Immunology, virology, and epidemiology of flaviviruses and other emerging viruses

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Characterizing protective anti-DENV antibodies. Specific concentrations of binding and neutralizing antibodies are associated with protection and enhancement of dengue disease (Katzelnick et al. Science 2017, 2020; Katzelnick et al. PNAS 2016). However, existing assays are crude, with neutralization detected even for antibodies that can enhance in vivo. Drawing on recent insights into flavivirus immunology, we are developing and evaluating assays to test whether antibodies that bind quaternary epitopes on the DENV virion correlate with protection against disease in dengue and Zika vaccine studies. Through collaborations, we are evaluating antibody quality in other natural infection cohorts (preprint: https://pubmed.ncbi.nlm.nih.gov/37502957/). We have also identified broadly neutralizing anti-DENV antibodies that are more potent than those identified previously using a rapid antibody discovery platform (provisional patent application serial number: 63/464,370). Factors shaping of dengue transmission and epidemics. After sequential DENV infection, binding antibodies wane for many years, sometimes to the level observed following first DENV infection, suggesting immunity after two infections may not be life-long (Katzelnick et al. Sci Trans Med 2021). We find that DENV re-exposure continues to boost antibody levels even in highly immune adults, and developed a mathematical model that shows boosts contribute to herd immunity and help explain observed dengue epidemic dynamics. Continuing our previous work showing that the four DENV serotypes are antigenically diverse and undergo cycles of evolving toward and away from co-circulating serotypes (Katzelnick et al. Science 2015, 2021; Huang et al. PLoS Pathogens 2022), we have collaborated with others to evaluate if specific antigenic distances between strains are associated with increased risk of disease (preprint: https://pubmed.ncbi.nlm.nih.gov/37577717/). Finally, we have evaluated factors contributing to the expansion of dengue globally using Ecuador as a case study (preprint: https://pubmed.ncbi.nlm.nih.gov/37398346/). Modeling the determinants of protective immunity using dengue vaccines. Existing dengue vaccines are tetravalent and aim to induce serotype-specific immunity, whereas natural sequential DENV infection with distinct serotypes is thought to induce broadly protective immunity against shared epitopes. We published a perspective piece on the potential for mix and match of licensed dengue vaccines as an approach for inducing protective immunity without increasing risk of enhancement (Odio and Katzelnick Vaccine 2023). To identify mechanisms of how sequential DENV infection induces broad protective immunity, we have established a Phase I clinical trial (n=45 participants) to safely model DENV infection with a monovalent dengue vaccine, rDEN3d30/31-7164, in healthy adults with no, one, or more than one previous natural DENV infections (Odio et al. BMC Infectious Diseases 2023; ClinicalTrials.gov Identifier NCT05691530). Participants are being closely followed from 0-15 days post-vaccination with return visits at days 28, 57, 90, 180, and 365, and a subset (n=15) are undergoing fine needle aspiration at days 15 and 28 to characterize germinal center responses. We are evaluating: 1) whether pre-vaccination infection history and immune characteristics are associated with safety, vaccine viremia and symptoms, and immunogenicity, 2) how vaccination modulates magnitude, durability, and breadth of protective antibodies, and 3) cellular surface, activation, and transcriptomic signatures at the single-cell level over time.