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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

Time-course of individual frequencies of PfCS102 specific T cells.Frequencies were evaluated by intracellular cytokine staining (ICS) using the PBMC of HLA-A2 and/or HLA-A3 volunteers. Results are expressed as percentage of IFN-γ positive cells upon PfCS stimulation in the selected cell population: A, CD4+ cells; B, CD8+ cells; C, CD3+CD8+ T cells (CD16−/56−, CTL, and CD16+/56+, NKT cells) in 8 responders. Dotted lines represent baseline. Statistical analysis was based on Wilcoxon's test with p<0.05 as the limit of significance. Arrows indicate the times of vaccination.
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pone-0007304-g006: Time-course of individual frequencies of PfCS102 specific T cells.Frequencies were evaluated by intracellular cytokine staining (ICS) using the PBMC of HLA-A2 and/or HLA-A3 volunteers. Results are expressed as percentage of IFN-γ positive cells upon PfCS stimulation in the selected cell population: A, CD4+ cells; B, CD8+ cells; C, CD3+CD8+ T cells (CD16−/56−, CTL, and CD16+/56+, NKT cells) in 8 responders. Dotted lines represent baseline. Statistical analysis was based on Wilcoxon's test with p<0.05 as the limit of significance. Arrows indicate the times of vaccination.

Mentions: The frequency of PfCS specific CD4+ and CD8+ T cells was evaluated by ICS in HLA-A2 and HLA-A3 volunteers (n = 22, 10 volunteers received AS02A, 12 received Montanide ISA 720) (Table 1). Overall, vaccination induced an increase in the frequency of malaria specific CD4+ and CD8+ lymphocytes in 16 out of 22 volunteers (73%) (Table 4). Frequencies of these responses were ranging from 0.02% to 0.19% for CD4+ T cells (median 0.06%) and from 0.02% to 0.53% for CD8+ T cells (median 0.07%). Responders with frequencies of PfCS specific CD4+ or CD8+ responses above the baseline (frequencies of 0.038% and 0.086% respectively) represented 36.2% (8/22) of volunteers (Figure 6, A and B). A further descriptive analysis of the PfCS102 specific CD8+ lymphocyte subsets in these 8 responders allowed to discriminate antigen specific NK (CD3− CD8+ CD16/56+) from NKT cells (CD3+ CD8+ CD16/56+) and from CTL (CD3+ CD8+ CD16/56−). The 8 responders displayed a frequency of CD8+ NK responses that was about as high as half the frequency of IFN-γ secreting CD8+ lymphocytes (57.6% and 47.8% at day 75 and 195 respectively, data not shown). Nevertheless, five volunteers showed a marked increase in their antigen specific CD3+CD8+ T cells with vaccination (Figure 6C), mostly CTL (80%) and to a lesser extend NKT cells (data not shown). No distinction between doses or adjuvants could be drawn. Using the CD8+ cultured ELISPOT, we detected the presence of PfCS specific IFN-γ producing CD8+ T cells in only one volunteer out of the 14 HLA-A2 selected volunteers. This responder was one of the 5 responders by ICS described above. Virus specific CD8+ positive responses were obtained in 13 out of these 14 volunteers.


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)

Time-course of individual frequencies of PfCS102 specific T cells.Frequencies were evaluated by intracellular cytokine staining (ICS) using the PBMC of HLA-A2 and/or HLA-A3 volunteers. Results are expressed as percentage of IFN-γ positive cells upon PfCS stimulation in the selected cell population: A, CD4+ cells; B, CD8+ cells; C, CD3+CD8+ T cells (CD16−/56−, CTL, and CD16+/56+, NKT cells) in 8 responders. Dotted lines represent baseline. Statistical analysis was based on Wilcoxon's test with p<0.05 as the limit of significance. Arrows indicate the times of vaccination.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0007304-g006: Time-course of individual frequencies of PfCS102 specific T cells.Frequencies were evaluated by intracellular cytokine staining (ICS) using the PBMC of HLA-A2 and/or HLA-A3 volunteers. Results are expressed as percentage of IFN-γ positive cells upon PfCS stimulation in the selected cell population: A, CD4+ cells; B, CD8+ cells; C, CD3+CD8+ T cells (CD16−/56−, CTL, and CD16+/56+, NKT cells) in 8 responders. Dotted lines represent baseline. Statistical analysis was based on Wilcoxon's test with p<0.05 as the limit of significance. Arrows indicate the times of vaccination.
Mentions: The frequency of PfCS specific CD4+ and CD8+ T cells was evaluated by ICS in HLA-A2 and HLA-A3 volunteers (n = 22, 10 volunteers received AS02A, 12 received Montanide ISA 720) (Table 1). Overall, vaccination induced an increase in the frequency of malaria specific CD4+ and CD8+ lymphocytes in 16 out of 22 volunteers (73%) (Table 4). Frequencies of these responses were ranging from 0.02% to 0.19% for CD4+ T cells (median 0.06%) and from 0.02% to 0.53% for CD8+ T cells (median 0.07%). Responders with frequencies of PfCS specific CD4+ or CD8+ responses above the baseline (frequencies of 0.038% and 0.086% respectively) represented 36.2% (8/22) of volunteers (Figure 6, A and B). A further descriptive analysis of the PfCS102 specific CD8+ lymphocyte subsets in these 8 responders allowed to discriminate antigen specific NK (CD3− CD8+ CD16/56+) from NKT cells (CD3+ CD8+ CD16/56+) and from CTL (CD3+ CD8+ CD16/56−). The 8 responders displayed a frequency of CD8+ NK responses that was about as high as half the frequency of IFN-γ secreting CD8+ lymphocytes (57.6% and 47.8% at day 75 and 195 respectively, data not shown). Nevertheless, five volunteers showed a marked increase in their antigen specific CD3+CD8+ T cells with vaccination (Figure 6C), mostly CTL (80%) and to a lesser extend NKT cells (data not shown). No distinction between doses or adjuvants could be drawn. Using the CD8+ cultured ELISPOT, we detected the presence of PfCS specific IFN-γ producing CD8+ T cells in only one volunteer out of the 14 HLA-A2 selected volunteers. This responder was one of the 5 responders by ICS described above. Virus specific CD8+ positive responses were obtained in 13 out of these 14 volunteers.

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