There is now an increasingly solid body of scientific evidence which demonstrates that the binding of small molecular weight compounds, peptides and antibodies (Abs) to fusion-intermediate conformations of gp41 leads to an inhibition of HIV cell entry. The principal aim of this project is to exploit this information by establishing a platform where gp41-derived vaccine candidates will be designed to elicit neutralising Abs. Several families of immunogens which mimic gp41 in its fusion intermediate conformations are already available and others will be designed using modelisation approaches. Candidates will be submitted to a thorough biophysical characterisation followed by a preclinical development in order to identify the most promising for clinical evaluation. A crucial selection parameter is the capacity of antigens to elicit neutralising Abs using internationally standardized assays. Since sexual transmission accounts for more than 90% of HIV infection, the capacity of Abs to inhibit infection at the mucosal level will also be determined. This cross-disciplinary project gathers top European scientists with expertise in protein engineering and characterisation, adjuvantation, formulation for systemic and mucosal delivery, evaluation of functional antibody response, efficacy testing in animal models, medium to large scale vaccine production as well as conduct of clinical trials in both developed and third-world countries. In contrast to previous more empirical attempts, this project is based on the rational exploitation of the knowledge on the mechanism of HIV entry and is thus a promising approach to generate a protective vaccine. It will be the first European project targeting intermediate conformations of gp41 and it could complement/synergize other international strategies focusing on the membrane proximal region of gp41 or gp140 trimer to induce neutralising Abs or aiming at reducing the viral load by eliciting a cellular immunity against HIV.