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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI195784

Intranasal DC-targeting vaccine booster elicits durable and cross-clade protective immunity against sarbecoviruses in mice

You Zhi Nicholas CHEANG,1 Wee Chee Yap,1 Kirsteen M. TULLETT,2 Xinlei QIAN,3 Peck S. TAN,2 Kiren PURUSHOTORMAN,3 Wan Yi TAN,1 Yun Yan MAH,1 Paul MACARY,3 Chee Wah TAN,1 Mireille H. LAHOUD,5 and Sylvie ALONSO1

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by CHEANG, Y. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by Yap, W. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by TULLETT, K. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by QIAN, X. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by TAN, P. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by PURUSHOTORMAN, K. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by TAN, W. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by MAH, Y. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by MACARY, P. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by TAN, C. in: PubMed | Google Scholar |

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by LAHOUD, M. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore

2Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Brisbane, Australia

3Immunology Programme, National University of Singapore, Singapore, Singapore

4Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash Univeristy, Melbourne, Australia

5Monash Biomedicine Discovery Institute & Department of Biochemistry and Mol, Monash University, Melbourne, United Kingdom

Find articles by ALONSO, S. in: PubMed | Google Scholar

Published January 15, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI195784.
Copyright © 2026, CHEANG et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 15, 2026 - Version history
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Abstract

Short-lived, clade-specific immune responses with limited mucosal priming are limitations faced by current COVID-19 mRNA vaccines. We have developed a nasal booster vaccine candidate that induced robust, sustained, cross-clade, systemic and mucosal protective immunity. Two recombinant Clec9A-specific monoclonal antibodies fused to the Receptor Binding Domain (RBD) from Omicron XBB.1.5 and SARS-CoV-1, respectively were generated. In Comirnaty mRNA-vaccinated mice, boosting with both constructs combined (Clec9AOMNI) induced cross-clade neutralizing antibodies (nAbs) and T-cell responses that were greater in magnitude and more sustained compared to bivalent Comirnaty (BC) mRNA vaccine booster. Persistence of RBD-specific follicular helper CD4+ T cells, germinal centre B cells, and long-lived plasma cells that facilitated affinity maturation, correlated with detection of triple cross-reactive B cells binding the RBDs of SARS-CoV-2 ancestral, XBB.1.5, and SARS-CoV-1. Remarkably, intranasal boosting with Clec9AOMNI elicited robust and durable immunity across the upper and lower airways while concurrently boosting the systemic immunity to levels matching or exceeding those from systemic boosting. Correspondingly, Clec9AOMNI nasal booster conferred superior protection against SARS-CoV-2 challenge compared to BC mRNA booster, with undetectable viral titers in the respiratory tract. Hence, Clec9AOMNI is a promising nasal booster vaccine candidate that has the potential to mitigate pandemic threats from emerging sarbecoviruses.

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