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Vaccines activate na\u00efve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-na\u00efve hosts. In this study, we use high-throughput sequencing of memory CD4 TCR\u03b2 repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCR\u03b2 sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination.<\/jats:p>","DOI":"10.7554\/elife.68388","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T07:15:25Z","timestamp":1641798925000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68388","source":"Crossref","is-referenced-by-count":26,"title":["Preexisting memory CD4 T cells in na\u00efve individuals confer robust immunity upon hepatitis B vaccination"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8419-9544","authenticated-orcid":true,"given":"George","family":"Elias","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute, University of Antwerp","place":["Antwerp, Belgium"]},{"name":"Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of 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