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The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial.

Audran R, Lurati-Ruiz F, Genton B, Blythman HE, Ofori-Anyinam O, Reymond C, Corradin G, Spertini F - PLoS ONE (2009)

Bottom Line: The two adjuvant formulations were well tolerated and their safety profile was good.Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months.For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

ABSTRACT

Background: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults.

Methodology and principal findings: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well 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 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-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma 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 microg formulated with AS02A appeared the most appropriate choice for such studies.

Trial registration: Swissmedic.ch 2002 DR 1227.

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Related in: MedlinePlus

Study flow chart.Design of the Phase I, double-blind, dose-ranging study of 3 vaccine dosing regimens combined to two different adjuvants AS02A and Montanide ISA 720. For each dose, volunteers were randomized by blocks of 12, with 6 individuals per adjuvant. Volunteers were seen 2 and 30 d after the first injection, 2 and 15 d after the second injection and 2, 15, 180, and 360 d after the third injection. A phone call was addressed to all volunteers at d 30 after the 2nd and 3rd injection.
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pone-0007304-g001: Study flow chart.Design of the Phase I, double-blind, dose-ranging study of 3 vaccine dosing regimens combined to two different adjuvants AS02A and Montanide ISA 720. For each dose, volunteers were randomized by blocks of 12, with 6 individuals per adjuvant. Volunteers were seen 2 and 30 d after the first injection, 2 and 15 d after the second injection and 2, 15, 180, and 360 d after the third injection. A phone call was addressed to all volunteers at d 30 after the 2nd and 3rd injection.

Mentions: Statistical analysis of clinical response (safety and reactogenicity) was descriptive and per total vaccinated subjects. When indicated, two-sided statistical tests were performed regarded as exploratory. Differences between adjuvant or dose groups were analyzed by Fisher's exact test for safety and reactogenicity data (numbers of AEs). For immunological data, comparisons of adjuvant groups were performed using a Kruskal-Wallis Rank-Sum test on the log of the ratio of the “per time” values on those at D0 (SAS software). Other comparisons of immunological data including CD8+ and CD4+ T cell responses were calculated using non parametric Wilcoxon or Mann-Whitney t tests for paired within-group and between-groups comparisons respectively (GraphPad Prism software). Data were considered significant when p was <0.05.


The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial.

Audran R, Lurati-Ruiz F, Genton B, Blythman HE, Ofori-Anyinam O, Reymond C, Corradin G, Spertini F - PLoS ONE (2009)

Study flow chart.Design of the Phase I, double-blind, dose-ranging study of 3 vaccine dosing regimens combined to two different adjuvants AS02A and Montanide ISA 720. For each dose, volunteers were randomized by blocks of 12, with 6 individuals per adjuvant. Volunteers were seen 2 and 30 d after the first injection, 2 and 15 d after the second injection and 2, 15, 180, and 360 d after the third injection. A phone call was addressed to all volunteers at d 30 after the 2nd and 3rd injection.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2749339&req=5

pone-0007304-g001: Study flow chart.Design of the Phase I, double-blind, dose-ranging study of 3 vaccine dosing regimens combined to two different adjuvants AS02A and Montanide ISA 720. For each dose, volunteers were randomized by blocks of 12, with 6 individuals per adjuvant. Volunteers were seen 2 and 30 d after the first injection, 2 and 15 d after the second injection and 2, 15, 180, and 360 d after the third injection. A phone call was addressed to all volunteers at d 30 after the 2nd and 3rd injection.
Mentions: Statistical analysis of clinical response (safety and reactogenicity) was descriptive and per total vaccinated subjects. When indicated, two-sided statistical tests were performed regarded as exploratory. Differences between adjuvant or dose groups were analyzed by Fisher's exact test for safety and reactogenicity data (numbers of AEs). For immunological data, comparisons of adjuvant groups were performed using a Kruskal-Wallis Rank-Sum test on the log of the ratio of the “per time” values on those at D0 (SAS software). Other comparisons of immunological data including CD8+ and CD4+ T cell responses were calculated using non parametric Wilcoxon or Mann-Whitney t tests for paired within-group and between-groups comparisons respectively (GraphPad Prism software). Data were considered significant when p was <0.05.

Bottom Line: The two adjuvant formulations were well tolerated and their safety profile was good.Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months.For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

ABSTRACT

Background: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults.

Methodology and principal findings: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well 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 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-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma 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 microg formulated with AS02A appeared the most appropriate choice for such studies.

Trial registration: Swissmedic.ch 2002 DR 1227.

Show MeSH
Related in: MedlinePlus