Protective immunity following dengue virus natural infections and vaccination

SUMMARY (OVERALL) The four dengue virus serotypes (DENV1-4) cause the most important mosquito-borne viral disease of humans. Yet, no treatment is available, and the only registered vaccines are problematic. A major challenge is the dual potential of the immune response to protect against or enhance future infection with a different DENV serotype. Thus, it is critical to better understand immune responses to natural DENV infections and vaccines and to identify robust correlates of protection. The overall goal of this P01 is to apply state-of-the-art immunological and virological methods in the context of clinical and epidemiological studies of DENV infections and vaccines to elucidate how adaptive immunity shapes clinical and immunological outcomes. Our current P01 has been very successful, generating ~80 high-level publications since its inception and ~30 publications in the last 3.5 years, producing key findings that are timely and impactful. Further, our P01 consortium has served as a go-to resource for multiple agencies and regulatory bodies regarding dengue medical countermeasures. Here, we build on new tools and hypotheses that emerged from our current P01 to study immunological imprinting and evaluate biomarkers of protection and risk. The overall hypothesis of this P01 is that the magnitude and quality (i.e., repertoire and functionality) of DENV antibody (Ab), B cell, and T cell responses are shaped by distinct structural and antigenic characteristics of the 4 serotypes both in primary (1°) infections and, via immunological imprinting, secondary (2°) infections -- impacting clinical and epidemiological outcomes, with important implications for vaccine design and efficacy. We propose a coordinated P01 with 3 projects: 1) Immunological imprinting and immune correlates of Ab and B cell responses in natural DENV infections; 2) Linkage of vaccine-induced human B cell and Ab response to protective or dengue disease-enhancing immunity; and 3) Immunological imprinting of T cell responses following DENV natural infection and vaccination, supported by 4 cores: 1) Administrative; 2) Viral Assays; 3) Clinical, Data Management, and Statistical Modeling, and 4) Antibodyomics. We leverage unique sample sets from the longest continuous cohort study of dengue (in Nicaragua), currently in its 20th year; a placebo-controlled cohort study of the Dengvaxia® vaccine in the Philippines; and a human vaccine challenge study of a monovalent NIH vaccine. The P01 is highly synergistic in that samples are shared and infection sequences aligned among Projects and Cores. Specific Aims are: 1) Determine how DENV1-4 B cell and Ab responses are shaped by distinct structural and antigenic characteristics in 1° and, via immunological imprinting, in 2° infections; 2) Reveal Ab-mediated mechanisms responsible for vaccine-mediated protection, vaccine failure and vaccine-enhanced dengue disease; 3) Profile the quantity and quality of imprinted DENV-specific memory T cell response in relation to immunophenotype and vaccine outcomes; 4) Compare the breadth of Ab and T cell responses induced by DENV vaccines vs. natural infections; 5) Identify robust correlates of protection or risk enhancement of dengue disease in different contexts.