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Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16–65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4–91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities. [ABSTRACT FROM AUTHOR]

The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18–59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4–46·6), with a median follow-up duration of 161 days. Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University. [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. 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. [ABSTRACT FROM AUTHOR]