Contribution of rare mutational outcomes to broadly neutralizing antibodies: Rare features of unique anti-viral antibodies

Antibodies are important immune molecules that are elicited by B cells to protect our bodies during viral infections or vaccinations. In humans, the antibody repertoire is diversified by programmed DNA lesion processes to ensure specific and high affinity binding to various antigens. Broadly neutralizing antibodies (bnAbs) are antibodies that have strong neutralizing activities against different variants of a virus. bnAbs such as anti-HIV bnAbs often have special characteristics including insertions and deletions, long complementarity determining region 3 (CDR3), and high frequencies of mutations, often at improbable sites of the variable regions. These unique features are rare mutational outcomes that are acquired during antibody diversification processes. In this review, we will discuss possible mechanisms that generate these rare antibody mutational outcomes. The understanding of the mechanisms that generate these rare mutational outcomes during antibody diversification will have implications in vaccine design strategies to elicit bnAbs.