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Ad35.CS.01-RTS,S/AS01 Heterologous Prime Boost Vaccine Efficacy against Sporozoite Challenge in Healthy Malaria-Naïve Adults.

Ockenhouse CF, Regules J, Tosh D, Cowden J, Kathcart A, Cummings J, Paolino K, Moon J, Komisar J, Kamau E, Oliver T, Chhoeu A, Murphy J, Lyke K, Laurens M, Birkett A, Lee C, Weltzin R, Wille-Reece U, Sedegah M, Hendriks J, Versteege I, Pau MG, Sadoff J, Vanloubbeeck Y, Lievens M, Heerwegh D, Moris P, Guerra Mendoza Y, Jongert E, Cohen J, Voss G, Ballou WR, Vekemans J - PLoS ONE (2015)

Bottom Line: The RRR-group had greater anti-CS specific IgG titers than did the ARR-group.An increase in vaccine efficacy of ARR-group over RRR-group was not achieved.Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.

View Article: PubMed Central - PubMed

Affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.

ABSTRACT

Methods: In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection.

Results: ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001).

Conclusions: An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.

Trial registration: ClinicalTrials.gov NCT01366534.

No MeSH data available.


Related in: MedlinePlus

Cellular immune responses by vaccine group and days post immunization.A. Geometric mean CS-specific CD4+ T cells producing IFN-γ by ELISpot. Comparisons between ARR and RRR on days 42, 77, 105,140, and 236 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. B. Geometric mean CS-specific CD4+ T cell responses expressing ≥2 cytokine/activation markers among IL2, IFN-γ, TNF-α, and CD40L, per million PBMC. Comparisons between ARR and RRR on days 42, 77, 105, 140 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. C. Pie charts showing the pattern of CS-specific polyfunctional CD4+ CD40L+ T cells expressing ≥2 cytokine markers at Day 77 (day of challenge). Each slice within the pie chart represents a specific combination of two or three cytokines. The size of the pie chart is proportional to the magnitude of the response.
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pone.0131571.g003: Cellular immune responses by vaccine group and days post immunization.A. Geometric mean CS-specific CD4+ T cells producing IFN-γ by ELISpot. Comparisons between ARR and RRR on days 42, 77, 105,140, and 236 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. B. Geometric mean CS-specific CD4+ T cell responses expressing ≥2 cytokine/activation markers among IL2, IFN-γ, TNF-α, and CD40L, per million PBMC. Comparisons between ARR and RRR on days 42, 77, 105, 140 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. C. Pie charts showing the pattern of CS-specific polyfunctional CD4+ CD40L+ T cells expressing ≥2 cytokine markers at Day 77 (day of challenge). Each slice within the pie chart represents a specific combination of two or three cytokines. The size of the pie chart is proportional to the magnitude of the response.

Mentions: CS-specific IFN-γ ELISpot responses were significantly greater in the ARR group as compared to the RRR group at all time points from day 42 (post dose 2) through day 236 (Fig 3A). CS-specific CD4 T cell responses expressing two or more immune markers among CD40L, IL-2, TNF-α and IFN-γ were induced post vaccination in both vaccine groups, and T cell responses were significantly higher in the ARR group compared to the RRR group from day 42 (post dose 2) to day 140 (Fig 3B). There was a trend towards more simultaneous expression of cytokine/activation markers (polyfunctionality) and differentiation towards IFN-γ production in the ARR group as compared to the RRR group. The proportion and magnitude of these polyfunctional CD4 T cell responses differed between the two vaccine groups (Fig 3C).


Ad35.CS.01-RTS,S/AS01 Heterologous Prime Boost Vaccine Efficacy against Sporozoite Challenge in Healthy Malaria-Naïve Adults.

Ockenhouse CF, Regules J, Tosh D, Cowden J, Kathcart A, Cummings J, Paolino K, Moon J, Komisar J, Kamau E, Oliver T, Chhoeu A, Murphy J, Lyke K, Laurens M, Birkett A, Lee C, Weltzin R, Wille-Reece U, Sedegah M, Hendriks J, Versteege I, Pau MG, Sadoff J, Vanloubbeeck Y, Lievens M, Heerwegh D, Moris P, Guerra Mendoza Y, Jongert E, Cohen J, Voss G, Ballou WR, Vekemans J - PLoS ONE (2015)

Cellular immune responses by vaccine group and days post immunization.A. Geometric mean CS-specific CD4+ T cells producing IFN-γ by ELISpot. Comparisons between ARR and RRR on days 42, 77, 105,140, and 236 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. B. Geometric mean CS-specific CD4+ T cell responses expressing ≥2 cytokine/activation markers among IL2, IFN-γ, TNF-α, and CD40L, per million PBMC. Comparisons between ARR and RRR on days 42, 77, 105, 140 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. C. Pie charts showing the pattern of CS-specific polyfunctional CD4+ CD40L+ T cells expressing ≥2 cytokine markers at Day 77 (day of challenge). Each slice within the pie chart represents a specific combination of two or three cytokines. The size of the pie chart is proportional to the magnitude of the response.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492580&req=5

pone.0131571.g003: Cellular immune responses by vaccine group and days post immunization.A. Geometric mean CS-specific CD4+ T cells producing IFN-γ by ELISpot. Comparisons between ARR and RRR on days 42, 77, 105,140, and 236 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. B. Geometric mean CS-specific CD4+ T cell responses expressing ≥2 cytokine/activation markers among IL2, IFN-γ, TNF-α, and CD40L, per million PBMC. Comparisons between ARR and RRR on days 42, 77, 105, 140 were significant (P < .05) by Student’s t-test on log-transformed data. Error bars represent standard deviation of the mean. C. Pie charts showing the pattern of CS-specific polyfunctional CD4+ CD40L+ T cells expressing ≥2 cytokine markers at Day 77 (day of challenge). Each slice within the pie chart represents a specific combination of two or three cytokines. The size of the pie chart is proportional to the magnitude of the response.
Mentions: CS-specific IFN-γ ELISpot responses were significantly greater in the ARR group as compared to the RRR group at all time points from day 42 (post dose 2) through day 236 (Fig 3A). CS-specific CD4 T cell responses expressing two or more immune markers among CD40L, IL-2, TNF-α and IFN-γ were induced post vaccination in both vaccine groups, and T cell responses were significantly higher in the ARR group compared to the RRR group from day 42 (post dose 2) to day 140 (Fig 3B). There was a trend towards more simultaneous expression of cytokine/activation markers (polyfunctionality) and differentiation towards IFN-γ production in the ARR group as compared to the RRR group. The proportion and magnitude of these polyfunctional CD4 T cell responses differed between the two vaccine groups (Fig 3C).

Bottom Line: The RRR-group had greater anti-CS specific IgG titers than did the ARR-group.An increase in vaccine efficacy of ARR-group over RRR-group was not achieved.Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.

View Article: PubMed Central - PubMed

Affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.

ABSTRACT

Methods: In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection.

Results: ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001).

Conclusions: An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.

Trial registration: ClinicalTrials.gov NCT01366534.

No MeSH data available.


Related in: MedlinePlus