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Background: Vaccines are promising tools to control the spread of COVID-19. An effective vaccination campaign requires government policies and community engagement, sharing experiences for social support, and voicing concerns about vaccine safety and efficiency. The increasing use of online social platforms allows us to trace large-scale communication and infer public opinion in real-time.Objective: This study aims to identify the main themes in COVID-19 vaccine-related discussion on Twitter in Japan and track how the popularity of the tweeted themes evolved during the vaccination campaign. Furthermore, we aim to understand the impact of critical social events on the popularity of the themes.Methods: We collected more than 100 million vaccine-related tweets written in Japanese and posted by 8 million users (approx. 6.4% of the Japanese population) from January 1 to October 31, 2021. We used the Latent Dirichlet Allocation to perform automated topic modeling of tweet texts during the vaccination campaign. In addition, we performed an interrupted time series regression to evaluate the impact of four critical social events on public opinion.Results: We identified 15 topics grouped into 4 themes: Personal issue, Breaking news, Politics, and Conspiracy and humour. The evolution of the popularity of themes revealed a shift in public opinion, initially sharing the attention over personal issues (individual aspect), collecting information from the news (knowledge acquisition), and government criticisms towards focusing on personal issues. Our analysis showed that the Tokyo Olympic Games affected public opinion more than other critical events but not the course of the vaccination. Public opinion about politics was significantly affected by various social events, positively shifting the attention in the early stages of the vaccination campaign and negatively later.Conclusions: This study showed a striking shift in public interest in Japan, with users splitting their attention to various themes early in the vaccination campaign and then focusing only on personal issues, as trust in vaccines and policies built up. An interrupted time series regression analysis showed that the vaccination rollout to the general population (under 65) increased the popularity of tweets about practical advice and personal vaccination experience and the Tokyo Olympic Games disrupted public opinions but not the course of the vaccination campaign. The methodology developed here allowed us to monitor the evolution of public opinion and evaluate the impact of social events on the public opinion from large-scale Twitter data. [ABSTRACT FROM AUTHOR]