Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein

• 成果类型: Article
• 署名作者: Dacon, Cherrelle; Moskovitz, Re'em; Swearingen, Kristian; Pereira, Lais Da Silva; Flores-Garcia, Yevel; Aleshnick, Maya; Kanatani, Sachie; Flynn, Barbara; Molina-Cruz, Alvaro; Wollenberg, Kurt; Traver, Maria; Kirtley, Payton; Purser, Lauren; Dillon, Marlon; Bonilla, Brian; Franco, Adriano; Petros, Samantha; Kritzberg, Jake; Tucker, Courtney; Paez, Gonzalo Gonzalez; Gupta, Priya; Shears, Melanie J.; Pazzi, Joseph; Edgar, Joshua M.; Teng, Andy A.; Belmonte, Arnel; Oda, Kyosuke; Doumbo, Safiatou; Krymskaya, Ludmila; Skinner, Jeff; Li, Shanping; Ghosal, Suman; Kayentao, Kassoum; Ongoiba, Aissata; Vaughan, Ashley; Campo, Joseph J.; Traore, Boubacar; Barillas-Mury, Carolina; Wijayalath, Wathsala; Idris, Azza; Crompton, Peter D.; Sinnis, Photini; Wilder, Brandon K.; Zavala, Fidel; Seder, Robert A.; Wilson, Ian A.; Tan, Joshua
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Scripps Research Institute; Institute for Systems Biology (ISB); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Oregon Health & Science University; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Catholic University of America; Seattle Children's Hospital; University of Washington; University of Washington Seattle; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc; University of Science & Technology of Bamako; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute; Harvard University Medical Affiliates; Massachusetts General Hospital; Scripps Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13797
• DOI: 10.1126/science.adr0510
• 发表日期: 2025-01-03
• 关键词: falciparum circumsporozoite protein; plasmodium-falciparum; monoclonal-antibodies; mass-spectrometry; infection; immunity; transmission; refinement; proteomics; migration

摘要

The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the Plasmodium falciparum circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines. MAD21-101, the most potent mAb in this class, confers sterile protection against Pf infection in a human liver-chimeric mouse model. These findings reveal a site of vulnerability on the sporozoite surface that can be targeted by next-generation antimalarial interventions.