The team, led by Professor Honglin Chen, developed the vaccine by utilising a live attenuated influenza virus (LAIV) vaccine platform – DelNS1 LAIV – which they originally developed in 2018. They first used the DelNS1 LAIV platform, which is designed for the development of influenza vector-based nasal spray vaccines, to guard against COVID-19 in 2020 when the pandemic was at its height. That vaccine was given approval in 2022 after completing three phases of clinical trials and was the first approved COVID-19 vaccine in nasal spray form. For this research, the DelNS1 LAIV platform enabled the scientists, who are from HKU’s State Key Laboratory of Emerging Infectious Diseases and the InnoHK Centre for Virology, Vaccinology and Therapeutics, to undertake the rapid development of the new nasal spray vaccine in collaboration with the Chinese Mainland’s Wantai BioPharm. Two key members of the team, Dr Pui Wang and Dr Shaofeng Deng, explained that while SARS-CoV-2 has gradually evolved into a seasonal respiratory virus, the chances of a similar virus emerging are inevitable – ‘Disease X’ as it is referred to in medical and scientific circles. The team chose to focus on a vaccine specifically for the H5N1 avian influenza virus as it has spawned multiple variants and is viewed as a highly likely candidate for triggering another human pandemic. Asked why they developed the vaccine as a nasal spray, Dr Deng said: “Intranasal vaccines work better than injections because they stop respiratory viruses like influenza right where they enter the body: the nose. While traditional shots mainly induce systemic immunity to fight the virus after infection (reducing severe illness but not blocking initial infection or spread), a nasal spray creates a frontline defence in the nasal mucosa. This triggers ‘mucosal immunity’, producing special antibodies (immunoglobulin A) that act like sticky traps in your nose, neutralising the virus on contact.” On the Nose Needle-free advantage “This not only prevents infection but also slashes the amount of virus you shed, making it far harder to spread to others. Add in the needle-free advantage – no pain or fear, especially helpful for kids and needleaverse groups – and you get a vaccine that blocks transmission and boosts real-world acceptance.” Implications for the vaccine are many, said Dr Wang: “As the findings in the paper demonstrate, our H5N1 DelNS1 LAIV is safe, immunogenic and can fully protect the upper (nasal) and lower respiratory tract (lung) in the two animal models – hamsters and mice – used for testing. Therefore, our vaccine provides good protection and can prevent transmission. “Also, the production yield is high, using an egg and cell culture system, which means the production cost is low and production can be scaled up easily.” Researching mucosal immunity is notoriously challenging, particularly when it comes to the generation of strong and long-lasting mucosal immunity. “We were trying to improve the antigen design to increase the immunogenicity of our vaccine,” said Dr Wang. “Also, due to our unique DelNS1 system, our vaccine can induce a strong innate immune response (interferon response). This serves as a natural adjuvant to strengthen the adaptive immune response. Another challenge with mucosal immunity is the safety issue. But our DelNS1 vaccine is very attenuated and had a very good safety profile in the clinical trials.” Should there be an H5N1 pandemic, the vaccine platform can serve as a valuable, rapid-response tool to be deployed immediately on a large scale if humanto-human transmission of a threat emerges. Dr Pui Wang Key innovations The team have also made significant improvements to the DelNS1-based receptor binding domain (RBD) LAIV vaccine design since the COVID-19 pandemic, Virologists have developed a nasal spray vaccine that is fast and effective against H5N1 in small animal models, and they are now set to start human trials. through two key innovations to enhance viral antigen expression and immunogenicity. “For the antigen design, we have used an immunefocussing approach,” said Dr Wang. “We added a glycosylation site to block the non-neutralising epitopes of the RBD and force the immune system to focus on the important receptor binding motif region. For antigen display, we added a transmembrane domain to the RBD antigen, so that the antigen would be expressed and displayed to the cell surface. This would greatly increase the immune response for the RBD antigen.” While they do not envision using the H5N1 vaccine as a general seasonal vaccine in the same way as annual influenza vaccines are now used, it could be used first as a preventative measure for high-risk groups. “Our vaccine can be used in affected areas, such as farms, for both humans and animals, to control any outbreaks,” said Dr Wang. “Should there be an H5N1 pandemic, the vaccine platform can serve as a valuable, rapid-response tool – leveraging its quick production capability – to be deployed immediately on a large scale if human-to-human transmission of a threat emerges.” For the future, Dr Deng also suggests wider applications. “This DelNS1 vaccine platform isn’t just for flu – it’s a plug-and-play system for respiratory viruses. Our next target is a multivalent vaccine: one spray for broader protection against flu, respiratory syncytial virus and COVID-19 at the same time. And to prepare for potential future pandemics caused by ‘Disease X’.” HKU Bulletin | Nov 2025 Research 18 19
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