Implementation of the malaria candidate vaccine RTS,S/AS01
318 www.thelancet.com Vol 387 January 23, 2016 As vaccine manufacturers tackle increasingly intractable pathogens, vaccines will be developed that show effi cacy, but that are less effi cacious than established vaccines. Consequently, regulatory and public health authorities will be faced with diffi cult decisions about whether such vaccines should be recommended for implementation and, if so, under what circumstances. The RTS,S/AS01 malaria candidate vaccine provides an important example of such a challenge. After a long period of development, a large phase 3 trial of RTS,S/AS01 in children aged 5 17 months at fi rst vaccination showed a vaccine effi cacy of 28*3% (95% CI 23*3 32*9% against clinical malaria in children who received three doses, and of 36*3% (31*8 40*5% in those given a fourth dose, during 48 months of follow up. The vaccine also provided signifi cant protection against severe malaria and hospital admissions in the group of children who received a fourth dose. An average of 1774 cases (95% CI 1387 2186) of clinical malaria were averted per 1000 children vaccinated in the four dose group. An unexplained increase in incidence of meningitis was identifi ed as a safety signal. Effi cacy was lower in infants who received their fi rst dose of vaccine aged 6 12 weeks than in children aged 5 17 months. Could this vaccine with restricted effi cacy still have a useful role in malaria control? In The Lancet, Melissa Penny and colleagues provide some important new information that suggests that it could. Four modelling groups have worked together to estimate the potential impact of RTS,S/AS01 on malaria cases and deaths. Overall, the models gave similar results. On the basis of assumptions of 72% coverage with a four dose schedule, a 15 year follow up period (needed to account for any age shift in malaria incidence) and a vaccine price of US$2 10 per dose, the models predicted that in the areas where the parasite prevalence in children aged 2 10 years (PfPR2 10; a widely used measure of the intensity of malaria transmission) lies between 10% and 65% RTS,S/AS01 would prevent 116 480 (range 31 450 160 410) cases of clinical malaria and 484 (190 860) deaths per 100 000 fully vaccinated children. At $5 a dose, the cost per disability adjusted life year (DALY) averted in areas with a PfPR2 10 of 10% or more would be less than $100, an amount comparable to that of other malaria control measures. As recognised by the investigators, the study includes several unproven assumptions. The most important of these is the assumption that RTS,S/AS01 will have a signifi cant impact on mortality, a key factor for decision makers and for calculation of DALYs; this assumption is not yet supported by empirical data. However, the quality of care provided to children in trials of RTS,S/AS01 was exemplary and, in the phase 3 trial, mortality was very low in all study groups. Trials of seasonal malaria chemoprevention also failed to show a statistically signifi cant impact on mortality, but this intervention is having a major impact when deployed on a large scale. By contrast, trials of insecticide treated nets did show an impact on mortality, but these studies were done at the community level, with less intensive follow up of individual participants. The assumption that RTS,S/AS01 will have a signifi cant impact on mortality if deployed in high transmission areas is a reasonable one. The European Medicines Agency reviewed the effi cacy and safety of RTS,S/AS01 and, under article 58, gave a positive opinion on its use in both the younger and older age groups included in the phase 3 trial. By contrast, WHO's Strategic Advisory Group of Experts on Immunization and Malaria Policy Advisory Committee only recommended use of the vaccine in children in the older age group. They also recommended that several pilot studies should be undertaken before widespread deployment of the vaccine. The objective of these pilot projects would be to assess whether routine immunisation programmes can deliver the four dose schedule eff ectively, whether the vaccine prevents deaths, and whether the safety signals detected in the phase 3 trial were just chance fi ndings. To abandon RTS,S/AS01 at this point would be a major setback in the endeavour to develop a malaria vaccine, in addition to vaccines against other infections present mainly in low income countries, and a discouragement to major pharmaceutical companies and public private partnerships to engage in these activities. Therefore, these pilot programmes must move forward quickly, should be large enough to evaluate Implementation of the malaria candidate vaccine RTS,S/AS01 11 Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug eluting stents. N Engl J Med 2014; 371: 2155 66. 12 Kalesan B, Pilgrim T, Heinimann K, et al. Comparison of drug eluting stents with bare metal stents in patients with ST segment elevation myocardial infarction. Eur Heart J 2012; 33: 977 87.
The Lancet