Seattle Children's Research Institute, Seattle, Washington.
Department of Pediatrics, University of Washington, Seattle, Washington.
PLoS Pathog. 2022 Jul 6;18(7):e1010671. doi: 10.1371/journal.ppat.1010671. eCollection 2022 Jul.
Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. 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 CSP-specific germinal center experienced B cells and 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 the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.
阻断疟原虫（疟疾的病原体）在无症状的红细胞前期会消除疾病病理学并阻止传播。然而，疫苗诱导的抗体反应中缺乏与保护相关的明确特征，这是改进现有疫苗的主要障碍。我们用 Py 环子孢子蛋白（CSP），即孢子上的主要表面抗原，对 BALB/cJ 和 C57BL/6J 小鼠进行了疫苗接种，并评估了疫苗诱导的体液免疫，并在蚊子叮咬挑战后确定了与保护相关的免疫因素。疫苗接种在 BALB/cJ 小鼠中实现了 60%的无菌保护，否则会延迟红细胞期的通透性。相比之下，所有 C57BL/6J 小鼠都像对照一样感染。保护是由抗体介导的，可以从免疫的 BALB/cJ 小鼠被动转移到未感染的 C57BL/6J 小鼠。对保护的潜在免疫特征的分析显示，C57BL/6J 小鼠的抗体滴度和多克隆亲和力早期出现缺陷。此外，PyCSP 疫苗接种在 BALB/cJ 中诱导的抗原特异性 B 细胞和类别转换记忆 B 细胞（MBC）群体的比例明显高于 C57BL/6J 小鼠。引人注目的是，与 BALB/cJ 小鼠相比，C57BL/6J 小鼠的 CSP 特异性生发中心经历 B 细胞和类别转换 MBC 也明显减少。通过下一代测序对 PyCSP 特异性记忆 B 细胞库中的 IgG γ 链库进行分析也表明，BALB/cJ 小鼠中的体细胞超突变率高于 C57BL/6J 小鼠。这些发现表明，与 C57BL/6J 小鼠相比，PyCSP 疫苗接种后 BALB/cJ 小鼠保护性抗体反应的发展与生发中心活性和体细胞突变增加有关，这突出了 B 细胞成熟在疫苗诱导的 CSP 保护性抗体中的关键作用。
