HMN 2026: How Intranasal vaccine booster shows stronger immune response and protection against sarbecoviruses

Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) and Monash University in Australia have demonstrated that an intranasal vaccine booster may confer significantly stronger and broader immune responses, and provide robust neutralizing antibody and resident T cell responses in the lung and nasal tissues, outperforming conventional mRNA booster vaccination.

Published in The Journal of Clinical Investigation, the study offers a promising and more effective method for delivering vaccine boosters that may offer stronger protection against infections and maintain optimal immunity.

Led by Associate Professor Sylvie Alonso and first author Dr. Nicholas Cheang, both from the Department of Microbiology and Immunology, and Infectious Diseases Translational Research Program at NUS Medicine, the study examined alternative vaccine booster candidates and administration methods that may improve protective immunity and longevity toward sarbecoviruses.

Sarbecoviruses are a category of coronaviruses that can cause respiratory infections, including SARS-CoV-2, the virus responsible for COVID-19, and SARS-CoV-1, responsible for the 2003 SARS outbreak.

Designing the Clec9A^OMNI nasal booster

Leveraging a dendritic cell (DC)-targeting platform that consists of fusing a DC-targeting monoclonal antibody (Clec9A) to a vaccine antigen candidate, the researchers developed Clec9A^OMNI, a dendritic cell-targeting booster vaccine that carries the receptor-binding domain (RBD) from SARS-CoV-2 omicron XBB.1.5 and SARS-CoV-1 viruses.

Dendritic cells are innate immune cells that are essential for initiating adaptive immune responses, which include antibody and T-cell responses. In the study, laboratory models vaccinated with mRNA COVID-19 vaccines three months prior received a single intranasal dose of Clec9A^OMNI. Immune responses were assessed in the blood and respiratory tract for up to six months, alongside efficacy against SARS-CoV-2 omicron infection.

Stronger and longer-lasting immune protection

Compared with intramuscular mRNA booster vaccination, the study found that nasal boosting with Clec9A^OMNI induced significantly stronger neutralizing antibody responses, robust T-cell responses in the lungs and nasal tissues, and sustained immunity for at least six months. Stronger protection against SARS-CoV-2 (omicron) infection was also observed with nasal boosting of Clec9A^OMNI, with undetectable virus in the lung and nasal tissues.

The findings also suggest that Clec9A^OMNI presents potential in addressing the current shortcomings of the current COVID-19 mRNA vaccines, including waning immunity, inadequate mucosal immunity and limited breadth as they do not provide protective coverage against sarbecoviruses beyond the SARS-CoV-2 family.

With Clec9A^OMNI‘s ability to confer broad and long-lasting protective immunity against SARS-CoV-2 variants when tested in the study, there is greater potential to eliminate the need for repeated booster shots and may likely contribute to maintaining the optimal immunity at a population level.

Assoc Prof Alonso said, “While existing vaccines remain highly effective at preventing severe disease, their protection against infection and transmission decreases within months, partly because they generate little immunity at mucosal surfaces such as the nose and lungs.

“Our findings suggest that the intranasal Clec9A^OMNI vaccine candidate addresses these shortcomings. It may also better protect the elderly and other vulnerable groups who are unable to receive conventional intramuscular vaccine administration.”

Clec9A platform and future applications

Currently, most vaccine formulations are largely not optimized for nasal administration, as the harsh mucosal environment can lead to rapid degradation of the vaccine components before effective immune responses are induced. The Clec9A targeting vaccine platform therefore offers a promising solution by ensuring vaccine efficacy and longevity in the respiratory tract.

“Targeting dendritic cells through the Clec9A platform opens a new avenue for vaccine design. By leveraging the role of dendritic cells in orchestrating immune responses, the study highlights the promise of intranasal booster vaccines in preventing infection at the point of viral entry,” noted collaborator Assoc Prof Mireille Lahoud, from the Monash Biomedicine Discovery Institute at Monash University.

Given that the dendritic cell subset targeted by the Clec9A platform is present in humans, the researchers plan to further validate their findings to ensure their relevance to human anatomical structures and immune landscape.

Ultimately, the team aims to apply this approach to other infectious and non-infectious diseases in preparation for future pandemics and health crises, harnessing its ease of deployment and versatility at a low cost.

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