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Current studies on PfEMP1-based immunity are constrained by the protein\u2019s high molecular weight, complex multidomain architecture, and extensive polymorphism. Controlled human malaria infection (CHMI) studies uniquely enable the assessment of strain-specific PfEMP1 immunity prior to exposure and its correlation with infection outcomes using the same parasite strain. In this study, different serological assays targeting both full-length native PfEMP1 and individual domains were applied to plasma samples obtained prior to challenge infection at study baseline from 25 individuals enrolled in a CHMI study of PfSPZ Challenge (NF54), that included malaria-na\u00efve Europeans and lifelong malaria-exposed Africans with varying degrees of immunity. All assays showed strong predictive value of both PfEMP1 antibody levels and breadth at study baseline for CHMI outcome. A random forest machine learning analysis of antibody recognition profiles, measured by AlphaScreen nearly covering all extracellular PfEMP1 domains of the NF54-CHMI parasite strain, suggested that a broad antibody repertoire, including antibodies against the most diversified group B PfEMP1s, represents a discriminative feature distinguishing volunteers with high versus low susceptibility to CHMI. In parasites re-isolated from the volunteers, dominant\n                    <jats:italic>var<\/jats:italic>\n                    transcripts encoded PfEMP1 variants are not recognized by the individuals\u2019 pre-existing antibodies at study baseline. Given that the CHMI strain NF54 predominantly expresses B-type\n                    <jats:italic>var<\/jats:italic>\n                    genes at the onset of blood-stage infection, effective control of CHMI was associated with a broad antibody repertoire, particularly including antibodies targeting B-type PfEMP1. In line with the \u201chole-in-the-wall\u201d theory, this likely reflects an antibody-mediated restriction of the parasite population emerging from the liver to parasites expressing PfEMP1 variants not previously encountered by the host immune system.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014377","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:43:42Z","timestamp":1782323022000},"page":"e1014377","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predictive value of PfEMP1 antibody profiles for the course of controlled human malaria infections"],"prefix":"10.1371","volume":"22","author":[{"given":"Yannick D.","family":"H\u00f6ppner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Krumkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Nagaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Wapler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Honner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Claude","family":"Dejon-Agob\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabo J.","family":"Honkpehedji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannot Fr\u00e9jus","family":"Zinsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Held","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meral","family":"Esen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidrun","family":"von Thien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Bruchhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Kim Lee","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Kremsner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim-Wolf","family":"Gilberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Lell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Tsuboi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lavstsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eizo","family":"Takashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Mordm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8397-7308","authenticated-orcid":true,"given":"Anna","family":"Bachmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ppat.1014377.ref001","doi-asserted-by":"crossref","DOI":"10.30875\/9789287074560","volume-title":"World malaria report 2025: addressing the threat of antimalarial drug resistance","author":"World Health Organization","year":"2025"},{"issue":"7","key":"ppat.1014377.ref002","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/ni.f.205","article-title":"Immunity to malaria: more questions than answers","volume":"9","author":"J Langhorne","year":"2008","journal-title":"Nat Immunol"},{"issue":"1","key":"ppat.1014377.ref003","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1128\/CMR.00025-08","article-title":"Acquired immunity to malaria","volume":"22","author":"DL Doolan","year":"2009","journal-title":"Clin Microbiol Rev"},{"key":"ppat.1014377.ref004","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/192733a0","article-title":"Gamma-globulin and acquired immunity to human malaria","volume":"192","author":"S Cohen","year":"1961","journal-title":"Nature"},{"issue":"3","key":"ppat.1014377.ref005","doi-asserted-by":"crossref","first-page":"297","DOI":"10.4269\/ajtmh.1991.45.297","article-title":"Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria","volume":"45","author":"A Sabchareon","year":"1991","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"ppat.1014377.ref006","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0092-8674(95)90054-3","article-title":"Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes","volume":"82","author":"DI Baruch","year":"1995","journal-title":"Cell"},{"issue":"1","key":"ppat.1014377.ref007","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0092-8674(95)90056-X","article-title":"Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes","volume":"82","author":"JD Smith","year":"1995","journal-title":"Cell"},{"issue":"1","key":"ppat.1014377.ref008","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0092-8674(95)90055-1","article-title":"The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes","volume":"82","author":"XZ Su","year":"1995","journal-title":"Cell"},{"issue":"9","key":"ppat.1014377.ref009","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1172\/JCI62182","article-title":"Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity","volume":"122","author":"J-A Chan","year":"2012","journal-title":"J Clin Invest"},{"issue":"211","key":"ppat.1014377.ref010","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3007432","article-title":"Piecing together the puzzle of severe malaria","volume":"5","author":"AJ Cunnington","year":"2013","journal-title":"Sci Transl Med"},{"issue":"12","key":"ppat.1014377.ref011","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.pt.2013.10.004","article-title":"Stuck in a rut? 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