Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

BACKGROUND: All currently available SARS-CoV-2 vaccines are administered by intramuscular injection. We aimed to evaluate the safety and immunogenicity of a live-attenuated influenza virus vector-based SARS-CoV-2 vaccine (dNS1-RBD) administered by intranasal spray in healthy adults. METHODS: We did double-blind, randomised, placebo-controlled phase 1 and 2 trials, followed by a phase 2 extension trial, at a single centre in Jiangsu, China. Healthy adults (≥18 years) who had negative serum or fingertip blood total antibody tests for SARS-CoV-2 (in phases 1 and 2), with no prevalent SARS-CoV-2 infection or history of infection and no SARS-CoV-2 vaccination history (in all three trials reported here), were enrolled. Participants were randomly allocated (4:1 in phase 1, 2:1 in phase 2, and 1:1 in the extension trial) to receive two intranasal doses of the dNS1-RBD vaccine or placebo on days 0 and 14 or, for half of the participants in phase 2, on days 0 and 21. To avoid cross-contamination during administration, vaccine and placebo recipients were vaccinated in separate rooms in the extension trial. The phase 1 primary outcome was safety (adverse events recorded on days 0-44; serious adverse events recorded from day 0 until 12 months after the second dose). In the phase 2 and extension trials, the primary immunogenicity outcomes were SARS-CoV-2-specific T-cell response in peripheral blood (measured by IFN-γ ELISpot), proportion of participants with positive conversion for SARS-CoV-2 receptor-binding domain (RBD)-specific IgG and secretory IgA (s-IgA) antibodies, and concentration of SARS-CoV-2 RBD IgG in serum and SARS-CoV-2 RBD s-IgA in the nasopharynx (measured by ELISA) at 1 month after the second dose in the per-protocol set for immunogenicity. χ2 test and Fisher's exact test were used to analyse categorical data, and t test and Wilcoxon rank sum test to compare the measurement data between groups. These trials were registered with the Chinese Clinical Trial Registry (ChiCTR2000037782, ChiCTR2000039715, and ChiCTR2100048316). FINDINGS: Between Sept 1, 2020, and July 4, 2021, 63, 724, and 297 participants without a history of SARS-CoV-2 vaccination were enrolled in the phase 1, phase 2, and extension trials, respectively. At least one adverse reaction after vaccination was reported in 133 (19%) of 684 participants in the vaccine groups. Most adverse reactions were mild. No vaccine-related serious adverse event was noted. Specific T-cell immune responses were observed in 211 (46% [95% CI 42-51]) of 455 vaccine recipients in the phase 2 trial, and in 48 (40% [31-49]) of 120 vaccine recipients compared with one (1% [0-5]) of 111 placebo recipients (p<0·0001) in the extension trial. Seroconversion for RBD-specific IgG was observed in 48 (10% [95% CI 8-13]) of 466 vaccine recipients in the phase 2 trial (geometric mean titre [GMT] 3·8 [95% CI 3·4-4·3] in responders), and in 31 (22% [15-29]) of 143 vaccine recipients (GMT 4·4 [3·3-5·8]) and zero (0% [0-2]) of 147 placebo recipients (p<0·0001) in the extension trial. 57 (12% [95% CI 9-16]) of 466 vaccine recipients had positive conversion for RBD-specific s-IgA (GMT 3·8 [95% CI 3·5-4·1] in responders) in the phase 2 trial, as did 18 (13% [8-19]) of 143 vaccine recipients (GMT 5·2 [4·0-6·8]) and zero (0% [0-2]) of 147 placebo recipients (p<0·0001) in the extension trial. INTERPRETATION: dNS1-RBD was well tolerated in adults. Weak T-cell immunity in peripheral blood, as well as weak humoral and mucosal immune responses against SARS-CoV-2, were detected in vaccine recipients. Further studies are warranted to verify the safety and efficacy of intranasal vaccines as a potential supplement to current intramuscular SARS-CoV-2 vaccine pools. Steps should be taken in future studies to reduce the potential for cross-contamination caused by the vaccine strain aerosol during administration. FUNDING: National Key Research and Development Program of China, National Science, Fujian Provincial Science, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai Biological Pharmacy Enterprise.

Effectiveness Evaluation of a Primary School-Based Intervention against Heatwaves in China.

BACKGROUND: Evidence of the effectiveness of intervention against extreme heat remains unclear, especially among children, one of the vulnerable populations. This study aimed to evaluate the effectiveness of a primary school-based intervention program against heatwave and climate change in China to provide evidence for development of policies for adaptation to climate change. METHODS: Two primary schools in Dongtai City, Jiangsu Province, China, were randomly selected as intervention and control schools (CTR registration number: ChiCTR2200056005). Health education was conducted at the intervention school to raise students' awareness and capability to respond to extreme heat during May to September in 2017. Knowledge, attitude, and practice (KAP) of students and their parents at both schools were investigated by questionnaire surveys before and after intervention. The changes in KAP scores after intervention were evaluated using multivariable difference-in-difference (DID) analysis, controlling for age, sex, etc. Results: The scores of knowledge, attitude, and practice of students and their parents increased by 19.9% (95%CI: 16.3%, 23.6%) and 22.5% (95%CI: 17.8%, 27.1%); 9.60% (95%CI: 5.35%, 13.9%) and 7.22% (95%CI: 0.96%, 13.5%); and 9.94% (95%CI: 8.26%, 18.3%) and 5.22% (95%CI: 0.73%, 9.71%), respectively, after intervention. The KAP score changes of boys were slightly higher than those of girls. Older students had higher score changes than younger students. For parents, the higher the education level, the greater the score change, and change in scores was greater in females than in males. All the health education activities in the program were significantly correlated with the changes in KAP scores of primary school students after intervention, especially those curricula with interesting activities and experiential learning approaches. CONCLUSIONS: Heat and health education program in primary school was an effective approach to improve cognition and behavior for both students and their parents to better adapt to heatwaves and climate change. The successful experience can be generalized to respond to the increasing extreme weather/climate events in the context of climate change, such as heatwaves, and other emergent occasions or public health education, such as the control and prevention of COVID-19.