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<p>To develop a <i>Plasmodium falciparum</i> (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, <i>P. berghei</i> 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.</p>

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Complete attenuation of Plasmodium falciparum sporozoites by atovaquone–proguanil

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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

摘要

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.