Abstract：
Neisseria meningitidis outer membrane vesicle (OMV) vaccines are safe and provide strain-specific protection against invasive meningococcal disease (IMD) primarily by inducing serum bactericidal antibodies against the outer membrane proteins (OMP). To design broader coverage vaccines, knowledge of the immunogenicity of all the antigens contained in OMVs is needed. In a Phase I clinical trial, an investigational meningococcal OMV vaccine, MenPF1, made from a meningococcus genetically modified to constitutively express the iron-regulated FetA induced bactericidal responses to both the PorA and the FetA antigen present in the OMP. Using peripheral blood mononuclear cells collected from this trial, we analyzed the kinetics of and relationships between IgG, IgA, and IgM B cell responses against recombinant PorA and FetA, including (i) antibody-secreting cells, (ii) memory B cells, and (iii) functional antibody responses (opsonophagocytic and bactericidal activities). Following MenPF1vaccination, PorA-specific IgG secreting cell responses were detected in up to 77% of participants and FetA-specific responses in up to 36%. Memory B cell responses to the vaccine were low or absent and mainly detected in participants who had evidence of preexisting immunity (P = 0.0069). Similarly, FetA-specific antibody titers and bactericidal activity increased in participants with preexisting immunity and is consistent with the idea that immune responses are elicited to minor antigens during asymptomatic Neisseria carriage, which can be boosted by OMV vaccines. IMPORTANCE Neisseria meningitidis outer membrane vesicles (OMV) are a component of the capsular group B meningococcal vaccine 4CMenB (Bexsero) and have been shown to induce 30% efficacy against gonococcal infection. They are composed of multiple antigens and are considered an interesting delivery platform for vaccines against several bacterial diseases. However, the protective antibody response after two or three doses of OMV-based meningococcal vaccines appears short-lived. We explored the B cell response induced to a dominant and a subdominant antigen in a meningococcal OMV vaccine in a clinical trial and showed that immune responses are elicited to minor antigens. However, memory B cell responses to the OMV were low or absent and mainly detected in participants who had evidence of preexisting immunity against the antigens. Failure to induce a strong B cell response may be linked with the low persistence of protective responses.
摘要：
脑膜炎奈瑟氏球菌外膜囊泡(OMV)疫苗是安全的,并且主要通过诱导针对外膜蛋白(OMP)的血清杀菌抗体来提供针对侵袭性脑膜炎球菌病(IMD)的菌株特异性保护。为了设计更广泛的疫苗，需要了解OMV中包含的所有抗原的免疫原性。在一期临床试验中,一种研究性脑膜炎球菌OMV疫苗，MenPFl，由经过遗传修饰的脑膜炎球菌制成，可对OMP中存在的PorA和FetA抗原组成性表达铁调节的FetA诱导的杀菌反应。使用从该试验中收集的外周血单核细胞，我们分析了IgG的动力学和之间的关系，IgA,和IgMB细胞对重组PorA和FetA的反应，包括（i）抗体分泌细胞，(ii)记忆B细胞，和(iii)功能性抗体应答(调理吞噬和杀菌活性)。在MenPF1疫苗接种后，在高达77%的参与者中检测到PorA特异性IgG分泌细胞反应，在高达36%的参与者中检测到FetA特异性反应。记忆B细胞对疫苗的反应较低或不存在，主要在有预先存在免疫证据的参与者中检测到（P=0.0069）。同样，在预先存在免疫力的参与者中，FetA特异性抗体滴度和杀菌活性增加，这与无症状奈瑟菌携带过程中对次要抗原引起免疫反应的观点一致，可以通过OMV疫苗促进。重要性脑膜炎奈瑟菌外膜囊泡（OMV）是B组脑膜炎球菌疫苗4CMenB（Bexsero）的组成部分，已显示可诱导30％的淋球菌感染功效。它们由多种抗原组成，被认为是针对几种细菌疾病的疫苗的有趣递送平台。然而,在使用2或3剂基于OMV的脑膜炎球菌疫苗后,保护性抗体反应似乎是短暂的.我们在临床试验中探索了脑膜炎球菌OMV疫苗中对显性和亚显性抗原诱导的B细胞反应，并表明免疫反应会引起次要抗原。然而,记忆B细胞对OMV的反应较低或不存在,主要在有预先存在针对该抗原的免疫证据的参与者中检测到.诱导强B细胞应答的失败可能与保护性应答的低持久性有关。
