TY - JOUR
T1 - Complete attenuation of Plasmodium falciparum sporozoites by atovaquone–proguanil
AU - Borrmann, Steffen
AU - Sulyok, Zita
AU - Müller, Katja
AU - Fendel, Rolf
AU - Sulyok, Mihály
AU - Friesen, Johannes
AU - Lalremruata, Albert
AU - Sandri, Thaisa Lucas
AU - Nguyen, The Trong
AU - Calle, Carlos Lamsfus
AU - Knoblich, Annette
AU - Sefried, Stephanie
AU - Ibáñez, Javier
AU - Lorenz, Freia Raphaella
AU - Heimann, Henri Lynn
AU - Weller, David M.
AU - Steuder, Regina
AU - Adukpo, Selorme
AU - Granados Bayon, Patricia
AU - Molnár, Zsófia
AU - Esen, Meral
AU - Metzger, Wolfram
AU - James, Eric R.
AU - Ruben, Adam
AU - Abebe, Yonas
AU - Chakravarty, Sumana
AU - Manoj, Anita
AU - KC, Natasha
AU - Murshedkar, Tooba
AU - Hafalla, Julius C.R.
AU - Woldearegai, Tamirat Gebru
AU - O’Rourke, Fiona
AU - Held, Jana
AU - Billingsley, Pete
AU - Sim, B. Kim Lee
AU - Richie, Thomas L.
AU - Hoffman, Stephen L.
AU - Kremsner, Peter G.
AU - Matuschewski, Kai
AU - Mordmüller, Benjamin
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/11/10
Y1 - 2025/11/10
N2 - 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 × 104 or 1.5 × 105 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 × 103 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.
AB - 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 × 104 or 1.5 × 105 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 × 103 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.
KW - Atovaquone–proguanil
KW - Chemo-attenuation
KW - Controlled Human Malaria Infection
KW - Malaria Vaccine
KW - Plasmodium falciparum
UR - https://www.scopus.com/pages/publications/105017381463
U2 - 10.1038/s44321-025-00301-8
DO - 10.1038/s44321-025-00301-8
M3 - Article
AN - SCOPUS:105017381463
SN - 1757-4676
VL - 17
SP - 2875
EP - 2900
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 11
ER -
