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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

Kaplan-Meier curves for time to parasitemia by blood smear (A) and PCR (B) for ARR (green), RRR (red), infectivity control (black) subjects (ATP efficacy).Log-rank analysis showed statistically significant differences between ARR and control subjects (P < .0001) and RRR and control subjects (P < .0001).
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pone.0131571.g002: Kaplan-Meier curves for time to parasitemia by blood smear (A) and PCR (B) for ARR (green), RRR (red), infectivity control (black) subjects (ATP efficacy).Log-rank analysis showed statistically significant differences between ARR and control subjects (P < .0001) and RRR and control subjects (P < .0001).

Mentions: Patent parasitemia developed in 14 of 25 (56.0%) ARR vaccinees, 10 of 21 (47.6%) RRR vaccinees, and 12 of 12 (100%) infectivity controls (Table 1). VE in the ARR group was 44% (95% CI: 21–60; p = .007) and in the RRR group 52% (95% CI: 25–70; p = .002), representing a decrease in VE of -18% (95% CI: -108, -33; p = .77) in ARR. The time to first parasitemia is shown in a plot of the Kaplan Meier survival estimate in Fig 2, indicating no significant difference between ARR and RRR groups by blood smear (P = .46) and by PCR (P = .41) in contrast to highly significant differences between ARR and RRR compared to infectivity controls (P < .0001). The futility criteria for efficacy were met, and it was determined that further immunization of ARR and RRR groups in cohorts B and C were not indicated.


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)

Kaplan-Meier curves for time to parasitemia by blood smear (A) and PCR (B) for ARR (green), RRR (red), infectivity control (black) subjects (ATP efficacy).Log-rank analysis showed statistically significant differences between ARR and control subjects (P < .0001) and RRR and control subjects (P < .0001).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131571.g002: Kaplan-Meier curves for time to parasitemia by blood smear (A) and PCR (B) for ARR (green), RRR (red), infectivity control (black) subjects (ATP efficacy).Log-rank analysis showed statistically significant differences between ARR and control subjects (P < .0001) and RRR and control subjects (P < .0001).
Mentions: Patent parasitemia developed in 14 of 25 (56.0%) ARR vaccinees, 10 of 21 (47.6%) RRR vaccinees, and 12 of 12 (100%) infectivity controls (Table 1). VE in the ARR group was 44% (95% CI: 21–60; p = .007) and in the RRR group 52% (95% CI: 25–70; p = .002), representing a decrease in VE of -18% (95% CI: -108, -33; p = .77) in ARR. The time to first parasitemia is shown in a plot of the Kaplan Meier survival estimate in Fig 2, indicating no significant difference between ARR and RRR groups by blood smear (P = .46) and by PCR (P = .41) in contrast to highly significant differences between ARR and RRR compared to infectivity controls (P < .0001). The futility criteria for efficacy were met, and it was determined that further immunization of ARR and RRR groups in cohorts B and C were not indicated.

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