Dengue virus (DENV) represents a major threat to global health. However, the precise role of the immune system in protecting against and pathogenesis of the four DENV serotypes, which share antigenic similarities and geographic ranges with each other and other closely related flaviviruses are poorly understood. In particular, antibodies can contribute to DENV pathogenesis by mediating antibody (Ab)-dependent enhancement of infection (ADE). This project focuses on defining the features of the anti-flavivirus Ab response that contributes to ADE vs protection using epidemiologically relevant mouse models in which DENV infection of mouse pups is enhanced by maternally acquired flavivirus Abs. Our published and new data demonstrate that flavivirus vaccination-infection combinations can promote either pathogenesis or protection. Our preliminary data also show that mice lacking T follicular helper (Tfh) cell responses are unable to induce DENV IgG response, and that mice treated with an agonistic Ab that stimulates OX40, a T cell costimulatory molecule belonging to the TNF receptor superfamily, exhibit a boosted DENV IgG response, suggesting that the magnitude of the Tfh response correlates with the level of Ab response to DENV. Therefore, we hypothesize that promoting Tfh responses will increase the production of broadly-neutralizing Ab (bnAb) responses that mediate protection and minimize ADE during DENV infection. We will test this hypothesis by using an RNA replicon-based vaccine platform that induces robust T cell and Ab responses in the following Specific Aims: (1) Determine how vaccination with different flavivirus antigens affects Tfh cell and Ab responses in maternal mice and susceptibility to DENV ADE in their offspring. (2) Test whether manipulation of immunization variables and candidate T cell costimulatory pathways boosts maternal Tfh cell and Ab responses and induces a protective response to DENV2 infection in offspring. These studies will provide critical insights into the factors and mechanisms that regulate ADE vs protective immunity to DENV2 infection. This knowledge is urgently needed to inform development of DENV vaccines that protect infants and young children, the highly vulnerable populations, and other flaviviral vaccines that are safe and effective worldwide, including in countries with co-circulation of 2 or more flaviviruses. The proposed work is based on our strong track record in investigating humoral and cellular immune mechanisms during flavivirus infections using state-of-the-art mouse models. The project will also benefit from our collaborators? expertise in Tfh cells, T cell costimulatory molecules, flaviviral Ab response in humans, development of novel vaccine platforms, and genomics assays.
The four serotypes of DENV are significant causes of morbidity and mortality worldwide, as half of the world?s population is at risk of DENV infection. The recently licensed DENV vaccine is not approved for use in people who are younger than 9 years old and are nave with respect to prior DENV exposure. At present, a DENV vaccine that protects infants and young children, who represent highly vulnerable populations for manifesting severe dengue disease, and nave individuals of all ages is a global health priority. This project will advance our understanding of the mechanisms regulating protective vs pathological Ab responses to DENV, and in so doing, contribute to the development of safe and effective DENV vaccines.
