The public health impact and cost-effectiveness of the R21/Matrix-M malaria vaccine: a mathematical modelling study.

BACKGROUND: The R21/Matrix-M vaccine has demonstrated high efficacy against Plasmodium falciparum clinical malaria in children in sub-Saharan Africa. Using trial data, we aimed to estimate the public health impact and cost-effectiveness of vaccine introduction across sub-Saharan Africa. METHODS: We fitted a semi-mechanistic model of the relationship between anti-circumsporozoite protein antibody titres and vaccine efficacy to data from 3 years of follow-up in the phase 2b trial of R21/Matrix-M in Nanoro, Burkina Faso. We validated the model by comparing predicted vaccine efficacy to that observed over 12-18 months in the phase 3 trial. Integrating this framework within a mathematical transmission model, we estimated the cases, malaria deaths, and disability-adjusted life-years (DALYs) averted and cost-effectiveness over a 15-year time horizon across a range of transmission settings in sub-Saharan Africa. Cost-effectiveness was estimated incorporating the cost of vaccine introduction (dose, consumables, and delivery) relative to existing interventions at baseline. We report estimates at a median of 20% parasite prevalence in children aged 2-10 years (PfPR2-10) and ranges from 3% to 65% PfPR2-10. FINDINGS: Anti-circumsporozoite protein antibody titres were found to satisfy the criteria for a surrogate of protection for vaccine efficacy against clinical malaria. Age-based implementation of a four-dose regimen of R21/Matrix-M vaccine was estimated to avert 181 825 (range 38 815-333 491) clinical cases per 100 000 fully vaccinated children in perennial settings and 202 017 (29 868-405 702) clinical cases per 100 000 fully vaccinated children in seasonal settings. Similar estimates were obtained for seasonal or hybrid implementation. Under an assumed vaccine dose price of US$3, the incremental cost per clinical case averted was $7 (range 4-48) in perennial settings and $6 (3-63) in seasonal settings and the incremental cost per DALY averted was $34 (29-139) in perennial settings and $30 (22-172) in seasonal settings, with lower cost-effectiveness ratios in settings with higher PfPR2-10. INTERPRETATION: Introduction of the R21/Matrix-M malaria vaccine could have a substantial public health benefit across sub-Saharan Africa. FUNDING: The Wellcome Trust, the Bill & Melinda Gates Foundation, the UK Medical Research Council, the European and Developing Countries Clinical Trials Partnership 2 and 3, the NIHR Oxford Biomedical Research Centre, and the Serum Institute of India, Open Philanthropy.

Insights from modelling malaria vaccines for policy decisions: the focus on RTS,S.

Mathematical models are increasingly used to inform decisions throughout product development pathways from pre-clinical studies to country implementation of novel health interventions. This review illustrates the utility of simulation approaches by reviewing the literature on malaria vaccine modelling, with a focus on its link to the development of policy guidance for the first licensed product, RTS,S/AS01. The main contributions of modelling studies have been in inferring the mechanism of action and efficacy profile of RTS,S; to predicting the public health impact; and economic modelling mainly comprising cost-effectiveness analysis. The value of both product-specific and generic modelling of vaccines is highlighted.

Costs of continuing RTS,S/ASO1E malaria vaccination in the three malaria vaccine pilot implementation countries.

BACKGROUND: The RTS,S/ASO1E malaria vaccine is being piloted in three countries-Ghana, Kenya, and Malawi-as part of a coordinated evaluation led by the World Health Organization, with support from global partners. This study estimates the costs of continuing malaria vaccination upon completion of the pilot evaluation to inform decision-making and planning around potential further use of the vaccine in pilot areas. METHODS: We used an activity-based costing approach to estimate the incremental costs of continuing to deliver four doses of RTS,S/ASO1E through the existing Expanded Program on Immunization platform, from each government's perspective. The RTS,S/ASO1E pilot introduction plans were reviewed and adapted to identify activities for costing. Key informant interviews with representatives from Ministries of Health (MOH) were conducted to inform the activities, resource requirements, and assumptions that, in turn, inform the analysis. Both financial and economic costs per dose, cost of delivery per dose, and cost per fully vaccinated child (FVC) are estimated and reported in 2017 USD units. RESULTS: At a vaccine price of $5 per dose and assuming the vaccine is donor-funded, our estimated incremental financial costs range from $1.70 (Kenya) to $2.44 (Malawi) per dose, $0.23 (Malawi) to $0.71 (Kenya) per dose delivered (excluding procurement add-on costs), and $11.50 (Ghana) to $13.69 (Malawi) per FVC. Estimates of economic costs per dose are between three and five times higher than financial costs. Variations in activities used for costing, procurement add-on costs, unit costs of per diems, and allowances contributed to differences in cost estimates across countries. CONCLUSION: Cost estimates in this analysis are meant to inform country decision-makers as they face the question of whether to continue malaria vaccination, should the intervention receive a positive recommendation for broader use. Additionally, important cost drivers for vaccine delivery are highlighted, some of which might be influenced by global and country-specific financing and existing procurement mechanisms. This analysis also adds to the evidence available on vaccine delivery costs for products delivered outside the standard immunization schedule.

Cost-effective analysis of childhood malaria vaccination in endemic hotspots of Bangladesh.

INTRODUCTION: Bangladesh has a history of endemic malaria transmission, with 17.5 million people at risk. The objective of this study was to assess the cost-effectiveness of universal childhood malaria vaccination in Chittagong Hill Tracts (CHT) of Bangladesh with newly developed RTS,S/AS01 malaria vaccines. METHODS: A decision model was been developed using Microsoft® Excel to examine the potential impact of future vaccination in Bangladesh. We estimated the economic and health burden due to malaria and the cost-effectiveness of malaria vaccination from the health system and societal perspective. The primary outcomes include the incremental cost per Disability-Adjusted Life Year (DALY) averted, incremental cost per case averted, and the incremental cost per death averted. RESULTS: Introducing childhood malaria vaccination in CHT in Bangladesh for a single birth cohort could prevent approximately 500 malaria cases and at least 30 deaths from malaria during the first year of vaccination. The cost per DALY averted of introducing the malaria vaccine compared to status quo is US$ 2,629 and US$ 2,583 from the health system and societal perspective, respectively. CONCLUSIONS: Introduction of malaria vaccination in CHT region is estimated to be a cost-effective preventive intervention and would offer substantial future benefits particularly for young children vaccinated today. Policies should, thus, consider the operational advantages of targeting these populations, particularly in the CHT area, with the vaccine along with other malaria control initiatives.

Health gains and financial risk protection afforded by public financing of selected malaria interventions in Ethiopia: an extended cost-effectiveness analysis.

BACKGROUND: Malaria is a public health burden and a major cause for morbidity and mortality in Ethiopia. Malaria also places a substantial financial burden on families and Ethiopia's national economy. Economic evaluations, with evidence on equity and financial risk protection (FRP), are therefore essential to support decision-making for policymakers to identify best buys amongst possible malaria interventions. The aim of this study is to estimate the expected health and FRP benefits of universal public financing of key malaria interventions in Ethiopia. METHODS: Using extended cost-effectiveness analysis (ECEA), the potential health and FRP benefits were estimated, and their distributions across socio-economic groups, of publicly financing a 10% coverage increase in artemisinin-based combination therapy (ACT), long-lasting insecticide-treated bed nets (LLIN), indoor residual spraying (IRS), and malaria vaccine (hypothetical). RESULTS: ACT, LLIN, IRS, and vaccine would avert 358, 188, 107 and 38 deaths, respectively, each year at a net government cost of $5.7, 16.5, 32.6, and 5.1 million, respectively. The annual cost of implementing IRS would be two times higher than that of the LLIN interventions, and would be the main driver of the total costs. The averted deaths would be mainly concentrated in the poorest two income quintiles. The four interventions would eliminate about $4,627,800 of private health expenditures, and the poorest income quintiles would see the greatest FRP benefits. ACT and LLINs would have the largest impact on malaria-related deaths averted and FRP benefits. CONCLUSIONS: ACT, LLIN, IRS, and vaccine interventions would bring large health and financial benefits to the poorest households in Ethiopia.

The Economics of Malaria Vaccine Development.

Vaccines that do not take a comprehensive endpoint view of the pathogen population they want to tackle early in their developmental process, may find it financially prohibitive to redesign them once they have progressed down a costly regulatory and human trial pathway. Specifically, the lead malaria vaccine candidate RTS,S has limited ability to tackle parasite polymorphism and may induce sex-specific nonspecific effects (NSEs).

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa.

BACKGROUND: RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions. METHODS: The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted. RESULTS: If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78-$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%. CONCLUSION: RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule.

The Future of the RTS,S/AS01 Malaria Vaccine: An Alternative Development Plan.

Roly Gosling and Lorenz von Seidlein consider a potential future development plan for the RTS,S/AS01 malaria vaccine.

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

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.

Costing RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda: A generalizable approach drawing on publicly available data.

Recent results from the phase 3 trial of RTS,S/AS01 malaria vaccine show that the vaccine induced partial protection against clinical malaria in infants and children; given the high burden of the disease it is currently considered for use in malaria endemic countries. To inform adoption decisions the paper proposes a generalizable methodology to estimate the cost of vaccine introduction using routinely collected and publicly available data from the cMYP, UNICEF, and WHO-CHOICE. Costing is carried out around a set of generic activities, assumptions, and inputs for delivery of immunization services adapted to a given country and deployment modality to capture among other factors the structure of the EPI program, distribution model, geography, and demographics particular to the setting. The methodology is applied to estimate the cost of RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda. At an assumed vaccine price of $5 per dose and given our assumptions on coverage and deployment strategy, we estimate total economic program costs for a 6-9 months cohort within $23.11-$28.28 per fully vaccinated child across the 6 countries. Net of procurement, costs at country level are substantial; for instance in Tanzania these could add as much as $4.2 million per year or an additional $2.4 per infant depending on the level of spare capacity in the system. Differences in cost of vaccine introduction across countries are primarily driven by differences in cost of labour. Overall estimates generated with the methodology result in costs within the ranges reported for other new vaccines introduced in SSA and capture multiple sources of heterogeneity in costs across countries. Further validation with data from field trials will support use of the methodology while also serving as a validation for cMYP and WHO-CHOICE as resources for costing health interventions in the region.

RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap.

The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3-4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels.

Development of malaria transmission-blocking vaccines: from concept to product.

Despite decades of effort battling against malaria, the disease is still a major cause of morbidity and mortality. Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. In the 1950s, Huff et al. first demonstrated the induction of transmission-blocking immunity in chickens by repeated immunizations with Plasmodium gallinaceum-infected red blood cells. Since then, significant progress has been made in identification of parasite antigens responsible for transmission-blocking activity. Recombinant technologies accelerated evaluation of these antigens as vaccine candidates, and it is possible to induce effective transmission-blocking immunity in humans both by natural infection and now by immunization with recombinant vaccines. This chapter reviews the efforts to produce TBVs, summarizes the current status and advances and discusses the remaining challenges and approaches.

Assessing the economic benefits of vaccines based on the health investment life course framework: a review of a broader approach to evaluate malaria vaccination.

BACKGROUND: Economic evaluations have routinely understated the net benefits of vaccination by not including the full range of economic benefits that accrue over the lifetime of a vaccinated person. Broader approaches for evaluating benefits of vaccination can be used to more accurately calculate the value of vaccination. METHODOLOGY: This paper reflects on the methodology of one such approach - the health investment life course approach - that looks at the impact of vaccine investment on lifetime returns. The role of this approach on vaccine decision-making will be assessed using the malaria health investment life course model example. RESULTS: We describe a framework that measures the impact of a health policy decision on government accounts over many generations. The methodological issues emerging from this approach are illustrated with an example from a recently completed health investment life course analysis of malaria vaccination in Ghana. Beyond the results, various conceptual and practical challenges of applying this framework to Ghana are discussed in this paper. DISCUSSION AND CONCLUSIONS: The current framework seeks to understand how disease and available technologies can impact a range of economic parameters such as labour force participation, education, healthcare consumption, productivity, wages or economic growth, and taxation following their introduction. The framework is unique amongst previous economic models in malaria because it considers future tax revenue for governments. The framework is complementary to cost-effectiveness and budget impact analysis. The intent of this paper is to stimulate discussion on how existing and new methodology can add to knowledge regarding the benefits from investing in new and underutilized vaccines.