Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: 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.

Figure 1

Trial profile *The 384 Colombian participants without previous SARS-CoV-2 vaccinations who received at least one dose were excluded from the primary efficacy analysis during the blind data review meeting for this trial because the sample size from each site was too small. †An addendum was made to the protocol to permit the enrolment of individuals in Viet Nam who received their last vaccine dose 3–6 months before signing the informed consent because of the ongoing national SARS-CoV-2 vaccine booster campaign, but these participants were not included in the primary efficacy analysis. ‡Eight participants had vaccination errors. Five participants (four with previous SARS-CoV-2 vaccinations and one without) were assigned to the placebo group but received at least one dose of dNS1-RBD, and were included in the vaccine group for the safety analysis; one participant without previous SARS-CoV-2 vaccinations who was assigned to the vaccine group but received two doses of placebo was included in the placebo group for the safety analysis; and two participants with previous SARS-CoV-2 vaccinations who were assigned to the vaccine group but received one dose of placebo and one dose of vaccine were included in the vaccine group for the safety analysis.

Figure 2

Solicited local and systemic adverse reactions that occurred within 7 days after any dose in the safety population* Incidence and severity of local and systemic adverse reactions in participants without a previous SARS-CoV-2 vaccination history (A) and in those with a SARS-CoV-2 vaccination history (B). All adverse reactions were graded according to the China National Medical Products Administration guidelines. *Participants who received at least one dose of vaccine or placebo.

Figure 3

Vaccine efficacy 15 days or more after the second dose in the per-protocol population* and in the modified intention-to-treat population† The vertical line at 30% shows the prespecified vaccine efficacy target. *Participants who received two doses of vaccine or placebo, were followed up for 15 days or longer after the second dose, and had no major protocol deviations. †Participants who received two doses of vaccine or placebo and were followed up for 15 days or longer after the second dose.