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Public sentiment toward the COVID-19 vaccine as expressed on social media can interfere with communication by public health agencies on the importance of getting vaccinated. We investigated Twitter data to understand differences in sentiment, moral values, and language use between political ideologies on the COVID-19 vaccine. We estimated political ideology, conducted a sentiment analysis, and guided by the tenets of moral foundations theory (MFT), we analyzed 262,267 English language tweets from the United States containing COVID-19 vaccine-related keywords between May 2020 and October 2021. We applied the Moral Foundations Dictionary and used topic modeling and Word2Vec to understand moral values and the context of words central to the discussion of the vaccine debate. A quadratic trend showed that extreme ideologies of both Liberals and Conservatives expressed a higher negative sentiment than Moderates, with Conservatives expressing more negative sentiment than Liberals. Compared to Conservative tweets, we found the expression of Liberal tweets to be rooted in a wider set of moral values, associated with moral foundations of care (getting the vaccine for protection), fairness (having access to the vaccine), liberty (related to the vaccine mandate), and authority (trusting the vaccine mandate imposed by the government). Conservative tweets were found to be associated with harm (around safety of the vaccine) and oppression (around the government mandate). Furthermore, political ideology was associated with the expression of different meanings for the same words, e.g. “science” and “death.” Our results inform public health outreach communication strategies to best tailor vaccine information to different groups.