Needlessly to say most volunteers produced anti-R-peptide antibodies only after a boosting dose on Month 4, thereafter they followed a pattern comparable to that produced by peptide N

Needlessly to say most volunteers produced anti-R-peptide antibodies only after a boosting dose on Month 4, thereafter they followed a pattern comparable to that produced by peptide N. disease because it would block the infection during the initial asymptomatic phase. Indeed, GRK4 it has been extensively confirmed that animals1,2 and humans3,4 vaccinated with irradiated sporozoites become immune to experimental infections induced by sporozoites, and do not develop patent blood-stage infections or clinical malaria symptoms. Sera and cells from these individuals recognize proteins expressed around the sporozoites and the parasite liver forms5C9 that have been incriminated in this protection and therefore have been proposed as malaria vaccine candidates.10,11 Among them, the circumsporozoite (CS) protein that is abundantly expressed around the sporozoite surface has been shown to be involved in the Azelaic acid process of parasite invasion to the hepatocyte12,13 and its Azelaic acid immunological blockage prevents the development of malaria infection.6,7,14 The RTS-S vaccine based on a construct of the CS protein and the S antigen of human hepatitis B virus has proven to be immunogenic and partially protective in phase II studies conducted with human malaria-naive volunteers15C18 and in adults and children from malaria-endemic areas of Africa.19C22 Regarding the CS protein, three long synthetic peptides (LSP) homologous to the amino (N), central repeat (R), and carboxyl (C) regions were initially evaluated in preclinical studies and showed high immunogenicity in mice and monkeys.23,24 On the basis of those studies the same LSPs were formulated in Montanide ISA 720 and assessed in phase Ia clinical trial conducted by the Malaria Vaccine and Drug Development Center (MVDC) in Cali, Colombia. Immunization with this formulation indicated to be safe, well tolerated, and immunogenic.25 All three peptides induced production of high titers of specific antibodies that cross-reacted with the protein around the parasite and production of interferon-gamma (IFN-) in most vaccinated subjects. Even though N peptide induced the highest antibody titers at three different doses tested (10, 30, and 100 g/dose), peptides R and C were also immunogenic at Azelaic acid high doses. In the search for an optimal vaccine formulation for human use we have conducted pre-clinical studies in mice, monkeys, and clinical trials in malaria-naive volunteers, and we performed a new series of studies to assess the security and immunogenicity of a combination of the three peptides formulated either in Montanide ISA 720 or in Montanide ISA 51. The rationale for these mixtures was to determine the possibility of immunological interference among the different peptides or their potential synergism. These adjuvants were selected because they form stable water-in-oil emulsions and induced high antibody Azelaic acid levels that lasted for up to 1 year in mice, rabbits, and monkeys in previous studies using recombinant malaria proteins.23,26C32 More recently, a recombinant CS protein Azelaic acid produced in and formulated in Montanide ISA 720 showed to be highly immunogenic in mice.33 Several phase I clinical trials have been conducted using different malaria vaccine antigens in which these two adjuvants have been able to stimulate both humoral and cellular immune responses.34C37 We present here a phase I clinical trial conducted with the same CS derived peptides formulated in two different adjuvants, and provide further safety and immunogenicity data as part of a clinical development plan that aims at developing vaccines to prevent malaria. Materials and Methods Study design and populace. This was a phase I double-blind, controlled vaccine trial, evaluating security, tolerability, and immunogenicity of mixtures of N, R and C LSP derived from the CS protein formulated in two adjuvants Montanide ISA 720 and Montanide ISA 51. The primary objective was to assess in malaria-naive adults, the security and reactogenicity of these peptides formulated in the two adjuvants. Study protocol was approved by the Institutional Review Boards (IRB) of the Universidad del Valle and Centro.