Mechanisms of superior respiratory IgA responses against SARS-CoV-2 after mucosal vaccination
Year: 2025
Type: preprint
Abstract: Summary Mucosal immunization and respiratory IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. It is also currently debatable whether mucosal vaccination is still warranted given that most individuals in developed countries have established a hybrid immunity from vaccination and infection. Here we characterized respiratory mucosal immune responses after SARS-CoV-2 infection, vaccination or both in humans. We found that hybrid immunity resulted in moderately increased respiratory IgA and neutralizing antibody responses compared to infection or vaccination alone. However, a direct comparison of hybrid immunity and a mucosal adenovirus-based booster vaccination in animal models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we found that mucosal booster immunization induced local IgA- secreting cells in the respiratory mucosa, aided by pulmonary CD4 + T cells in situ . Strikingly, local IL-21-producing Blimp-1 + Th1 effector cells were critical in mediating the CD4 + T cell help for respiratory IgA production. Furthermore, lung macrophages were important for this respiratory IgA response via the production of TGF-β. Consequently, we demonstrated delivery of adenoviral booster to the lower airway was necessary to generate robust upper and lower airway IgA responses. Collectively, our results uncover a local cellular network supporting enhanced respiratory IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens.
Authors: Jinyi Tang, Arka Sen Chaudhuri, Panke Qu, Pei Li, Yajie Liu, Yue Wu, Kristin Wavell, MarthaJoy M. Spano, In Su Cheon, Chaofan Li, Jane Yu, Harish Narasimhan, Mohd Arish, Wei Qian, Gislane de Almeida Santos, Samuel P. Young, Anika Agarwal, Fangming Zhu, Takao Kobayashi, Maria Velegraki, Mark H. Kaplan, Justin J. Taylor, Guizhi Zhu, Haitao Hu, Zihai Li, Hui Hu, Hirohito Kita, Nu Zhang, Shan-Lu Liu, W. Gerald Teague, Jie Sun
Institutions: University of Virginia, The Ohio State University, University of Alabama at Birmingham, Mayo Clinic in Arizona, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Pelotonia, Indiana University Indianapolis, Indiana University School of Medicine, University of Michigan, The University of Texas Medical Branch at Galveston, The University of Texas at San Antonio Health Science Center, South Texas Veterans Health Care System
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Center for Serological Testing to Improve Outcomes from Pandemic COVID-19 (STOP-COVID), Roles of tissue-resident helper T cells in mucosal immunity against influenzainfection, Molecular regulation of protective CD8 immunity against influenza infection, Immune-epithelial progenitor interactions drive age-associated dysplastic lung repair post viral pneumonia, Sony MA900 Cell Sorter, G9000057425, G9000133990, G9000140724, G9000182982, G9000267656, G9000313051, Uncover mechanisms underlying the development of chronic lung sequelae post COVID-19, Determinants of Convalescent and Vaccine-induced Mucosal Specific Immunity to SARS-CoV-2 and Variants of Concern in Children with Asthma, Host cellular network governing the development of post SARS-CoV-2 tissue sequelae, Cancer Research Training Program: From Molecular Mechanisms to Therapeutic Strategies, Elucidating the roles of alveolar macrophage inflammation and self renewal during influenza infection
OpenAlex ID: W4414413871