Complete attenuation of Plasmodium falciparum sporozoites by atovaquone–proguanil
To develop a Plasmodium falciparum (Pf) vaccine that precludes replication inside the host for improved vaccine safety, we tested chemo-attenuation (CVac) of sporozoites (SPZ) with atovaquone-proguanil (AP). In mice, P. berghei sporozoites administered with AP invaded hepatocytes, arrested early, and induced robust protection, which correlated with parasite-specific effector-memory CD8+ T cell responses. In a clinical trial of PfSPZ-CVac (AP), in which three doses of 5.12 × 10<sup>4</sup> or 1.5 × 10<sup>5</sup> PfSPZ were administered by direct venous inoculation combined with oral single-dose AP (1000/400 mg), blood stage infections were fully prevented during immunisation. 2/8 and 2/10 of vaccinees, respectively, were protected when challenged with 3.2 × 10<sup>3</sup> PfSPZ 10 weeks later, inferior to PfSPZ-CVac (chloroquine/CQ) that allows in-host replication. Comparative analysis of responses to 228 Pf proteins revealed that protection with PfSPZ-CVac (CQ) was associated with antibodies to two liver-stage antigens (LISP2, LSA1) and a multi-stage antigen (PfMSP5), but not to the major surface protein PfCSP. The complete arrest of high numbers of Pf sporozoites by single-dose AP should allow a significant dose-frequency reduction of the current daily AP malaria chemoprophylaxis regimen.
Authors
- Jana Held (ORCID: https://orcid.org/0000-0002-7970-1429)
- Anita Manoj
- Freia-Raphaella Lorenz (ORCID: https://orcid.org/0000-0002-7401-2720)
- Julius Clemence R. Hafalla (ORCID: https://orcid.org/0000-0002-5452-9263)
- Natasha KC
- Wolfram Metzger
- Kai Matuschewski (ORCID: https://orcid.org/0000-0001-6147-8591)
- Katja Müller (ORCID: https://orcid.org/0000-0001-5100-0981)
- Tooba Murshedkar
- Fiona O’Rourke
- Javier Ibáñez (ORCID: https://orcid.org/0000-0001-6215-6332)
- Thomas L. Richie (ORCID: https://orcid.org/0000-0002-2946-5456)
- Nguyen Trong The (ORCID: https://orcid.org/0000-0002-5433-7712)
- Zita Sulyok
- Albert Lalremruata (ORCID: https://orcid.org/0000-0002-4692-7835)
- Peter G. Kremsner (ORCID: https://orcid.org/0000-0002-3926-4113)
- Benjamin Mordmüller (ORCID: https://orcid.org/0000-0001-9101-2768)
- B. Kim Lee Sim (ORCID: https://orcid.org/0000-0002-8598-8905)
- Annette Knoblich
- Regina Steuder
- Mihály Sulyok (ORCID: https://orcid.org/0000-0002-6960-5126)
- Patricia Granados Bayon (ORCID: https://orcid.org/0000-0003-1851-7588)
- Eric R. James (ORCID: https://orcid.org/0000-0002-2184-745X)
- Thaisa Lucas Sandri (ORCID: https://orcid.org/0000-0001-6039-5241)
- Carlos Lamsfus Calle (ORCID: https://orcid.org/0000-0002-6766-1765)
- Selorme Adukpo (ORCID: https://orcid.org/0000-0003-3173-996X)
- Peter F. Billingsley (ORCID: https://orcid.org/0000-0003-1142-4813)
- Johannes Friesen (ORCID: https://orcid.org/0000-0002-8632-2988)
- Rolf Fendel (ORCID: https://orcid.org/0000-0003-4716-0311)
- David M. Weller (ORCID: https://orcid.org/0000-0001-8533-7136)
- Stephanie Sefried
- Sumana Chakravarty (ORCID: https://orcid.org/0000-0002-0426-6418)
- Steffen Borrmann (ORCID: https://orcid.org/0000-0001-9189-4393)
- Tamirat Gebru Woldearegai (ORCID: https://orcid.org/0000-0001-9508-1787)
- Zsófia Molnár
- Meral Esen (ORCID: https://orcid.org/0000-0002-7657-6458)
- Yonas Abebe (ORCID: https://orcid.org/0000-0002-8814-5129)
- Stephen L. Hoffman
- H Heimann
- Adam J. Ruben
Institutions
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Humboldt-Universität zu Berlin (DE)
- Sanaria (US)
- London School of Hygiene & Tropical Medicine (GB)
- Centre de Recherche Médicales de Lambaréné (GA)
- German Center for Infection Research (DE)
- Protein Potential (United States) (US)
- University of Tübingen (DE)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s44321-025-00301-8
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 3.76