Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseasesgrid.419681.3, National Institutes of Health, Bethesda, Maryland, USA.
Department of Cellular Immunology, Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Infect Immun. 2021 Oct 15;89(11):e0016521. doi: 10.1128/IAI.00165-21. Epub 2021 Jul 26.
Preerythrocytic vaccines prevent malaria by targeting parasites in the clinically silent sporozoite and liver stages and preventing progression to the virulent blood stages. The leading preerythrocytic vaccine, RTS,S/AS01E (Mosquirix), entered implementation programs in 2019 and targets the major sporozoite surface antigen, circumsporozoite protein (CSP). However, in phase III clinical trials, RTS,S conferred partial protection with limited durability, indicating a need to improve CSP-based vaccination. Previously, we identified highly expressed liver-stage proteins that could potentially be used in combination with CSP; they are referred to as preerythrocytic vaccine antigens (PEVAs). Here, we developed heterologous prime-boost CSP vaccination models to confer partial sterilizing immunity against Plasmodium yoelii (protein prime-adenovirus 5 [Ad5] boost) and Plasmodium berghei (DNA prime-Ad5 boost) in mice. When combined as individual antigens with P. yoelii CSP (PyCSP), three of eight P. yoelii PEVAs significantly enhanced sterile protection against sporozoite challenge, compared to PyCSP alone. Similar results were obtained when three P. berghei PEVAs and P. berghei CSP were combined in a single vaccine regimen. In general, PyCSP antibody responses were similar after CSP alone versus CSP plus PEVA vaccinations. Both P. yoelii and P. berghei CSP plus PEVA combination vaccines induced robust CD8 T cell responses, including signature gamma interferon (IFN-γ) increases. In the P. berghei model system, IFN-γ responses were significantly higher in hepatic versus splenic CD8 T cells. The addition of novel antigens may enhance the degree and duration of sterile protective immunity conferred by a human vaccine such as RTS,S.
前期血阶段疫苗通过针对临床无症状的子孢子和肝阶段寄生虫并阻止其向毒力血阶段进展来预防疟疾。领先的前期血阶段疫苗 RTS,S/AS01E（Mosquirix）于 2019 年进入实施计划，针对主要的子孢子表面抗原环子孢子蛋白（CSP）。然而，在 III 期临床试验中，RTS,S 提供了部分保护，但其持久性有限，表明需要改进基于 CSP 的疫苗接种。此前，我们鉴定了高度表达的肝阶段蛋白，它们可能与 CSP 联合使用；它们被称为前期血阶段疫苗抗原（PEVA）。在这里，我们开发了异源初免-加强 CSP 疫苗接种模型，以在小鼠中针对约氏疟原虫（蛋白初免-腺病毒 5 [Ad5] 加强）和伯氏疟原虫（DNA 初免-Ad5 加强）提供部分绝育免疫。当作为单独抗原与 P. yoelii CSP（PyCSP）联合使用时，八种 P. yoelii PEVA 中的三种与单独使用 PyCSP 相比，显著增强了对子孢子挑战的无菌保护。当三种 P. berghei PEVA 和 P. berghei CSP 组合在单个疫苗方案中使用时，也得到了类似的结果。一般来说，单独使用 CSP 与 CSP 加 PEVA 接种后的 PyCSP 抗体反应相似。PyCSP 加 PEVA 组合疫苗均可诱导强烈的 CD8 T 细胞反应，包括特征性的伽马干扰素（IFN-γ）增加。在 P. berghei 模型系统中，肝 CD8 T 细胞中的 IFN-γ 反应显著高于脾 CD8 T 细胞。添加新抗原可能会增强人类疫苗（如 RTS,S）提供的无菌保护免疫的程度和持续时间。
