Mucosal vaccination against SARS-CoV-2 using recombinant influenza viruses delivering self-assembling nanoparticles

Devaki Pilapitiya; Wen Shi Lee; Mai N Vu; Andrew Kelly; Rosela H Webster; Marios Koutsakos; Stephen J Kent; Jennifer A Juno; Hyon-Xhi Tan; Adam K Wheatley

doi:10.1016/j.vaccine.2024.126668

Mucosal vaccination against SARS-CoV-2 using recombinant influenza viruses delivering self-assembling nanoparticles

Vaccine. 2024 Dec 30:46:126668. doi: 10.1016/j.vaccine.2024.126668. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
² 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.
³ Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia. Electronic address: hxtan@unimelb.edu.au.
⁴ Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia. Electronic address: a.wheatley@unimelb.edu.au.

PMID: 39740385
DOI: 10.1016/j.vaccine.2024.126668

Abstract

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.

Keywords: COVID-19 vaccines; Germinal centres; Memory B cells; Mucosal immunisation; Nanoparticle vaccines; Neutralising antibodies; Recombinant influenza viruses; Respiratory viral infections.