Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.
Author summary The licensed tetravalent dengue vaccine Dengvaxia is indicated for individuals with previous exposure to dengue. In subjects with no past dengue infection, vaccine trials showed low efficacy against some serotypes and increased risk of severe disease upon post-vaccination infection. The development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a measure of safe and effective immunity. However, the absolute level of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Recent studies suggest that a better correlate may be levels of antibodies to epitopes that are unique to each serotype and are independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies. Here, we mapped the antibody specificity induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The vaccine induces high levels of dengue serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the dengue serotype 1, 3 and 4 specific responses are lower and predominantly consist of cross-reactive antibodies binding to antigenic regions conserved between serotypes. It remains to be determined whether these cross-reactive antibodies, most likely induced by the serotype 2 component, contribute to long-term protection after vaccination.