Analysis of innate responses and vaccination-induced serotype-specific B and T cell responses associated with protection against controlled human dengue virus challenge

Summary This proposal aims to define the vaccine-induced B cell responses, T cell responses, and innate responses that are associated with effective protection against dengue virus (DENV) infection. DENV has become the most important arbovirus worldwide with estimates of ~390 million dengue infections occurring annually, more than 2 million of which are classified as severe disease. Dengue is now endemic in more than 100 countries with approximately 2.5 billion people at risk for infection. Dengue was ranked third in infectious disease threats to the US military, highlighting the need for a dengue vaccine to protect U.S. service members deployed abroad. There are four distinct serotypes of DENV, and the goal of vaccines is to induce balanced immunity against all four serotypes, since unbalanced immunity across serotypes can lead to more severe dengue disease rather than protection. We will study immune responses to vaccines that were tested in a controlled human infection model (CHIM) of DENV infection. These vaccines contained either three of four dengue serotypes, and provided a range of protection against serotype 2 (DENV2) in the CHIM model. The first aim will define the impact of DENV vaccine serotype composition on specificity, function, and durability of serotype- specific memory B cell and monoclonal antibody (mAb) responses and on subsequent responses to DENV2 challenge. We hypothesize that vaccine serotype composition will determine the balance and function of serotype-specific and cross-reactive B cell responses after vaccination, as well as the proportions and neutralizing potency of serotype-specific and cross-reactive mAbs, and that these responses will dictate capacity to effectively prevent DENV2 infection after challenge. In the second aim, we will define the role of T cell function, including metabolic function, on control of challenge DENV2 and on specificity, phenotype and durability of DENV-specific memory B cell and neutralizing antibody responses. We hypothesize that vaccine- induced CD4 T cell phenotype, particularly expression of glucose transporter 1, and function promote effective B and CD8 T cell responses upon DENV challenge, and that CD8 T cell phenotype and function are correlated with control of DENV infection. In the third aim, we will dissect innate immune cell responses to DENV vaccination and challenge. We hypothesize that protective innate cell responses will promote robust CD4 T cell help and facilitate cross-reactive B cell responses. The results from this proposal will define the immune mechanisms underlying effective dengue protection, aid in interpretation of ongoing vaccine trials, and may inform design of next-generation dengue vaccines.