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

Cherrelle Dacon; Re'em Moskovitz; Kristian Swearingen; Lais Da Silva Pereira; Yevel Flores-Garcia; Maya Aleshnick; Sachie Kanatani; Barbara Flynn; Alvaro Molina-Cruz; Kurt Wollenberg; Maria Traver; Payton Kirtley; Lauren Purser; Marlon Dillon; Brian Bonilla; Adriano Franco; Samantha Petros; Jake Kritzberg; Courtney Tucker; Gonzalo Gonzalez Paez; Priya Gupta; Melanie J. Shears; Joseph Pazzi; Joshua M. Edgar; Andy A. Teng; Arnel Belmonte; Kyosuke Oda; Safiatou Doumbo; Ludmila Krymskaya; Jeff Skinner; Shanping Li; Suman Ghosal; Kassoum Kayentao; Aissata Ongoiba; Ashley Vaughan; Joseph J. Campo; Boubacar Traore; Carolina Barillas-Mury; Wathsala Wijayalath; Azza Idris; Peter D. Crompton; Photini Sinnis; Brandon K. Wilder; Fidel Zavala; Robert A. Seder; Ian A. Wilson; Joshua Tan

doi:10.1126/science.adr0510

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

Cherrelle Dacon, Re'em Moskovitz, Kristian Swearingen, Lais Da Silva Pereira, Yevel Flores-Garcia, Maya Aleshnick, Sachie Kanatani, Barbara Flynn, Alvaro Molina-Cruz, Kurt Wollenberg, Maria Traver, Payton Kirtley, Lauren Purser, Marlon Dillon, Brian Bonilla, Adriano Franco, Samantha Petros, Jake Kritzberg, Courtney Tucker, Gonzalo Gonzalez PaezPriya Gupta, Melanie J. Shears, Joseph Pazzi, Joshua M. Edgar, Andy A. Teng, Arnel Belmonte, Kyosuke Oda, Safiatou Doumbo, Ludmila Krymskaya, Jeff Skinner, Shanping Li, Suman Ghosal, Kassoum Kayentao, Aissata Ongoiba, Ashley Vaughan, Joseph J. Campo, Boubacar Traore, Carolina Barillas-Mury, Wathsala Wijayalath, Azza Idris, Peter D. Crompton, Photini Sinnis, Brandon K. Wilder, Fidel Zavala, Robert A. Seder, Ian A. Wilson, Joshua Tan

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	eadr0510
Journal	Science (New York, N.Y.)
Volume	387
Issue number	6729
DOIs	https://doi.org/10.1126/science.adr0510
State	Published - Jan 3 2025

ASJC Scopus subject areas

General

Access to Document

10.1126/science.adr0510

Cite this

Dacon, C., Moskovitz, R., Swearingen, K., Da Silva Pereira, L., Flores-Garcia, Y., Aleshnick, M., Kanatani, S., Flynn, B., Molina-Cruz, A., Wollenberg, K., Traver, M., Kirtley, P., Purser, L., Dillon, M., Bonilla, B., Franco, A., Petros, S., Kritzberg, J., Tucker, C., ... Tan, J. (2025). Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein. Science (New York, N.Y.), 387(6729), eadr0510. https://doi.org/10.1126/science.adr0510

Dacon, C, Moskovitz, R, Swearingen, K, Da Silva Pereira, L, Flores-Garcia, Y, Aleshnick, M, Kanatani, S, Flynn, B, Molina-Cruz, A, Wollenberg, K, Traver, M, Kirtley, P, Purser, L, Dillon, M, Bonilla, B, Franco, A, Petros, S, Kritzberg, J, Tucker, C, Paez, GG, Gupta, P, Shears, MJ, Pazzi, J, Edgar, JM, Teng, AA, Belmonte, A, Oda, K, Doumbo, S, Krymskaya, L, Skinner, J, Li, S, Ghosal, S, Kayentao, K, Ongoiba, A, Vaughan, A, Campo, JJ, Traore, B, Barillas-Mury, C, Wijayalath, W, Idris, A, Crompton, PD, Sinnis, P, Wilder, BK, Zavala, F, Seder, RA, Wilson, IA & Tan, J 2025, 'Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein', Science (New York, N.Y.), vol. 387, no. 6729, pp. eadr0510. https://doi.org/10.1126/science.adr0510

@article{01d758a1fe01483491699576354726e4,

title = "Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein",

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.",

author = "Cherrelle Dacon and Re'em Moskovitz and Kristian Swearingen and {Da Silva Pereira}, Lais and Yevel Flores-Garcia and Maya Aleshnick and Sachie Kanatani and Barbara Flynn and Alvaro Molina-Cruz and Kurt Wollenberg and Maria Traver and Payton Kirtley and Lauren Purser and Marlon Dillon and Brian Bonilla and Adriano Franco and Samantha Petros and Jake Kritzberg and Courtney Tucker and Paez, {Gonzalo Gonzalez} and Priya Gupta and Shears, {Melanie J.} and Joseph Pazzi and Edgar, {Joshua M.} and Teng, {Andy A.} and Arnel Belmonte and Kyosuke Oda and Safiatou Doumbo and Ludmila Krymskaya and Jeff Skinner and Shanping Li and Suman Ghosal and Kassoum Kayentao and Aissata Ongoiba and Ashley Vaughan and Campo, {Joseph J.} and Boubacar Traore and Carolina Barillas-Mury and Wathsala Wijayalath and Azza Idris and Crompton, {Peter D.} and Photini Sinnis and Wilder, {Brandon K.} and Fidel Zavala and Seder, {Robert A.} and Wilson, {Ian A.} and Joshua Tan",

year = "2025",

month = jan,

day = "3",

doi = "10.1126/science.adr0510",

language = "English (US)",

volume = "387",

pages = "eadr0510",

journal = "Science (New York, N.Y.)",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6729",

}

TY - JOUR

T1 - Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein

AU - Dacon, Cherrelle

AU - Moskovitz, Re'em

AU - Swearingen, Kristian

AU - Da Silva Pereira, Lais

AU - Flores-Garcia, Yevel

AU - Aleshnick, Maya

AU - Kanatani, Sachie

AU - Flynn, Barbara

AU - Molina-Cruz, Alvaro

AU - Wollenberg, Kurt

AU - Traver, Maria

AU - Kirtley, Payton

AU - Purser, Lauren

AU - Dillon, Marlon

AU - Bonilla, Brian

AU - Franco, Adriano

AU - Petros, Samantha

AU - Kritzberg, Jake

AU - Tucker, Courtney

AU - Paez, Gonzalo Gonzalez

AU - Gupta, Priya

AU - Shears, Melanie J.

AU - Pazzi, Joseph

AU - Edgar, Joshua M.

AU - Teng, Andy A.

AU - Belmonte, Arnel

AU - Oda, Kyosuke

AU - Doumbo, Safiatou

AU - Krymskaya, Ludmila

AU - Skinner, Jeff

AU - Li, Shanping

AU - Ghosal, Suman

AU - Kayentao, Kassoum

AU - Ongoiba, Aissata

AU - Vaughan, Ashley

AU - Campo, Joseph J.

AU - Traore, Boubacar

AU - Barillas-Mury, Carolina

AU - Wijayalath, Wathsala

AU - Idris, Azza

AU - Crompton, Peter D.

AU - Sinnis, Photini

AU - Wilder, Brandon K.

AU - Zavala, Fidel

AU - Seder, Robert A.

AU - Wilson, Ian A.

AU - Tan, Joshua

PY - 2025/1/3

Y1 - 2025/1/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85214448753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85214448753&partnerID=8YFLogxK

U2 - 10.1126/science.adr0510

DO - 10.1126/science.adr0510

M3 - Article

C2 - 39745947

AN - SCOPUS:85214448753

SN - 0036-8075

VL - 387

SP - eadr0510

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6729

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this