactively to mitigate safety concerns before rolling out DengiAll in the future. First, the panacea must analyze a representative subset of sera from vaccinated volunteers for type-specific antibodies against all four serotypes. The medicines regulator must ensure that these data are available and rule out the potential risks of ADE.
Strong pharmacovigilance
Furthermore, once DengiAll is launched, the regulator must implement a robust pharmacovigilance program for an extended period of time. Vaccine recipients should be clinically monitored periodically and their blood should be collected at regular intervals to check for the presence of viruses, antibodies and other parameters to quickly implement therapeutic measures. Continuous real-world monitoring is key to identifying rare or long-term adverse events.
ADE concerns also apply to other tetravalents Dengue vaccine, Qdengawhich is also a physical combination of four attenuated versions of DENV serotypes. It is being marketed by Japan-based Takeda, and Indian approval is imminent.
The Brazilian authorities stressed that the 42 cases of severe adverse events out of half a million vaccinated represent only 0.008%. There is no doubt that this risk is small at the population level. However, at the individual level, losing one life to a serious adverse event is one too many.
S Swaminathan is a retired Professor of Biology from BITS Pilani-Hyderabad and a former Dengue Vaccine Scientist at ICGEB, New Delhi.
Published – 15 June 2026 at 08:00 AM IST
