Background Various modalities of vaccines against coronavirus disease 2019 (COVID-19), based on different platforms and immunization procedures, have been successively approved for marketing worldwide. A comprehensive review for clinical trials assessing the safety of COVID-19 vaccines is urgently needed to make an accurate judgment for mass vaccination. Main text A systematic review and meta-analysis was conducted to determine the safety of COVID-19 vaccine candidates in randomized controlled trials (RCTs). Data search was performed in PubMed, Embase, Cochrane library, Scopus, Web of Science, and MedRxiv. Included articles were limited to RCTs on COVID-19 vaccines. A total of 73,633 subjects from 14 articles were included to compare the risks of adverse events following immunization (AEFI) after vaccinating different COVID-19 vaccines. Pooled risk ratios (RR) of total AEFI for inactivated vaccine, viral-vectored vaccine, and mRNA vaccine were 1.34 [95% confidence interval (CI) 1.11–1.61, P < 0.001], 1.65 (95% CI 1.31–2.07, P < 0.001), and 2.01 (95% CI 1.78–2.26, P < 0.001), respectively. No significant differences on local and systemic AEFI were found between the first dose and second dose. In addition, people aged ≤ 55 years were at significantly higher risk of AEFI than people aged ≥ 56 years, with a pooled RR of 1.25 (95% CI 1.15–1.35, P < 0.001). Conclusions The safety and tolerance of current COVID-19 vaccine candidates are acceptable for mass vaccination, with inactivated COVID-19 vaccines candidates having the lowest reported AEFI. Long-term surveillance of vaccine safety is required, especially among elderly people with underlying medical conditions. Graphic Abstract

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The relationship between cAMP levels and thermogenesis was investigated in brown fat cells from Syrian hamsters. Irrespective of whether the selective ␤ 3 -, ␤ 2 -, and ␤ 1 -agonists BRL 37344, salbutamol, and dobutamine or the physiological agonist norepinephrine was used to stimulate the cells, increases in cAMP levels were mediated via the ␤ 3 -receptor, as were the thermogenic effects. However, the relationship "thermogenesis per cAMP" was much lower for agents other than norepinephrine. Similarly, forskolin, although more potent than norepinephrine in elevating cAMP, was less potent in inducing thermogenesis. The selective ␣ 1 -agonist cirazoline was in itself without effect on cAMP levels or thermogenesis, but when added to forskolin-stimulated cells, potentiated thermogenesis, up to the norepinephrine level, without affecting cAMP. This potentiation could not be inhibited by chelerythrine, but could be mimicked by Ca 2؉ ionophores. It was apparently not mediated via calmodulin-dependent protein kinase and was not an effect on mitochondrial respiratory control. The ability of all cAMP-elevating agents to induce thermogenesis in brown fat cells has earlier been interpreted to mean that it is only through the ␤-receptors and the resulting increase in cAMP levels that thermogenesis is induced. However, it is here concluded that the thermogenic response to norepinephrine involves two interacting parts, one mediated via ␤-receptors and cAMP and the other via ␣ 1 -receptors and increases in cytosolic Ca 2؉ levels.

The possible significance of the coexisting beta 1-, beta 2-, and beta 3-adrenoceptors in brown adipose tissue for the thermogenic response was investigated. Oxygen consumption of isolated hamster brown fat cells was analyzed as a measure of thermogenesis. Thermogenesis could be evoked not only by the physiological agent norepinephrine but also by BRL-37344 and CGP-12177. No evidence for biphasic inhibition curves was found with either the selective beta 1-antagonist ICI-89406, the beta 2-antagonist ICI-118551, or the beta 1/beta 2-nonselective beta-antagonist propranolol against 1 microM norepinephrine; pI50 (the negative logarithm of the inhibitory constant for an antagonist, as estimated from the dose-response curve for an antagonist vs. a constant agonist concentration) values for ICI-89406 and ICI-118551 were very low (4-5), implying nonselective inhibition; the pI50 for propranolol was approximately 6 (as expected for the beta 3-receptor). Even with suboptimal norepinephrine, no biphasic inhibition was found. CGP-12177 at concentrations where it is primarily an antagonist to the beta 1-receptor did not influence the dose-response curve for either norepinephrine or BRL-37344. BRL-37344- or CGP-12177-induced thermogenesis was inhibited by the beta-antagonists in a manner similar to norepinephrine-induced thermogenesis. Schild plots for propranolol inhibition of norepinephrine-, isoprenaline-, BRL-37344- and CGP-12177-induced thermogenesis yielded similar pA2 (the negative logarithm of the inhibitory constant for an antagonist, as calculated from a series of agonist dose-response curves at different antagonist concentrations) (approximately 5.5), for interaction with either agonist, implying that the same receptor was stimulated by all agonists. Thus, despite the fact that different beta-receptor subtypes coexist in the tissue, we find no evidence for the participation of beta 1- or beta 2-receptors in the thermogenic response. Within the resolution of the experiments, the results therefore imply that it is predominantly or solely the beta 3-receptor that is coupled to thermogenesis, and it is via this beta-adrenergic receptor that not only norepinephrine but also CGP-12177 and BRL-37344 induce thermogenesis.