Dacon Cherrelle, Moskovitz Re'em, Swearingen Kristian, Da Silva Pereira Lais, 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
Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Science. 2025 Jan 3;387(6729):eadr0510. doi: 10.1126/science.adr0510.
The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the 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 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.
最先进的抗疟疾单克隆抗体（mAb）和疫苗靶向环子孢子蛋白（PfCSP）内的中央重复区域或密切相关序列。在此，我们采用一种不依赖抗原的策略来研究人类对完整子孢子的抗体反应，鉴定出一类靶向PfCSP隐秘表位的单克隆抗体，该表位仅在新形成的N端裂解并随后焦谷氨酸化（pGlu）后才暴露。这种pGlu-CSP表位未被当前的抗PfCSP单克隆抗体靶向，也未包含在已获许可的疟疾疫苗中。该类中最有效的单克隆抗体MAD21-101在人肝嵌合小鼠模型中赋予针对感染的无菌保护。这些发现揭示了子孢子表面上一个可被下一代抗疟干预措施靶向的脆弱位点。
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