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This report presents the results of an evaluation of the root causes of COVID-19 vaccine hesitancy to inform strategies to boost vaccine acceptance among vaccine-hesitant populations in the United States. The authors conducted a literature review of the causes of vaccine hesitancy and vaccine acceptance; focus groups with patients, pre-hospital first responders, and hospital-based health care providers; a social media platform sentiment analysis to review attitudes regarding the COVID-19 vaccine; and a roundtable discussion with experts on vaccine hesitancy. Drawing on this mixed-methods analysis, the authors recommend strategies to help boost COVID-19 vaccine acceptance in the United States, grouping them according to three overall goals: boosting confidence in the safety and effectiveness of the COVID-19 vaccines, combating complacency about the pandemic, and increasing the convenience of getting vaccinated. The authors emphasize that combating misinformation about the COVID-19 vaccine is key to achieving these goals. These recommendations can inform the development of a toolkit of strategies to reach herd immunity and end the pandemic.