Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.

中文翻译：

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生发中心活性和 B 细胞成熟促进对疟原虫红细胞前感染的保护性抗体反应

在无症状的红细胞前期阶段阻断疟原虫（疟疾的病原体）将消除疾病病理并防止传播。啮齿动物传染性疟原虫物种，如约氏疟原虫 (Py)，是研究具有免疫能力的实验动物的疫苗功效和疾病生物学的关键工具。在这里，我们评估了两种广泛使用且差异很大的近交小鼠品系 BALB/cJ 和 C57BL/6J 中疫苗引起的体液免疫的差异，并确定了与保护相关的免疫学因素。我们接种了Py环子孢子蛋白 (CSP)，子孢子上的主要表面抗原，并评估了蚊虫叮咬攻击后的保护功效。接种疫苗在 BALB/cJ 小鼠中实现了 60% 的无菌保护和其他延迟的血液阶段通畅，而；所有 C57BL/6J 小鼠的感染情况与对照组相似。有趣的是，保护是由抗体介导的，可以从免疫的 BALB/cJ 小鼠被动转移到幼稚的 C57BL/6J。对保护的潜在免疫学特征的剖析揭示了 C57BL/6J 小鼠中抗体效价和多克隆亲和力的早期缺陷。此外，Py与 C57BL/6J 小鼠相比，BALB/cJ 中的 CSP 疫苗接种诱导了显着更高比例的抗原特异性 B 细胞和类别转换记忆 B 细胞 (MBC) 群体。引人注目的是，与 BALB/cJ 小鼠相比，C57BL/6J 小鼠的生发中心经历显着减少，CSP 特异性类转换 MBC。通过下一代测序分析Py CSP 特异性记忆 B 细胞库中的 IgG γ 链库也显示 BALB/cJ 小鼠的体细胞超突变率高于 C57BL/6J 小鼠。这些发现表明 BALB/cJ 小鼠在接种Py疫苗后实现了更高水平的 B 细胞成熟CSP，这可能促进了保护性抗体反应的发展。总体而言，我们的研究表明，生发中心活性和 B 细胞成熟是开发疫苗引发的针对 CSP 的保护性抗体的关键过程。