Walters Kathie-Anne, Blatti Charles A, Zhu Ruoqing, Banbury Barbara, Giurgea Luca T, Bean Rachel, Han Eugene, Li Yuhan, Scherler Kelsey, Sherry Jenna, Formentini Sarah, Zhou Wenzhuo, Cervantes-Medina Adriana, Gouzoulis Monica, Rosas Luz Angela, Han Alison, Gatzke Lisa, Bushell Colleen, Sherry Ned, Taubenberger Jeffery K, Memoli Matthew J, Kash John C
Institute for Systems Biology, Seattle, WA 98109, USA.
National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Sci Transl Med. 2025 Aug 6;17(810):eadt1452. doi: 10.1126/scitranslmed.adt1452.
Each year in the United States, ~50% of adults ≥18 years old are vaccinated against influenza viruses, with protective efficacy averaging 40.5% over the past 20 years. To model annual seasonal influenza, a cohort of 74 adults, who were unscreened for preexisting A/H1N1 immunity and half of whom were recently immunized with licensed QIV (mean of 64 days), were challenged with A/H1N1 influenza virus. Transcriptomic, proteomic, and VDJ repertoire analyses were performed on nasal and peripheral blood samples from participants to identify nasal mucosal and systemic immune responses that correlated with viral shedding and immune correlates of protection. Viral-shedding participants showed increased T cell, but not B cell, VDJ diversity with expansion of low-frequency B cell clones postchallenge, including broadly neutralizing motifs. Nonshedding participants demonstrated decreased clonality and increased richness of B and T cell VDJ clones, increased preinoculation nasal mucosal immune gene and serum protein expression, and increased ex vivo peripheral blood mononuclear cell responses. Nasal mucosal responses in participants shedding virus for 2 or more days showed higher early viral loads and exhibited stronger induction of antiviral responses compared with those in participants who shed virus for 1 day. Last, participants with a single day of viral shedding were three times more likely to be female. These data shed light on the complex immune responses in the nasal mucosa and the periphery after influenza vaccination and infection, which will be critical for next-generation vaccine development.
在美国，每年约50%的18岁及以上成年人接种流感病毒疫苗，过去20年的保护效力平均为40.5%。为了模拟年度季节性流感，一组74名成年人（未筛查是否存在预先存在的甲型H1N1免疫力，其中一半最近接种了许可的四价流感病毒裂解疫苗[平均64天]）受到甲型H1N1流感病毒攻击。对参与者的鼻腔和外周血样本进行转录组学、蛋白质组学和VDJ库分析，以确定与病毒脱落及保护免疫相关指标相关的鼻黏膜和全身免疫反应。病毒脱落的参与者显示T细胞而非B细胞的VDJ多样性增加，攻击后低频B细胞克隆扩增，包括广泛中和基序。未出现病毒脱落的参与者表现出B细胞和T细胞VDJ克隆的克隆性降低和丰富度增加、接种前鼻黏膜免疫基因和血清蛋白表达增加，以及体外外周血单个核细胞反应增强。与病毒脱落1天的参与者相比，病毒脱落2天或更长时间的参与者的鼻黏膜反应显示出更高的早期病毒载量，并表现出更强的抗病毒反应诱导。最后，病毒仅脱落一天的参与者为女性的可能性是其他人的三倍。这些数据揭示了流感疫苗接种和感染后鼻黏膜和外周的复杂免疫反应，这对下一代疫苗开发至关重要。
