Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine

Further results from a phase IIb trial in Mozambican children

Caterina Guinovart, John Aponte, Jahit Sacarlal, Pedro Aide, Amanda Leach, Quique Bassat, Eusebio Macete, Carlota Dobano, Marc Lievens, Christian Loucq, Ripley Ballou, Joe Cohen, Pedro Alonso

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.

    Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0% (−30.6–36.6; p = 0.609) during the single-blind phase.

    Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.
    Original languageEnglish
    Article numbere5165
    Pages (from-to)1-8
    Number of pages8
    JournalPLoS One
    Volume4
    Issue number4
    DOIs
    Publication statusPublished - 14 Apr 2009

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    Malaria Vaccines
    malaria
    Malaria
    Vaccines
    vaccines
    Parasitemia
    parasitemia
    endpoints
    duration
    Blood
    early diagnosis
    Health Facilities
    Health
    dosage
    Infection
    Antigens
    infection
    RTS,S-AS02A vaccine
    malaria vaccines
    Early Diagnosis

    Cite this

    Guinovart, Caterina ; Aponte, John ; Sacarlal, Jahit ; Aide, Pedro ; Leach, Amanda ; Bassat, Quique ; Macete, Eusebio ; Dobano, Carlota ; Lievens, Marc ; Loucq, Christian ; Ballou, Ripley ; Cohen, Joe ; Alonso, Pedro. / Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine : Further results from a phase IIb trial in Mozambican children. In: PLoS One. 2009 ; Vol. 4, No. 4. pp. 1-8.
    @article{a7310bb39a754d58bbba4e006c61282d,
    title = "Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: Further results from a phase IIb trial in Mozambican children",
    abstract = "Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4{\%} (95{\%} CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0{\%} (−30.6–36.6; p = 0.609) during the single-blind phase.Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.",
    author = "Caterina Guinovart and John Aponte and Jahit Sacarlal and Pedro Aide and Amanda Leach and Quique Bassat and Eusebio Macete and Carlota Dobano and Marc Lievens and Christian Loucq and Ripley Ballou and Joe Cohen and Pedro Alonso",
    year = "2009",
    month = "4",
    day = "14",
    doi = "10.1371/journal.pone.0005165",
    language = "English",
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    Guinovart, C, Aponte, J, Sacarlal, J, Aide, P, Leach, A, Bassat, Q, Macete, E, Dobano, C, Lievens, M, Loucq, C, Ballou, R, Cohen, J & Alonso, P 2009, 'Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: Further results from a phase IIb trial in Mozambican children', PLoS One, vol. 4, no. 4, e5165, pp. 1-8. https://doi.org/10.1371/journal.pone.0005165

    Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine : Further results from a phase IIb trial in Mozambican children. / Guinovart, Caterina; Aponte, John; Sacarlal, Jahit; Aide, Pedro; Leach, Amanda; Bassat, Quique; Macete, Eusebio; Dobano, Carlota; Lievens, Marc; Loucq, Christian; Ballou, Ripley; Cohen, Joe; Alonso, Pedro.

    In: PLoS One, Vol. 4, No. 4, e5165, 14.04.2009, p. 1-8.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine

    T2 - Further results from a phase IIb trial in Mozambican children

    AU - Guinovart, Caterina

    AU - Aponte, John

    AU - Sacarlal, Jahit

    AU - Aide, Pedro

    AU - Leach, Amanda

    AU - Bassat, Quique

    AU - Macete, Eusebio

    AU - Dobano, Carlota

    AU - Lievens, Marc

    AU - Loucq, Christian

    AU - Ballou, Ripley

    AU - Cohen, Joe

    AU - Alonso, Pedro

    PY - 2009/4/14

    Y1 - 2009/4/14

    N2 - Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0% (−30.6–36.6; p = 0.609) during the single-blind phase.Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.

    AB - Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0% (−30.6–36.6; p = 0.609) during the single-blind phase.Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.

    U2 - 10.1371/journal.pone.0005165

    DO - 10.1371/journal.pone.0005165

    M3 - Article

    VL - 4

    SP - 1

    EP - 8

    JO - PLoS One

    JF - PLoS One

    SN - 1932-6203

    IS - 4

    M1 - e5165

    ER -