BackgroundThe COVID-19 pandemic has shown a high severity in terms of mortality, and to mitigate the impact of the COVID-19 pandemic, a great deal of reliance has been placed on vaccines with defensive effects. In the context of the transmission of hazardous Omicron variant strains, vaccine popularization and acceptance are very important to ensure world health security. Social media can spread information and increase public confidence in and acceptance of vaccines.MethodIn this study, weibos related to “vaccine science popularization” during the COVID-19 pandemic in China were collected, and Weibo publishers were divided into Individuals, Organizations, Media, Government, and Scientists. The communication strategies were analyzed with content analysis from the four dimensions of Issue, Topic, Frame, and Position. SnowNLP was used to mine the audience comments and to assess their emotional tendencies. Finally, hierarchical regression was used to verify the causal relationship between vaccine science popularization strategies and audiences’ emotions.ResultsWe found that the higher the scientific authority of the weibo publisher, the more positive the emotional tendency of the audience toward the weibo. Issues that are scientific, authoritative, and positive topics that positively present the advantages of the COVID-19 vaccine, and frames with detailed narratives, scientific arguments, diversified forms of presentations, and positions in support of the COVID-19 vaccine, positively affect the effect of vaccine popularization.DiscussionBased on the experience of COVID-19 vaccine promotion in China, the results may serve as a reference for promoting innovative vaccines and handling public health affairs around the world.