The safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in Chinese adults aged 18-59 years: A phase I randomized, double-blinded, controlled trial

Abstract

Background: This study examined the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine.

Method: In a phase I randomized, double-blinded, placebo-controlled trial involving 192 healthy adults 18-59 years old, two injections of three doses (50 EU, 100 EU, 150 EU) of an inactivated SARS-CoV-2 vaccine or placebo were administered intramuscularly at a 2- or 4-week interval. The safety and immunogenicity of the vaccine were evaluated.

Results: Vaccination was completed in 191 subjects. Forty-four adverse reactions occurred within 28 days, most commonly mild pain and redness at the injection site or slight fatigue. At days 14 and 28, the seroconversion rates were 87.5% and 79.2% (50 EU), 100% and 95.8% (100 EU), and 95.8% and 87.5% (150 EU), respectively, with geometric mean titers (GMTs) of 18.1 and 10.6, 54.5 and 15.4, and 37.1 and 18.5, respectively, for the schedules with 2-week and 4-week intervals. Seroconversion was associated with synchronous upregulation of antibodies against the S protein, N protein and virion and a cytotoxic T lymphocyte (CTL) response. No cytokines and immune cells related to immunopathology were observed. Transcriptome analysis revealed the genetic diversity of immune responses induced by the vaccine.

Interpretation: In a population aged 18-59 years in this trial, this inactivated SARS-CoV-2 vaccine was safe and immunogenic.

Trial registration: CTR20200943 and NCT04412538.

Keywords: Inactivated vaccine; Phase I; SARS-CoV-2.

Fig. 1

Screening, randomization and inclusion in phase I clinical trial.

Fig. 2

Variations in the levels of 48 cytokines in sera from immunized individuals. The levels of 48 cytokines in the sera of subjects who received the vaccine or the placebo were monitored. Subjects were assigned to the immunization procedure with an interval of 14 days (black) or with an interval of 28 days (blue). The measured cytokines included chemokines, interleukins (ILs), growth factors (GFs), colony-stimulating factors (CSFs), tumor necrosis factors (TNFs), and interferon (IFNs). The levels of 48 cytokines (pg/ml) in the sera of subjects before receiving the vaccine and placebo are shown as gray intervals between red dots in each figure. Control (Con, 0 EU); low dose (LD, 50 EU); medium dose (MD, 100 EU); and high dose (HD, 150 EU).

Fig. 3

T cell populations in peripheral blood from individuals immunized with the inactivated vaccine. The percentage of various T cell populations among PBMCs obtained from individuals assigned to the immunization procedure with an interval of 14 days (0, 14 procedure) or with an interval of 28 days (0, 28 procedure) after booster immunization. Control (Con, 0 EU); low dose (LD, 50 EU); medium dose (MD, 100 EU); and high dose (HD, 150 EU).

Fig. 4

Immune responses induced in human individuals immunized with inactivated SARS-Cov-2 vaccine in the 0, 14 and 0, 28 schedule groups. (a) Neutralizing antibodies (NAb) and ELISA antibodies (IgGs) against the S protein (Anti-S IgG), N protein (Anti-N IgG) and virion (Anti-Virion IgG) and specific positive CTL responses (IFN-γ ELISpot) against the S, N and virion antigens (displayed on abscissa) induced by the inactivated vaccine in individuals assigned to the immunization procedure with an interval of 14 days after booster immunization. The corresponding seroconversion rate is also shown in the figure. (b) Neutralizing antibodies (NAb) and ELISA antibodies (IgGs) against the S protein (Anti-S IgG), the N protein (Anti-N IgG) and virion (Anti-Virion IgG) and specific positive CTL responses (IFN-γ ELISpot) against the S, N and virion antigens (displayed on abscissa) induced by the inactivated vaccine in individuals assigned to the immunization procedure with an interval of 28 days after booster immunization. The corresponding seroconversion rate is also shown in the figure. (c) Neutralizing antibodies induced by the inactivated vaccine could identify pandemic strains from all over the world, including the strain carrying the D614G mutation from America and strains from Hong Kong, Indonesia, Canada, and the United Kingdom with the same S protein sequence as that of the strain used to produce the vaccine. Control (Con, 0 EU); low dose (LD, 50 EU); medium dose (MD, 100 EU); and high dose (HD, 150 EU). The antibody positive judgment threshold is marked with a dotted line in the figure. *, 0.01 < p < 0.05; **, 0.001 < p < 0.01; ***, p < 0.001. The significant differences compared to the control group (Con) are shown in black, those compared to the low-dose group in purple, and those compared to the middle-dose group in red.

Fig. 5

Genetic diversity of genes related to the immune response induced by the inactivated SARS-Cov-2 vaccine. (a) The fold changes in some of the differentially expressed genes involved in cytokine production. Some important genes reported relating to COVID-19 are marked with a pink rectangle. (b) The fold changes in some of the differentially expressed genes involved in T cell activation. (c) The fold changes in some of the differentially expressed genes involved in B cell activation. (d) The fold changes in some of the differentially expressed genes involved in DC cell activation. (e) The fold changes in some of the differentially expressed genes involved in mononuclear cell/macrophage activation. (f) The fold changes in some of the differentially expressed genes involved in NK cell activation. Each row represents one gene, and the samples are depicted in the columns. Red indicates genes that were expressed at higher levels, and blue denotes genes that were expressed at lower levels compared with the control group at the same time point. The color bars represent the log2 fold change.