BACKGROUND: In response to the COVID-19 pandemic, the first vaccine was administered in December 2020 in England. However, vaccination uptake has historically been lower in London than in other English regions. METHODS: Mixed-methods: This comprised an analysis of cumulative percentage uptake across London between 8 December 2020 and 6 June 2021 by vaccine priority cohorts and ethnicity. We also undertook thematic analyses of uptake barriers, interventions to tackle these and key learning from a qualitative survey of 27 London local authority representatives, vaccine plans from London's five Integrated Care Systems and interviews with 38 London system representatives. RESULTS: Vaccine uptake was lower in Black ethnic (57-65% uptake) compared with the White British group (90% uptake). Trust was a critical issue, including mistrust in the vaccine itself and in authorities administering or promoting it. The balance between putative costs and benefits of vaccination created uptake barriers for zero-hour and shift workers. Intensive, targeted and 'hyper-local' initiatives, which sustained community relationships and were not constrained by administrative boundaries, helped tackle these barriers. CONCLUSIONS: The success of the national vaccination programme depended on conceding local autonomy, investing in responsive and long-term partnerships to engender trust through in-depth understanding of communities' beliefs.