(C) PLOS One [1]. This unaltered content originally appeared in journals.plosone.org.
Licensed under Creative Commons Attribution (CC BY) license.
url:https://journals.plos.org/plosone/s/licenses-and-copyright

------------



Human leishmaniasis vaccines: Use cases, target population and potential global demand

['Stefano Malvolti', 'Mmgh Consulting', 'Zurich', 'Melissa Malhame', 'Carsten F. Mantel', 'Epke A. Le Rutte', 'Department Of Epidemiology', 'Public Health', 'Swiss Tropical', 'Public Health Institute']

Date: 2021-10

Abstract The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300–830 million doses for a vaccine preventing visceral leishmaniasis and 557–1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.

Author summary The leishmaniases are potentially vaccine-preventable diseases of global importance, yet no vaccines for human use have attained registration. This work sheds lights on the potential size of demand for a human vaccine for the prevention of visceral and cutaneous leishmaniasis as well as for the prevention and treatment of post-kala-azar dermal leishmaniasis. The analysis is grounded in the definition of vaccine use cases which, by transparently defining different applications of the vaccines in the immunisation programs, provides the basis for defining the target populations and vaccine characteristics. The output of this work, the first-of-its-kind for leishmaniasis, fills a critical information gap and will provide policy makers and vaccine developers with important insights into the public health relevance of a human leishmaniasis vaccine and the strengths of its commercial value proposition. Ultimately this research aims to inform future decisions on disease prioritization and on investments by key stakeholders, as well as to identify areas for further research.

Citation: Malvolti S, Malhame M, Mantel CF, Le Rutte EA, Kaye PM (2021) Human leishmaniasis vaccines: Use cases, target population and potential global demand. PLoS Negl Trop Dis 15(9): e0009742. https://doi.org/10.1371/journal.pntd.0009742 Editor: Dhafer Laouini, Insitut Pasteur de Tunis, TUNISIA Received: April 26, 2021; Accepted: August 18, 2021; Published: September 21, 2021 Copyright: © 2021 Malvolti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The demand modelling has been performed in Microsoft Excel. All information and assumptions related to the calculation are included in the methodological annex. The excel file can be made available upon request by MMGH Consulting [email protected]. Funding: This work was funded by a Translation Award from the Wellcome Trust (Grant No. 108518; to PMK). EALR gratefully acknowledges funding of the NTD Modelling Consortium by the Bill and Melinda Gates Foundation (OPP1184344). MMGH Consulting (SM, MM, CFM) work was funded by University of York (Consulting Agreement UYPROC_582). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript with the exception of University of York (PK) contribution to the study design and preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PMK is co-author of a patent protecting the gene insert used in Leishmania candidate vaccine ChAd63-KH (Europe 10719953.1; India 315101) and is funded by the UK Medical Research Council / Department for International Development to develop a controlled human infection model for sand fly-transmitted cutaneous leishmaniasis. MMGH Consulting (SM, MM, CFM) were appointed to lead the work under contract from the University of York.

Introduction Neglected tropical diseases (NTDs) impose a significant health and economic burden on the world’s poorest populations and nations [1]. The latest Global Burden of Disease analysis for 2019 (GBD 2019) [2] estimates that the 20 NTDs recognised by the World Health Organization (WHO) account for 62.9 million disability-adjusted life years (DALYs) lost and up to 1.25 million deaths annually. A growing number of those NTDs are currently or may soon become vaccine-preventable, including Yellow Fever, Rabies, Ebola, Malaria and Dengue. Yet globally, vaccine development for NTDs progresses at a snail’s pace [3], limited by scientific challenges in target antigen identification, the lack of correlates of protection and often unsuitable animal models. In addition, the lack of data on potential market size and value creation reduces financial incentives for vaccine developers to invest in those diseases [4]. In commercial vaccine development efforts, the size of the target population, the revenue potential, the required investment, the clinical development feasibility and the regulatory feasibility are the most influential drivers of decisions [5]. An in-depth understanding of the target populations and of the likely demand are critical inputs for those decisions; this is even more important in the case of NTDs that disproportionally affect low and lower-middle income countries with limited fiscal space. Before proceeding with the clinical development of vaccines for these diseases, commercial developers seek validation of the potential financial return that can be generated by taking them to market. Beyond vaccine developers, policy makers, donors and those responsible for regional health systems also need to take into account the size of the target populations and of the demand for a newly introduced vaccine. This will determine the public health impact in terms of reduction of mortality and morbidity and the financial resources required to implement the vaccination program. In low-and lower-middle income countries, those resources may be provided by the public budget or benefit from direct or indirect donor support (e.g., via Gavi, The Vaccine Alliance (Gavi)). Among the NTDs, leishmaniasis ranks highly in terms of both mortality and morbidity. According to the GBD 2019, between 498,000 and 862,000 new cases of all forms of leishmaniasis are estimated to occur each year [2] resulting in up to 18,700 deaths and up to 1.6 million DALYs lost [2]. The leishmaniases are a group of diseases caused by infection with a protozoan parasite of the genus Leishmania (L. Leishmania spp and L. Viannia spp). Visceral leishmaniasis (VL; kala azar) is a systemic disease affecting the internal organs and is usually fatal if untreated [6]. Transmission of VL may be zoonotic (L. infantum) or anthroponotic (L. donovani). Although new treatment modalities for VL in South Asia (notably single dose liposomal amphotericin B; AmBisome) have considerably improved patient experience and outcome, with reported cure rates of up to 95% [7], treatment in other regions remains predominantly based on pentavalent antimonials [8], drugs with a number of severe limitations in convenience and outcome. Post-kala-azar dermal leishmaniasis (PKDL) is a stigmatizing disease that usually follows treatment of VL caused by L. donovani. PDKL patients carry a significant socio-economic and psychosocial burden. In addition, the skin of PKDL patients is a site of parasitism and data derived from xenodiagnosis [9, 10] lends support to the long held view that PKDL patients play a pivotal role in the interepidemic transmission of VL [11, 12]. Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting humans. This disease is considered to be a zoonosis, with the exception of L. tropica, which in certain areas is an anthroponotic disease. Healing of localised CL is usually achieved within 3 to 18 months without intervention, though sterile immunity is not thought to be achieved. Nevertheless, CL carries a significant burden of psychosocial risk that, once accounted for and added to the GBD estimates could lead to estimates of DALYs lost which are up to 10 times higher than current figures [13]. Chemotherapeutic options for CL have changed little in over 50 years [14]; those medicines remains expensive and questions are still unanswered about their effectiveness and safety [15]. Once cured, protection against reinfection is believed to be the norm [16, 17] and this supports the argument that vaccine-induced protection should be achievable. Localised lesions can evolve into more severe disease characterized by metastasis to mucosal sites (mucocutaneous leishmaniasis; MCL) or the occurrence of multiple (>10) discrete lesions (disseminated cutaneous leishmaniasis; DSL). Rarely, parasites may grow uncontrolled in diffuse lesions across the skin (diffuse cutaneous leishmaniasis; DCL). The availability of vaccines against one or more forms of leishmaniasis could provide an affordable way to reduce mortality and morbidity, addressing the above-mentioned constraints. Vaccines may be deployed to prevent disease (i.e., prophylactically) or used as alternatives to or in conjunction with existing drugs (i.e., as therapeutic vaccines) for prevention of primary disease or prevention of secondary sequelae. Practical considerations including for example population at risk or alternative treatment options would dictate the relative value or prophylactic vs therapeutic vaccines. While the public health need for a vaccine exists, clinical development efforts have been limited. Numerous vaccine candidates have been evaluated in preclinical models of disease [18] but few have progressed to the clinical trial stage [19]. Currently, only one therapeutic clinical trial is ongoing (Clinicaltrials.gov NCT03969134), and a clinical-grade genetically attenuated live L. major vaccine is due to be manufactured in 2021 [20] to support future trials. Recent progress towards the development of a controlled human challenge model for CL [21, 22] may also provide a stimulus for the clinical development of other candidate vaccines. However, the absence of a consensus on the size of the target populations, the paucity of data to support an indication for use in each disease state and the lack of realistic demand scenarios are likely determinants of the scarce interest from the pharmaceutical industry and philanthropic donors. Estimates of the total burden of leishmaniases have been difficult due to the prevailing poor knowledge of the geographical distribution of the diseases. A further difficulty in burden estimation is the epidemic nature of the disease, leading to significant interannual variation in disease burden [23]. Those factors have made the definition of a reliable demand forecast for a leishmaniasis vaccine very challenging. To address this critical gap, we developed a first in-depth demand forecast for a leishmaniasis vaccine that indicates that prophylactic vaccines for visceral and cutaneous leishmaniasis could have not only a solid public health value proposition but also, subject to countries confirming their interest for the vaccine and willingness to pay, a commercial potential that can attract the interest of vaccine developers and manufacturers.

Discussion In order to fully ascertain the potential interest of developers for a program aimed at developing a vaccine against leishmaniasis, we conducted an in-depth analysis of the potential global demand for leishmaniasis vaccines that is generally agnostic to the nature of the vaccine. The assessment of the use cases for leishmaniasis vaccines emphasizes four main indications: two for the prevention of VL and CL respectively, and two for the prevention and treatment of PKDL. In endemic countries, those vaccines will reduce cases of disease and decrease community transmission. Based on the estimates of the populations at risk and the consequent demand, prophylactic VL and CL vaccine indications are the most attractive scenarios both from a public health and commercial standpoint. A vaccine that is cross-protective against VL and CL has the strongest value proposition, whilst only one indication still allows for a significant demand size and public health impact. PKDL indications also retain their importance from a public health standpoint or in view of existing progress in clinical development that may lead to the earlier availability of this vaccine. Availability of a vaccine for one or more of these indications will provide an opportunity to reduce the threat of leishmaniasis as a public health problem in 57 countries (split as follow: India and Sudan, for the 3 manifestations of the disease, 4 countries for VL and CL, 7 countries for VL and PKDL, 14 countries for VL only, and 30 countries for CL only). This includes 22 countries in the African continent, 14 in the Americas, 19 in Asia, and 2 in the European region. At the same time 3 of these countries are High-Income (HICs), 18 Upper Middle-income (UMICs), 19 Lower-Middle-Income (LMICs) and 15 Low-income (LICs) [55] as defined by the World Bank income classification. Of the latter two groups, 22 countries are, and 10 have previously been, eligible for Gavi support including funding for vaccine procurement. It is assumed that HICs or UMICs would potentially be able to self-finance, while LMICs and LICs could benefit from the financial support of Gavi and other donors. The total population potentially targeted by leishmaniasis vaccines approximates 1.1 billion in 2030 by the time of introduction of the vaccine. On the basis of data from 2018, the population at risk of VL (404 million with a range between 235 and 646 million) and at risk of CL (765 million with a range between 392 million and 1 billion) represents the near totality of the potential target for the vaccine while the numbers of VL cases in the targeted countries (16,129 new cases per year for 2030 with a range between 2,843 and 25,068 cases) and of PKDL (3,104 new cases per year for 2030 in absence of a vaccine, with a range between 600 and 4,752 cases) are much more limited. It is evident that vaccine use in such large populations could result in significant public health benefits. The vaccine supply required over 10 years (2030–2040) for the implementation of immunisation programs against VL or CL could be substantial: approximately 1.1 billion doses of vaccine against CL (range: 0.5–1.4 billion doses) and 0.5 billion doses of vaccine against VL (range: ~ 0.3–0.8 billion doses). Markets of this size have the potential to attract the interest of vaccine manufacturers, even more so in view of the mix of economies involved, some of which may self-finance a respective immunization program. For this interest to materialise, utmost transparency will be necessary on the countries’ willingness and ability to pay for the vaccines, as well as clarity on WHO recommendations for vaccine use. Establishment of incentive mechanisms, such as Advanced Market Commitments [56] and Priority Review Vouchers [57], can also play an important incentivizing role. This will be critical for supporting the progress of current vaccine development efforts. It is not yet established whether a vaccine that prevents clinical VL will also prevent the development of PKDL. If this were not the case, making available a vaccine that is selective for PKDL may be more challenging in view of the more limited potential demand. However, a different approach may be pursued for this indication leveraging the limited demand as an opportunity instead of a constraint. Regulatory frameworks for orphan or compassionate use indications could be exploited and combined with limited manufacturing needs and investments, reducing greatly the cost and the risk for a manufacturer. Such a focused approach to vaccine financing should be explored to address the burden of PKDL. To support countries in their assessment of the public health impact of a leishmaniasis vaccine and prospective manufacturers of the commercial value proposition of those vaccines, clarity on target populations and demand is paramount. The Hib Initiative, as well as the Pneumococcal and Rotavirus Vaccine Accelerated Development and Introduction Plans (PneumoADIP and RotaADIP) provide examples on how a concurrent effort on data generation, clinical development and public advocacy was able to raise awareness on diseases with a heavy burden on populations of LMICs and LICs [58]. Such an approach is even more critical for neglected tropical diseases such as leishmaniasis. The limitations of this analysis, as for any forecasting exercise, relate to various elements of uncertainty. Firstly, the forecast is dependent on the estimates of the at-risk populations in endemic or potentially endemic areas as well as on the assumed future incidence and prevalence of the disease. With current leishmaniasis control programmes in place in certain parts of the world, such incidence will depend on the success of these programmes. There is no clear consensus among experts and estimates show a high degree of variability while an agreed definition of the target population at risk, by countries or sub populations of countries, is missing. Secondly, assumptions concerning the probability of country vaccine introduction are subject to a high degree of uncertainty given that vaccines will likely not be available for another decade. Thirdly, the estimate of the impact of the use of vaccines in the target populations is based on a set of assumptions while awaiting the outcomes of vaccine trials. Work done by Erasmus MC (University Medical Center, Rotterdam) provides information on the potential impact of various VL vaccines on VL incidence in an Indian setting [44], but not elsewhere. Whilst our modelling assumptions include transmission by asymptomatic cases of VL, a recent study from India suggests that this may be more limited than previously thought [10]. Studies of transmission competence across the disease spectrum in other regions where VL is endemic are clearly warranted. Additional simulations of the impact of vaccines in CL and VL populations at risk (including the likelihood of interruption of transmission and of the impact of a VL prophylactic vaccine), will further improve our understanding of population dynamics and vaccine effectiveness. Finally, a number of initial assumptions were made on variables such as the sequence of country introduction, vaccine uptake, achievable and desired coverage and vaccination schedules. Changes in these parameters and the priority countries introducing the vaccines will impact the forecasted demand. As an example, the impact of a different immunisation schedule, as captured in the conservative scenario described in the results section (with a reduced series of 3 doses instead of 6), has the potential to reduce demand by up to 50%. Getting closer to registration, more precise information about vaccine product characteristics, and the likely program designs and country interest will allow for more refined estimates. In conclusion, there is a growing consensus on the need for a vaccine against leishmaniasis to achieve a reduction of the burden of disease [59–61]. Clarity about the prospective size of the vaccine demand in terms of target population and number of doses required is crucial to inform decisions of manufacturers, donors and countries. Our first-of-a-kind analysis provides a global estimate of the potential demand for leishmaniasis vaccines across a set of different indications. Subject to prioritization of country and global decision makers, a leishmaniasis vaccine with a VL and/or CL indication could not only provide a significant contribution to the reduction of the burden of NTDs but also has the potential of being an interesting commercial prospect for vaccine developers. Further analyses to confirm the likelihood and strength of interest of country decision makers in prioritising leishmaniasis vaccines in their adoption decisions are warranted. This will enable further clarification on the potential reduction in the burden of the disease and cost-effectiveness of these vaccines.

Acknowledgments The authors of this article wish to thank the members of the expert group who provided insights and guidance in the development of the use cases and who critically reviewed the manuscript: Jorge Alvar (DNDi), Simon Croft (LSHTM), Tom Evans (Vaccitec), Nirmal Kumar Ganguly (ICMR), Birgitte Giersing (WHO), Bethan Hughes (Wellcome Trust), Christiane Juhls (Mologen), Paul Kaye (Univ. of York), Ahmed Musa (Sudan MOH), Richard Muscat (Wellcome Trust), Steve Reed (IDRI). In particular, we thank Jorge Alvar, Simon Croft and Nirmal Kumar Ganguly who dedicated time to validate some of our assumptions. Finally, we are grateful to the Wellcome Trust for supporting expert meetings during the project timeline and allowing for additional fruitful interactions.

[END]

[1] Url: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009742

(C) Plos One. "Accelerating the publication of peer-reviewed science."
Licensed under Creative Commons Attribution (CC BY 4.0)
URL: https://creativecommons.org/licenses/by/4.0/


via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/

You are viewing proxied material from magical.fish. The copyright of proxied material belongs to its original authors. Any comments or complaints in relation to proxied material should be directed to the original authors of the content concerned. Please see the disclaimer for more details.