B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models
September 15, 2020
Proc Natl Acad Sci USA
Volume and Number
Huang D, Abbott RK, Havenar-Daughton C, Skog PD, Al-Kolla R, Groschel B, Blane TR, Menis S, Tran JT, Thinnes TC, Volpi SA, Liguori A, Schiffner T, Villegas SM, Kalyuzhniy O, Pintea M, Voss JE, Phelps N, Tingle R, Rodriguez AR, Martin G, Kupryianov S, deCamp A, Schief WR, Nemazee D, Crotty S
Animal models of human antigen-specific B cell receptors (BCRs) 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 BCR knockin 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, and they affinity matured, 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.
- 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 antigenspecific 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.