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For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), much of the population has been imprinted by a viral spike from an early strain, either through vaccination or infection during the early stages of the COVID-19 pandemic. As a consequence of this imprinting, infection with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited by the imprinting strain. Here we compare the neutralizing antibody specificities of imprinted individuals versus infants infected with a recent strain. Specifically, we use pseudovirus-based deep mutational scanning to measure how spike mutations affect neutralization by the serum antibodies of adults and children imprinted by the original vaccine versus infants with a primary infection by an XBB* variant. While the serum neutralizing activity of the imprinted individuals primarily targets the spike receptor-binding domain (RBD), the serum neutralizing activity of infants infected with only XBB* mostly targets the spike N-terminal domain. In these infants, secondary exposure to the XBB* spike via vaccination shifts more of the neutralizing activity toward the RBD, although the specific RBD sites targeted are different from imprinted adults. The dramatic differences in neutralization specificities among individuals with different exposure histories likely impact SARS-CoV-2 evolution.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>We show that a person\u2019s exposure history to different SARS-CoV-2 strains strongly affects which regions on the viral spike that their neutralizing antibodies target. In particular, infants who have just been infected once with a recent viral strain make neutralizing antibodies that target different regions of the viral spike than adults or children who have been exposed to both older and more recent strains. This person-to-person heterogeneity means that the same viral mutation can have different impacts on the antibody immunity of different people.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00109-25","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T10:57:42Z","timestamp":1742900262000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0908-6982","authenticated-orcid":false,"given":"Bernadeta","family":"Dadonaite","sequence":"first","affiliation":[{"name":"Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison R.","family":"Burrell","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenni","family":"Logue","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen Y.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, USA"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine","place":["Cincinnati, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Haslam","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, USA"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine","place":["Cincinnati, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary A.","family":"Staat","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center","place":["Cincinnati, USA"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine","place":["Cincinnati, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-3408","authenticated-orcid":true,"given":"Jesse D.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center","place":["Seattle, USA"]},{"name":"Howard Hughes Medical Institute","place":["Seattle, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01970-2"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.02.016"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07539-1"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-43-3-534"},{"key":"e_1_3_5_6_2","first-page":"572","article-title":"On the doctrine of original antigenic sin","volume":"104","author":"Francis T","year":"1960","unstructured":"Francis T. 1960. 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