B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models
Deli Huang, Robert Abbott, Colin Havenar‐Daughton, Patrick Skog, Rita Al-Kolla, Bettina Gröschel, Tanya R. Blane, Sergey Menis, Jenny Tuyet Tran, Theresa C. Thinnes, Sabrina A. Volpi, Alessia Liguori, Torben Schiffner, Sophia M. Villegas, Oleksandr Kalyuzhniy, Mark Pintea, James E. Voss, Nicole Phelps, Ryan Tingle, Alberto R. Rodriguez, Greg Martin, Sergey Kupryianov, Allan C. deCamp, William R. Schief, David Nemazee, Shane Crotty
Abstract
Significance Rational development of successful vaccines requires utilization of predictive models of vaccination. One approach for development of an HIV vaccine has been to study broadly neutralizing antibodies (bnAbs) and revert the mutations back to germline. However, there are limitations to such models. Therefore, we generated three knockin mice expressing B cell receptors (BCRs) from authentic naive VRC01-class B cells from healthy human donors (“HuGL” mice). This approach revealed that human VRC01-class naive B cell BCRs are indeed competent for antigen-specific responses in vivo. Additionally, a series of experiments shows the importance of precursor frequency and affinity on B cell responses to vaccine antigens. Overall, these HuGL mouse models validate a central tenet of the germline-targeting approach to vaccine design.