Safety and Elicitation of Humoral and Cellular Responses in Colombian Malaria-Naive Volunteers by a Plasmodium Vivax Circumsporozoite Protein–derived Synthetic Vaccine

Abstract

Abstract. Substantial experimental evidence indicates that the Plasmodium circumsporozoite (CS) protein has great potential as a vaccine candidate. We tested the safety and immunogenicity of vaccines composed of P. vivax CS-derived synthetic peptides. Sixty-nine healthy, malaria-naive volunteers were randomized to receive three injections of placebo or synthetic proteins N, R, or C (10, 30, or 100 g/dose) in a double-blinded fashion. Vaccines were well tolerated and no serious adverse events were observed. Peptides N and R elicited humoral responses at all doses; peptide C elicicted these responses only at doses of 30 and 100 g. The N peptide at a dose of 100 g elicited the greatest antibody response. Antibodies to the three peptides recognized P. vivax sporozoites in an immunofluorescent antibody test. Peripheral blood mononuclear cells from most immunized volunteers also produced interferon-␥ upon peptide in vitro stimulation. These vaccines appear safe, well tolerated, and immunogenic in malaria-naive volunteers. Further optimization and development of this vaccine is being attempted to conduct phase II clinical trials.

Preclinical Vaccine Study of Plasmodium vivax Circumsporozoite Protein Derived-Synthetic Polypeptides Formulated in Montanide ISA 720 and Montanide ISA 51 Adjuvants

“…27 The mass and purity of the peptides were assessed by high performance liquid chromatography and mass spectrometry and was higher than 85%. 6 Proteins were lyophilized, packaged, and both…”

“…All three proteins induced high titers of specific antibodies that cross-reacted with P. vivax sporozoites and the production of interferon-gamma (IFN-γ) both in Aotus monkeys and in humans. 6,20 Additionally, antibodies to the three regions were able to partially block sporozoite invasion. 6,7 We designed a pre-clinical trial in mice and monkeys to assess here the immunogenicity of a combination of the three peptides formulated in Montanide ISA 720 or in Montanide ISA 51.…”

“…6,20 Additionally, antibodies to the three regions were able to partially block sporozoite invasion. 6,7 We designed a pre-clinical trial in mice and monkeys to assess here the immunogenicity of a combination of the three peptides formulated in Montanide ISA 720 or in Montanide ISA 51. Both adjuvants have been previously used extensively in clinical trials addressed to test vaccines against malaria and other infectious pathogens.…”

“…[2][3][4][5] In the case of P. vivax, the second most prevalent malaria species, only two parasite antigens, the sexual P. vivax surface protein 25 ( Pv s25) expressed during the sporogonic cycle and the CS protein expressed during the pre-erythrocytic phase of the cycle, have undergone phase I clinical trials. [5][6][7] Further development of these P. vivax vaccine candidates has been difficult mainly because of limited resources and the generalized misconception that P. vivax is a benign malaria species with minor epidemiological importance. 8 Moreover, the lack of continuous parasite cultures seriously impedes the discovery of more parasite antigens with vaccine potential.…”

“…19 Vaccine formulations based on the synthetic polypeptides corresponding to different regions of the CS protein and Montanide ISA 720 adjuvant have been proven to be safe, well tolerated, and highly immunogenic in a previous phase I vaccine trial conducted in Colombian naive volunteers. 6 The phase I trial was conducted using escalating vaccine doses (10,30, and 100 μg/dose) of three synthetic domains corresponding to the amino (N), central repeat (R), and carboxyl (C) regions of the CS protein formulated individually in Montanide ISA 720. Because it has been considered or suggested that the central repeat domain, which is highly immunogenic, represents an immune "smoke screen", the rationale of that first trial was to determine the immunogenicity of each of the three protein domains independently.…”