Human Responses to Influenza Vaccination Show Seroconversion Signatures and Convergent Antibody Rearrangements

Abstract

Summary B cells produce a diverse antibody repertoire by undergoing gene rearrangements. Pathogen exposure induces the clonal expansion of B cells expressing antibodies that can bind the infectious agent. To assess human B cell responses to trivalent seasonal influenza and monovalent pandemic H1N1 vaccination, we sequenced gene rearrangements encoding the immunoglobulin heavy chain, a major determinant of epitope recognition. The magnitude of B cell clonal expansions correlates with an individual’s secreted antibody response to the vaccine and the expanded clones are enriched for those expressing influenza-specific mAbs. Additionally, B cell responses to pandemic influenza H1N1 vaccination and infection in different people show a prominent family of convergent antibody heavy chain gene rearrangements specific to influenza antigens. These results indicate that microbes can induce specific signatures of immunoglobulin gene rearrangements and that pathogen exposure can potentially be assessed from B cell repertoires.

Focused antibody response to influenza linked to antigenic drift

“…An amino acid sequence dendrogram of the VDJ regions (Supplemental Figure 2) revealed the diversity in these sequences generated by V region somatic mutations (which induced an average of 7-amino acid changes per sequence) and clonal D-J combinations. This result is very similar to findings by Krause et al (28) and Jackson et al (29), who identified very similar sets of clones based on V H 3-7/ J H 6 rearrangements in individuals responding to the Sa site of H1N1pdm09 HA and discussed the evidence for intraclonal divergence and interclonal convergence of these sequences.…”

“…The dominance of HA head-specific V H 3-7*01/J H 6*02 sequences that we found in the largest V H -related set has been seen in other individual responses following exposure to H1N1pdm09 (28,29). For example, the V H 3-7/J H 6 antibodies rearranged with a different group of 4 D segments (3-16*02, 3-22*01, 6-13*01, and 4-17*01) from those from our donor (3-16*01, 3-3*01 in reading frame 2 and 3, and 3-3*02) (28).…”

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

“…However, previous work was limited by small numbers of elderly individuals analyzed (8), did not analyze in detail the composition of the oligoclonal lineages (8), or did not study the effect of applying an immune stimulus such as a vaccine (10). Furthermore, previous B-cell repertoire studies have focused only on isolated aspects of B-cell mutation counts, V/D/J-gene use levels, lineage sizes, and convergent CDR3 sequences (8,(10)(11)(12)(13) without analyzing the character of mutations and without using the full phylogenetic information inherent in the IGH repertoire to quantify dissimilarities between immune systems.…”

Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles

“…Previous studies have, for example: revealed the association of certain germline genotypes with susceptibility to such diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (5,6); found correlations of age with a reduced Ig clonal diversity and less intense response to immune challenge (7,8); found overly expanded clones in cases of lymphoma (9,10); and discovered convergent Ig evolution across subjects in response to certain immune challenges (11,12). These repertoire-sequencing (Rep-Seq) studies have benefitted from improvements in sequencing technologies, which allow for the generation of millions of reads per run (13).…”