Discussion
thrombosis, abnormal fasting glucose, HIT, venous or arterial thrombosis, diabetes
THROMBOSIS, ASH, THROMBOCYTOPENIA, HEPARIN-INDUCED THROMBOCYTOPENIA, STREPTOCOCCUS PNEUMONIAE INFECTION, THROMBOEMBOLISM, EVENTS, DIABETES
In this phase IV clinical trial, two doses of CoronaVac with an interval of 28 days exhibited good immunogenicity and safety profiles. CoronaVac did not have any effect on laboratory parameters related to coagulation function and blood glucose.Considering the vaccination policy in China stipulating that all participants who received post-marketing SARS-CoV-2 vaccines must know the lot number, this trial could not be blinded. For control vaccines, some studies have reported that Streptococcus pneumoniae infection could worsen the severity of COVID-19 (As a measure of immune system activation after vaccination, serum SARS-CoV-2 neutralizing antibodies were dynamically analyzed at seven time points after CoronaVac vaccination. Interestingly, we found that 4 days after either dose of CoronaVac, the neutralizing antibody level against the prototype strain did not show any difference compared to the prevaccination level of the corresponding dose. However, antibodies increased significantly 14 or 28 days after each dose. This indicated that it would take more than four days for each dose of CoronaVac to activate the humoral response. Our findings provide evidence supporting the statistical method used in previous studies evaluating the efficacy COVID-19 vaccines, whereby COVID-19 cases counted in the efficacy models occurred at least 14 days after the second dose of CoronaVac (CoronaVac vaccination could also activate neutralizing antibodies against the VOCs, however, it required a longer time. The GMT and seroconversion rate did not increase significantly until 42 days after the first dose (14 days after the second dose). Compared to the prototype strain, the values of GMT and the seroconversion rates against VOC decreased to different degrees. The greatest reduction was against beta VOC, followed by gamma and delta VOCs. Although antibody levels decreased, two doses of CoronaVac vaccines still showed effectiveness against different VOCs in real-world studies (According to the review published by the American Society of Hematology (ASH), five criteria were given to definitively diagnose TTS: 1) COVID-19 vaccination 4 to 42 days before symptom onset, 2) any venous or arterial thrombosis (often cerebral or abdominal), 3) thrombocytopenia, 4) positive for PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA, 5) markedly elevated D-dimer (> 4 times the upper limit of normal) (Previous laboratory studies have also shown that CoronaVac did not cause thrombosis or TTS. Signorelli et al. (Previous epidemiological findings in real-world studies did not report an increased risk of thrombocytopenia, thromboembolism, or diabetes associated with CoronaVac vaccinations (Compared to the rigorous screening methods and criteria in typical phase I–III clinical studies, the enrolled population in this trial was closer to the actual vaccination population. Through laboratory test results before vaccination on day 0, we found that 17% of participants had an abnormal fasting glucose value higher than the normal range and some were suspected to be patients with diabetes. This showed that many vaccine recipients may not know their medical conditions well in the real world. Our findings provided the reference baseline data of the real-world population for the assessment of pharmacovigilance risk in China, indicating that some pharmacovigilance events diagnosed after vaccination may already had occurred before vaccination, and the percentage may not be as low as we thought before.This trial has several limitations. Due to the lack of previous studies on laboratory parameters of the CoronaVac vaccine, the sample size of this trial was exploratory and small. As the incidence of TTS is very low, a TTS safety monitoring study in a larger population is required. Epidemiological studies of TTS are also available to further verify the effect of the CoronaVac vaccine on TTS in a larger population in China. Furthermore, in this study, neutralizing antibodies against Omicron VOC were not detected. They will be analyzed in the follow-up booster immunization study.In conclusion, the CoronaVac vaccine could activate humoral responses against SARS-CoV-2 with a good safety profile and did not affect coagulation function and blood glucose levels.