Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice

Anneliese S. Ashhurst, Matt D. Johansen, Joshua W. C. Maxwell, Skye Stockdale, Caroline L. Ashley, Anupriya Aggarwal, Rezwan Siddiquee, Stefan Miemczyk, Duc H. Nguyen, Joel P. Mackay, Claudio Counoupas, Scott N. Byrne, Stuart Turville, Megan Steain, James A. Triccas, Philip M. Hansbro, Richard J. Payne () and Warwick J. Britton ()
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Anneliese S. Ashhurst: The University of Sydney
Matt D. Johansen: University of Technology
Joshua W. C. Maxwell: The University of Sydney
Skye Stockdale: The University of Sydney
Caroline L. Ashley: The University of Sydney
Anupriya Aggarwal: Kirby Institute
Rezwan Siddiquee: The University of Sydney
Stefan Miemczyk: University of Technology
Duc H. Nguyen: University of Technology
Joel P. Mackay: The University of Sydney
Claudio Counoupas: The University of Sydney
Scott N. Byrne: The University of Sydney
Stuart Turville: Kirby Institute
Megan Steain: The University of Sydney
James A. Triccas: The University of Sydney
Philip M. Hansbro: University of Technology
Richard J. Payne: The University of Sydney
Warwick J. Britton: The University of Sydney

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam2Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4+ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam2Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.

Date: 2022
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DOI: 10.1038/s41467-022-34297-3

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