Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials.

This interim analysis of 2 randomized trials compares adverse reactions and neutralizing antibody responses to inactivated coronavirus disease 2019 (COVID-19) vs adjuvant-only control vaccination, and compares the outcomes at varying vaccine doses among healthy adults in China. Question What are the safety and immunogenicity of an inactivated vaccine against coronavirus disease 2019 (COVID-19)? Findings This was an interim analysis of 2 randomized placebo-controlled trials. In 96 healthy adults in a phase 1 trial of patients randomized to aluminum hydroxide (alum) only and low, medium, and high vaccine doses on days 0, 28, and 56, 7-day adverse reactions occurred in 12.5%, 20.8%, 16.7%, and 25.0%, respectively; geometric mean titers of neutralizing antibodies at day 14 after the third injection were 316, 206 and 297 in the low-, medium-, and high-dose groups, respectively. In 224 healthy adults randomized to the medium dose, 7-day adverse reactions occurred in 6.0% and 14.3% of the participants who received injections on days 0 and 14 vs alum only, and 19.0% and 17.9% who received injections on days 0 and 21 vs alum only, respectively; geometric mean titers of neutralizing antibodies in the vaccine groups at day 14 after the second injection were 121 vs 247, respectively. Meaning This inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy will require phase 3 trials. Importance A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. Objective To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China. Interventions In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 mu g/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 mu g/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]). Design, Setting, and Participants Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020. Main Outcomes and Measures The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups. Conclusions and Relevance In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.