Abstract
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.
Highlights
The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions [1,2,3]
The development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a measure of safe and effective immunity
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
Summary
The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions [1,2,3]. DENV infections can be inapparent or present as a febrile illness that may or may not progress to severe dengue hemorrhagic fever and shock syndrome. DENV serotype-specific neutralizing antibodies, which circulate for life, are correlated with durable protection against re-infection by the same serotype [6,7,8]. Individuals experiencing second DENV infections with heterologous serotypes are at greater risk for developing severe dengue hemorrhagic fever and shock syndrome compared to individuals experiencing their first infection. To minimize the risk of DENV vaccines inducing antibodies that enhance DENV infections, leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. We characterize the properties of neutralizing antibodies (nAbs) induced by a leading live attenuated tetravalent DENV vaccine (TAK003) to determine the contribution of each vaccine component to the serotype-specific neutralizing antibody response
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