Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination in mouse models

EBioMedicine. 2022 Jan;75:103762. doi: 10.1016/j.ebiom.2021.103762. Epub 2021 Dec 21.


Background: Vaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal.

Methods: Since mucosal immunity is critical for nasal prevention, we investigated the efficacy of an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2.

Findings: Substantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity.

Interpretation: Our results demonstrated that intranasal influenza-based boost vaccination induces mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems.

Funding: This study was supported by the Research Grants Council Collaborative Research Fund, General Research Fund and Health and Medical Research Fund in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program and matching fund from Shenzhen Immuno Cure BioTech Limited; the Health@InnoHK, Innovation and Technology Commission of Hong Kong; National Program on Key Research Project of China; donations from the Friends of Hope Education Fund; the Theme-Based Research Scheme.

Keywords: Live-attenuated influenza-based vaccine; Mucosal immunity; Nasal prevention; PD1-based DNA vaccine; Receptor binding domain; SARS-CoV-2.

MeSH terms

  • Administration, Intranasal
  • Animals
  • COVID-19 / genetics
  • COVID-19 / immunology
  • COVID-19 / prevention & control*
  • COVID-19 Vaccines* / genetics
  • COVID-19 Vaccines* / immunology
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Dogs
  • Female
  • HEK293 Cells
  • Humans
  • Immunity, Mucosal
  • Immunization, Secondary*
  • Influenza Vaccines* / genetics
  • Influenza Vaccines* / immunology
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / immunology
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / immunology
  • Vaccines, DNA* / genetics
  • Vaccines, DNA* / immunology
  • Vero Cells


  • COVID-19 Vaccines
  • Influenza Vaccines
  • Vaccines, Attenuated
  • Vaccines, DNA