Dengue is evolving, and the vaccine intended for people in India is still under development.
As of 16 September, Karnataka has reported 27,351 dengue cases in 2024 with 12 deaths. Bengaluru leads with a whopping 12,594 cases, highlighting the city’s growing dengue crisis and the associated vaccine challenge.
A recently published article in The Lancet highlights a shift in the dengue serotype distribution in Bangalore, with a significant rise in the dominance of dengue virus serotype 3 (DENV-3).
This shift poses critical implications for vaccine efficacy, as current dengue vaccines have shown limited effectiveness against DENV-3 in clinical trials. The study emphasizes the importance of region-specific serotype understanding, which is essential as India moves toward phase 3 trials of quadrivalent dengue vaccines.
“India’s substantial dengue disease burden, with an estimated 12.9 million primary infections annually, presents a significant public health challenge. This extensive disease prevalence, coupled with the complex immunological dynamics of dengue virus serotypes, poses considerable obstacles to the development and implementation of effective dengue vaccines in India,” states the article published in *The Lancet*.
The article was authored by Shruthi Uppoor from H Siddaiah Referral Hospital, Bengaluru; Tina Damodar, Lonika Lodha, and Reeta S. Mani from the Department of Neurovirology, National Institute of Mental Health & Neurosciences (NIMHANS), Bengaluru; and Madhusudhan Huluvadi Nagarajaiah from the Vector Borne Disease Control Programme, Bruhat Bengaluru Mahanagara Palike, Bengaluru.
The authors emphasise that as India prepares for phase 3 trials of quadrivalent dengue vaccines, understanding region-specific circulating dengue virus serotypes is crucial. Southern India, in particular, reports the highest dengue seroprevalence, estimated at 77 percent.
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What the study reveals?
Dengue fever is caused by one of four dengue viruses: DENV-1, DENV-2, DENV-3, and DENV-4. Since there are four distinct strains, a person can be infected with dengue up to four times in their lifetime. Each subsequent infection weakens the immune system and increases the severity of the illness. Experts are concerned that a surge in dengue cases is imminent.
Each of these viruses has a different serotype, which is a specific strain of the virus. When a person is infected with dengue, their immune system produces antibodies specific to the serotype they were exposed to.
To understand the current serotype distribution, the authors of the study analyzed 1,600 samples from acute febrile illness patients across all eight zones of urban Bangalore (East, South, West, Bommanahalli, Dasarahalli, Mahadevapura, Rajarajeshwari Nagar, and Yelahanka).
The samples were collected from health centers under the Bruhat Bengaluru Mahanagara Palike (BBMP) between April and July 2024 and tested at the Department of Neurovirology at the National Institute of Mental Health and Neurosciences (NIMHANS).
Of these, 549 (34.3 percent) tested positive for the dengue NS1 antigen and/or anti-dengue IgM by ELISA. Real-time PCR analysis of 507 (92.3 percent) NS1 positive samples found that 228 (45 percent) were positive for DENV serotypes, revealing a predominance of DENV-3 (182, 79.8 percent), followed by DENV-1 (27, 11.8 percent), DENV-2 (19, 8.3 percent), and DENV-4 (3, 1.3 percent). Additionally, three samples (1.3 percent) showed co-infection of DENV-2 and DENV-3.
“Our findings may indicate a potential shift in serotype dominance towards DENV-3 from DENV-4, which has been the predominant serotype in Southern India since 2015, based on evolutionary studies of DENV,” the authors noted.
It should be also noted that Karnataka has become the first state in India to declare dengue an epidemic. The government has enacted strict regulations and penalties to prevent mosquito breeding and control the outbreak, addressing the significant rise in cases.
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The vaccine issue
The authors highlighted that the dominance of DENV-3 is particularly significant given the challenges faced by some vaccine candidates in providing effective protection against this serotype.
“For instance, the TAK-003 (Takeda Pharmaceutical, Tokyo, Japan) vaccine showed limited efficacy of 62.6 percent against DENV-3 in trials conducted in dengue-endemic regions of Asia and Latin America,” the authors explained.
On 15 May, the World Health Organisation (WHO) announced that it had prequalified a new vaccine for dengue.
TAK-003 is the second dengue vaccine to receive WHO prequalification. Developed by Takeda, it is a live-attenuated vaccine containing weakened versions of all four serotypes of the dengue virus. In February 2024, Takeda partnered with Hyderabad-based Biological E to produce 50 million doses of the vaccine. WHO recommends TAK-003 for children aged six to 16 in regions with high dengue transmission. The vaccine is administered in two doses, three months apart.
Another promising vaccine candidate is the Butantan–Dengue Vaccine (Butantan-DV), a single-dose, live attenuated tetravalent vaccine developed by the Butantan Institute in Brazil to target all four dengue serotypes.
“However, trials of the Butantan–Dengue Vaccine (a collaboration between the Butantan Institute, Brazil, and the National Institutes of Health (NIH) in the United States) lacked efficacy data for DENV-3 and DENV-4, as these serotypes were not in circulation during the follow-up period,” the authors noted.
They emphasised that the co-circulation of all four serotypes in Southern India highlights the urgent need for quadrivalent vaccines that are effective against all serotypes, especially given India’s significant role in the global dengue burden.
The study’s findings on the high prevalence of DENV-3 provide a valuable opportunity to gather comprehensive efficacy data for this serotype in upcoming phase 3 trials in India, addressing a critical gap identified in earlier international trials.
Importance of sequencing
The authors emphasised that to deepen our understanding of dengue epidemiology and advance vaccine development efforts, dengue virus sequencing is essential. Sequencing data will enable the correlation of disease severity and outcomes with specific genotypes or mutations.
Additionally, sequencing may uncover novel clades or genotypes, providing valuable insights into the molecular diversity, antigenic evolution, and potential vaccine escape mutants of the dengue virus in this region. Recent challenges to the conventional belief in lifelong immunity against homologous dengue serotype infections further highlight the need for more detailed investigations into genotypes and clades.
“It has been demonstrated for dengue serotype 2 that genetic diversity within the serotype affects antibody neutralisation activity. By developing a comprehensive genetic profile of circulating dengue viruses, we can better assess the potential effectiveness of current vaccine candidates and guide the creation of future vaccines tailored to the specific strains prevalent in India,” the authors explained.