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In December 2020, 11 months after identifying the first laboratory-confirmed case of COVID-19 in the United States, the U.S. Food and Drug Administration authorized emergency use of two COVID-19 vaccines. To prepare the public for a large-scale vaccination campaign and build confidence in COVID-19 vaccines, the U.S. Centers for Disease Control and Prevention (CDC) funded more than 200 partners and developed a national Vaccinate with Confidence (VwC) COVID-19 framework to support Americans in their decision to get vaccinated. The evolving nature of the pandemic and highly variable confidence in vaccines across populations has resulted in many unique complexities and challenges to reaching universally high vaccination coverage. Here, we describe how 23 professional health associations and national partner organizations, focused solely on building vaccine confidence, operationalized CDC's VwC COVID-19 framework from February 2021 to March 2022. Capturing how partners deployed and adapted their activities to meet a shifting pandemic landscape, which began with high demand for vaccines that waned over time, is an important first step to understanding how this new strategy was utilized and could be implemented for future surges in COVID-19 cases and other routine immunization efforts. Going forward, evaluation of partner activities should be prioritized to capture learnings and assess VwC program effectiveness. [ABSTRACT FROM AUTHOR]