Cao Yi, da Silva Araujo Maisa, Lorang Cynthia G, Dos Santos Najara Akira Costa, Tripathi Abhai, Vinetz Joseph, Kumar Nirbhay
Department of Global Health, George Washington University, Washington, D.C., USA.
Plataforma de Produção e Infecção de Vetores da Malária, Laboratório de Entomologia - FIOCRUZ RO, Rua da Beira 7671, CEP 76812-245 Porto Velho, RO, Brazil; Laboratório de Pesquisa Translacional e Clínica, Centro de Pesquisa em Medicina Tropical, Porto Velho, Rondônia, Brazil.
Vaccine. 2025 Feb 15;47:126696. doi: 10.1016/j.vaccine.2024.126696. Epub 2025 Jan 8.
Transmission-blocking vaccines (TBVs) targeting sexual-stage antigens represent a critical tool for malaria control and elimination through inhibiting parasite development within mosquitoes. P230, displayed on the surface of gametocytes and gametes, plays a crucial role in gamete fertilization and is one of the leading TBV candidates for both Plasmodium falciparum and P. vivax. Antibodies induced by immunization with a recombinant P. falciparum protein encompassing a portion of N-terminal prodomain and domain 1 (Pfs230D1M) have revealed strong transmission-reducing activity (TRA) in preclinical studies. While a recombinant Pvs230D1, the P. vivax homolog of Pfs230D1M, has not been evaluated in preclinical immunogenicity studies, both Pfs230D1M and Pvs230D1 are currently scheduled for evaluation in clinical trials. In this study, we developed DNA vaccines encoding Pfs230D1M and Pvs230D1 for a side-by-side comparison of their immunogenicity. Potent antibody responses were induced in mice immunized with each DNA vaccine delivered by in vivo electroporation (EP). Anti-Pfs230D1M IgG exhibited potent dose-dependent TRA in a complement-dependent manner in standard membrane feeding assays (SMFA). In contrast, anti-Pvs230D1 IgG exhibited only moderate TRA in direct membrane feeding assay (DMFA) using blood from multiple P. vivax-infected donors. Antibodies induced by the Pfs230D1M DNA vaccine revealed a strong IgG1 bias and higher avidity as compared to a balanced IgG1/IgG2 response and lower antibody avidity by the Pvs230D1 DNA vaccine. Our results demonstrate the potential of both Pfs230D1M and Pvs230D1 DNA vaccines as TBV candidates against P. falciparum and P. vivax, and provide a rationale for future optimization to enhance the efficacy of DNA vaccines based on Pfs230 and Pvs230.
针对有性阶段抗原的传播阻断疫苗（TBV）是通过抑制疟原虫在蚊子体内发育来控制和消除疟疾的关键工具。P230存在于配子体和配子表面，在配子受精过程中起关键作用，是恶性疟原虫和间日疟原虫主要的TBV候选抗原之一。用包含部分N端前结构域和结构域1的重组恶性疟原虫蛋白（Pfs230D1M）免疫诱导产生的抗体，在临床前研究中显示出很强的传播减少活性（TRA）。虽然间日疟原虫的Pvs230D1（Pfs230D1M的间日疟原虫同源物）尚未在临床前免疫原性研究中进行评估，但Pfs230D1M和Pvs230D1目前都已列入临床试验评估计划。在本研究中，我们开发了编码Pfs230D1M和Pvs230D1的DNA疫苗，以并排比较它们的免疫原性。通过体内电穿孔（EP）递送的每种DNA疫苗免疫小鼠后，均诱导出强效的抗体反应。在标准膜饲实验（SMFA）中，抗Pfs230D1M IgG以补体依赖的方式表现出强效的剂量依赖性TRA。相比之下，在使用来自多个间日疟原虫感染供体血液的直接膜饲实验（DMFA）中，抗Pvs230D1 IgG仅表现出中等程度的TRA。与Pvs230D1 DNA疫苗诱导的IgG1/IgG2反应平衡且抗体亲和力较低相比，Pfs230D1M DNA疫苗诱导的抗体表现出强烈的IgG1偏向性和更高的亲和力。我们的结果证明了Pfs230D1M和Pvs230D1 DNA疫苗作为针对恶性疟原虫和间日疟原虫的TBV候选疫苗的潜力，并为未来基于Pfs230和Pvs230优化DNA疫苗以提高其疗效提供了理论依据。
