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B cells expressing authentic naive human VRC01-class BCRs can be primed and recruited to germinal centers in multiple independent mouse models

By Deli Huang, Robert K. Abbott, Colin Havenar-Daughton, Patrick D. Skog, Rita Al-Kolla, Bettina Groschel, Tanya R. Blane, Sergey Menis, Jenny Tuyet Tran, Theresa C. Thinnes, Sabrina A. Volpi, Mark Pintea, James E. Voss, Nicole Phelps, Ryan Tingle, Alberto R. Rodriguez, Greg Martin, Sergey Kupryianov, William R. Schief, David Nemazee, Shane Crotty

Posted 26 Feb 2020
bioRxiv DOI: 10.1101/2020.02.24.963629

Animal models of human antigen-specific B cell receptors (BCR) generally depend on “inferred germline” sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three new BCR knock-in mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18HL) or medium (HuGL17HL) affinity BCRs were primed, recruited to germinal centers, accrued substantial somatic hypermutation, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.

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