Walk Jona, Reuling Isaie J, Behet Marije C, Meerstein-Kessel Lisette, Graumans Wouter, van Gemert Geert-Jan, Siebelink-Stoter Rianne, van de Vegte-Bolmer Marga, Janssen Thorsten, Teelen Karina, de Wilt Johannes H W, de Mast Quirijn, van der Ven André J, Diez Benavente Ernest, Campino Susana, Clark Taane G, Huynen Martijn A, Hermsen Cornelus C, Bijker Else M, Scholzen Anja, Sauerwein Robert W
Department of Medical Microbiology, Radboud University Medical Center, Geert Grooteplein 28, Microbiology 268, 6500 HB, Nijmegen, The Netherlands.
Radboud Institute of Molecular Life Sciences and Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Geert Grooteplein 28, CMBI 260, 6500 HB, Nijmegen, The Netherlands.
BMC Med. 2017 Sep 13;15(1):168. doi: 10.1186/s12916-017-0923-4.
A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains.
We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones.
NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation.
Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection.
This trial is registered in clinicaltrials.gov, under identifier NCT02098590 .
疟疾的控制与根除需要一种高效疫苗。在化学预防（化学预防与子孢子（CPS）免疫）情况下用恶性疟原虫NF54寄生虫进行免疫接种，可诱导针对同源寄生虫的最有效持久保护。然而，寄生虫遗传多样性是抵御异源菌株的主要障碍。
我们对39名健康参与者进行了一项双盲、随机对照试验，通过叮咬45只感染NF54的蚊子（n = 24名志愿者）或未感染的蚊子（安慰剂；n = 15名志愿者）进行NF54 - CPS免疫，以抵抗同源NF54或基因不同的NF135.C10和NF166.C8克隆的受控人体疟疾感染。进行了细胞和体液免疫测定以及寄生虫克隆的基因特征分析。
NF54 - CPS免疫接种在免疫后14周使5/5名志愿者对NF54攻击感染产生了完全保护，但仅分别使2/10和1/9名志愿者对NF135.C10和NF166.C8攻击感染产生了无菌保护。与NF54相比，免疫后血浆在原代人肝细胞中阻断异源寄生虫发育的能力显著降低。全基因组测序表明，NF135.C10和NF166.C8在CPS诱导抗体靶向的多种抗原中存在氨基酸变化。对异源攻击有保护作用的志愿者是体外寄生虫刺激的较强免疫应答者。
尽管NF54 - CPS诱导的免疫对同源寄生虫具有高度保护作用，但在体内和体外对异源寄生虫克隆的效果均较差。我们的数据表明，基于全子孢子的疫苗方法需要更强有力的免疫应答来实现异源保护。
本试验已在clinicaltrials.gov上注册，标识符为NCT02098590。
