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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

Reverse cumulative distribution curves by post challenge protection status for CS anti-repeat antibodies on day 77-Day of challenge for subjects in ARR protected (solid red) and non-protected (dashed red) compared to RRR protected (solid black) and non-protected (dashed black) subjects.Y-axis represents proportion of subjects at each antibody level.
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pone.0131571.g004: Reverse cumulative distribution curves by post challenge protection status for CS anti-repeat antibodies on day 77-Day of challenge for subjects in ARR protected (solid red) and non-protected (dashed red) compared to RRR protected (solid black) and non-protected (dashed black) subjects.Y-axis represents proportion of subjects at each antibody level.

Mentions: Protected subjects had higher anti-CS repeat IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .0013). The IgG titers were significantly higher in protected compared to non-protected subjects post Dose 3 (Day 77; DOC) in the RRR group (P = .01) (Table 2). Reverse cumulative distribution curves (RCDC) comparing protected and non-protected subjects in both groups confirmed these differences over a range of antibody titers (Fig 4). Of note, the RCDC of protected subjects in the ARR group overlapped with the RCDC from non-protected subjects in the RRR group suggesting that immune response(s) other than anti-CS repeat IgG or contributions from the Fc immunoglobulin domain accounted for the differences in protection between the two sub-groups.


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)

Reverse cumulative distribution curves by post challenge protection status for CS anti-repeat antibodies on day 77-Day of challenge for subjects in ARR protected (solid red) and non-protected (dashed red) compared to RRR protected (solid black) and non-protected (dashed black) subjects.Y-axis represents proportion of subjects at each antibody level.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131571.g004: Reverse cumulative distribution curves by post challenge protection status for CS anti-repeat antibodies on day 77-Day of challenge for subjects in ARR protected (solid red) and non-protected (dashed red) compared to RRR protected (solid black) and non-protected (dashed black) subjects.Y-axis represents proportion of subjects at each antibody level.
Mentions: Protected subjects had higher anti-CS repeat IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .0013). The IgG titers were significantly higher in protected compared to non-protected subjects post Dose 3 (Day 77; DOC) in the RRR group (P = .01) (Table 2). Reverse cumulative distribution curves (RCDC) comparing protected and non-protected subjects in both groups confirmed these differences over a range of antibody titers (Fig 4). Of note, the RCDC of protected subjects in the ARR group overlapped with the RCDC from non-protected subjects in the RRR group suggesting that immune response(s) other than anti-CS repeat IgG or contributions from the Fc immunoglobulin domain accounted for the differences in protection between the two sub-groups.

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