The speed at which social media is propagating COVID-19 misinformation and its potential reach and impact is growing, yet little work has focused on the potential applications of these data for informing public health communication about COVID-19 vaccines. We used Twitter to access a random sample of over 78 million vaccine-related tweets posted between December 1, 2020 and February 28, 2021 to describe the geographical and temporal variation in COVID-19 vaccine discourse. Urban suburbs posted about equitable distribution in communities, college towns talked about in-clinic vaccinations near universities, evangelical hubs posted about operation warp speed and thanking God, exurbs posted about the 2020 election, Hispanic centers posted about concerns around food and water, and counties in the ACP African American South posted about issues of trust, hesitancy, and history. The graying America ACP community posted about the federal government’s failures; rural middle American counties posted about news press conferences. Topics related to allergic and adverse reactions, misinformation around Bill Gates and China, and issues of trust among Black Americans in the healthcare system were more prevalent in December, topics related to questions about mask wearing, reaching herd immunity and natural infection, and concerns about nursing home residents and workers increased in January, and themes around access to black communities, waiting for appointments, keeping family safe by vaccinating and fighting online misinformation campaigns were more prevalent in February. Twitter discourse around COVID-19 vaccines in the United States varied significantly across different communities and changed over time; these insights could inform targeted messaging and mitigation strategies.