A Phase 1, Randomized, Double-Blinded, Placebo-Controlled and Dose-Escalation Study to Evaluate the Safety and Immunogenicity of the Intranasal Delns1-nCoV-RBD LAIV for COVID-19 in Healthy Adults

Abstract

Background: An intranasal vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. 

Methods: We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March to September 2021. Participants were enrolled and randomly assigned (2:2:1) into the low and high dose DelNS1-nCoV-RBD LAIV manufactured in chicken embryonated eggs or placebo groups. The low and high-dose vaccine composed of 1x 10⁷ EID₅₀/ dose and 1x 10^7.7 EID₅₀ / dose in 0.2mL respectively. The placebo vaccine composed of inert excipients/dose in 0.2mL. Recruited participants were administered the vaccine intranasally on day 0 and day 28. The primary end-point was the safety of the vaccine. The secondary endpoints included cellular, humoral and mucosal immune responses post-vaccination at pre-specified time-points. The cellular response was measured by T-cell ELISpot assay. The humoral response was measured by the serum anti-RBD IgG and live-virus neutralizing antibody against SARS-CoV-2. The saliva total Ig antibody responses in mucosal secretion against SARS-CoV-2 RBD was also assessed. 

Findings Twenty-nine healthy Chinese participants were vaccinated (low-dose: 11; high-dose: 12 and placebo: 6). The median age was 26 years. Twenty participants (69%) were male. No participant was discontinued due to an adverse event or COVID-19 infection during the clinical trial. There was no significant difference in the incidence adverse events (p=0.620). The T-cell response was higher in the high-dose than the placebo group on day 14 and day 42 (day 14: 15 vs. 0 SFU/10^6 PBMC; p=0.17 and day 42: 12.5 vs. 5 SFU/10^6 PBMC; p=0.18) but no difference on day 7 and day 35. The total saliva mucosal Ig of the high-dose group was significantly higher than the placebo group (4 days after the second vaccination) (p=0.046) but no difference on day 3 and day 56. There was no difference in T-cell and saliva Ig response between the low-dose and placebo groups. The serum anti-RBD IgG and live virus neutralizing antibody against SARS-CoV-2 were undetectable in all samples. 

Interpretation: The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with significant mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted. 

Trial Registration Details: This trial was registered at the clinicaltrial.gov (NCT04809389).

Funding Information: This study was partly supported by the Health and Medical Research Fund (Project no.: COVID190123), Hong Kong Special Administrative Region, China and the Coalition for Epidemic Preparedness Innovations (CEPI).

Declaration of Interests: We declare that we have no conflicts of interest.

Ethics Approval Statement: The trial protocol was reviewed and approved by the Hong Kong Department of Health and the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 21- 054). The study was conducted in compliance with the Declaration 118 of Helsinki and ICH Guideline for Good Clinical Practice.

Keywords: Phase-1, intranasal, DelNS1-nCoV-RBD LAIV, COVID-19