Pilapitiya Devaki, Lee Wen Shi, Vu Mai N, Kelly Andrew, Webster Rosela H, Koutsakos Marios, Kent Stephen J, Juno Jennifer A, Tan Hyon-Xhi, Wheatley Adam K
Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia; Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Vaccine. 2025 Feb 6;46:126668. doi: 10.1016/j.vaccine.2024.126668. Epub 2024 Dec 30.
Recombinant influenza viruses are promising vectors that can bolster antibody and resident lymphocyte responses within mucosal sites. This study evaluates recombinant influenza viruses with SARS-CoV-2 RBD genes in eliciting mucosal and systemic responses. Using reverse genetics, we generated replication-competent recombinant influenza viruses carrying heterologous RBD genes in monomeric, trimeric, or ferritin-based nanoparticle forms. Following intranasal immunisation, mice developed potent serological anti-RBD responses, with ferritin nanoparticles superseding monomeric or trimeric RBD responses. While parenteral and mucosal immunisation elicited robust anti-RBD IgG in serum, mucosal immunisation seeded respiratory IgA, RBD-specific lung-resident memory and germinal centre (GC) B cells. In animals with prior intramuscular vaccination, intranasal boosting with recombinant influenza vectors augmented mucosal IgG, IgA, GC and memory B cells, and SARS-CoV-2 lung neutralising titres. Recall of RBD-specific memory B cells via antigen re-exposure in the lung increased antibody-secreting cells in the lung-draining lymph nodes, with maintenance of lung GC B cells. Recombinant influenza-based vaccines effectively deliver highly immunogenic self-assembling nanoparticles, generating antibodies and B cells in the respiratory mucosa. This strategy provides a tractable pathway to augment lung-localised responses against recurrent respiratory viral infections.
重组流感病毒是很有前景的载体，能够增强黏膜部位的抗体和驻留淋巴细胞反应。本研究评估携带严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体结合域（RBD）基因的重组流感病毒引发黏膜和全身反应的能力。利用反向遗传学技术，我们构建了具有复制能力的重组流感病毒，这些病毒携带单体、三聚体或基于铁蛋白的纳米颗粒形式的异源RBD基因。经鼻内免疫后，小鼠产生了强效的血清学抗RBD反应，其中铁蛋白纳米颗粒的反应超过了单体或三聚体RBD的反应。虽然肠胃外免疫和黏膜免疫均在血清中引发了强烈的抗RBD IgG反应，但黏膜免疫产生了呼吸道IgA、RBD特异性肺驻留记忆细胞和生发中心（GC）B细胞。在先前接受过肌肉注射疫苗的动物中，用重组流感病毒载体进行鼻内加强免疫可增强黏膜IgG、IgA、GC和记忆B细胞，以及SARS-CoV-2肺部中和效价。通过在肺部再次接触抗原激活RBD特异性记忆B细胞，增加了引流肺淋巴结中的抗体分泌细胞，并维持了肺部GC B细胞。基于重组流感病毒的疫苗能有效递送高度免疫原性的自组装纳米颗粒，在呼吸道黏膜中产生抗体和B细胞。这一策略为增强针对复发性呼吸道病毒感染的肺部局部反应提供了一条可行途径。
