There is a pressing need for safe and highly effective Plasmodium falciparum (Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high levels of sterilizing immunity and constitute a promising approach to effective immunization against malaria. Here, we describe a novel WSp malaria vaccine that employs transgenic sporozoites of rodent P. berghei (Pb) parasites as cross-species immunizing agents and as platforms for expression and delivery of PfCS (PbVac). We show that both wild-type Pb and PbVac sporozoites unabatedly infect and develop in human hepatocytes while unable to establish an infection in human red blood cells. In a rabbit model, similarly susceptible to Pb hepatic but not blood infection, we show that PbVac elicits cross-species cellular immune responses, as well as PfCS-specific antibodies that efficiently inhibit Pf sporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus, PbVac is safe and induces functional immune responses in preclinical studies, warranting clinical testing and development.

迫切需要安全有效的恶性疟原虫（Pf）疟疾疫苗。在子孢子和肝早期阶段表达的环子孢子蛋白（CS）是主要的靶疫苗候选者，但迄今为止临床疗效尚不理想。相反，全子孢子（WSp）疫苗一直显示出高水平的杀菌免疫力，构成了有效预防疟疾的有前途的方法。在这里，我们描述了一种新颖的WSp疟疾疫苗，该疫苗采用了啮齿类伯氏疟原虫（Pb）寄生虫的转基因子孢子作为跨物种免疫剂以及作为Pf CS（Pb真空）。我们显示，野生型Pb和Pb Vac子孢子均无减弱地感染并在人肝细胞中发育，而无法在人红细胞中建立感染。在类似地易受Pb肝感染但不受血液感染的兔模型中，我们显示Pb Vac会引起跨物种的细胞免疫反应，以及有效抑制Pf子孢子肝侵袭人类肝细胞和小鼠的Pf CS特异性抗体。人性化的肝脏。因此，Pb Vac是安全的，并且在临床前研究中会诱导功能性免疫反应，因此有必要进行临床测试和开发。