Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models

Melissa A Penny, Robert Verity, Caitlin A Bever, Christophe Sauboin, Katya Galactionova, Stefan Flasche, Michael T White, Edward A Wenger, Nicolas Van de Velde, Peter Pemberton-Ross, Jamie T Griffin, Thomas A Smith, Philip A Eckhoff, Farzana Muhib, Mark Jit, Azra C Ghani, Melissa A Penny, Robert Verity, Caitlin A Bever, Christophe Sauboin, Katya Galactionova, Stefan Flasche, Michael T White, Edward A Wenger, Nicolas Van de Velde, Peter Pemberton-Ross, Jamie T Griffin, Thomas A Smith, Philip A Eckhoff, Farzana Muhib, Mark Jit, Azra C Ghani

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.

Findings: 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.

Interpretation: 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.

Funding: PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.

Copyright © 2016 Penny et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Observed and model-predicted vaccine efficacy against clinical and severe malaria from month 0 to study end (≥32 months) by study site in the 5–17 month age category Vaccine efficacy against all episodes of clinical malaria (primary case definition) in the three-dose group (A) and the four-dose group (B), and against severe malaria (primary case definition) in the three-dose group (C) and the four-dose group (D). Error bars show 95% CIs estimated from the trial data. *Intention-to-treat analysis.
Figure 2
Figure 2
Model predictions of clinical cases and deaths averted per 100 000 children fully vaccinated with a three-dose or four-dose immunisation schedule for a range of baseline PfPR2–10 levels Results for the three-dose (A, C) and four-dose (B, D) schedules are cumulative following 15 years of routine use of RTS,S. Bars show median estimates and error bars show 95% credible intervals. Negative cases averted at low transmission are due to stochastic variation between model runs at low prevalence, rather than to any modelled biological mechanism. PfPR2–10=parasite prevalence in 2–10 year olds.
Figure 3
Figure 3
Clinical cases averted in the vaccinated cohort at low (A) and high (B) endemicity after 15 years of routine use of RTS,S in a four-dose immunisation schedule Bars show median predictions over all four models and error bars show the range of predictions. Uncertainty within each model is not shown (see appendix pp 5–7). PfPR2–10=parasite prevalence in 2–10 year olds.
Figure 4
Figure 4
Cost per clinical case or DALY averted as a function of baseline parasite prevalence in 2–10 year olds (PfPR2–10) Results assume a vaccine price of $2 (A, D), $5 (B, E), or $10 (C, E) per dose. Solid lines represent a three-dose immunisation schedule and dashed lines represent a four-dose immunisation schedule. Similar estimates of incremental cost-effectiveness ratios were obtained for the three-dose and four-dose schedules because the additional public health benefit of the boosted schedule is offset by the incremental cost of implementation of the additional dose. Uncertainty estimates surrounding the models' predictions are omitted for readability but overlap. DALY=disability-adjusted life-year.

References

    1. WHO . World malaria report 2013. World Health Organization; Geneva: 2014.
    1. Bhatt S, Weiss DJ, Cameron E. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015;526:207–211.
    1. RTSS Clinical Trials Partnership Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015;386:31–45.
    1. Patil AP, Okiro EA, Gething PW. Defining the relationship between Plasmodium falciparum parasite rate and clinical disease: statistical models for disease burden estimation. Malar J. 2009;8:186.
    1. Hamel MJ, Oneko M, Williamson J. A marked reduction in mortality among participants in a clinical trial that removed barriers to care and implemented national case management guidelines. 63rd Annual meeting of the American Society of Tropical Medicine and Hygiene; New Orleans, LA; Nov 2–6, 2014. 631 (abstr).
    1. Hutubessy R, Henao AM, Namgyal P, Moorthy V, Hombach J. Results from evaluations of models and cost-effectiveness tools to support introduction decisions for new vaccines need critical appraisal. BMC Med. 2011;9:55.
    1. Moorthy VS, Hutubessy R, Newman RD, Hombach J. Decision-making on malaria vaccine introduction: the role of cost-effectiveness analyses. Bull World Health Organ. 2012;90:864–866.
    1. Lee LA, Franzel L, Atwell J. The estimated mortality impact of vaccinations forecast to be administered during 2011–2020 in 73 countries supported by the GAVI Alliance. Vaccine. 2013;31:B61–B72.
    1. McCarthy KA, Wenger EA, Huynh GH, Eckhoff PA. Calibration of an intrahost malaria model and parameter ensemble evaluation of a pre-erythrocytic vaccine. Malar J. 2015;14:6.
    1. Sauboin C, Van Vlaenderen I, Van Bellinghen LA, Standaert B. Cost-effectiveness of RTS,S malaria vaccine candidate in children estimated using a Markov cohort model and phase 3 trial results. 3rd International Conference of the African Health Economics and Policy Association; Nairobi, Kenya; March 11–13, 2014. 40 (abstr).
    1. Griffin JT, Ferguson NM, Ghani AC. Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa. Nat Commun. 2014;5:3136.
    1. Smith T, Ross A, Maire N. Ensemble modeling of the likely public health impact of a pre-erythrocytic malaria vaccine. PLoS Med. 2012;9:44.
    1. Penny MA, Galactionova K, Tarantino M, Tanner M, Smith TA. The public health impact of malaria vaccine RTS, S in malaria endemic Africa: country-specific predictions using 18 month follow-up phase III data and simulation models. BMC Med. 2015;13:170.
    1. White MT, Verity R, Griffin JT. Immunogenicity of the RTS,S/AS01 malaria vaccine over time and implications for duration of vaccine efficacy: analysis of data from a phase 3 randomised controlled trial. Lancet Infect Dis. 2015 published online Sept 2.
    1. INDEPTH Network . Model life tables for sub-Saharan Africa. Ashgate Publishing; Aldershot: 2004.
    1. WHO WHO–UNICEF estimates of DTP3 coverage. 2013. (accessed Dec 1, 2014).
    1. World Health Organization . Global technical strategy for malaria 2016–2030. World Health Organization; Geneva: 2015.
    1. The RTSS Clinical Trials Partnership Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African Sites. PLoS Med. 2014;11:e1001685.
    1. Greenwood BM, David PH, Otoo-Forbes LN. Mortality and morbidity from malaria after stopping malaria chemoprophylaxis. Trans R Soc Trop Med Hyg. 1995;89:629–633.
    1. Aponte JJ, Menendez C, Schellenberg D. Age interactions in the development of naturally acquired immunity to Plasmodium falciparum and its clinical presentation. PLoS Med. 2007;4:e242.
    1. Gosling RD, Ghani AC, Deen JL, von Seidlein L, Greenwood BM, Chandramohan D. Can changes in malaria transmission intensity explain prolonged protection and contribute to high protective efficacy of intermittent preventive treatment for malaria in infants? Malar J. 2008;7:54.
    1. WHO. UN Children's Fund . Achieving the malaria MDG target: reversing the incidence of malaria 2000–2015. World Health Organization; Geneva: 2015.
    1. Marsh K, Snow R. Malaria transmission and morbidity. Parassitologia. 1999;41:241–246.
    1. Olotu A, Fegan G, Wambua J. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N Engl J Med. 2013;368:1111–1120.
    1. White MT, Conteh L, Cibulskis R, Ghani AC. Costs and cost-effectiveness of malaria control interventions—a systematic review. Malar J. 2011;10:337.
    1. Yukich JO, Lengeler C, Tediosi F. Costs and consequences of large-scale vector control for malaria. Malar J. 2008;7:258.
    1. Lengeler C. Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Syst Rev. 2004;2 CD000363.
    1. White MT, Griffin JT, Akpogheneta O. Dynamics of the antibody response to Plasmodium falciparum infection in African children. J Infect Dis. 2014;210:1115–1122.
    1. WHO . WHO guide for standardization of economic evaluations of immunization programmes. World Health Organization; Geneva: 2008.
    1. WHO Global Advisory Committee on Vaccine Safety, 11–12 June 2014. Wkly Epidemiol Rec. 2014;89:325–335.

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