A knock-in mouse to test vaccines for the broadly neutralizing influenza response

Abstract Influenza virus is a major public health burden controlled by vaccination. However, influenza viruses develop mutants at a high frequency. The yearly vaccine elicits a specific response that fails to protect against most influenza strains, and its efficacy and production is risky every flu season. It would be ideal to develop a universal vaccine conferring life-long, broad protection. So far, the academic field has isolated several broadly neutralizing antibodies that target conserved regions of viral proteins from donors. However, how to elicit these antibodies in human through designed vaccines remains challenging and inefficient. Herein we generated humanized BCR mice to facilitate testing of strategies to induce broadly neutralizing antibodies in humans. CR9114 is one of the most broadly neutralizing antibodies known with activity against group 1 and group 2 influenza A and also influenza B virus. Most contacts are with the H-chain only, which uses VH1-69. We knocked in a promoter-germline VDJ element to the physiological Igh locus, allowing analysis of the response of B cells capable in principle of broad neutralization and the testing of vaccine candidates.