key: cord-0276839-3h724alo authors: Mohan, S.; Revill, P.; Malvolti, S.; Malhame, M.; Sculpher, M.; Kaye, P. M. title: Estimating the global demand curve for a leishmaniasis vaccine: a generalisable approach based on global burden of disease estimates date: 2021-08-28 journal: nan DOI: 10.1101/2021.08.26.21262379 sha: f3382acd24c3ea1480b2d3a7c83217cb9db83112 doc_id: 276839 cord_uid: 3h724alo Background A pressing need exists to develop vaccines for neglected diseases, including leishmaniasis. However, the development of new vaccines is dependent on their value to two key players -vaccine developers and manufacturers who need to have confidence in the global demand in order to commit to research and production; and governments (or other international funders) who need to signal demand based on the potential public health benefits of the vaccine in their local context, as well as its affordability. A detailed global epidemiological analysis is rarely available before a vaccine enters a market due to lack of resources as well as insufficient global data necessary for such an analysis. Our study seeks to bridge this information gap by providing a generalisable approach to estimating the commercial and public health value of a vaccine in development relying primarily on publicly available Global Burden of Disease (GBD) data. This simplified approach is easily replicable and can be used to guide discussions and investments into vaccines and other health technologies where evidence constraints exist. The approach is demonstrated through the estimation of the demand curve for a future leishmaniasis vaccine. Methodology/Principal findings We project the ability to pay over the period 2030-2040 for a vaccine preventing cutaneous and visceral leishmaniasis (CL / VL), using an illustrative set of countries which account for most of the global disease burden. First, based on previous work on vaccine demand projections in these countries and CL / VL GBD-reported incidence rates, we project the potential long-term impact of the vaccine on disability-adjusted life years (DALYs) averted as a result of reduced incidence. Then, we apply an economic framework to our estimates to determine vaccine affordability based on the abilities to pay of governments and global funders, leading to estimates of the demand and market size. Based on our estimates, the maximum ability-to-pay of a leishmaniasis vaccine (per course, including delivery costs), given the current estimates of incidence and population at risk, is higher than $5 for nearly half of the 24 countries considered, with a median value-based maximum price of $4.4-$5.3, and total demand of over 560 million courses. Conclusion/Significance Our results demonstrate that both the quantity of vaccines estimated to be required by the countries considered as well as their ability-to-pay could make a vaccine for leishmaniasis commercially attractive to potential manufacturers. The methodology used can be equally applied to other technology developments targeting health in developing countries. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 4 treatment remains low(6,7). Given low treatment coverage, the occurrence of poor compliance and 77 the emergence of drug resistance(8), challenges in sustaining vector control strategies(9), and the 78 ability of parasites to persist in animal reservoirs, vaccines are widely regarded as having the 79 potential to significantly impact the health burden posed by leishmaniasis and to contribute to However, it is not enough just to develop a clinically effective vaccine. Rather, the vaccine also needs 88 to be affordable and suitable for delivery and administration in health systems. In particular, for a 89 vaccine to be produced and used, it needs to offer value to two key players: vaccine developers and 90 manufacturers who need to have confidence in global demand in order to commit to research and 91 production; and governments (or other international funders) who need to be sure of the potential 92 public health benefits of the vaccine in their local context, as well as affordability of the vaccine, in 93 order to signal demand. This study seeks to fill this information gap about the commercial value proposition and likely is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 5 More generally, this study seeks to develop a simplified and generalizable framework which employs 102 publicly available burden of disease data to project the affordability, market size and public health 103 value of new interventions in order to inform and spur continued product development that can 104 improve health in low and middle-income countries (LMICs). This study assesses the value associated with the introduction of a vaccine to prevent CL / VL. Value 109 is assessed in terms of the vaccine's potential impact on mortality and morbidity taking into account 110 its affordability within an illustrative set of countries in which the disease in endemic. First, based on 111 previous work on vaccine demand projections in these countries(14) and CL / VL incidence rates(1), we project the potential long-term impact of a leishmaniasis vaccine on disability-adjusted life years 113 (DALYs) averted as a result of reduced incidence. Ideally, such an analysis would require a detailed 114 modeling of the disease epidemiology, disease dynamics, and health system capabilities of each 115 country under consideration. However, such models are not currently available for most countries 116 but planning for vaccine research and manufacturing needs to continue in their absence. Therefore, 117 we sought to develop a simplified approach, which uses publicly available data on disease incidence 118 and burden and population growth projections to assess the public health value of a future vaccine. Second, we apply a health economic framework to our estimates of the future health impact of a 121 vaccine to determine the vaccine's affordability based upon the abilities to pay of governments and 122 global funders, leading to estimates of the demand and market size in this illustrative set of is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 6 The analysis in this paper is focused on a representative sample of 24 countries belonging to a range 127 of income levels(15), geographic regions, type of endemic leishmaniasis, and Gavi, The Vaccine 128 Alliance (GAVI) support status(16) ( Table 1) . In 2019, these countries together represented 80% of 129 the global DALY burden of CL and VL, and 70% and 82% of the global incidence of CL and VL 130 respectively (1). In the absence of a rigorous epidemiological model, we project the health effect of a vaccine using 134 the following estimates: i) total population susceptible to the disease (or population at risk); ii) 135 incidence of the disease among the population at risk; iii) per person burden of disease; and iv) 136 vaccine coverage and efficacy. This sub-section describes how these estimates were obtained and 137 used. Environmental factors that affect the relationship between hosts, vectors (human, animal or sandfly) Incidence estimates were obtained from the Global Burden of Disease (GBD) study in 2019(1). These 147 were converted into incidence rates specific to populations at risk for 2019 by dividing the incidence 148 by the size of the population at risk (note that this assumes that no one outside the main population 149 at risk contracts the disease) for the different age groups included in the vaccine demand projections is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint significant decline in incidence over the last five years(20), we make the assumption that the Similarly, the per person DALY burden of the disease was obtained from the 2019 GBD study for 160 each country and age group considered by dividing the relevant total DALY burden by the incidence, given that the average duration of both CL and VL is less than a year(21). The 2019 values of the 162 epidemiological parameters used are shown in Table 2 . This approach was taken due to the lack of 163 country-level data on the per-case DALY burden of the disease. We considered it important to use 164 country-level estimates due to the disparity between countries(2) in terms of clinical and 165 epidemiological presentations, comorbidities, treatment coverage, and fatality rates. Based on previously developed vaccines(22), efficacy was assumed to be 75% in the base case 168 (based on the efficacy of previously researched leishmanization methods(22,23)). However, an 169 efficacy range between 50% and 95% is considered under sensitivity analysis. The duration of the 170 efficacy was assumed to be 10 years and an annual discount rate of three percent applied to health 171 gains in the future. Quantity demanded or demand here refers to the total vaccines projected to be required by a is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint 8 routine immunization program. Routine immunization includes two age groups -0-4 years, and 5-14 179 years. The catch-up campaign for CL includes two groups -5-14 years, and 15-29 years; and for VL 180 only the 5-14 years age group was assumed to be targeted. Coverage estimates (those vaccinated as We assume that a heath intervention should be provided if it produces more health than could be 187 generated elsewhere in the health care system with the same resources (i.e. the benefits exceed the 188 opportunity costs). For every DALY averted (or QALY gained) from a new intervention, a health 189 system should pay no more than the cost at the margin at which it is already able to avert a DALY is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. Using these concepts, we were able to calculate the value-based maximum price for a course of the 227 leishmaniasis vaccine that each country is able to pay during each year of rollout, given the potential is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint and VL prevention) are aggregated to derive each country's global ability-to-pay for the vaccine (Box 231 1, equation 3). Combined with the vaccine courses estimated to be required for each country, these are used to 234 construct global demand curves for the vaccine during the 11-year period between 2030 and 2040. For this purpose, we estimate the average value-based maximum price over 11 years, by dividing the 236 sum of the maximum resources which could be committed towards the leishmaniasis vaccine during 237 each year (price times demand) by the aggregate demand between 2030 and 2040. The value-based maximum price or ability-to-pay for a course of a leishmaniasis vaccine that each country is able to pay is estimated using the following formula: is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10. 1101 /2021 We evaluate the sensitivity of the projected global demand curves to three factors -i) vaccine 242 efficacy, ii) contributions from GAVI, and iii) adjustment for underreporting of leishmaniasis 243 incidence. Under the first sensitivity analysis, the value-based maximum prices and global demand curves are 246 reevaluated for vaccine efficacy rates of 50% and 95%. Sensitivity analysis is also carried out to assess the effect on global demand curves with GAVI 249 contribution towards countries which are expected to be eligible for support between 2030 and 250 2040 based on GDP per capita projections(29) using GAVI's criterion for support as of 2019 (16). We 251 assume that a country is eligible for GAVI support during the 11 years under consideration if its 252 projected GDP per capita between 2026 and 2028 is under $1580 (i.e. the country is either in the 253 initial self-financing or preparatory transition phase) or if its GDP per capita has been greater than 254 $1580 for 5 years or less between 2022 and 2028 (i.e. the country is in the accelerated transition 255 phase). Given GAVI's current portfolio of vaccines, we expect GAVI's maximum ability to pay for 256 vaccines to be higher than that of some of the countries eligible for support. Based on previous work 257 on GAVI's willingness to pay for the rotavirus vaccine(33), we assume GAVI's cost effectiveness 258 threshold to be $285 in 2019 USD. Therefore, under this sensitivity analysis, we re-estimate the Finally, we also assess the potential effect of adjusting for the underreporting of cases on the value- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint We calculated the country-wise value-based maximum price per course of the leishmaniasis vaccine 270 and total demand based on equations 1,2 and 3, presented in tabular format ( Table 3 ) and in the 271 form of a demand curve for the illustrative set of 24 countries (Figure 1) . As expected, the median The estimated prices in the above scenario assume a vaccine efficacy of 75% in preventing CL / VL. Since vaccines against leishmaniasis are still under development or under testing, the actual efficacy 284 is unknown. We therefore also consider the effect of a change in vaccine efficacy on value-based 285 maximum prices (Figure 2) . At an efficacy of 95%, the vaccine would prevent a larger number of 286 cases of CL / VL, averting more DALYs, and allowing countries to be able to pay a higher price at the 287 margin per course. This shifts the demand curve upwards from the earlier scenario assuming 75% is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint the efficacy falls from 75% to 50%. At 95% efficacy, the median values rise to $5.5 and $6.5 292 respectively (Table 4) .
295 296 Impact of GAVI support for vaccine introduction The results described above treat countries as independent buyers of the vaccine whose ability to 298 pay per vaccine course depends on their respective CET. However, international donors are often 299 able to ensure the expansion of important health interventions to low and lower-middle income 300 countries even when these may be locally cost-ineffective as a result of budget constraints. We 301 consider the effect of future GAVI funding of a potential leishmaniasis vaccine for countries eligible 302 for its support based on current criteria(16). We project that 11 of the 24 countries in our illustrative 303 list will be in one of the GAVI support phases (Supplementary table 3) , of which six countries have a 304 CET lower than $285 in 2030. Using a CET of $285/DALY averted for these six countries, provides an 305 alternate demand curve (Figure 3) . The mean value-based price nearly doubles under both 306 treatment coverage scenarios ( Table 4) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint This study has sought to provide a generalizable approach to estimating the commercial and public 319 health value of new technologies in development relying primarily on publicly available GBD data. This simplified approach is easily replicable and can be used to guide discussions and investments 321 into health technology development, particularly in low and middle-income countries (LMICs), which 322 face significant constraints in acquiring and generating evidence compared with higher-income Our results demonstrate that both the quantity of vaccines estimated to be required by the 335 countries considered, which represent a majority of the global burden of disease from leishmaniasis, 336 as well as their ability-to-pay make the vaccine commercially attractive to potential manufacturers. The global demand stands at over 560 million courses, and the value-based maximum price per 338 course, given the current estimates of incidence and population at risk, is higher than $5 for nearly is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint 16 countries also presents an opportunity for differential pricing to secure wide access. With possible 344 future contributions from GAVI considering its current willingness to pay for the rotavirus 345 vaccine(33), we estimate that the global demand curve would move further upwards. A similar 346 upward effect in abilities to pay is observed with adjustment for underreporting. It should be noted that the prices presented above represent the maximum full health system cost is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 characterizing the leishmaniasis epidemic, addressing which will be crucial to better understanding 370 the future value of a vaccine against these diseases. With better data, a full epidemiological model capturing disease dynamics should form the basis of 373 projections of the public health value of potential technologies. Such analysis is rarely feasible 374 before a product enters a market due to lack of resources as well as global data on necessary 375 parameters. Our framework overcomes these challenges, albeit through various simplifications, and 376 we suggest that our results can be used to guide investments into improving the data available on is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.26.21262379 doi: medRxiv preprint 23 Institute for Health Metrics and Evaluation Data Resources Complexities of assessing the disease burden attributable to 386 leishmaniasis PLoS Neglected Tropical Diseases Ethiopia 9 Nigeria 5,015 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted August 28, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021