Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.
Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany.
EMBO Mol Med. 2021 Apr 9;13(4):e13390. doi: 10.15252/emmm.202013390. Epub 2021 Mar 11.
Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8 T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen-specific CD8 T-cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced effector CD8 T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen-specific CD8 T-cell killing, which has wide-ranging implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines.
免疫原性被认为是候选疫苗进一步临床评估的一个重要标准。我们在疟原虫原虫和疫苗接种模型中测试了这一假设,该模型用于研究疟原虫的早期阶段感染和免疫。我们设计了携带一种已知的 CD8 T 细胞刺激表位的伯氏疟原虫寄生虫,该表位在疟原虫的子孢子表面表达的环子孢子蛋白或在子孢子中上调的虫体滋养液膜相关蛋白 4(UIS4)中表达。我们发现抗原来源会导致免疫原性的显著差异,子孢子抗原能引发强烈、优越的抗原特异性 CD8 T 细胞反应,而虫体滋养液膜相关蛋白 4 (UIS4)抗原则引发较差的反应。尽管它们的免疫原性特性截然不同,但无论是子孢子还是虫体滋养液膜相关蛋白 4 (UIS4)抗原都能够进入肝细胞的抗原呈递途径,因为疫苗诱导的效应 CD8 T 细胞的识别和靶向作用导致针对这两种抗原的高水平保护。我们的研究首次证明,免疫原性差的虫体滋养液膜相关蛋白 4 (UIS4)抗原并不排除它们对 CD8 T 细胞杀伤的敏感性,这对下一代疟原虫早期阶段疫苗的抗原优先化具有广泛的意义。