Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis
Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis
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DOI：
10.1128/jvi.02435-16
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发表时间：
2017-04-01
影响因子：
5.4
通讯作者：
McGettigan, James P.
中科院分区：
文献类型：
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作者：
Haley, Shannon L.;Tzvetkov, Evgeni P.;McGettigan, James P.
疫苗诱导的B细胞沿沿着两条途径分化。卵泡途径产生生发中心（GC），可能需要数周才能完全发育。滤泡外途径产生短寿命的浆细胞（PC），可在接种后数天内快速分泌保护性抗体。狂犬病病毒（RABV）的暴露后预防（PEP）需要快速疫苗诱导的体液免疫保护。因此，我们假设靶向滤泡外B细胞应答激活将提高RABV PEP的速度和幅度。为了验证这一假设，我们构建、回收并表征了表达鼠B细胞活化因子（BAFF）的重组RABV疫苗（rRABV-mBAFF）。BAFF是改善B细胞活化的早期途径的理想分子，因为它连接先天性和适应性免疫，促进有效的B细胞应答。事实上，与rRABV相比，rRABV-mBAFF在小鼠中诱导更快、更高的抗体应答，并在PEP环境中增强存活率。有趣的是，rRABV-mBAFF和rRABV诱导相同数量的GC B细胞，表明rRABV-mBAFF增强了滤泡外B细胞途径。为了证实rRABV-mBAFF调节滤泡外途径，我们使用信号淋巴细胞活化分子（SLAM）相关蛋白（SAP）缺陷小鼠模型。在对抗原的应答中，SAP缺陷小鼠形成滤泡外B细胞应答，但不产生GC。rRABV-mBAFF在SAP缺陷型和野生型小鼠中诱导了相似的抗RABV抗体应答，表明BAFF通过滤泡外而不是GC B细胞途径调节免疫。总的来说，操纵B细胞活化途径的策略可以促进单剂量RABV疫苗的开发，该疫苗取代当前复杂且昂贵的RABV PEP。重要性有效的RABV PEP目前在世界上RABV最流行的地区资源和成本过高。为了减少对狂犬病免疫球蛋白（RIG）的需求和多次接种以有效预防临床狂犬病，需要更快速的保护性疫苗。这项工作提出了一种成功的方法，以快速产生抗体分泌PC响应于疫苗接种，通过靶向滤泡外B细胞途径。我们证明了rRABV-mBAFF诱导的改善的早期抗体应答在PEP模型中赋予针对RABV的改善的保护。值得注意的是，激活早期滤泡外B细胞通路，如本文所示，可以提高针对其他病原体的疫苗的效力，快速保护可以降低发病率和死亡率。
Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP.IMPORTANCE Effective RABV PEP is currently resource-and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.