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Sources of information:

• Professor Yuen Kwok-yung, Chair professor of Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong
• Professor Chen Honglin, Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong
• HKU Clinical Trials Centre

Introduction:
The intranasal vaccine is a TEAM effort. The Department of Microbiology at the Li Ka Shing Faculty of Medicine innovated and made the seed. The research team is led by Professor Honglin Chen, along with team members Professor Zhiwei Chen, Professor Ivan Hung, Professor Yiwu He and Professor Yuen Kwok-yung. The Mainland vaccine factory manufactured and packaged it. The HKU/QMH Clinical Trials Centre led by Mr. Henry Yau will conduct the trial. Professor Ivan Hung will assess the patients. The antibody test and immune testing will be done in our HKU microbiology laboratory.

Question: How to come up with the idea of a nasal spray, instead of the traditional injection method for the vaccine?
Answer:

• The research project originally started off to try to solve the seasonal influenza problem.
• Most people do not like yearly injection of influenza vaccine. There is only one intranasal flu live attenuated vaccine which cannot be used in very young, elderly, immunosuppressed, pregnant and those with underlying medical illness such as asthma and other airway disease. This is because this presently used intranasal vaccine still contain the virulence gene called NS1 and theoretically can multiply and invade inside our body.
• We knock out the NS1 gene segment so that the virus can only multiply for one round inside the cells at the upper airway (nasopharynx) which is at a lower temperature after intranasal spray. Therefore, it cannot multiply even for one round in the lungs and will not disseminate inside the body.
• Also, NS1 produces a protein that antagonize the host interferon response and may induce inflammation.
• However, we also realize that there is an empty space remaining after knocking out/taking away the NS1. Then we try putting into this empty space the gene of the surface SPIKE protein receptor binding domain (RBD) of COVID-19 (or MERS-Coronavirus) or any other viruses. This makes our concept a SAFE MUCOSAL VACCINE PLATFORM which can be used for many other purposes.
• The research began three to four years ago.

Question: What is the mechanism behind this intranasal vaccine?
Answer: This is both a live attenuated (NOT inactivated) and replication defective but highly antigenic nasopharyngeal mucosal vaccine (one round of replication in infected cell which will not further disseminate) NS1 supports virus replication and antagonizes host immune response. Without NS1, influenza virus cannot replicate. With the patented adaptive mutations we discovered, DelNS1 LAIV can replicate in eggs or vaccine producing MDCK cells. Weakened DelNS1 LAIV can only replicate one cycle in airway cells. The empty space in the NS1 gene can be used to express surface protein (such as RBD) of SARS-CoV2 or antigen of other viruses.

Question: What are the key advantages of nasal vaccine?
Answer: Immunization via muscle injection will induce systematic immune response but it is not clear how much immunity will reach the respiratory tract, especially the upper respiratory tract. Nasal spray vaccine is designated more specially to induce immunity in the airway. Animal experiments also show it can induce systematic immunity as other vaccines. It can be used in combination with other vaccines to boost immunity in the airway, if the original immunity diminishes after a period of time of vaccination. Our DelNS1 nasal can be used multiple times through change of HA and NA. Other vaccines such as adenoviral vector cannot be used repeatedly. 

Question: What improvements still needed to be made on nasal vaccines?
Answer: We are continuing to improve this nasal spray vaccine platform for more immunogenicity and make it easier to manufacture. We are also making vaccine to target emerging variants. More importantly, we have made bivalent vaccines which can be used for flu and COVID-19 in one dose.

Question: Is it effective against SARS-CoV-2 variants and to what extent?
Answer: We can easily change the SPIKE RBD gene to defend against whatever antigenic changes if this happens. In the meantime, we still do not know how efficacious is our first-generation vaccine against these virus variants.

Question: How to carry out the clinical trials?
Answer: After finishing the phase 1 clinical trial in HKSAR with chicken embryo production in Chang Chun BK, the data will be reviewed and published in journal. Then we would go for the phase 2 clinical trial. Note that we already know that our vaccine produced with cell culture by Wantai is safe in clinical trial performed by Xiamen University. All these would take time and will depend on the safety and immunogenicity data before we would conduct a large-scale phase 3 clinical trial in areas with continuing epidemic. Therefore, we cannot be dogmatic about the timing.

Question: What are the major difficulties encountered?
Answer: We need to have investor funding first. But most HK investor do not like to take risk. Our vaccine has been in the laboratory for 3 to 4 years, but there is not enough funding to go forward until the emergence of COVID-19. After that, the biggest difficulty is the absence of vaccine production plant in HKSAR. It finally has to be manufactured in collaboration with Xiamen University, Wantai and Chang Chun BK corporations. Same as mRNA vaccine, there are more investors during the pandemic. Nasal delivery of vaccine is being actively explored right now for the response in the next stage of the pandemic.

Question: Why take such a rather long time to start the phase 1 clinical trial in HK?
Answer: There is no clear approval mechanism or precedence for the exportation of an HKSAR produced vaccine seed which is expanded and manufactured in Mainland vaccine plants. Therefore, it will take time and effort. We are grateful to Mr. Matthew Cheung, the Chief Secretary of HKSAR government who spent time to clarify and facilitate this process and finally got the vaccine to HKSAR for phase 1 clinical trial.

Question: Which group/groups of people are suitable to take the HKU vaccine?
Answer: This is too early to say till phase 3 clinical trial is successfully completed. But besides allergy to vaccine protein and components, there should be little contraindications as the NS1 virulence gene is absent.

Question: Any side effects expected?
Answer: Should be very few such as allergy.

Question: What is the production cost and the price for the vaccine?
Answer: It depends on the market volume. The price and production cost will markedly decrease with mass production.

Question: What is the time schedule for conducting the phase 1 clinical trial in HK?
Answer:

• The phase 1 clinical trial is conducted by the HKU Clinical Trials Centre 
• This is a phase 1 trial which consists of 2 parts. Part 1 is for dose identification and will involve 30 volunteers. Part 2 is an expansion study and will involve 85 volunteers at the dose level identified from Part 1.
• Part 1 has started in March. The main stage will last for about 6 months. The volunteers will however need to come back 12 months after the first vaccination to follow up on their immune responses.
• Part 2 will start in July. Again, the main stage will last for about 6 months, with an immune responses follow up in 12 months from first vaccination.
• The phase 1 trial is supported by CEPI’s funding of US$4.89 million and the Health and Medical Research Fund (HMRF) grant. Phase 2 trial has not been planned yet and separate funding will be required. We would need further funding from CEPI for phase 2 and 3 , hopefully also from investors when phase 1 data are promising.

Question: What diseases work best with nasal vaccine?
Answer: Respiratory tract infections caused by viruses, or bacteria. The DelNS1 LAIV can also be used as a adjuvant with other vaccines, because it lacks the NS1 and is able to induce optimal immune response. We are exploring the application of this platform for other chronic diseases, including cancers. While it can be used for nasal spray, it can also be used via injection. 

(Updated on April 13, 2021)