Department of Global Health, Milken Institute School of Public 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; Programa de Pós-Graduação em Saúde Pública, Faculdade de Saúde Pública, Universidade Federal de São Paulo, São Paulo 01246-904, SP, Brazil.
Vaccine. 2024 Aug 30;42(21):126140. doi: 10.1016/j.vaccine.2024.07.041. Epub 2024 Jul 20.
Transmission-blocking vaccines interrupting malaria transmission within mosquitoes represent an ideal public health tool to eliminate malaria at the population level. Plasmodium falciparum and P. vivax account for more than 90% of the global malaria burden, co-endemic in many regions of the world. P25 and P48/45 are two leading candidates for both species and have shown promising transmission-blocking activity in preclinical and clinical studies. However, neither of these target antigens as individual vaccines has induced complete transmission inhibition in mosquitoes. In this study, we assessed immunogenicity of combination vaccines based on P25 and P48/45 using a DNA vaccine platform to broaden vaccine specificity against P. falciparum and P. vivax. Individual DNA vaccines encoding Pvs25, Pfs25, Pvs48/45 and Pfs48/45, as well as various combinations including (Pvs25 + Pvs48/45), (Pfs25 + Pfs48/45), (Pvs25 + Pfs25), and (Pvs48/45 + Pfs48/45), were evaluated in mice using in vivo electroporation. Potent antibody responses were induced in mice immunized with individual and combination DNA vaccines, and specific antibody responses were not compromised when combinations of DNA vaccines were evaluated against individual DNA vaccines. The anti-Pvs25 IgG from individual and combination groups revealed concentration-dependent transmission-reducing activity (TRA) in direct membrane feeding assays (DMFA) using blood from P. vivax-infected donors in Brazil and independently in ex vivo MFA using Pvs25-transgenic P. berghei. Similarly, anti-Pfs25 and anti-Pfs48/45 IgGs from mice immunized with Pfs25 and Pfs48/45 DNA vaccines individually and in various combinations revealed antibody dose-dependent TRA in standard membrane feeding assays (SMFA) using culture-derived P. falciparum gametocytes. However, antibodies induced by immunization with Pvs48/45 DNA vaccines were ineffective in DMFA and require further vaccine construct optimization, considering the possibility of induction of both transmission-blocking and transmission-enhancing antibodies revealed by competition ELISA. These studies provide a rationale for combining multiple antigens to simultaneously target transmission of malaria caused by P. falciparum and P. vivax.
阻断疟疾在蚊子中的传播的疫苗可以在人群层面上消灭疟疾，这是一种理想的公共卫生工具。恶性疟原虫和间日疟原虫占全球疟疾负担的 90%以上，在世界许多地区同时流行。P25 和 P48/45 是这两种寄生虫的主要候选疫苗，在临床前和临床研究中均表现出有希望的阻断传播活性。然而，作为单一疫苗，这两种靶抗原都没有在蚊子中完全抑制传播。在这项研究中，我们使用 DNA 疫苗平台评估了基于 P25 和 P48/45 的联合疫苗的免疫原性，以扩大针对恶性疟原虫和间日疟原虫的疫苗特异性。单独的 DNA 疫苗编码 Pvs25、Pfs25、Pvs48/45 和 Pfs48/45，以及包括（Pvs25 + Pvs48/45）、（Pfs25 + Pfs48/45）、（Pvs25 + Pfs25）和（Pvs48/45 + Pfs48/45）在内的各种组合，均在使用体内电穿孔的小鼠中进行了评估。用单独和联合 DNA 疫苗免疫的小鼠均诱导出有效的抗体应答，并且当评估 DNA 疫苗组合与单独 DNA 疫苗时，特异性抗体应答不受影响。来自个体和组合组的抗 Pvs25 IgG 在直接膜喂养试验（DMFA）中显示出浓度依赖性的传播减少活性（TRA），使用来自巴西感染间日疟原虫的供体的血液，并在使用 Pvs25 转基因伯氏疟原虫的离体 MFA 中独立地显示出 TRA。同样，用 Pfs25 和 Pfs48/45 DNA 疫苗单独和组合免疫的小鼠产生的抗 Pfs25 和抗 Pfs48/45 IgG 在使用培养衍生的恶性疟原虫配子体的标准膜喂养试验（SMFA）中显示出抗体剂量依赖性的 TRA。然而，用 Pvs48/45 DNA 疫苗免疫诱导的抗体在 DMFA 中无效，需要进一步优化疫苗构建，因为竞争 ELISA 显示出可能诱导传播阻断和增强抗体。这些研究为同时针对恶性疟原虫和间日疟原虫引起的疟疾传播提供了联合多种抗原的原理。
