Alves Eduardo, Salman Ahmed M, Leoratti Fabiana, Lopez-Camacho Cesar, Viveros-Sandoval Martha Eva, Lall Amar, El-Turabi Aadil, Bachmann Martin F, Hill Adrian V S, Janse Chris J, Khan Shahid M, Reyes-Sandoval Arturo
The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Clin Vaccine Immunol. 2017 Apr 5;24(4). doi: 10.1128/CVI.00501-16. Print 2017 Apr.
Four different vaccine platforms, each targeting the human malaria parasite cell-traversal protein for ookinetes and sporozoites (CelTOS), were generated and assessed for protective efficacy. These platforms consisted of a recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing CelTOS (Ad), a recombinant modified vaccinia virus Ankara expressing CelTOS (MVA), CelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and a recombinant CelTOS protein expressed in eukaryotic HEK293T cells (protein). Inbred BALB/c mice and outbred CD-1 mice were immunized using the following prime-boost regimens: Ad-MVA, Ad-VLPs, and Ad-protein. Protective efficacy against sporozoite challenge was assessed after immunization using a novel chimeric rodent parasite (CelTOS). This chimeric parasite expresses CelTOS in place of the endogenous CelTOS and produces fully infectious sporozoites. A single Ad immunization in BALB/c and CD-1 mice induced anti-CelTOS antibodies which were boosted efficiently using MVA, VLP, or protein immunization. CelTOS-specific gamma interferon- and tumor necrosis factor alpha-producing CD8 T cells were induced at high frequencies by all prime-boost regimens in BALB/c mice but not in CD-1 mice; in CD-1 mice, they were only marginally increased after boosting with MVA. Despite the induction of anti-CelTOS antibodies and CelTOS-specific CD8 T-cell responses, only low levels of protective efficacy against challenge with CelTOS sporozoites were obtained using any immunization strategy. In BALB/c mice, no immunization regimens provided significant protection against a CelTOS chimeric sporozoite challenge. In CD-1 mice, modest protective efficacy against challenge with chimeric sporozoites expressing either CelTOS or CelTOS was observed using the Ad-protein vaccination regimen.
构建了四种不同的疫苗平台，每种平台都靶向疟原虫动合子和子孢子的细胞穿透蛋白（CelTOS），并评估了其保护效力。这些平台包括表达CelTOS的重组黑猩猩腺病毒载体63（ChAd63）（Ad）、表达CelTOS的重组改良安卡拉痘苗病毒（MVA）、与噬菌体Qβ病毒样颗粒（VLP）偶联的CelTOS，以及在真核HEK293T细胞中表达的重组CelTOS蛋白（蛋白）。使用以下初免-加强免疫方案对近交系BALB/c小鼠和远交系CD-1小鼠进行免疫：Ad-MVA、Ad-VLPs和Ad-蛋白。免疫后，使用一种新型嵌合啮齿动物寄生虫（CelTOS）评估针对子孢子攻击的保护效力。这种嵌合寄生虫表达CelTOS以替代内源性CelTOS，并产生完全具有感染性的子孢子。在BALB/c和CD-1小鼠中进行单次Ad免疫可诱导抗CelTOS抗体，使用MVA、VLP或蛋白免疫可有效增强这些抗体。在BALB/c小鼠中，所有初免-加强免疫方案均能高频诱导产生CelTOS特异性γ干扰素和肿瘤坏死因子α的CD8 T细胞，但在CD-1小鼠中则不能；在CD-1小鼠中，用MVA加强免疫后这些细胞仅略有增加。尽管诱导产生了抗CelTOS抗体和CelTOS特异性CD8 T细胞反应，但使用任何免疫策略针对CelTOS子孢子攻击获得的保护效力都很低。在BALB/c小鼠中，没有任何免疫方案能提供针对CelTOS嵌合子孢子攻击的显著保护。在CD-1小鼠中，使用Ad-蛋白疫苗接种方案观察到针对表达CelTOS或CelTOS的嵌合子孢子攻击有适度的保护效力。
