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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 the IFN-γ production by PBMC in response to PfCS102.IFN-γ was evaluated in the supernatant of stimulated peripheral blood mononuclear cells (PBMC). Results are expressed as individual IFN-γ secretion, expressed in pg/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.
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pone-0007304-g005: Time-course of the IFN-γ production by PBMC in response to PfCS102.IFN-γ was evaluated in the supernatant of stimulated peripheral blood mononuclear cells (PBMC). Results are expressed as individual IFN-γ secretion, expressed in pg/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.

Mentions: After two immunizations, the level of the IFN-γ response in PBMC cultures (median and quartiles: 1630 pg/ml (499;8549, n = 36) increased above baseline (84.7 pg/ml) in 34 out of 36 volunteers (Figure 5). With Montanide ISA 720, significant responses were already obtained after the first injection, and no boosting effect was induced by the following injections. Moreover, there was no dose effect. With AS02A, the dose of 10 µg induced delayed responses, with only one responder after the first injection, and two non-responders overall. Whatever the dose, responses increased after the second injection, but not after the third one. Combining peptide dose groups for comparison of adjuvants, AS02A formulations induced 10-fold higher level of responses than Montanide ISA 720 after the 2nd or the 3rd immunization (p<0.02, generally p<0.003, Kruskal-Wallis Rank-Sum test). Like in proliferation assays, CS 310–340 and 310–383 peptides induced IFN-γ responses similar to PfCS102, CS 282–318 inducing only weak responses Overall, the frequency of volunteers responding by the production of IFN-γ (34 out of 36) was higher than in the proliferation assay (32 out of 36). However, there was a strong correlation between T cell proliferation and IFN-γ production (r = 0.8562, p<0.0001 at day 195, r = 0.8282, p<0.0001 at day 75, Spearman's rank correlation).


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 the IFN-γ production by PBMC in response to PfCS102.IFN-γ was evaluated in the supernatant of stimulated peripheral blood mononuclear cells (PBMC). Results are expressed as individual IFN-γ secretion, expressed in pg/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0007304-g005: Time-course of the IFN-γ production by PBMC in response to PfCS102.IFN-γ was evaluated in the supernatant of stimulated peripheral blood mononuclear cells (PBMC). Results are expressed as individual IFN-γ secretion, expressed in pg/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.
Mentions: After two immunizations, the level of the IFN-γ response in PBMC cultures (median and quartiles: 1630 pg/ml (499;8549, n = 36) increased above baseline (84.7 pg/ml) in 34 out of 36 volunteers (Figure 5). With Montanide ISA 720, significant responses were already obtained after the first injection, and no boosting effect was induced by the following injections. Moreover, there was no dose effect. With AS02A, the dose of 10 µg induced delayed responses, with only one responder after the first injection, and two non-responders overall. Whatever the dose, responses increased after the second injection, but not after the third one. Combining peptide dose groups for comparison of adjuvants, AS02A formulations induced 10-fold higher level of responses than Montanide ISA 720 after the 2nd or the 3rd immunization (p<0.02, generally p<0.003, Kruskal-Wallis Rank-Sum test). Like in proliferation assays, CS 310–340 and 310–383 peptides induced IFN-γ responses similar to PfCS102, CS 282–318 inducing only weak responses Overall, the frequency of volunteers responding by the production of IFN-γ (34 out of 36) was higher than in the proliferation assay (32 out of 36). However, there was a strong correlation between T cell proliferation and IFN-γ production (r = 0.8562, p<0.0001 at day 195, r = 0.8282, p<0.0001 at day 75, Spearman's rank correlation).

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