Abstract
The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue using a phylogenetic test of measurable immunoglobulin sequence evolution. We first validate this test through simulations and survey measurable evolution across multiple conditions. We find significant heterogeneity in measurable B cell evolution across conditions, with enrichment in primary response conditions such as HIV infection and early childhood development. We then show that measurable evolution following influenza vaccination is highly compartmentalized: while lineages in the blood are rarely measurably evolving following influenza vaccination, lineages containing GC B cells are frequently measurably evolving. Many of these lineages appear to derive from memory B cells. We conclude from these findings that seasonal influenza virus vaccination can stimulate additional evolution of responding B cell lineages, and imply that the poor efficacy of seasonal influenza vaccination is not due to a complete inhibition of vaccine-specific B cell evolution.
Highlights
Evolving populations are systems that undergo evolution rapidly enough for significant genetic differences to be detected in longitudinally-sampled timepoints (Drummond et al, 2003)
We develop a framework to test for measurable evolution in B cells based on longitudinally 89 sampled sequence data from the B cell receptor (BCR) variable region
After pre-processing the sequencing data, we first identify clonal lineages – B cells that descend from a common V(D)J rearrangement – using clustering based on nucleotide sequence similarity, which we have previously shown detects clonal relationships with high confidence (Gupta et al, 2017; Zhou and Kleinstein, 2019)
Summary
Evolving populations are systems that undergo evolution rapidly enough for significant genetic differences to be detected in longitudinally-sampled timepoints (Drummond et al, 2003) While this concept is frequently applied to viruses such as HIV (Rambaut et al, 2004) and SARS-CoV-2 (e.g. du Plessis et al, 2020), B cells experience rapid evolution during affinity maturation. Somatic hypermutation (SHM) introduces mutations into the B cell receptor (BCR) loci at a rate orders of magnitude higher than the background rate of somatic mutations (McKean et al, 1984; Murphy et al, 2008) These modified BCRs are selected based on their binding affinity, and the process repeats cyclically within GCs (Teng and Papavasiliou, 2007; Victora and Nussenzweig, 2012). While recent work has shown that antigen-specific B cell lineages can be recruited into GCs following influenza vaccination (Turner et al, 2020), other work has been unable to detect significant increases in SHM frequency among circulating influenza-binding antibody lineages following vaccination (Ellebedy et al, 2016)
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