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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya. Electronic address: Lucas.Tina@usamru-k.org.
authors.forename: Lucas
authors.initials: L
authors.lastname: Otieno
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Martina
authors.initials: M
authors.lastname: Oneko
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Walter
authors.initials: W
authors.lastname: Otieno
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Joseph
authors.initials: J
authors.lastname: Abuodha
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Owino
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Chris
authors.initials: C
authors.lastname: Odero
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Yolanda Guerra
authors.initials: YG
authors.lastname: Mendoza
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Ben
authors.initials: B
authors.lastname: Andagalu
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Norbert
authors.initials: N
authors.lastname: Awino
authors.affiliation: PATH Malaria Vaccine Initiative, Washington, DC, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ivinson
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heerwegh
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Nekoye
authors.initials: N
authors.lastname: Otsyula
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Maria
authors.initials: M
authors.lastname: Oziemkowska
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Effua Abigail
authors.initials: EA
authors.lastname: Usuf
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Allan
authors.initials: A
authors.lastname: Otieno
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Kephas
authors.initials: K
authors.lastname: Otieno
authors.affiliation: PATH Malaria Vaccine Initiative, Washington, DC, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Leboulleux
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Amanda
authors.initials: A
authors.lastname: Leach
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Janet
authors.initials: J
authors.lastname: Oyieko
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Slutsker
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Lievens
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cowden
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Lapierre
authors.affiliation: KEMRI/Centers for Disease Control and Prevention Research and Public Health Collaboration, Kisumu, Kenya.
authors.forename: Simon
authors.initials: S
authors.lastname: Kariuki
authors.affiliation: Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kombewa, Kenya.
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.affiliation: GlaxoSmithKline Vaccines, Wavre, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Hamel
mesh_terms: D004311:Double-Blind Method; D006678:HIV; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007223:Infant; D007630:Kenya / Q000453:epidemiology; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D017780:Malaria Vaccines; D011819:Rabies Vaccines