BACKGROUND: We investigated how social and contextual factors, including a pandemic, shape vaccine perceptions and attitudes among people living in KwaZulu-Natal in South Africa. We assessed how participants' views, acceptance, and uptake of vaccines for a range of infectious diseases, may be influenced by experiences and events linked to the COVID-19 pandemic. METHODS: We conducted 30 in-depth face-to-face and telephonic interviews with participants living in diverse rural and urban communities in two districts within KwaZulu-Natal. Participants were adults (≥ 18 years) consisting of ordinary citizens, traditional healers, and nurses. We combined non-representative convenience, snowballing and purposeful sampling techniques to recruit participants. Data collection was conducted in IsiZulu, and we used both inductive and deductive thematic analysis approaches to identify key themes linked to participants' perceptions and attitudes towards vaccines. FINDINGS: Our study participants were mostly those who had accepted vaccination. The main reasons given for vaccine uptake included understanding the importance of vaccines for disease prevention and survival, and securing the health of family members, the fear of death, government campaigns, vaccine mandates and penalties. Older participants (≥ 40 years) demonstrated more positive attitudes towards vaccines. Most participants downplayed the role of culture and religion in attitudes towards vaccines. However, some of the drivers of vaccine hesitancy were having an ancestral calling, medical pluralism, or local myths around the treatment of infections such as influenza and mumps, and a perceived depopulation agenda couched in mistrust and the use of incentives and penalties to force people to accept COVID-19 vaccines. CONCLUSION: Exploring what shapes attitudes towards vaccines in communities provides opportunities to understand the reasoning behind how people make decisions about whether to take a vaccine in different geographical and cultural spaces. The exploration of contexts, exposures and circumstances provide insights into perceptions and behaviour. Deeper engagement with local communities is crucial to develop evidence that can inform vaccine interventions. Assumptions about how culture and religion affect vaccine hesitancy or acceptance should be avoided in the process of developing such evidence.