{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T09:47:30Z","timestamp":1782380850440,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,23]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Ragon Institute Sundry to G.A. and B.J, US CDC","award":["U19AI167899, 75D30120R67837and 75D30122C15467"],"award-info":[{"award-number":["U19AI167899, 75D30120R67837and 75D30122C15467"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Despite high vaccination coverage, pertussis has resurged globally. Whole-cell (wP) and acellular (aP) pertussis vaccines induce distinct immune profiles, yet immune correlates of protection against infection and symptomatic disease remain incompletely defined. We leveraged a controlled human infection model (CHIM) to identify systemic and mucosal humoral signatures associated with resistance to\n                    <jats:italic>Bordetella pertussis<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Adults with documented history of vaccination had previously been enrolled in a CHIM study and challenged intranasally with\n                    <jats:italic>B. pertussis<\/jats:italic>\n                    D420. For the present work, longitudinal serum and nasal wash samples were analyzed using systems serology to comprehensively profile antibody features. Multivariate modeling and network analyses were performed to define discriminatory immune features.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>\n                    Baseline aP vaccine antigen\u2013specific antibodies did not distinguish infection outcomes. In wP-primed individuals, protection from\n                    <jats:italic>B. pertussis<\/jats:italic>\n                    infection was associated with broad, high-magnitude, polyfunctional antibody responses targeting non\u2013canonical antigens, including BrkA, TcfA, OmpP, OmlA, FauA, and Pal. Protective signatures associated with resistance to symptomatic disease in both vaccine groups were characterized by enhanced Fc-receptor-engaging antibody profiles with distinct antigenic patterns shaped by vaccine history. Importantly, while conventional aP vaccine antigens failed to reliably distinguish individuals susceptible to infection or symptom development, correlates generated by integrated serum and mucosal models based on select non-canonical antigens achieved near-perfect discrimination of infection and symptom outcomes, outperforming models restricted to aP-vaccine. antigens only.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>Resistance to infection was largely restricted to wP-primed individuals and was associated with integrated systemic and mucosal antibody responses directed against antigens beyond those included in acellular vaccines. Protection from symptomatic disease in both vaccine groups was linked to distinct antibody response signatures, shaped by prior vaccination history. These findings indicate that immune mechanisms preventing infection differ from those limiting clinical disease and provide a framework for redesign of next-generation pertussis vaccines aimed at blocking infection and symptomatic disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>This work was supported by Ragon Institute Sundry to G.A. and B.J, U19AI167899 to D.L., and US CDC through 75D30120R67837 to Dalhousie University and 75D30122C15467 to the University of Maryland, Baltimore.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.18.26355881","type":"posted-content","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:05:18Z","timestamp":1782237918000},"source":"Crossref","is-referenced-by-count":0,"title":["Systemic and Mucosal Antibody Correlates of Protection Against Bordetella pertussis in a Controlled Human Infection Model"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2780-4119","authenticated-orcid":false,"given":"Mehak Zahoor","family":"Khan","sequence":"first","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-1755","authenticated-orcid":false,"given":"Yogita","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-2138","authenticated-orcid":false,"given":"Evgenii","family":"Kliuchnikov","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thendral","family":"Selvam","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agness E.","family":"Lakudzala","sequence":"additional","affiliation":[{"name":"Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fontana","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MaryBeth","family":"Culp","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, Division of Bacterial Diseases, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Hariri","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, Division of Bacterial Diseases, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Elsherif","sequence":"additional","affiliation":[{"name":"Canadian Center for Vaccinology (Dalhousie University, IWK Health and Nova Scotia Health), 5850 University Avenue, Halifax, NS B3K 6R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0050-989X","authenticated-orcid":false,"given":"Doug","family":"Lauffenburger","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Halperin","sequence":"additional","affiliation":[{"name":"Canadian Center for Vaccinology (Dalhousie University, IWK Health and Nova Scotia Health), 5850 University Avenue, Halifax, NS B3K 6R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0894-4009","authenticated-orcid":false,"given":"Marcela F.","family":"Pasetti","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9221-6735","authenticated-orcid":false,"given":"Galit","family":"Alter","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"},{"name":"AstraZeneca, Gaithersburg, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-9626","authenticated-orcid":false,"given":"Boris","family":"Julg","sequence":"additional","affiliation":[{"name":"Ragon Institute of Mass General, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062502101985000_2026.06.18.26355881v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008625"},{"key":"2026062502101985000_2026.06.18.26355881v1.2","doi-asserted-by":"crossref","unstructured":"Burdin N , Handy LK , Plotkin SA . What Is Wrong with Pertussis Vaccine Immunity? The Problem of Waning Effectiveness of Pertussis Vaccines. Cold Spring Harb Perspect Biol 2017; 9(12).","DOI":"10.1101\/cshperspect.a029454"},{"key":"2026062502101985000_2026.06.18.26355881v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314688110"},{"key":"2026062502101985000_2026.06.18.26355881v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2019.03.006"},{"key":"2026062502101985000_2026.06.18.26355881v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003264"},{"key":"2026062502101985000_2026.06.18.26355881v1.6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.11.1841"},{"key":"2026062502101985000_2026.06.18.26355881v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-018-0080-x"},{"key":"2026062502101985000_2026.06.18.26355881v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003264"},{"issue":"2","key":"2026062502101985000_2026.06.18.26355881v1.9","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.vaccine.2017.11.066","article-title":"Whole-cell or acellular pertussis vaccination in infancy determines IgG subclass profiles to DTaP booster vaccination","volume":"36","year":"2018","journal-title":"Vaccine"},{"key":"2026062502101985000_2026.06.18.26355881v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2012.117"},{"key":"2026062502101985000_2026.06.18.26355881v1.11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1602051"},{"key":"2026062502101985000_2026.06.18.26355881v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiac502"},{"key":"2026062502101985000_2026.06.18.26355881v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.027"},{"key":"2026062502101985000_2026.06.18.26355881v1.14","doi-asserted-by":"crossref","unstructured":"ElSherif MS , Redden KL , Langley JM , et al. A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420. MedRxiv 2026.","DOI":"10.64898\/2026.06.09.26355227"},{"key":"2026062502101985000_2026.06.18.26355881v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.04.013"},{"issue":"3","key":"2026062502101985000_2026.06.18.26355881v1.16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.coviro.2012.04.002","article-title":"How respiratory viruses overcome mucosal defenses and exploit the unique environment of the respiratory tract","volume":"2","year":"2012","journal-title":"Curr Opin Virol"},{"issue":"3","key":"2026062502101985000_2026.06.18.26355881v1.17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.mucimm.2024.12.013","article-title":"Immune crosstalk between respiratory and intestinal mucosal tissues in respiratory infections","volume":"18","year":"2025","journal-title":"Mucosal Immunol"},{"key":"2026062502101985000_2026.06.18.26355881v1.18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01158"},{"key":"2026062502101985000_2026.06.18.26355881v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00081-07"},{"key":"2026062502101985000_2026.06.18.26355881v1.20","doi-asserted-by":"crossref","unstructured":"Goldsmith JA , Nguyen AW , Wilen RE , Wijagkanalan W , McLellan JS , Maynard JA. Structural Basis for Antibody Neutralization of Pertussis Toxin. bioRxiv 2024.","DOI":"10.1101\/2024.09.23.614357"},{"issue":"4","key":"2026062502101985000_2026.06.18.26355881v1.21","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1093\/infdis\/151.4.646","article-title":"Neutralizing antibodies to pertussis toxin in whooping cough","volume":"151","year":"1985","journal-title":"J Infect Dis"},{"key":"2026062502101985000_2026.06.18.26355881v1.22","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00561-10"},{"key":"2026062502101985000_2026.06.18.26355881v1.23","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.12.7152-7155.2000"},{"issue":"7","key":"2026062502101985000_2026.06.18.26355881v1.24","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1128\/jcm.28.7.1502-1505.1990","article-title":"Immunoglobulin A antibodies to pertussis toxin and filamentous hemagglutinin in saliva from patients with pertussis","volume":"28","year":"1990","journal-title":"J Clin Microbiol"},{"key":"2026062502101985000_2026.06.18.26355881v1.25","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2012-3836"},{"key":"2026062502101985000_2026.06.18.26355881v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(98)00227-8"},{"issue":"1","key":"2026062502101985000_2026.06.18.26355881v1.27","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/s41598-020-72092-6","article-title":"Tracheal colonization factor A (TcfA) is a biomarker for rapid and specific detection of Bordetella pertussis","volume":"10","year":"2020","journal-title":"Sci Rep"},{"key":"2026062502101985000_2026.06.18.26355881v1.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105011"},{"key":"2026062502101985000_2026.06.18.26355881v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(01)00269-9"},{"key":"2026062502101985000_2026.06.18.26355881v1.30","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.19.5958-5966.1999"},{"key":"2026062502101985000_2026.06.18.26355881v1.31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01851"},{"key":"2026062502101985000_2026.06.18.26355881v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.01.001"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.18.26355881","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T09:11:00Z","timestamp":1782378660000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.06.18.26355881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":32,"URL":"https:\/\/doi.org\/10.64898\/2026.06.18.26355881","relation":{},"subject":[],"published":{"date-parts":[[2026,6,23]]},"subtype":"preprint"}}