Engaging an HIV vaccine target through the acquisition of low B cell affinity

Abstract

Low affinity is common for germline B cell receptors (BCR) seeding development of broadly neutralizing antibodies (bnAbs) that engage hypervariable viruses, including HIV. Antibody affinity selection is also non-homogenizing, insuring the survival of low affinity B cell clones. To explore whether this provides a natural window for expanding human B cell lineages against conserved vaccine targets, we deploy transgenic mice mimicking human antibody diversity and somatic hypermutation (SHM) and immunize with simple monomeric HIV glycoprotein envelope immunogens. We report an immunization regimen that focuses B cell memory upon the conserved CD4 binding site (CD4bs) through both conventional affinity maturation and reproducible expansion of low affinity BCR clones with public patterns in SHM. In the latter instance, SHM facilitates target acquisition by decreasing binding strength. This suggests that permissive B cell selection enables the discovery of antibody epitopes, in this case an HIV bnAb site.

Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses

“…Collectively, our results point to a general feature of the humoral response that intrinsically broadens antibodies against unmatched/diversified antigen targets upon repeated vaccination with the same novel antigen. This principle of preserving diversified or 'non-homogenized' antibody output during ongoing immune reactions has emerged as an important theme for germinal center and memory B cell responses to protein antigens (de Carvalho et al, 2023;Hagglof et al, 2023;Kuraoka et al, 2016;Mesin et al, 2016;Mesin et al, 2020;Radmacher et al, 1998;Ronsard L, 2023;Sabouri et al, 2014;Silver et al, 2018;Tas et al, 2016;Van Beek et al, 2022). Our in silico results would suggest that intrinsic broadening of the antibodies generated in response to homologous antigen is an extension of this fundamental principle, enabling polyspecific responses and broad B cell reactivities that are tuned by antigen presentation and epitope masking effects.…”

“…The immunodominance hierarchy of the three epitopes is reflected in the distribution of germline B cell affinities for antigen, an attribute that is important for B cell recruitment into GCs (Abbott and Crotty, 2020;Abbott et al, 2018;Amitai et al, 2020;Dosenovic et al, 2018;Sangesland and Lingwood, 2021). Detectable germline BCR affinities for antigen can range from 10 -7 to 10 -4 M (Feldman et al, 2021;Ronsard L, 2023;Sangesland, 2019;Sangesland et al, 2022), and a dissociation constant of ~10 -6 M is the estimate we use for the threshold for entry into GCs (Batista and Neuberger, 1998). Since high germline affinities are rare (Feldman et al, 2021;Kuraoka et al, 2016;Ronsard L, 2023;Sangesland, 2019;Sangesland et al, 2022), we consider the distribution of affinities to decay exponentially.…”

“…Detectable germline BCR affinities for antigen can range from 10 -7 to 10 -4 M (Feldman et al, 2021;Ronsard L, 2023;Sangesland, 2019;Sangesland et al, 2022), and a dissociation constant of ~10 -6 M is the estimate we use for the threshold for entry into GCs (Batista and Neuberger, 1998). Since high germline affinities are rare (Feldman et al, 2021;Kuraoka et al, 2016;Ronsard L, 2023;Sangesland, 2019;Sangesland et al, 2022), we consider the distribution of affinities to decay exponentially. More immunodominant epitopes constitute a larger fraction p i of germline B cells and exhibit a longer high-affinity tail (Figure 4B).…”