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.

An intranasal COVID-19 vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March and 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 were composed of 1 × 107 EID50/ dose and 1 × 107.7 EID50/ dose in 0.2 mL respectively. The placebo vaccine was composed of inert excipients/dose in 0.2 mL. 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 the 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. 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 of adverse events (p = 0.620). For the T-cell response elicited after full vaccination, the positive PBMC in the high-dose group increased to 12.5 SFU/106 PMBC (day 42) from 0 (baseline), while it increased to 5 SFU/106 PBMC (day 42) from 2.5 SFU/106 PBMC (baseline) in the placebo group. The high-dose group showed a slightly higher level of mucosal Ig than the control group after receiving two doses of the vaccine (day 31, 0.24 vs. 0.21, p = 0.046; day 56 0.31 vs. 0.15, p = 0.45). There was no difference in the 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. The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with moderate mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted.

Live-attenuated influenza vaccine effectiveness against hospitalization in children aged 2-6 years, the first three seasons of the childhood influenza vaccination program in England, 2013/14-2015/16.

INTRODUCTION: In 2013, the United Kingdom began to roll-out a universal annual influenza vaccination program for children. An important component of any new vaccination program is measuring its effectiveness. Live-attenuated influenza vaccines (LAIVs) have since shown mixed results with vaccine effectiveness (VE) varying across seasons and countries elsewhere. This study aims to assess the effectiveness of influenza vaccination in children against severe disease during the first three seasons of the LAIV program in England. METHODS: Using the screening method, LAIV vaccination coverage in children hospitalized with laboratory-confirmed influenza infection was compared with vaccination coverage in 2-6-year-olds in the general population to estimate VE in 2013/14-2015/16. RESULTS: The overall LAIV VE, adjusted for age group, week/month and geographical area, for all influenza types pooled over the three influenza seasons was 50.1% (95% confidence interval [CI] 31.2, 63.8). By age, there was evidence of protection against hospitalization from influenza vaccination in both the pre-school (2-4-year-olds) (48.1%, 95% CI 27.2, 63.1) and school-aged children (5-6-year-olds) (62.6%, 95% CI 2.6, 85.6) over the three seasons. CONCLUSION: LAIV vaccination in children provided moderate annual protection against laboratory-confirmed influenza-related hospitalization in England over the three influenza seasons. This study contributes further to the limited literature to date on influenza VE against severe disease in children.

Sequential Delivery of Live Attenuated Influenza Vaccine and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the Ferret Model Can Reduce SARS-CoV-2 Shedding and Does Not Result in Enhanced Lung Pathology.

Cocirculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses could pose unpredictable risks to health systems globally, with recent studies suggesting more severe disease outcomes in coinfected patients. The initial lack of a readily available coronavirus disease 2019 (COVID-19) vaccine has reinforced the importance of influenza vaccine programs during the COVID-19 pandemic. Live attenuated influenza vaccine (LAIV) is an important tool in protecting against influenza, particularly in children. However, it is unknown whether LAIV administration influences the outcomes of acute SARS-CoV-2 infection or disease. To investigate this, quadrivalent LAIV was administered to ferrets 3 days before or after SARS-CoV-2 infection. LAIV administration did not exacerbate the SARS-CoV-2 disease course or lung pathology with either regimen. In addition, LAIV administered before SARS-CoV-2 infection significantly reduced SARS-CoV-2 replication and shedding in the upper respiratory tract. This study demonstrated that LAIV administration in close proximity to SARS-CoV-2 infection does not exacerbate mild disease and can reduce SARS-CoV-2 shedding.

Demonstrating the capacity of the National Advisory Committee on Immunization for timely responses to post-market vaccine monitoring signals: Canada's experience with the live-attenuated influenza vaccine.

Over the last several years, the recommended use of the live-attenuated influenza vaccine (LAIV) for children has evolved in the United States (US) in response to evidence of a potential decrease in LAIV effectiveness based on post-market monitoring. These issues were not observed in Canada or elsewhere; consequently, recommendations from Canada's National Advisory Committee on Immunization (NACI) and the US Advisory Committee on Immunization Practices (ACIP) on whether to use LAIV differed for two influenza seasons (2016-2017 and 2017-2018). This retrospective describes how NACI arrived at its recommendations in response to post-market signals of reduced LAIV performance from the US in 2013-2014 and again in 2015-2016. NACI's experience with LAIV marks the first time in Canada where a preferential recommendation on the use of an influenza vaccine in a routine immunization program was reversed. This experience highlights the importance of ongoing post-market monitoring of vaccines, international collaboration and careful consideration of local context to inform vaccine recommendations. NACI's capacity for timely responses to post-market vaccine performance signals will facilitate responsiveness to similar post-market monitoring signals from the coronavirus disease 2019 (COVID-19) vaccines.

A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults.

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.