The first safe, effective, low-cost, and single-dose dengue vaccine: that is the result of a 15-year partnership between Instituto Butantan and the National Institutes of Health (NIH) of the United States. This agreement, one of the first between a Brazilian vaccine manufacturer and a North American governmental institution, aimed to address a public health issue that affects 4 billion people in the world, according to the World Health Organization (WHO) – particularly in low and middle-income countries like Brazil.
The studies that made this international collaboration possible began in the late 1990s, when the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) started testing several monovalent vaccine candidates of each of the four serotypes of dengue virus. A decade later, scientists identified the best candidates to formulate into a tetravalent vaccine (against DENV1, 2, 3 and 4). It was based on these strains that Butantan developed the tetravalent dengue vaccine, which is now at the final stage of Phase III clinical trials.
Researcher and scientific review officer from NIAID Anuja Mathew, who has 25 years of experience working on immune responses to dengue, visited Butantan as an Embassy Science Fellow from late January to middle March. In an interview with Portal do Butantan, she discussed the complexity of the dengue virus and the challenges encountered during the development of the vaccine.
“It’s like you were developing four vaccines. Researchers at NIAID had to identify which of the strains of the four viruses were able to replicate well, safe and also immunogenic. That is not an easy task”, the specialist says.
In 2009, the NIH sent the strains to Instituto Butantan so they could develop the vaccine in Brazil. It required four years and over 200 experiments to obtain the final version that would be administered in clinical trials – a challenge overcome by researcher Neuza Frazatti’s team, from Butantan.
“You have to be really careful that each virus is treated separately. During the process of concentration, purification, and lyophilization of each of the four vaccine strains, the virus titer can also drop. So, you have to account for a lot of loss when you are making batches of virus for clinical trials”, Anuja explains. “Butantan was able to overcome several challenges and produce four dengue virus serotypes to run the clinical trial.”
Advantages of the vaccine
According to Anuja Mathew, the vaccine has several advantages. The single-dose schedule eliminates the need for additional doses. Furthermore, the affordability of the vaccine will enable access to people who need it the most – those who live in Latin America, Africa and Asia, where dengue is endemic.
Another benefit is that the immunogenicity is equivalent in all 4 serotypes. Although researchers still need to verify the efficacy against DENV3 and DENV4, which have not circulated in Brazil during the period of the study, earlier results showed that the vaccine induces neutralizing antibodies against all 4 serotypes.
Anuja adds that the vaccine is a live virus vaccine for each of the four attenuated serotypes: it contains the four original sequences, with structural and non-structural proteins. Other dengue vaccines in the market only have structural proteins of the dengue virus, and are based on yellow fever virus or DENV2 backbone.
“Dengue virus has structural and non-structural proteins. Many T lymphocyte epitopes have been identified which is an important arm of the immune response”, explains Anuja. She published one of the early studies demonstrating that non-structural proteins are dominant targets of T-cell-specific response, as outlined in a study published in 1998 in Journal of Virology. T cells are responsible for eliminating infected cells.
The scientist received her PhD in 1999 from the University of Massachusetts Chan Medical School, in the United States, where she studied immune responses in peripheral blood mononuclear cells from children who had been exposed to dengue virus in Thailand. At the same university, she worked as a faculty member in the Center for Infectious Disease and Vaccine Research and then the Division of Infectious Disease and Immunology, where she continued to work on T and B cell responses to dengue virus.
For Anuja, the production of a dengue vaccine by a public institution in Brazil can benefit not only the country itself, but all Latin America, that has been facing dengue epidemics. The incidence has increased in the Americas over the past four decades, from 1.5 million cumulative cases in the 1980s to 16.2 million in the decade 2010-2019, according to Pan-American Health Organization (PAHO). The technology licensing for MSD will also help to increase vaccine access in other regions of the world.
“I grew up in India so I have seen poverty that is quite hard and it’s not easy to fix. In order to combat tropical neglected diseases like dengue, it is imperative to invest long-term in vaccines, vector control and public health education”, she states. “Science is long and hard and there are very few rewards. We cannot expect easy results, but collaboration among scientists all over the world is essential.”
Promoting new partnerships
Anuja Mathew spent two months as a consultant at Butantan to visit the production site of the dengue vaccine, in addition to presenting NIH’s work and discussing best research practices and possibilities of funding. Her goal was to strengthen the relationship between Butantan and NIH and to facilitate the establishment of new collaborations among researchers. The visit was a part of the Embassy Science Fellows Program, which promotes knowledge exchange between North American and foreign scientists.
“Butantan has all the facilities and expertise needed for large scale vaccine production and research development. They produce influenza vaccine for the entire country of Brazil, which is a huge accomplishment. Butantan is certainly an institution which NIH would like to continue collaborating with”, says the researcher.
The NIH supports Brazilian research since the 1980s, funding local projects about allergy, immunology, transplantation, fungal diseases, HIV, influenza, malaria, tuberculosis, among others. To enhance these collaborations, it was created in 2014 the U.S.-Brazil Collaborative Biomedical Research Program between NIH, the Brazil Ministry of Health, and the Ministry of Science, Technology, and Innovation.
Part of the Department of Health and Human Services, NIH has 27 public institutions with different goals of research and funding, and it is considered one of the main funders of biomedical research in the world.
State of emergency
In the beginning of March, Sao Paulo State Government announced emergency in public health for dengue, when the state reached 300 confirmed cases per 100 thousand habitants. In 2024 in Brazil, the number of probable cases already exceeds 1.5 million, with 450 deaths, according to the Monitoring Panel of the Ministry of Health.
If approved by the National Agency of Sanitarian Vigilance (Anvisa), Butantan’s vaccine will be made available in the Unified Health System (SUS). The single-dose schedule facilitates logistics and vaccination adherence – important factors in an epidemic context.
Efficacy data from phase 3 clinical trials referring to the first two years of follow-up will be sent to Anvisa in the second half of 2024, which will begin the process of requesting definitive registration.
Written by: Aline Tavares
Anuja also highlights the clinical trial network developed by Butantan, which has 16 research centers in all regions of Brazil where the study has been ongoing since 2016. In the two-year follow-up period, the vaccine showed a 79.6% efficacy, according to the results published in The New England Journal of Medicine.