This research builds on limited evidence of the ‘software’ of health biotechnology innovation in its political, social and cultural context, and the political channels open to those at the receiving end of global health policy. Although South Africa has the infrastructure, earlier government dispute over the causes of HIV infection and its treatment, combined with high levels of stigma, has constrained efforts to embed innovations in heterogeneous, mobile communities, with high rates of HIV infection and AIDS. Qualitative data from two South African clinical HIV vaccine trial sites identify the complexities of community engagement in trial site activities essential for ethical and sustainable health innovation. The seminar begins by focusing on the problems faced by community advisory board members engaged in knowledge exchange between trial site researchers and their communities. I then turn to the gains made by community advisory board members as they use valued resources for decision-making over health. Finally, data suggest that wider networks with local and national civil society organisations play an important role in building capabilities to address not only the problem of HIV and AIDS, but other health concerns and wider community development.