Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine (KCONVAC) in Healthy Adults: Two Randomized, Double-blind, and Placebo-controlled Phase 1/2 Clinical Trials (preprint)

ABSTRACT

Background The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine, KCONVAC, in healthy adults. Methods Two phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in Chinese healthy adults aged 18 through 59 years. The phase 1 trial was conducted in a manner of dosage escalation. The first 30 participants were randomized in a ratio of 41 to receive two doses of either KCONVAC at 5 g per dose or placebo on Day 0 and Day 14, and the second 30 participants were randomized to receive either KCONVAC at 10 g per dose or placebo following the same procedures. The participants in the phase 2 trial were randomized in a ratio of 221 to receive either KCONVAC at 5 g or 10 g per dose, or placebo on Day 0 and Day 14, or Day 0 and Day 28. In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following each vaccination. Antibody response and cellular response were assayed in the phase 1 trial. In the phase 2 trial, the primary immunogenicity endpoint was the seroconversion and titre of neutralization antibody, and the seroconversion of receptor binding domain (RBD)-IgG 28 days after the second dose. Findings In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-g vaccine (N=24), 10-g vaccine (N=24), or placebo (N=12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-g vaccine (N=100 for 0/14 or 0/28 regimens), 10-g vaccine (N=100 for each regimen), or placebo (N=50 for each regimen). In the phase 1 trial, 13 (54%), 11(46%), and 7 (58%) participants reported at least one adverse event (AE), of whom 10 (42%), 6 (25%), and 6 (50%) participants reported at least one vaccination-related AE after receiving 5-g vaccine, 10-g vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and 9 (18%) participants reported at least one AE, of whom 13 (13%), 17 (17%), and 6 (12%) participants reported at least one vaccination-related AE after receiving 5-g vaccine, 10-g vaccine, or placebo at the regimen of Day 0/14, respectively. Similar results were observed in the three treatment groups of Day 0/28 regimen. All the AEs were grade 1 or 2 in intensity. No AE of grade 3 or more was reported. One SAE (foot fracture) was reported in the phase 1 trial. KCONVAC induced significant antibody response. 87.5% (21/24) to 100% (24/24) of participants in the phase 1 trial and 83.0% (83/100) to 100% (99/99) of participants in the phase 2 trial seroconverted for neutralising antibody to live virus, neutralising antibody to pseudovirus, and RBD-IgG after receiving two doses. Across the treatment groups in the two trials, the geometric mean titres (GMTs) of neutralising antibody to live virus ranged from 29.3 to 49.1 at Day 0/14 regimen and from 100.2 to 131.7 at Day 0/28 regimen, neutralising antibody to pseudovirus ranged from 69.4 to 118.7 at Day 0/14 regimen and from 153.6 to 276.6 at Day 0/28 regimen, and RBD-IgG ranged from 605.3 to 1169.8 at Day 0/14 regimen and from 1496.8 to 2485.5 at Day 0/28 regimen. RBD-IgG subtyping assay showed that a significant part of RBD-IgG was IgG1. The vaccine induced obvious T-cell response with 56.5% (13/23) and 62.5% (15/24) of participants in 5-g and 10-g vaccine groups showed positive interferon-{gamma} enzyme-linked immunospot responses 14 days after the second dose in the phase 1 trial, respectively. Interpretation KCONVAC is well tolerated and able to induce robust antibody response and cellular response in adults aged 18 to 59 years, which warrants further evaluation with this vaccine in the upcoming phase 3 efficacy trial. Funding Guandong Emergency Program for Prevention and Control of COVID-19 (2020A1111340002) and Shenzhen Key Research Project for Prevention and Control of COVID-19.