Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein
Cherrelle Dacon, Re’em Moskovitz, Kristian E. Swearingen, Lais Da Silva Pereira, Yevel Flores-García, Maya Aleshnick, Sachie Kanatani, Barbara J. Flynn, Alvaro Molina-Cruz, Kurt Wollenberg, Maria Traver, Payton Kirtley, Lauren Purser, Marlon Dillon, Brian Bonilla, Adriano Franco, Samantha Petros, Jake E. Kritzberg, Courtney Tucker, Gonzalo E. González‐Páez, Priya Gupta, Melanie J. Shears, Joseph Pazzi, Joshua Edgar, Andy Teng, Arnel Belmonte, Kyosuke Oda, Safiatou Doumbo, Ludmila Krymskaya, Jeff Skinner, Shanping Li, Suman Ghosal, Kassoum Kayentao, Aïssata Ongoïba, Ashley M. Vaughan, Joseph J. Campo, Boubacar Traoré, Carolina Barillas‐Mury, Wathsala Wijayalath, Azza H. Idris, Peter D. Crompton, Photini Sinnis, Brandon K. Wilder, Fidel Zavala, Robert A. Seder, Ian A. Wilson, Joshua Tan
Abstract
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.