Antibody-Dependent, Gamma Interferon-Independent Sterilizing Immunity Induced by a Subunit Malaria Vaccine
Antibody-Dependent, Gamma Interferon-Independent Sterilizing Immunity Induced by a Subunit Malaria Vaccine
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DOI：
10.1128/iai.00236-19
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发表时间：
2019-10-01
影响因子：
3.1
通讯作者：
Kumar, Sanjai
中科院分区：
文献类型：
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作者：
Chawla, Bhavna;Mahajan, Babita;Kumar, Sanjai
由于对保护性免疫的免疫相关性的不完全了解，有效的疟疾疫苗的开发受到阻碍。最近，基于恶性疟原虫环子孢子蛋白 (CSP) 的 RTS、S/AS01E 疫苗在 3 期研究中取得了中等临床疗效，凸显了设计和测试更有效的下一代疟疾疫苗的紧迫性。在这项研究中，我们报道了用来自约氏疟原虫的重组 CSP (rPyCSP) 进行免疫，当在 Montanide ISA 51 中递送时，在 C57BL/6 和 BALB/c 品系的小鼠中诱导了针对子孢子攻击的绝育免疫。这种免疫力是抗体依赖性的，B 细胞敲除 (KO) 小鼠的免疫力完全丧失以及免疫血清中和小鼠子孢子感染性的能力证明了这一点。 Th2 型同种型 IgG1 抗体水平与保护性免疫相关。流式细胞术显示，免疫的γ干扰素（IFN-γ）-KO小鼠和野生型（WT）小鼠具有相似水平的保护性免疫，并且受保护的小鼠中不存在产生IFN-γ的CD4（+）和CD8（+）T细胞，这表明免疫是IFN-γ独立的。抵抗子孢子攻击的保护作用与表达白细胞介素 2 (IL-2)、IL-4 和肿瘤坏死因子 α (TNF-gamma) 的 CD4(+) T 细胞频率较高相关。在 RTS, S 研究中，临床免疫与较高的 IgG 水平以及产生 IL-2 和 TNF-γ 的 CD4(+) T 细胞的频率相关。我们研究中免疫的其他标志包括滤泡 B 细胞数量增加，但滤泡 T 辅助细胞数量减少。这些结果提供了一个出色的模型系统，用于评估新型佐剂和疫苗剂量的功效，并确定寻找优质疟疾候选疫苗时免疫的相关性。
The development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of the Plasmodium falciparum circumsporozoite protein (CSP)-based RTS, S/AS01E vaccine in phase 3 studies highlighted the urgency to design and test more efficacious next-generation malaria vaccines. In this study, we report that immunization with recombinant CSP from Plasmodium yoelii (rPyCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice. This immunity was antibody dependent, as evidenced by the complete loss of immunity in B-cell-knockout (KO) mice and by the ability of immune sera to neutralize sporozoite infectivity in mice. Th2-type isotype IgG1 antibody levels were associated with protective immunity. The fact that immunized gamma interferon (IFN-gamma)-KO mice and wild-type (WT) mice have similar levels of protective immunity and the absence of IFN-gamma-producing CD4(+) and CD8(+) T cells in protected mice, as shown by flow cytometry, indicate that the immunity is IFN-gamma independent. Protection against sporozoite challenge correlated with higher frequencies of CD4(+) T cells that express interleukin-2 (IL-2), IL-4, and tumor necrosis factor alpha (TNF-gamma). In the RTS, S study, clinical immunity was associated with higher IgG levels and frequencies of IL-2- and TNF-gamma -producing CD4(+) T cells. The other hallmarks of immunity in our study included an increased number of follicular B cells but a loss in follicular T helper cells. These results provide an excellent model system to evaluate the efficacy of novel adjuvants and vaccine dosage and determine the correlates of immunity in the search for superior malaria vaccine candidates.