The specific activity of IFN- kit standard was titrated against NIBSC IFN- European standard and was set at 3.61 IU for one ng IFN-. safety tests; secondary-end point (immunogenicity) on specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well Rabbit Polyclonal to CBLN2 tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups AGN 194310 experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN- production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN- secreting CD8+ T cell responses. Responses were only marginally boosted after AGN 194310 the 3rd vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 g was less immunogenic in comparison to 30 and 100 g that induced similar responses. AS02A formulations with 30 g or 100 g PfCS102 induced about 10-folds higher antibody and IFN- responses than Montanide formulations. Conclusions/Significance PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 g formulated with AS02A appeared the most appropriate choice for such studies. Trial Registration Swissmedic.ch 2002 DR 1227 Introduction induced malaria is a major cause of disease and death in tropical areas. The difficulty to obtain a protective malaria vaccine is largely related to the genetic complexity of the parasite, to its metamorphosis across several life stages within the human host and to its strategies, acquired with evolution, to escape host immune response. The hope for an efficient vaccine is based on the observation that natural exposure to repeated infections leads to some degree of immune protection and that humans can acquire a complete pre-erythrocytic protection after repeated immunization with irradiated sporozoites (reviewed in [1]). Studies performed in animals and in human volunteers have demonstrated that the anti-sporozoite protection depends on both humoral and cell-mediated immune (CMI) response [2]. Facing the difficulties of the large-scale production of an attenuated sporozoite based vaccine [3], subunit candidates were selected on the basis of the protective immune response obtained with irradiated sporozoites. The circumsporozoite protein (CSP), which is abundant at AGN 194310 the cell surface of sporozoite, appeared to play a crucial role in preclinical and clinical models of protection [4] implicating humoral [5], CD4+ and CD8+ T cell response [6]C[14]. Different CSP-derived vaccine constructs have been evaluated in clinical trials, including synthetic peptides, which have the advantage to be rapidly obtainable at high degree of purity and to have absent intrinsic toxicity in clinical grade batches. In preclinical studies, a long synthetic peptide (LSP), encoding the C-terminal 282C383 region of CSP, was found to be highly immunogenic and protective [15]C[18]. In addition, individuals living in malaria-endemic areas develop high titers of specific antibodies and a vigorous CMI response to this sequence [19]. A preliminary Phase I study was completed using a GLP grade PCSP 282C383 batch (PfCS102) [20]. The vaccine was well tolerated and safe. The humoral immune response induced by PfCS102 adjuvanted with Montanide was excellent, as well as the CMI response based on the induction of specific CD8+ T cells and IFN- secretion. In view of these results, in this Phase I study we evaluated the safety and immunogenicity of PfCS102 LSP synthesized under GMP conditions, as required for clinical trials, as well as its combination with two adjuvants, AS02A and Montanide, in six groups of healthy adult volunteers for three dose levels of LSP. Methods Objectives The objectives of this trial were to investigate the safety and tolerability of the intra-muscular administration of the PfCS102 LSP, injected in combination with two different adjuvants, as a candidate malaria vaccine. We determined the occurrence and AGN 194310 severity of vaccine-related adverse events (AE) for each combination of vaccine (primary objective) in order to define the optimal antigen-adjuvant combination, i.e. the combination inducing the highest humoral and CMI response (secondary objective). Participants Protocol and supporting CONSORT Checklist are available as supporting information; see Checklist S1 and Protocol S1. Volunteers, male and female between 18 and 45 years, were.