BackgroundGreat disparities in immunization coverage exist in Pakistan between urban and rural areas. However, coverage estimates for large peri-urban slums in Sindh are largely unknown and implementation challenges remain unexplored. This study explores key supply- and demand-side immunization barriers in peri-urban slums, as well as strategies to address them. It also assesses immunization coverage in the target slums.MethodsConducted in four peri-urban slums in Karachi, this mixed-methods study consists of a baseline cross-sectional coverage survey of a representative sample of 840 caregivers of children aged 12-23 months, and 155 in-depth interviews through purposive sampling of respondents (caregivers, community influencers and immunization staff). After identifying the barriers, a further 6 IDIs were then conducted with immunization policymakers and policy influencers to determine strategies to address them, resulting in the development of an original validated implementation framework for immunization in peri-urban slums. A thematic analysis approach was applied to qualitative data.Results49% of children were fully vaccinated, 43% were partially vaccinated and 8% were unvaccinated. Demand-side immunization barriers included household barriers, lack of knowledge and awareness, misconceptions and fears regarding vaccines, and social and religious barriers. Supply-side barriers included underperformance of staff, inefficient funds utilization, unreliable immunization and household data, and interference of polio campaigns with immunization. The implementation framework’s policy recommendations to address these barriers include: 1) improved Human Resource management 2) staff training on counseling, 3) re-allocation of funds towards incentives, outreach, salaries and infrastructure, 4) a digital platform integrating birth registry and vaccination tracking systems for monitoring and reporting by frontline staff 5) use of digital platform for immunization targets and generating dose reminders, and 6) mutual sharing of resources and data between the immunization, Lady Health Worker and polio programs for improved coverage.ConclusionsThe implementation framework is underpinned by the study of uncharted immunization barriers in complex peri-urban slums, and can be used by implementers in Pakistan and other developing countries to improve immunization programs in limited-resource settings, with possible application at a larger scale. Particularly, a digital platform integrating vaccination tracking and birth registry data can be expanded for nationwide use.