Complete attenuation of Plasmodium falciparum sporozoites by atovaquone-proguanil.
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Borrmann Steffen, Sulyok Zita, Müller Katja, Fendel Rolf, Sulyok Mihály, Friesen Johannes, Lalremruata Albert, Sandri Thaisa Lucas, Nguyen The Trong, Calle Carlos Lamsfus, Knoblich Annette, Sefried Stephanie, Ibáñez Javier, Lorenz Freia-Raphaella, Heimann Henri Lynn, Weller David M, Steuder Regina, Adukpo Selorme, Granados Bayon Patricia, Molnár Zsófia, Esen Meral, Metzger Wolfram, James Eric R, Ruben Adam, Abebe Yonas, Chakravarty Sumana, Manoj Anita, Kc Natasha, Murshedkar Tooba, Hafalla Julius C R, Woldearegai Tamirat Gebru, O'Rourke Fiona, Held Jana, Billingsley Pete, Sim B Kim Lee, Richie Thomas L, Hoffman Stephen L, Kremsner Peter G, Matuschewski Kai, Mordmüller Benjamin
Аннотация
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.