Variations in antibody repertoires correlate with vaccine responses

Authors: SAFONOVA, YANA - University Of California, San Diego; Shin, Sung; KRAMER, LUKE - Iowa State University; REECY, JAMES - Iowa State University; WATSON, COREY - University Of Louisville; Smith, Timothy - Tim; PEVZNER, PAVEL - University Of California, San Diego

Submitted to: Genome Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/28/2022
Publication Date: 3/31/2022
Citation: Safonova, Y., Shin, S.B., Kramer, L., Reecy, J., Watson, C.T., Smith, T.P.L., Pevzner, P.A. 2022. Variations in antibody repertoires correlate with vaccine responses. Genome Research. 32:791-804. https://doi.org/10.1101/gr.276027.121.
DOI: https://doi.org/10.1101/gr.276027.121

Interpretive Summary: Vaccines against bovine respiratory disease (BRD) generally target a handful of viruses known to make cattle susceptible to this disease. However, success of vaccination varies among individuals and the availability of vaccines has not substantially reduced the incidence of BRD in the United States, or the associated losses that have been estimated to approach $1 billion dollars annually. In an effort to identify factors that affect vaccine success, the study examined the immune response by massive sequencing of the antibody genes expressed in a group of over 200 Angus breed calves that were also evaluated for the success of their immune response by quantifying the level of targeted antibodies against BRD viruses. During the evaluation, a new method for identifying variants in the expressed antibody "repertoire" that responded to vaccination was developed. Using this new tool, called IgQTL, specific variants in antibody genes were discovered that correlated with successful response. The results also revealed the importance of a specific class of bovine antibodies, called "ultralong" antibodies, to successful development of an immune response.

Technical Abstract: An important challenge in vaccine development is to figure out why a vaccine succeeds in some individuals and fails in others. Although antibody repertoires hold the key to answering this question, there have been very few personalized immunogenomics studies so far aimed at revealing how variations in immunoglobulin genes affect a vaccine response. We conducted an immunosequencing study of 204 calves vaccinated against bovine respiratory disease (BRD) with the goal to reveal variations in immunoglobulin genes and somatic hypermutations that impact the efficacy of vaccine response. Our study represents the largest longitudinal personalized immunogenomics study reported to date across all species, including humans. To analyze the generated data set, we developed an algorithm for identifying variations of the immunoglobulin genes (as well as frequent somatic hypermutations) that affect various features of the antibody repertoire and titers of neutralizing antibodies. In contrast to relatively short human antibodies, cattle have a large fraction of ultralong antibodies that have opened new therapeutic opportunities. Our study reveals that ultralong antibodies are a key component of the immune response against the costliest disease of beef cattle in North America. The detected variants of the cattle immunoglobulin genes, which are implicated in the success/failure of the BRD vaccine, have the potential to direct the selection of individual cattle for ongoing breeding programs.