title: Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models.
abstract: BACKGROUND
  The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings.
  
  
  METHODS
  We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose.
  
  
  RESULTS
  In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels.
  
  
  CONCLUSIONS
  We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine.
  
  
  BACKGROUND
  PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland. Electronic address: melissa.penny@unibas.ch.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Penny
authors.affiliation: Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Verity
authors.affiliation: Institute for Disease Modeling, Bellevue, WA, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Bever
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Sauboin
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Katya
authors.initials: K
authors.lastname: Galactionova
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Flasche
authors.affiliation: Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK.
authors.forename: Michael T
authors.initials: MT
authors.lastname: White
authors.affiliation: Institute for Disease Modeling, Bellevue, WA, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Wenger
authors.affiliation: GSK Vaccines, Wavre, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Van de Velde
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Pemberton-Ross
authors.affiliation: Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK.
authors.forename: Jamie T
authors.initials: JT
authors.lastname: Griffin
authors.affiliation: Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Smith
authors.affiliation: Institute for Disease Modeling, Bellevue, WA, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Eckhoff
authors.affiliation: PATH, Washington, DC, USA.
authors.forename: Farzana
authors.initials: F
authors.lastname: Muhib
authors.affiliation: Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Modelling and Economics Unit, Public Health England, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Jit
authors.affiliation: Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London, London, UK.
authors.forename: Azra C
authors.initials: AC
authors.lastname: Ghani
mesh_terms: D000349:Africa / Q000453:epidemiology; D017326:Clinical Trials, Phase III as Topic; D003362:Cost-Benefit Analysis; D006801:Humans; D007115:Immunization Schedule; D007223:Infant; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000191:economics*; D016778:Malaria, Falciparum / Q000191:economics / Q000453:epidemiology / Q000517:prevention & control*; D008962:Models, Theoretical; D015337:Multicenter Studies as Topic; D011634:Public Health
chemical_list: D017780:Malaria Vaccines