Infectious Diseases Division, University of Rochester, Rochester, New York, USA.
Department of Microbiology & Immunology, University of Rochester, Rochester, New York, USA.
mBio. 2019 Mar 12;10(2):e00066-19. doi: 10.1128/mBio.00066-19.
Although most seasonal inactivated influenza vaccines (IIV) contain neuraminidase (NA), the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Due to the propensity of influenza virus for antigenic drift and shift and its tendency to elicit predominantly strain-specific antibodies, humanity remains susceptible to waves of new strains of seasonal viruses and is at risk from viruses with pandemic potential for which limited or no immunity may exist. Here we demonstrate that the use of IIV results in increased levels of influenza B virus (IBV) NA-specific serum antibodies. Detailed analysis of the IBV NA B cell response indicates concurrent expansion of IBV NA-specific peripheral blood plasmablasts 7 days after IIV immunization which express monoclonal antibodies with broad and potent antiviral activity against both IBV Victoria and Yamagata lineages and prophylactic and therapeutic activity in mice. These IBV NA-specific B cell clonal lineages persisted in CD138 long-lived bone marrow plasma cells. These results represent the first demonstration that IIV-induced NA human antibodies can protect and treat influenza virus infection and suggest that IIV can induce a subset of IBV NA-specific B cells with broad protective potential, a feature that warrants further study for universal influenza vaccine development. Influenza virus infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets such as regions within the influenza neuraminidase protein. We have demonstrated that seasonal immunization stimulates neuraminidase-specific antibodies in humans that are broad and potent in their protection from influenza B virus when tested in mice. These antibodies further persist in the bone marrow, where they are expressed by long-lived antibody-producing cells, referred to here as plasma cells. The significance in our research is the demonstration that seasonal influenza immunization can induce a subset of neuraminidase-specific B cells with broad protective potential, a process that if further studied and enhanced could aid in the development of a universal influenza vaccine.
尽管大多数季节性灭活流感疫苗(IIV)含有神经氨酸酶(NA),但疫苗接种诱导的保护性人 NA 特异性体液反应的程度和作用机制仍不清楚。由于流感病毒具有抗原漂移和转变的倾向,并且倾向于引起主要是株特异性抗体,人类仍然容易受到季节性病毒新株的侵袭,并且存在对有限或不存在免疫力的具有大流行潜力的病毒的风险。在这里,我们证明使用 IIV 会导致流感 B 病毒(IBV)NA 特异性血清抗体水平升高。对 IBV NA B 细胞反应的详细分析表明,在 IIV 免疫接种后 7 天,IBV NA 特异性外周血浆母细胞同时扩增,这些浆母细胞表达具有广泛而强大的抗病毒活性的单克隆抗体,可针对 IBV Victoria 和 Yamagata 谱系,并在小鼠中具有预防和治疗活性。这些 IBV NA 特异性 B 细胞克隆谱系存在于 CD138 长寿骨髓浆细胞中。这些结果代表了第一个证明 IIV 诱导的 NA 人抗体可以保护和治疗流感病毒感染的证明,并表明 IIV 可以诱导具有广泛保护潜力的 IBV NA 特异性 B 细胞亚群,这一特征值得进一步研究,以开发通用流感疫苗。尽管有季节性疫苗,但流感病毒感染仍会导致大量发病率和死亡率。季节性和潜在大流行流感株的广泛遗传变异需要新的疫苗策略,该策略可以通过将免疫反应集中在产生针对流感神经氨酸酶蛋白等保守靶标的保护性抗体上来诱导通用保护。我们已经证明,季节性免疫刺激人类产生针对神经氨酸酶的抗体,这些抗体在小鼠中对流感 B 病毒具有广泛而强大的保护作用。这些抗体进一步在骨髓中持续存在,在骨髓中由长寿的产生抗体的细胞(称为浆细胞)表达。我们研究的意义在于证明季节性流感免疫可以诱导具有广泛保护潜力的神经氨酸酶特异性 B 细胞亚群,进一步研究和增强这一过程可能有助于开发通用流感疫苗。