Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease

a randomised, double-blind, controlled trial

Lucas Otieno, Martina Oneko, Walter Otieno, Joseph Abuodha, Emmanuel Owino, Chris Odero, Yolanda Guerra Mendoza, Ben Andagalu, Norbert Awino, Karen Ivinson, Dirk Heerwegh, Nekoye Otsyula, Maria Oziemkowska, Effua Abigail Usuf, Allan Otieno, Kephas Otieno, Didier Leboulleux, Amanda Leach, Janet Oyieko, Laurence Slutsker & 7 others Marc Lievens, Jessica Cowden, Didier Lapierre, Simon Kariuki, Bernhards Ogutu, Johan Vekemans, Mary J. Hamel

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. 

    Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)–Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks–4 months, 5–17 months), and by baseline CD4% (<10, 10–14, 15–19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459. 

    Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6–51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3–46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8–1·6). 20 (20·2%, 95% CI 12·8–29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3–19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7–11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1–9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients). 

    Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. Funding GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

    Original languageEnglish
    Pages (from-to)1134-1144
    Number of pages11
    JournalLancet Infectious Diseases
    Volume16
    Issue number10
    DOIs
    Publication statusPublished - 1 Oct 2016

    Fingerprint

    Rabies Vaccines
    Malaria Vaccines
    HIV-2
    HIV-1
    Safety
    Kenya
    Vaccination
    HIV
    Vaccines
    Sulfamethoxazole Drug Combination Trimethoprim
    Malaria
    Biomedical Research
    Sepsis
    Pneumonia
    Haemophilus Meningitis
    RTS,S-AS01 vaccine
    Therapeutics
    Febrile Seizures
    Africa South of the Sahara
    Intramuscular Injections

    Cite this

    Otieno, Lucas ; Oneko, Martina ; Otieno, Walter ; Abuodha, Joseph ; Owino, Emmanuel ; Odero, Chris ; Mendoza, Yolanda Guerra ; Andagalu, Ben ; Awino, Norbert ; Ivinson, Karen ; Heerwegh, Dirk ; Otsyula, Nekoye ; Oziemkowska, Maria ; Usuf, Effua Abigail ; Otieno, Allan ; Otieno, Kephas ; Leboulleux, Didier ; Leach, Amanda ; Oyieko, Janet ; Slutsker, Laurence ; Lievens, Marc ; Cowden, Jessica ; Lapierre, Didier ; Kariuki, Simon ; Ogutu, Bernhards ; Vekemans, Johan ; Hamel, Mary J. / Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease : a randomised, double-blind, controlled trial. In: Lancet Infectious Diseases. 2016 ; Vol. 16, No. 10. pp. 1134-1144.
    @article{68d5e250aa3d451a8e1aee24d91f2871,
    title = "Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial",
    abstract = "Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)–Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks–4 months, 5–17 months), and by baseline CD4{\%} (<10, 10–14, 15–19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459. Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89{\%}) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4{\%}, 95{\%} CI 31·6–51·8) of 99 RTS,S/AS01 recipients and 37 (36·6{\%}, 27·3–46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95{\%} CI 0·8–1·6). 20 (20·2{\%}, 95{\%} CI 12·8–29·5) of 99 RTS,S/AS01 recipients and 12 (11·9{\%}, 6·3–19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1{\%}, 95{\%} CI 1·7–11·4) of 99 RTS,S/AS01 recipients and four (4·0{\%}, 1·1–9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1{\%} RTS,S/AS01 recipients vs 3{\%} rabies-vaccine recipients), five cases of gastroenteritis (3{\%} RTS,S/AS01 recipients vs 2{\%} rabies-vaccine recipients), five cases of malnutrition (2{\%} RTS,S/AS01 recipients vs 3{\%} rabies-vaccine recipients), one case of sepsis (1{\%} rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1{\%} rabies-vaccine recipients), and one case of tuberculosis (1{\%} RTS,S/AS01 recipients). Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. Funding GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.",
    author = "Lucas Otieno and Martina Oneko and Walter Otieno and Joseph Abuodha and Emmanuel Owino and Chris Odero and Mendoza, {Yolanda Guerra} and Ben Andagalu and Norbert Awino and Karen Ivinson and Dirk Heerwegh and Nekoye Otsyula and Maria Oziemkowska and Usuf, {Effua Abigail} and Allan Otieno and Kephas Otieno and Didier Leboulleux and Amanda Leach and Janet Oyieko and Laurence Slutsker and Marc Lievens and Jessica Cowden and Didier Lapierre and Simon Kariuki and Bernhards Ogutu and Johan Vekemans and Hamel, {Mary J.}",
    year = "2016",
    month = "10",
    day = "1",
    doi = "10.1016/S1473-3099(16)30161-X",
    language = "English",
    volume = "16",
    pages = "1134--1144",
    journal = "The Lancet Infectious Diseases",
    issn = "1473-3099",
    publisher = "The Lancet Publishing Group",
    number = "10",

    }

    Otieno, L, Oneko, M, Otieno, W, Abuodha, J, Owino, E, Odero, C, Mendoza, YG, Andagalu, B, Awino, N, Ivinson, K, Heerwegh, D, Otsyula, N, Oziemkowska, M, Usuf, EA, Otieno, A, Otieno, K, Leboulleux, D, Leach, A, Oyieko, J, Slutsker, L, Lievens, M, Cowden, J, Lapierre, D, Kariuki, S, Ogutu, B, Vekemans, J & Hamel, MJ 2016, 'Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial', Lancet Infectious Diseases, vol. 16, no. 10, pp. 1134-1144. https://doi.org/10.1016/S1473-3099(16)30161-X

    Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease : a randomised, double-blind, controlled trial. / Otieno, Lucas; Oneko, Martina; Otieno, Walter; Abuodha, Joseph; Owino, Emmanuel; Odero, Chris; Mendoza, Yolanda Guerra; Andagalu, Ben; Awino, Norbert; Ivinson, Karen; Heerwegh, Dirk; Otsyula, Nekoye; Oziemkowska, Maria; Usuf, Effua Abigail; Otieno, Allan; Otieno, Kephas; Leboulleux, Didier; Leach, Amanda; Oyieko, Janet; Slutsker, Laurence; Lievens, Marc; Cowden, Jessica; Lapierre, Didier; Kariuki, Simon; Ogutu, Bernhards; Vekemans, Johan; Hamel, Mary J.

    In: Lancet Infectious Diseases, Vol. 16, No. 10, 01.10.2016, p. 1134-1144.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease

    T2 - a randomised, double-blind, controlled trial

    AU - Otieno, Lucas

    AU - Oneko, Martina

    AU - Otieno, Walter

    AU - Abuodha, Joseph

    AU - Owino, Emmanuel

    AU - Odero, Chris

    AU - Mendoza, Yolanda Guerra

    AU - Andagalu, Ben

    AU - Awino, Norbert

    AU - Ivinson, Karen

    AU - Heerwegh, Dirk

    AU - Otsyula, Nekoye

    AU - Oziemkowska, Maria

    AU - Usuf, Effua Abigail

    AU - Otieno, Allan

    AU - Otieno, Kephas

    AU - Leboulleux, Didier

    AU - Leach, Amanda

    AU - Oyieko, Janet

    AU - Slutsker, Laurence

    AU - Lievens, Marc

    AU - Cowden, Jessica

    AU - Lapierre, Didier

    AU - Kariuki, Simon

    AU - Ogutu, Bernhards

    AU - Vekemans, Johan

    AU - Hamel, Mary J.

    PY - 2016/10/1

    Y1 - 2016/10/1

    N2 - Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)–Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks–4 months, 5–17 months), and by baseline CD4% (<10, 10–14, 15–19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459. Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6–51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3–46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8–1·6). 20 (20·2%, 95% CI 12·8–29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3–19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7–11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1–9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients). Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. Funding GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

    AB - Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)–Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks–4 months, 5–17 months), and by baseline CD4% (<10, 10–14, 15–19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459. Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6–51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3–46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8–1·6). 20 (20·2%, 95% CI 12·8–29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3–19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7–11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1–9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients). Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. Funding GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

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    U2 - 10.1016/S1473-3099(16)30161-X

    DO - 10.1016/S1473-3099(16)30161-X

    M3 - Article

    VL - 16

    SP - 1134

    EP - 1144

    JO - The Lancet Infectious Diseases

    JF - The Lancet Infectious Diseases

    SN - 1473-3099

    IS - 10

    ER -