Butantan InstituteUpdate on Phase 3 trial of tetravalent dengue vaccine

Dengue, a significant global health challenge, necessitates a secure and efficacious vaccine as part of a holistic response strategy. Despite sustained efforts, only two vaccines have been globally approved. However, their universal deployment has been hindered due to several factors. These include the complexities of dengue vaccine development including four potentially deadly dengue virus (DENV) serotypes; the absence of a validated correlates of protection; the requirement for large, diverse participant groups over a long-term study; and the limitations of animal models in replicating human dengue infection.

In response to these hurdles and the pressing medical need, the non-profit Instituto Butantan (IB) launched a dengue clinical development program in 2016 to assess the Butantan-DV vaccine, similar to NIH’s TV003 formulation. This single-dose, live, attenuated, tetravalent vaccine consists of the full-genome DENV-1, -3, and -4 components with a DENV-2/-4 chimeric backbone. Its unique structure, incorporating all wild-type structural and non-structural proteins from DENV-1, -3, and -4, potentially enhances efficacy and immunogenicity.

The pivotal Butantan-DV study (NCT02406729) involved participants stratified by age, randomized to receive a single dose of Butantan-DV or placebo. Conducted at 16 sites in Brazil, this ongoing double-blind trial has a projected five-year follow-up. The primary objective was to assess the vaccine’s efficacy in preventing symptomatic, virologically confirmed dengue. Both efficacy and safety were examined during the first two years.

Out of 16,235 participants, 10,259 received Butantan-DV, achieving the primary efficacy endpoint with an overall efficacy of 79.6%. The vaccine’s efficacy was higher (89.2%) in participants previously exposed to dengue and 73.6% for those without prior exposure. The vaccine showed 89.5% efficacy against DENV-1 and 69.6% against DENV-2. No cases of DENV-3 or DENV-4 were detected, reflecting the circulating serotypes during the study. The vaccine was well-tolerated, with minor systemic vaccine-related adverse events. Importantly, the safety profile remained consistent irrespective of participants’ baseline serostatus.

Fernanda Boulos, Chief Medical Officer at IB, stated: “This data represents a significant milestone for the Brazilian scientific community in the fight against dengue, a global public health problem. There is a great expectation that this vaccine will become a preventive measure for symptomatic and severe cases of dengue, positively impacting the population.” José Moreira, Clinical Development Medical Director at Butantan, added: “The availability of a single-shot dengue vaccine candidate that provides protection against symptomatic disease, regardless of baseline serostatus, marks a historic achievement. Its ease of implementation in national immunization programs and potential deployment during outbreaks or for travelers from non-endemic countries visiting endemic regions further adds to its advantages”.

Clearly, a multi-faceted approach is necessary to tackle the global dengue burden, selecting tools specific to varying populations and contexts. These pivotal efficacy and safety findings will be submitted for publication in a peer-reviewed journal in 2023.

EU Flag

The GloPID-R Secretariat is a project which receives funding from the European Union’s Horizon Europe research and innovation programme under grant agreement No 101094188.