C.-F.Q. together, these results demonstrate that heterologous improving with AWcorna induces higher neutralization and IgG antibodies against WT, Delta and Omicron variants than homologous booster. Additionally, we observed the security profile of the booster dose of AWcorna. Solicited local and systemic adverse events (AEs) were recorded within 30?min and in a windows of 0C14 days, and unsolicited AEs were documented within 0C28 days post-booster vaccination (Supplementary information, Table?S4). For both vaccines, pain at the injection site is the most reported local AE (incidence rate, IR:?17% in AWcorna vs 2% in CoronaVac; em P /em ? ?0.0001), Fenoldopam mostly at the Grade 1 level (Fig.?1f). Fever was the most common systemic AE (IR: 33.5%), followed by headache (IR: 26.0%) and muscle mass aches (IR: 7.5%) in AWcorna group (Fig.?1g). A total of 8 subjects reported grade 3 fever (IR:?4%) among the 200 participants in AWcorna group. For Fenoldopam the CoronaVac group, headache represented the most frequent systemic AE (IR: 7.0%), followed by fever (IR: 4.0%). No severe adverse events (SAEs) were reported in both groups. Collectively, our present study clearly demonstrated that a 3rd dose of heterologous GP5 improving with AWcorna was safe and protective against the circulating Delta and Omicron variants. Compared with phase 1 trial, the total IRs of local and systemic AEs for AWcorna booster showed significant improvement, 10 especially the IR of grade 3 fever that was?reduced to 4% (Supplementary information, Table?S4), comparable to the other two approved mRNA vaccines.11 The phase 1 trial of AWcorna only included 20 adults aged 18C59 (15?g group), while our present cohort enrolled 200 participants, including 10 subjects aged over 60. The growth of sample size and improvement in vaccine developing technologies contributed to the improved security profile observed in our present study. The ongoing international phase 3 trials with 28,000 participants will provide more about the security profile of AWcorna. Previously, we have exhibited that homologous improving with AWcorna readily induced high neutralization antibodies against WT and Omicron variant in mice.12 and our present getting in human further supported heterologous booster with this China-made mRNA vaccine AWcorna in Chinese populations. Many cities in China are under the attack of Delta and Omicron variants, while few or no neuralization antibodies against Omicron were detected in most Chinese populations.7,13 A third dose booster has been recommended by the WHO and National Health Commission of China. Of all COVID-19 vaccines generated from different technology platforms, mRNA vaccine represent the most affordable choice as either homologous or heterologous booster. The neutralization titers against Delta and Omicron variants in AWcorna booster group were 6.5-fold and Fenoldopam 4.4-fold higher than those in CoronaVac booster group, respectively (Fig.?1b, c), and the AWcorna booster induced the seroconversion of Omicron neutralization in over 83% individuals (Fig.?1d). A third dose of S-targeting mRNA vaccine was evidenced to increase the number of RBD-specific memory B cells with expanded potency and breadth, thus contributing to the additional protection against VOCs including Omicron,14,15 highlighting the rationale of RBD-targeting mRNA vaccine as a booster. Given that Chinese population who have received three-dose inactivated vaccines is growing, additional clinical trials are being conducted to assay the benefits of heterologous improving with AWcorna. Finally, despite the vaccine effectiveness of AWcorna booster in preventing contamination by SARS-CoV-2 and other VOCs remains to be determined, the induction of potent neutralization antibodies against WT and VOCs, as well as the affordable security profile, support the emergency use of AWcorna as heterologous booster in China. A more potent mRNA vaccine and improved booster strategy should be warranted to meet the urgent and huge need to quit the ongoing Omicron outbreaks in China and COVID-19 pandemic worldwide. Supplementary information Supplementary Information(515K, pdf) Acknowledgements We thank all the participants in this trial and all staff in the research sites at Lancang CDC and Yunnan CDC. The authors acknowledge members Fenoldopam from your Guangzhou Institute of Respiratory Health, Guangzhou Customs Technology Center, the Vazyme Medical Technology, the Beijing Important Tech Statistical Consulting, and the Beijing Stem Technology for technical support and collaboration. We sincerely thank Prof. Xuanyi Wang and Prof. Haifeng Li for crucial reading and insightful suggestion for this manuscript. This work was supported in part by grants from your National Key R&D Program of China (2021YFC2302400) and the National Natural?Science Foundation of China (82151222). C.-F.Q. was supported by the National Science Fund for Distinguished Small Scholars (81925025), the Innovative Research Group (81621005) from your National Natural?Science Foundation of China and the Development Fund for Medical Sciences (2019-I2M-5-049) from your Chinese Academy of.