Haley Shannon L, Tzvetkov Evgeni P, Meuwissen Samantha, Plummer Joseph R, McGettigan James P
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
J Virol. 2017 Mar 29;91(8). doi: 10.1128/JVI.02435-16. Print 2017 Apr 15.
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. 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.
疫苗诱导的B细胞沿两条途径分化。滤泡途径产生生发中心（GCs），其完全发育可能需要数周时间。滤泡外途径产生短寿命浆细胞（PCs），其可在接种疫苗数天内迅速分泌保护性抗体。狂犬病病毒（RABV）暴露后预防（PEP）需要快速的疫苗诱导体液免疫来提供保护。因此，我们假设靶向滤泡外B细胞反应以激活将提高RABV PEP的速度和强度。为了验证这一假设，我们构建、回收并鉴定了一种表达鼠B细胞活化因子（BAFF）的重组RABV疫苗（rRABV-mBAFF）。BAFF是改善B细胞活化早期途径的理想分子，因为它连接先天免疫和适应性免疫，促进强大的B细胞反应。事实上，与rRABV相比，rRABV-mBAFF在小鼠中诱导了更快、更高的抗体反应，并在PEP环境中提高了存活率。有趣的是，rRABV-mBAFF和rRABV诱导的GC B细胞数量相当，这表明rRABV-mBAFF增强了滤泡外B细胞途径。为了证实rRABV-mBAFF调节了滤泡外途径，我们使用了一种信号淋巴细胞活化分子（SLAM）相关蛋白（SAP）缺陷小鼠模型。响应抗原时，SAP缺陷小鼠形成滤泡外B细胞反应，但不产生GCs。rRABV-mBAFF在SAP缺陷小鼠和野生型小鼠中诱导了相似的抗RABV抗体反应，表明BAFF通过滤泡外而非GC B细胞途径调节免疫。总体而言，操纵B细胞活化途径的策略可能有助于开发单剂量RABV疫苗，以取代目前复杂且昂贵的RABV PEP。有效的RABV PEP目前在RABV最流行的世界地区资源和成本上令人望而却步。为了减少狂犬病免疫球蛋白（RIG）的需求以及有效预防临床狂犬病所需的多次接种，需要一种保护更快的疫苗。这项工作提出了一种成功的方法，通过靶向滤泡外B细胞途径，在接种疫苗后快速产生分泌抗体的PCs。我们证明，rRABV-mBAFF诱导的早期抗体反应改善在PEP模型中赋予了对RABV更好的保护。重要的是，早期滤泡外B细胞途径的激活，如此处所示，可以提高针对其他病原体的疫苗的效力，针对这些病原体的快速保护将降低发病率和死亡率。
