NUS Medicine and Monash University Study: Intranasal Vaccine Booster Delivers Stronger Immune Response and Protection Against Sarbecoviruses

Breakthrough in Vaccine Research at NUS Medicine and Monash University

Researchers from the National University of Singapore's Yong Loo Lin School of Medicine (NUS Medicine) and Monash University's Biomedicine Discovery Institute have unveiled a groundbreaking intranasal vaccine booster designed to combat sarbecoviruses, the viral subfamily responsible for outbreaks like SARS-CoV-1 in 2003 and SARS-CoV-2, which caused the COVID-19 pandemic. This collaborative effort highlights the power of international partnerships in higher education institutions driving infectious disease innovation.

The study, published ahead of print in the Journal of Clinical Investigation on January 15, 2026, introduces Clec9A-OMNI, a dendritic cell (DC)-targeting nasal booster that delivers superior systemic and mucosal immunity compared to traditional intramuscular mRNA boosters. Dendritic cells are specialized antigen-presenting cells crucial for kickstarting adaptive immune responses, including the production of antibodies and T cells that fight infections. By fusing a monoclonal antibody specific to Clec9A—a receptor on certain DCs—with receptor-binding domain (RBD) antigens from SARS-CoV-2 Omicron XBB.1.5 (clade 1b) and SARS-CoV-1 (clade 1a), the vaccine ensures broad cross-clade protection.

Understanding Sarbecoviruses and the Need for Pan-Protective Vaccines

Sarbecoviruses belong to the betacoronavirus genus and pose a persistent zoonotic threat due to their ability to jump from animal reservoirs, such as bats, to humans. SARS-CoV-2 variants continue to evolve, evading immunity from existing vaccines, while the potential for novel sarbecoviruses remains high. In Singapore, where NUS Medicine has been at the forefront of COVID-19 research, such threats underscore the urgency for vaccines that provide not just systemic but also mucosal defense at entry points like the nasal passages and lungs.

Current mRNA vaccines like Pfizer-BioNTech's Comirnaty excel at preventing severe disease but wane quickly against infection and transmission. They primarily induce serum immunoglobulin G (IgG) antibodies, with limited secretory immunoglobulin A (IgA) in mucosal surfaces and clade-specific responses confined mostly to SARS-CoV-2 (clade 1b). This gap motivated NUS and Monash researchers to pioneer a booster that addresses these limitations through targeted nasal delivery.

The Science Behind Clec9A-Targeting Technology

The Clec9A platform, co-developed by Monash researchers, leverages a monoclonal antibody to deliver antigens directly to Clec9A-expressing cross-presenting DCs (cDC1 subtype). These cells excel at activating CD8+ T cells for cytotoxic responses and CD4+ T follicular helper (TFH) cells for B cell maturation in germinal centers (GCs). In the Clec9A-OMNI formulation, two constructs—Clec9A-XBB and Clec9A-CoV1—are combined to balance breadth (SARS-CoV-1 for cross-clade) and potency (XBB.1.5 for sustained responses against recent variants).

Adjuvanted with polyinosinic:polycytidylic acid (poly I:C), a toll-like receptor 3 agonist mimicking viral RNA, the vaccine enhances DC activation without the inflammation associated with lipid nanoparticles (LNPs) in mRNA shots. This design allows plug-and-play adaptability for emerging threats, a boon for Singapore's agile biomedical research ecosystem at NUS.

Detailed Methodology: From Priming to Challenge

The study used female BALB/c mice, aged 5-6 weeks, primed intramuscularly with two low doses (0.05 µg each, three weeks apart) of original Comirnaty mRNA to mimic human vaccination waning over three months. Boosters were administered as a single dose: intranasal Clec9A-OMNI (4 µg XBB + 1 µg CoV1 + 25 µg poly I:C per nostril) or intramuscular bivalent Comirnaty (BC, targeting ancestral and BA.4/5).

• Immune monitoring: Serum neutralizing antibodies (nAbs) via surrogate virus neutralization test (sVNT); IgG/IgA via ELISA; antigen-specific antibody-secreting cells (ASCs) and long-lived plasma cells (LLPCs) via ELISPOT; B/T cell phenotyping via flow cytometry and FluoroSPOT.
• Mucosal sampling: Bronchoalveolar lavage fluid (BALF) and nasal lavage fluid (NLF) for IgA/nAbs.
• Challenge: Intranasal 10⁶ PFU SARS-CoV-2 Omicron BA.1 at 1 and 6 months post-boost; viral titers in lungs/nasal turbinates via plaque assay.

This rigorous, longitudinal design (up to 6 months) provides robust evidence in a preclinical model relevant to human upper/lower respiratory infection dynamics.

Superior Immune Responses: Antibodies, T Cells, and Mucosal Defense

Clec9A-OMNI nasal boosting elicited markedly higher cross-clade nAbs against ancestral SARS-CoV-2, XBB.1.5, and SARS-CoV-1, persisting at peak levels through 6 months—unlike BC, which waned rapidly and lacked clade 1a coverage. Triple cross-reactive switched memory B cells (swIg+ binding all three RBDs) were detected in spleen, lung, and nasal-associated lymphoid tissue (NALT).

T cell responses were polyfunctional (IFN-γ, IL-2, TNF-α producing CD4+/CD8+) and resident memory (TRM: CD69+CD103+CD49a+), abundant in lungs/NALT—absent in BC-boosted mice. Persistent TFH (Bcl6+PSGL-1 lo PD-1 hi), GC B cells (GL7+CD38 lo), and bone marrow LLPCs correlated with affinity-matured antibodies. Mucosal IgA ASCs and nAbs dominated BALF/NLF, crucial for blocking viral entry.

Proven Protection: Undetectable Virus Post-Challenge

In SARS-CoV-2 Omicron challenges, nasal Clec9A-OMNI prevented detectable virus in lungs and nasal turbinates at both 1 and 6 months, outperforming BC (significant titers at 6 months). This reflects comprehensive mucosal/systemic barriers: IgA neutralization at portals, TRM-mediated clearance, and systemic nAbs/T cells for spillover protection.

These results position Clec9A-OMNI as a sterilizing immunity candidate, reducing transmission—a key for pandemic control in dense urban settings like Singapore.Read the full study in JCI

Insights from Lead Researchers at NUS and Monash

Assoc Prof Sylvie Alonso, from NUS Medicine's Department of Microbiology and Immunology, emphasized: “While existing vaccines remain highly effective at preventing severe disease, their protection against infection and transmission decreases within months... Our findings suggest that the intranasal Clec9A OMNI vaccine candidate addresses these shortcomings.”

Assoc Prof Mireille Lahoud from Monash added: “Targeting dendritic cells through the Clec9A platform opens a new avenue for vaccine design... highlighting the promise of intranasal booster vaccines in preventing infection at the point of viral entry.”NUS Press Release

This collaboration exemplifies how Singapore's universities like NUS foster global ties, supported by the National Medical Research Council (NMRC) PREPARE platform.

Implications for Singapore's Higher Education and Public Health

At NUS Medicine, this research bolsters Singapore's reputation as a biomedical hub, attracting talent and funding. It aligns with national priorities for pandemic preparedness, potentially reducing booster frequency and aiding vulnerable populations like the elderly.

• Enhanced mucosal immunity for better transmission control in high-density cities.
• Broad sarbecovirus coverage for future threats.
• Scalable, low-cost platform for rapid deployment.

For academics, it opens avenues in DC-targeting and mucosal vaccinology. Explore research jobs at NUS or similar institutions.

NUS Medicine's Role in Infectious Diseases Innovation

NUS Medicine's Infectious Diseases Translational Research Programme has pioneered COVID-19 responses, from early diagnostics to variant surveillance. This study builds on prior nasal vaccine work, positioning Singapore universities as leaders. Collaborations like this with Monash enhance cross-disciplinary training for PhD students and postdocs.

Future Directions: Towards Human Trials and Beyond

Next steps include non-human primate studies and phase 1 human trials to confirm translatability. The platform's versatility could target influenza, RSV, or even non-infectious diseases. Funded by Singapore's NMRC, it promises cost-effective solutions for global health equity.

In higher education, such breakthroughs inspire curricula in vaccinology and immunology at NUS, preparing the next generation. Check career advice for vaccine research roles.

Photo by CDC on Unsplash

Opportunities in Vaccine Research Careers

This study underscores demand for experts in immunology and vaccinology. Singapore universities like NUS offer research positions, fellowships, and postdoc roles. Aspiring researchers can leverage platforms like AcademicJobs.com for university jobs in Singapore. For career guidance, visit postdoc success tips.

Rate professors and courses via Rate My Professor to choose programs in microbiology at NUS.