<p>The persistence of infectious diseases poses a continued threat to health security across Africa, revealing deep-rooted challenges in achieving effective transnational collaboration. The COVID-19 pandemic has exposed both the potential and limitations of transnational collaboration in Africa’s infectious disease response. While regional mechanisms such as the African Vaccine Acquisition Task Team (AVATT) demonstrated that collective action can achieve significant results when political will is mobilized, persistent challenges in surveillance, data sharing, and capacity building reveal deeper structural barriers to sustained collaboration. This review examines transnational collaboration in Africa through the lens of political determinants, analyzing how politics, agency, and will interact to shape collaborative outcomes in infectious disease response. We conducted a review of literature published between 2020 and 2024, supplemented with grey literature from regional organizations, yielding 40 articles that inform a scorecard analysis of COVID-19 response across three domains: Information and Laboratory Systems (prevention phase), Vaccine Deployment and Development (vaccination phase), and Response Coordination and Public Health Research Capacity (control/elimination phase). Our analysis reveals two key patterns: the Paradox of Agency, whereby strong individual state and local action coexist with weak collective transnational mechanisms, and the Governance-Capacity Loop, whereby political fragmentation perpetuates capacity gaps that in turn reinforce governance weaknesses, which together provide a novel analytical framework for understanding the political determinants of health security in Africa. The scorecard demonstrates that challenges are systemic and political rather than disease-specific: similar patterns of fragmented collaboration, sovereignty concerns, and financing gaps emerge across COVID-19, Ebola, mpox, and cholera responses. While Africa has exercised reactive sovereignty mobilizing crisis-driven responses, it has not yet achieved structural sovereignty: the embedded capacity and political commitment for sustained, African-led health security governance. We propose a roadmap for strengthening transnational collaboration through sustained investment in regional data governance, vaccine manufacturing capacity, health diplomacy mechanisms, and African-led financing frameworks. This analysis demonstrates that effective transnational collaboration requires not only technical capacity but fundamental political transformation: from fragmentation to coordination, from reactive crisis response to proactive capacity building, and from external dependence to African ownership of health security agendas.</p>