Chance and contingency in B cell evolution limit the similarity of antibody responses to infection across individuals

Antibody responses emerge from the competition of B cell lineages with different antigen receptors, each produced by the recombination of germline immunoglobulin genes. Which lineages win out can depend on subsequent somatic mutations that improve antigen binding, yet lineages using specific germline alleles can have higher affinity than others from the start or a higher propensity to adapt. How much do those germline-encoded advantages determine the outcome of B cell competition, potentially leading to predictable allele frequencies and sequence motifs in the response to the same antigen in different individuals? In simulations, we show that selection for receptors with germline-encoded specificity can lead to similar germline allele frequencies between individuals early in the response. As B cell lineages evolve, those early advantages are often overcome by lineages using different germline alleles in different individuals, leading to increasingly contingent patterns of germline allele usage over time. Consistent with simulations, mice experimentally infected with influenza virus have increasingly dissimilar germline allele frequencies and do not converge on similar CDR3 sequences or similar somatic mutations. These results suggest germline-encoded specificities might be selected to enable fast recognition of specific antigens early in the response, while diverse evolutionary routes to high affinity limit the predictability of responses to infection and vaccination in the long term. ### Competing Interest Statement C.T.S. has consulted for Alvea / Telis Bioscience Inc. on the design of universal influenza vaccines. The other authors report no competing interests.