抗体依赖、γ干扰素非依赖的亚单位疟疾疫苗诱导的绝育性免疫。
Antibody-Dependent, Gamma Interferon-Independent Sterilizing Immunity Induced by a Subunit Malaria Vaccine.
机构信息
Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Naval Medical Research Center, Silver Spring, Maryland, USA.
出版信息
Infect Immun. 2019 Sep 19;87(10). doi: 10.1128/IAI.00236-19. Print 2019 Oct.
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 circumsporozoite protein (CSP)-based RTS,S/AS01 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 (rCSP), 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-γ)-KO mice and wild-type (WT) mice have similar levels of protective immunity and the absence of IFN-γ-producing CD4 and CD8 T cells in protected mice, as shown by flow cytometry, indicate that the immunity is IFN-γ 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-α). In the RTS,S study, clinical immunity was associated with higher IgG levels and frequencies of IL-2- and TNF-α-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.
有效的疟疾疫苗的发展受到对保护性免疫的免疫相关因素认识不完全的阻碍。最近,在 3 期研究中,基于环子孢子蛋白(CSP)的 RTS,S/AS01 疫苗具有中等的临床疗效,突出表明迫切需要设计和测试更有效的下一代疟疾疫苗。在这项研究中,我们报告说,用重组 CSP(rCSP)免疫,当用 Montanide ISA 51 递送时,在 C57BL/6 和 BALB/c 两种小鼠品系中诱导了针对孢子虫挑战的绝育性免疫。这种免疫是抗体依赖性的,这从 B 细胞敲除(KO)小鼠完全丧失免疫和免疫血清能够中和小鼠中的孢子虫感染力这两个事实中得到证明。Th2 型同种型 IgG1 抗体水平与保护性免疫相关。免疫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,以及在受保护的小鼠中没有 IFN-γ 产生的 CD4 和 CD8 T 细胞,如流式细胞术所示,表明免疫是 IFN-γ 非依赖性的。对孢子虫挑战的保护与表达白细胞介素 2(IL-2)、IL-4 和肿瘤坏死因子α(TNF-α)的 CD4 T 细胞的更高频率相关。在 RTS,S 研究中,临床免疫与更高的 IgG 水平和产生 IL-2 和 TNF-α 的 CD4 T 细胞的频率相关。我们研究中的免疫的其他特征包括滤泡 B 细胞数量增加,但滤泡 T 辅助细胞丧失。这些结果为评估新型佐剂和疫苗剂量的疗效以及确定免疫相关性提供了一个极好的模型系统,以寻找更优秀的疟疾疫苗候选物。