Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania

a randomised controlled trial

Ally Olotu, John Lusingu, Amanda Leach, Marc Lievens, Johan Vekemans, Salum msham, Trudie Lang, Jayne Gould, Marie-Claude Dubois, Erik Jongert, Preeti vansadia, Terrell Carter, Patricia Njuguna, Ken O Awuondo, Anangisye Malabeja, Omar Abdul, Samwel Gesase, Neema Mturi, Chris Drakeley, Barbara Savarese & 10 others Tonya Villafana, Didier Lapierre, Ripley Ballou, Joe Cohen, Martha Lemnge, Norbert Peshu, Kevin Marsh, Eleanor Riley, Lorenz Von Seidlein, Phillip Bejon

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.

    Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.

    Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.

    Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.

    Original languageEnglish
    Pages (from-to)961-966
    Number of pages6
    JournalLancet Infectious Diseases
    Volume11
    Issue number2
    DOIs
    Publication statusPublished - 2011

    Fingerprint

    Malaria Vaccines
    Tanzania
    Kenya
    Anti-Idiotypic Antibodies
    Randomized Controlled Trials
    Malaria
    Rabies Vaccines
    Febrile Seizures
    Rabies
    Antibodies
    Falciparum Malaria
    Gastroenteritis
    Random Allocation
    RTS,S-AS01E vaccine
    Pneumonia
    Fever
    Vaccines
    Public Health
    Temperature

    Cite this

    Olotu, Ally ; Lusingu, John ; Leach, Amanda ; Lievens, Marc ; Vekemans, Johan ; msham, Salum ; Lang, Trudie ; Gould, Jayne ; Dubois, Marie-Claude ; Jongert, Erik ; vansadia, Preeti ; Carter, Terrell ; Njuguna, Patricia ; O Awuondo, Ken ; Malabeja, Anangisye ; Abdul, Omar ; Gesase, Samwel ; Mturi, Neema ; Drakeley, Chris ; Savarese, Barbara ; Villafana, Tonya ; Lapierre, Didier ; Ballou, Ripley ; Cohen, Joe ; Lemnge, Martha ; Peshu, Norbert ; Marsh, Kevin ; Riley, Eleanor ; Von Seidlein, Lorenz ; Bejon, Phillip. / Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania : a randomised controlled trial. In: Lancet Infectious Diseases. 2011 ; Vol. 11, No. 2. pp. 961-966.
    @article{01422b05bbbf421ab6093cd15c0ba113,
    title = "Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial",
    abstract = "Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2{\%} (95{\%} CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8{\%} (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.",
    keywords = "malaria vaccine, rabies vaccine, antibody titer, article, body temperature, child, childhood disease, controlled study, disease association, double blind procedure, drug efficacy, febrile convulsion, fever, follow up, gastroenteritis, human, infant, Kenya, major clinical study, malaria, malaria falciparum, Plasmodium falciparum, pneumonia, preschool child, priority journal, randomized controlled trial, sporozoite, Tanzania, Antibodies, Protozoan, Blood, Fever, Follow-Up Studies, Humans, Infant, Malaria Vaccines, Malaria, Falciparum, Protozoan Proteins",
    author = "Ally Olotu and John Lusingu and Amanda Leach and Marc Lievens and Johan Vekemans and Salum msham and Trudie Lang and Jayne Gould and Marie-Claude Dubois and Erik Jongert and Preeti vansadia and Terrell Carter and Patricia Njuguna and {O Awuondo}, Ken and Anangisye Malabeja and Omar Abdul and Samwel Gesase and Neema Mturi and Chris Drakeley and Barbara Savarese and Tonya Villafana and Didier Lapierre and Ripley Ballou and Joe Cohen and Martha Lemnge and Norbert Peshu and Kevin Marsh and Eleanor Riley and {Von Seidlein}, Lorenz and Phillip Bejon",
    year = "2011",
    doi = "10.1016/S1473-3099(10)70262-0",
    language = "English",
    volume = "11",
    pages = "961--966",
    journal = "The Lancet Infectious Diseases",
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    number = "2",

    }

    Olotu, A, Lusingu, J, Leach, A, Lievens, M, Vekemans, J, msham, S, Lang, T, Gould, J, Dubois, M-C, Jongert, E, vansadia, P, Carter, T, Njuguna, P, O Awuondo, K, Malabeja, A, Abdul, O, Gesase, S, Mturi, N, Drakeley, C, Savarese, B, Villafana, T, Lapierre, D, Ballou, R, Cohen, J, Lemnge, M, Peshu, N, Marsh, K, Riley, E, Von Seidlein, L & Bejon, P 2011, 'Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial', Lancet Infectious Diseases, vol. 11, no. 2, pp. 961-966. https://doi.org/10.1016/S1473-3099(10)70262-0

    Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania : a randomised controlled trial. / Olotu, Ally; Lusingu, John; Leach, Amanda; Lievens, Marc; Vekemans, Johan; msham, Salum; Lang, Trudie; Gould, Jayne; Dubois, Marie-Claude; Jongert, Erik; vansadia, Preeti; Carter, Terrell; Njuguna, Patricia; O Awuondo, Ken; Malabeja, Anangisye; Abdul, Omar; Gesase, Samwel; Mturi, Neema; Drakeley, Chris; Savarese, Barbara; Villafana, Tonya; Lapierre, Didier; Ballou, Ripley; Cohen, Joe; Lemnge, Martha; Peshu, Norbert; Marsh, Kevin; Riley, Eleanor; Von Seidlein, Lorenz; Bejon, Phillip.

    In: Lancet Infectious Diseases, Vol. 11, No. 2, 2011, p. 961-966.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania

    T2 - a randomised controlled trial

    AU - Olotu, Ally

    AU - Lusingu, John

    AU - Leach, Amanda

    AU - Lievens, Marc

    AU - Vekemans, Johan

    AU - msham, Salum

    AU - Lang, Trudie

    AU - Gould, Jayne

    AU - Dubois, Marie-Claude

    AU - Jongert, Erik

    AU - vansadia, Preeti

    AU - Carter, Terrell

    AU - Njuguna, Patricia

    AU - O Awuondo, Ken

    AU - Malabeja, Anangisye

    AU - Abdul, Omar

    AU - Gesase, Samwel

    AU - Mturi, Neema

    AU - Drakeley, Chris

    AU - Savarese, Barbara

    AU - Villafana, Tonya

    AU - Lapierre, Didier

    AU - Ballou, Ripley

    AU - Cohen, Joe

    AU - Lemnge, Martha

    AU - Peshu, Norbert

    AU - Marsh, Kevin

    AU - Riley, Eleanor

    AU - Von Seidlein, Lorenz

    AU - Bejon, Phillip

    PY - 2011

    Y1 - 2011

    N2 - Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.

    AB - Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.

    KW - malaria vaccine

    KW - rabies vaccine

    KW - antibody titer

    KW - article

    KW - body temperature

    KW - child

    KW - childhood disease

    KW - controlled study

    KW - disease association

    KW - double blind procedure

    KW - drug efficacy

    KW - febrile convulsion

    KW - fever

    KW - follow up

    KW - gastroenteritis

    KW - human

    KW - infant

    KW - Kenya

    KW - major clinical study

    KW - malaria

    KW - malaria falciparum

    KW - Plasmodium falciparum

    KW - pneumonia

    KW - preschool child

    KW - priority journal

    KW - randomized controlled trial

    KW - sporozoite

    KW - Tanzania

    KW - Antibodies, Protozoan

    KW - Blood

    KW - Fever

    KW - Follow-Up Studies

    KW - Humans

    KW - Infant

    KW - Malaria Vaccines

    KW - Malaria, Falciparum

    KW - Protozoan Proteins

    U2 - 10.1016/S1473-3099(10)70262-0

    DO - 10.1016/S1473-3099(10)70262-0

    M3 - Article

    VL - 11

    SP - 961

    EP - 966

    JO - The Lancet Infectious Diseases

    JF - The Lancet Infectious Diseases

    SN - 1473-3099

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    ER -