Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation
Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation
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DOI：
10.1172/jci.insight.136653
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发表时间：
2020-05-21
期刊：
影响因子：
8
通讯作者：
Wheatley, Adam K.
中科院分区：
文献类型：
--
作者：
Kelly, Hannah G.;Tan, Hyon-Xhi;Wheatley, Adam K.
与可溶性蛋白质疫苗相比，基于蛋白质的自组装纳米颗粒引发了上级免疫，但支撑这种效应的免疫机制仍然不清楚。在这里，我们研究了原型铁蛋白为基础的纳米粒子展示流感血凝素（HA）在小鼠和猕猴的免疫原性。与可溶性HA蛋白相比，用HA-铁蛋白纳米颗粒接种小鼠引起更高的血清抗体滴度和更大的对实验性流感攻击的保护。HA-铁蛋白疫苗接种后，引流淋巴结中的生发中心扩大并持续存在，与滤泡树突状细胞共定位的抗原沉积更多。我们的研究结果表明，一个高度有序和重复的抗原阵列可能直接驱动生发中心通过B细胞的内在机制，不依赖于铁蛋白特异性T滤泡辅助细胞。与小鼠相反，在猪尾猕猴中未观察到HA-铁蛋白的免疫原性增强，其中抗体滴度和淋巴结免疫与可溶性疫苗接种相当。对在小型和大型动物模型中驱动纳米颗粒疫苗免疫原性的因素的更好理解将促进纳米颗粒疫苗的临床开发，以针对多种病原体提供广泛和持久的保护。
Protein-based, self-assembling nanoparticles elicit superior immunity compared with soluble protein vaccines, but the immune mechanisms underpinning this effect remain poorly defined. Here, we investigated the immunogenicity of a prototypic ferritin-based nanoparticle displaying influenza hemagglutinin (HA) in mice and macaques. Vaccination of mice with HA-ferritin nanoparticles elicited higher serum antibody titers and greater protection against experimental influenza challenge compared with soluble HA protein. Germinal centers in the draining lymph nodes were expanded and persistent following HA-ferritin vaccination, with greater deposition of antigen that colocalized with follicular dendritic cells. Our findings suggest that a highly ordered and repetitive antigen array may directly drive germinal centers through a B cell-intrinsic mechanism that does not rely on ferritin-specific T follicular helper cells. In contrast to mice, enhanced immunogenicity of HA-ferritin was not observed in pigtail macaques, where antibody titers and lymph node immunity were comparable to soluble vaccination. An improved understanding of factors that drive nanoparticle vaccine immunogenicity in small and large animal models will facilitate the clinical development of nanoparticle vaccines for broad and durable protection against diverse pathogens.