The authors sequentially antigen panned a yeast antibody library derived from healthy donors against the dengue virus (DENV) envelope protein domain III (DIII) combined with depletion by an entry defective DIII mutant. From this they were able to identify a cross-reactive human monoclonal antibody (mAb), m366.6, that binds with high affinity to DENV DIII from all four DENV serotypes. Immunogenetic analyses found that m366.6 is a germline-like mAb with very few somatic mutations from the closest VH and Vλ germline genes. It potently neutralises DENV, both in vitro and in mouse models of DENV infection, without any detectable antibody-dependent enhancement (ADE) effect. The epitope of m366.6 was then mapped to a highly conserved region on DIII, which can be used to guide the rational design of effective dengue vaccine immunogens. As the first germline-like mAb derived from a naïve antibody library that neutralises all four DENV serotypes, m366.6 can also be used as a tool for understanding the mechanisms of DENV infection.
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