A New Approach for Dengue-Zika Vaccine

A safe and effective vaccine is urgently needed for Zika virus (ZIKV), a flavivirus that causes Congenital Zika Syndrome, and the closely-related dengue virus (DENV), which causes Severe Dengue. DENV vaccine development, which has been ongoing for the past 70 years, has been challenging because the vaccine needs to provide robust protection against all four DENV serotypes, as the vaccine-induced antibody (Ab) response can play a harmful role under certain conditions. DENV and ZIKV share the same mosquito vector and overlapping geographic ranges, resulting in individuals with multiple infections. They share similarity at both structural and genetic sequence levels, leading to recognition of both viruses by cross-reactive Abs.

The majority of vaccines have been designed empirically to generate an Ab response that neutralizes or destroys the virus. However, Abs may play both a protective and harmful role during DENV/ZIKV infection. Thus, there is an urgency to develop a new approach for safe and effective vaccine design for solving the global DENV/ZIKV problem. Our goal is to enhance T and B cell interactions that are required for generation of highly protective, broadly neutralizing Abs against DENV and ZIKV. Specifically, we will first evaluate T follicular helper (Tfh) cell responses, which regulate the quality of the Ab response, in various DENV and ZIKV infection settings in mice, including primary and sequential infections in adults and infants with maternal DENV/ZIKV Abs. These infection scenarios involve both protective and pathogenic Ab response, allowing us to correlate Tfh and Ab responses in the context of neutralization vs. adverse outcomes.

Second, we will modulate the Tfh response in order to boost the generation of neutralizing Abs and avoid induction of pathogenic Abs. This research will help us understand how the magnitude and quality of the Tfh and Ab responses to DENV and ZIKV vary in different infection contexts. Our approach is essential towards generation of pan-flaviviral vaccines that provides protection against multiple, closely-related viruses such as the four DENV serotypes and ZIKV, thereby addressing the global problems associated with expanding and merging ranges of flaviviruses, which include Japanese Encephalitis Virus and Yellow Fever Virus.