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

Deli Huang, Robert K. Abbott, Colin Havenar-Daughton, Patrick Skog, Rita Al-Kolla, Bettina Groschel, Tanya Blane, Sergey Menis, Jenny Tuyet Tran, Theresa C. Thinnes, Sabrina A. Volpi, Mark Pintea (+9 others)
2020 bioRxiv   pre-print
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
more » ... -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.
doi:10.1101/2020.02.24.963629 fatcat:i2u3sm75wvcmlktmhb73bt533u