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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 anti-PfCS102 antibody response upon PfCS102 immunization.Anti-PfCS102 antibodies were measured in plasma samples by ELISA. Results are expressed as individual data in U/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.
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pone-0007304-g002: Time course of anti-PfCS102 antibody response upon PfCS102 immunization.Anti-PfCS102 antibodies were measured in plasma samples by ELISA. Results are expressed as individual data in U/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.

Mentions: Two weeks after the second and the third injection, 97% of immunized volunteers (35/36 and 34/35 respectively) produced antibodies against PfCS102 above the baseline (2.9 U/ml) (medians and quartiles of all responses: 559 U/ml [237.5; 1162.9] and 695.9 U/ml [262.8; 3047.8] respectively) (Figure 2). At day 360, 94% (32/34) of volunteers still displayed a positive response although of decreasing intensity (median  = 157.9 U/ml [39.0; 636.6]. The level of response was largely higher than the response obtained in the preliminary PfCS102 study (maximum163 U/ml, titer of 25600) [20] or than those observed in endemic area (median 17.8 U/ml [6.1; 55.5], n = 6). Frequencies of responders were similar among all six groups. Nevertheless, after the 2nd and the 3rd immunization, volunteers who received AS02A developed the highest levels of anti-PfCS102 antibodies without differences between the 30 µg and 100 µg doses, but a significantly lower response with the 10 µg dose. In contrast, no dose effect was observed with Montanide ISA 720. Overall, pooling results of doses 30 µg and 100 µg, antibody levels were at each time-points higher in the A group than in the M group, and significant at days 180, 195, 360 (p<0.004, Kruskal-Wallis Rank-Sum test). At day 360, levels of antibody responses were at least one log higher in groups immunized with 30 µg or 100 µg PfCS102 formulated with AS02A than with Montanide ISA 720 (p = 0.0065 and 0.0039, respectively, Kruskal-Wallis Rank-Sum test).


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 anti-PfCS102 antibody response upon PfCS102 immunization.Anti-PfCS102 antibodies were measured in plasma samples by ELISA. Results are expressed as individual data in U/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-g002: Time course of anti-PfCS102 antibody response upon PfCS102 immunization.Anti-PfCS102 antibodies were measured in plasma samples by ELISA. Results are expressed as individual data in U/ml for each immunization group, with quartiles. Arrows indicate the times of vaccination.
Mentions: Two weeks after the second and the third injection, 97% of immunized volunteers (35/36 and 34/35 respectively) produced antibodies against PfCS102 above the baseline (2.9 U/ml) (medians and quartiles of all responses: 559 U/ml [237.5; 1162.9] and 695.9 U/ml [262.8; 3047.8] respectively) (Figure 2). At day 360, 94% (32/34) of volunteers still displayed a positive response although of decreasing intensity (median  = 157.9 U/ml [39.0; 636.6]. The level of response was largely higher than the response obtained in the preliminary PfCS102 study (maximum163 U/ml, titer of 25600) [20] or than those observed in endemic area (median 17.8 U/ml [6.1; 55.5], n = 6). Frequencies of responders were similar among all six groups. Nevertheless, after the 2nd and the 3rd immunization, volunteers who received AS02A developed the highest levels of anti-PfCS102 antibodies without differences between the 30 µg and 100 µg doses, but a significantly lower response with the 10 µg dose. In contrast, no dose effect was observed with Montanide ISA 720. Overall, pooling results of doses 30 µg and 100 µg, antibody levels were at each time-points higher in the A group than in the M group, and significant at days 180, 195, 360 (p<0.004, Kruskal-Wallis Rank-Sum test). At day 360, levels of antibody responses were at least one log higher in groups immunized with 30 µg or 100 µg PfCS102 formulated with AS02A than with Montanide ISA 720 (p = 0.0065 and 0.0039, respectively, Kruskal-Wallis Rank-Sum test).

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