Immunogenicity and Safety of a Severe Acute Respiratory Syndrome Coronavirus 2 Inactivated Vaccine in Healthy Adults: Randomized, Double-Blind, and Placebo-Controlled Phase 1 and Phase 2 Clinical Trials
The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to significant morbidity and mortality, necessitating the urgent development of effective and safe vaccines. This article presents the findings from phase 1 and phase 2 clinical trials of an inactivated SARS-CoV-2 vaccine, KCONVAC, conducted in healthy Chinese adults aged 18 to 59 years. The trials aimed to evaluate the vaccine’s immunogenicity and safety, providing critical data to support its further development and potential deployment.
The phase 1 trial was designed as a randomized, double-blind, and placebo-controlled study. Participants were randomized to receive two doses of either KCONVAC (5 or 10 mg/dose) or placebo on Days 0 and 14. The primary safety endpoint was the proportion of participants experiencing adverse reactions or events within 28 days following each dose. The phase 2 trial expanded on this design, randomizing participants to receive KCONVAC (5 or 10 mg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). The primary immunogenicity endpoints in the phase 2 trial were neutralization antibody seroconversion and titer, as well as anti-receptor-binding domain immunoglobulin G (RBD-IgG) seroconversion at 28 days after the second dose.
In the phase 1 trial, 60 participants were enrolled and received at least one dose of the 5-mg vaccine (n = 24), 10-mg vaccine (n = 24), or placebo (n = 12). The phase 2 trial included 500 participants, with 100 receiving the 5-mg vaccine, 100 receiving the 10-mg vaccine, and 50 receiving placebo in each regimen (0/14 and 0/28). The safety analysis included all participants who received at least one dose, while the immunogenicity analysis was conducted on a per-protocol subset of participants who completed the study as planned.
Safety outcomes in the phase 1 trial revealed that 54% (13/24) of participants in the 5-mg vaccine group, 46% (11/24) in the 10-mg vaccine group, and 58% (7/12) in the placebo group reported at least one adverse event (AE). All AEs were of grade 1 or 2 intensity, with no grade 3 or higher AEs reported. The most common solicited injection-site AE was pain, while the most common systemic AE was fatigue. One serious AE (foot fracture) was reported in the 10-mg vaccine group, which was deemed unrelated to the vaccine.
In the phase 2 trial, the incidence of AEs was similar across the treatment groups. In the 0/14 regimen, 16% (16/100) of participants in the 5-mg vaccine group, 19% (19/100) in the 10-mg vaccine group, and 18% (9/50) in the placebo group reported at least one AE. The 0/28 regimen showed comparable AE incidences. All AEs were of grade 1 or 2 intensity, with no grade 3 or higher AEs reported. No serious AEs were observed in the phase 2 trial.
Immunogenicity results demonstrated that KCONVAC induced robust antibody responses. In the phase 1 trial, seroconversion rates for neutralizing antibody to live virus, neutralizing antibody to pseudovirus, and RBD-IgG ranged from 88% to 100% across the treatment groups at 14 or 28 days post-administration of the second dose. In the phase 2 trial, seroconversion rates were similarly high, ranging from 83% to 100% for the same antibodies. Placebo groups showed minimal seroconversion, with only 2% (1/49) of participants in the 0/28 regimen group seroconverting for RBD-IgG.
Geometric mean titers (GMTs) of neutralizing antibody to live virus in the phase 2 trial ranged from 29.3 to 49.1 for the 0/14 regimen and from 100.2 to 131.7 for the 0/28 regimen. GMTs of neutralizing antibody to pseudovirus ranged from 69.4 to 118.7 for the 0/14 regimen and from 153.6 to 276.6 for the 0/28 regimen. RBD-IgG GMTs ranged from 605.3 to 1169.8 for the 0/14 regimen and from 1496.8 to 2485.5 for the 0/28 regimen. These values were significantly higher than baseline titers, indicating a strong immune response.
The 0/28 regimen induced higher GMTs compared to the 0/14 regimen. At 14 days post-administration of the second dose, GMTs in the 0/28 regimen were 2.0 to 3.9 times higher than those in the 0/14 regimen (P < 0.0001 for all comparisons). At 28 days post-administration, GMTs in the 0/28 regimen were 1.6 to 3.5 times higher than those in the 0/14 regimen (P ≤ 0.0005 for all comparisons). This suggests that a longer interval between doses may enhance the immune response.
RBD-IgG subtyping revealed that the majority of RBD-IgG was IgG1, with minimal amounts of IgG2 and IgG3 detected. The GMT ratio of IgG1 to IgG4 was 2.8 in the 5-mg vaccine group and 2.5 in the 10-mg vaccine group at 14 days post-administration of the second dose. Additionally, high levels of anti-nucleocapsid protein antibody (N-IgG) were detected, with GMTs ranging from 122.0 to 394.7 in the vaccine groups at 28 days post-administration.
T-cell responses were also assessed in the phase 1 trial. Positive interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot) responses were observed in 57% (13/23) of participants in the 5-mg vaccine group and 63% (15/24) in the 10-mg vaccine group at 14 days post-administration of the first dose. The numbers of IFN-γ-positive spot-forming cells (SFCs) per 200,000 cells were 14.8 and 24.3 in the 5-mg and 10-mg vaccine groups, respectively, at 28 days post-administration. No IFN-γ-ELISpot responses were detected in the placebo group.
Serum cytokine assays detected interleukin-2 (IL-2) in a significant percentage of participants at 14 or 28 days post-administration of the second dose. Other cytokines were generally not detected, suggesting that the vaccine-induced immune response may be transient and associated with mild AEs.
The trials demonstrated that KCONVAC is well tolerated and induces robust immune responses in healthy adults aged 18 to 59 years. The 0/28 regimen showed higher immune responses compared to the 0/14 regimen, supporting its use in further clinical trials. The safety profile of KCONVAC is consistent with other inactivated SARS-CoV-2 vaccines, with no severe AEs reported.
Limitations of the study include the lack of data for older adults, who are at higher risk of severe COVID-19. The sample sizes were relatively small, and only physically healthy participants were included, which may limit the generalizability of the results. The study duration was short, and long-term safety and antibody persistence were not assessed. Additionally, the use of a single wildtype SARS-CoV-2 strain for neutralizing antibody measurement may not fully represent the vaccine’s efficacy against emerging variants.
In conclusion, the phase 1 and phase 2 trials of KCONVAC provide strong evidence of its safety and immunogenicity in healthy adults. The results support the continued development of KCONVAC, with the 5-mg dose in the 0/28 regimen recommended for further testing in phase 3 efficacy trials.
doi.org/10.1097/CM9.0000000000001573
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