This chapter examines how lessons from the implementation of HIV pre-exposure prophylaxis (PrEP) in Africa can inform preparedness for the future rollout of an HIV vaccine. Drawing on a synthesis of secondary literature, it situates PrEP within the broader evolution of HIV prevention, highlighting how biomedical innovations are shaped by social, political, and health system dynamics. While Africa has played a central role in PrEP clinical trials and demonstration studies, access to PrEP has been constrained by persistent “last-mile” challenges, including stigma, weak supply chains, policy ambiguities, donor dependence, and limited community-level delivery systems. Using the vaccine system dynamics framework, the chapter conceptualizes vaccine distribution as a dynamic interaction between creation, regulation, and delivery rather than a purely technical process. It argues that scientific breakthroughs alone are insufficient to ensure equitable access. Instead, effective HIV vaccine preparedness must address the social architecture of access by prioritizing decentralization, inclusive eligibility, community engagement, trust-building, and integration into routine health systems. These insights position PrEP as a critical lens for anticipating and overcoming future barriers to equitable HIV vaccine distribution across Africa.