B cell immunodominance is defined as the hierarchical antibody response to distinct antigenic proteins found in pathogens. Various factors shape the preference of antibody targeting to certain viral epitopes over others, including preexisting immunity, age, sex, and disease severity. Our understanding of human antibody immunodominance to conserved antigenic sites of viruses is limited, despite its importance for developing universal vaccines that protect against pandemic-threat viruses such as influenza and SARS-CoV-2. The ability of these viruses to rapidly mutate, re-circulate seasonally, and pose the threat of future deadly pandemics necessitates a better understanding of human antibody immunodominance to conserved and protective antigenic sites. In this work, we utilized monoclonal antibody (mAb) technology, single-cell RNA sequencing approaches, and in vivo infection challenge studies to dissect human antibody immunodominance and protective responses to influenza and SARS-CoV-2 viruses. We reveal that natural infection induces a considerable antibody response to non-neutralizing viral targets, shaped by factors such as age, preexisting immunity, and disease severity. This work has implications for epitope-guided universal vaccine design for two distinct viruses, one century-old and the other completely novel. Finally, our study stresses the importance of considering host-intrinsic factors such as preexisting immunity and age in the design of next generation vaccination strategies.




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