Introduction

Abstract

Neglected Tropical Diseases (NTDs) are caused by a diversity of pathogens including viruses, bacteria, parasites, fungi, and toxins, which affect 2–3 billion people globally who live in the least developed countries (LDC) and low-to-middle income countries (LMIC). The World Health Organization classifies around 24 NTDs that are prevalent mainly in tropical and sub-tropical areas and these conditions impact enormously on personal and population health, with debilitating social and economic consequences to communities and countries. The overall focus of the book is vaccines for NTDs caused by the organisms studied by the VALIDATE (VAccine deveLopment for complex Intracellular neglecteD pAThogEns) network, i.e. Mycobacterium tuberculosis, M. leprae, Leishmania spp. and Burkholderia pseudomallei.

1.1 Neglected Tropical Diseases and the VALIDATE Pathogens

Neglected Tropical Diseases (NTDs) are caused by a diversity of pathogens including viruses, bacteria, parasites, fungi, and toxins, which affect 2–3 billion people globally who live in the least developed countries (LDC) and low-to-middle income countries (LMIC). The World Health Organization classifies around 24 NTDs (Table 1.1) that are prevalent mainly in tropical and sub-tropical areas and these conditions impact enormously on personal and population health, with debilitating social and economic consequences to communities and countries. The WHO has launched a roadmap for NTDs entitled ‘Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030’, with relevant documents available at https://www.who.int/teams/control-of-neglected-tropical-diseases/ending-ntds-together-towards-2030.

Table 1.1 The World Health Organization list of NTDs and their causative agents

Despite the global efforts to understand and control these NTDs, their burden is still one major factor (mingling amongst the complex inter-related issues of health, social and economic inequalities, poverty, lack of clean water and malnutrition, war and displacement, colonial legacies and tenacious autocratic, oligarchic, totalitarian and/or theocratic forms of government, low educational attainment, high childhood mortality and low life expectancy) that contributes to keeping countries firmly entrenched in the Development Assistance Committee (DAC) list for Official Development Assistance (ODA) (https://www.oecd.org/dac/financing-sustainable-development/development-finance-standards/daclist.htm).

These pathogens, particularly the eukaryotes and prokaryotes, are complex organisms that are difficult to treat and challenging to vaccine developers seeking prophylactic solutions. In this book, our focus is the pathogens that are central to the VAccine deveLopment for complex Intracellular neglecteD pAThogEns (VALIDATE) network of global researchers. This network’s members seek to develop vaccines against Mycobacterium leprae (causing leprosy), Leishmania spp. (causing leishmaniasis), Mycobacterium tuberculosis (causing tuberculosis) and Burkholderia pseudomallei (causing melioidosis). Leprosy and tuberculosis are diseases of antiquity, and one must marvel at the resilience of mycobacterial pathogens. The earliest evidence of human tuberculosis comes from ancient Egypt circa 3700 BC [1, 2] and of animal tuberculosis circa 2000 BC in an Indian elephant [2]. Humans hypothetically obtained Mycobacteria from the first domesticated cattle and goat herds, occurring circa 8000–6000 BC in the north-eastern basin of the Mediterranean and the Middle East (today Iraq, Iran, Israel-Palestine, Syria) [2]. And how old is leprosy? Clinical descriptions of leprosy are available from India circa 600 BC and the disease may have been established already in China during the first millennium BC. The earliest osteological evidence of leprosy comes from 200 BC in skeletons of 4 adult males in Ptolemaic Egypt [2, 3]. The history of leishmaniasis is arguably more fascinating from a paleoparasitological perspective, and reviewed exhaustively by Steverding [4]. Leishmania-like species have been documented in extinct sand fly species preserved in 20-million- and 100-million-year-old fossil ambers and the genus Leishmania is believed to have evolved in the Mesozoic era, 252–66 million years ago. Descriptions of leishmaniasis lesions date back to the 7th Century BC Assyria and remarkably a paleoparasitological study of 42 Egyptian mummies dating from 2050 to 1650 BC found Leishmania donovani mitochondrial DNA in 4 specimens, suggesting that visceral leishmaniasis was present in ancient Egypt [5]. The George Ebers Papyrus (https://digi.ub.uni-heidelberg.de/diglit/ebers1875ga), dating from 1555 BC in Egypt, but most certainly reflecting circumstances dating back to 3000 BC [6], also mentions what may be a description of cutaneous leishmaniasis. By comparison, melioidosis [variously called Whitmore’s disease, Nightcliff gardener’s disease (referring to Nightcliff, a northern suburb of Darwin, Australia, where melioidosis is endemic), pseudoglanders, or the ‘Vietnam time bomb’ [which refers to American soldiers that had been infected with B. pseudomallei during the war and suffered no ill effects at the time, but then developed fatal disease many years later] appears to be a more recent infection, and was first recognised in Rangoon, Myanmar (Burma), in 1911 by Whitmore and Krishnaswami [7, 8]. Its relatively recent appearance is perhaps a consequence of human contact with B. pseudomallei contaminated soil and water in environments, recently settled.

Following the WHO’s classification, only leishmaniasis and leprosy figure as NTDs, but all four pathogens share a distinguishing feature of an intracellular stage of their life cycle within human cells. A strong argument can be made for categorising melioidosis as a NTD of global importance, since it is difficult to treat and cases number ~165,000 annually with 89,000 deaths (https://www.validate-network.org/pathogens/melioidosis). The WHO defines a NTD as a disease that is ‘almost absent from the global health agenda’, ‘has very limited resources’ and is ‘overlooked by global funding agencies’—melioidosis satisfies all their criteria.

Analysis of the data within the 2021 G-FINDER Neglected Disease Report (from the global health think tank Policy Cures) Research) (https://www.policycuresresearch.org/about-us/) allows comparison of the expenditure on research and development into these diseases (Table 1.2). Although funding for tuberculosis research has fallen marginally in relative terms over the past few years (down by 33 million US$ from 2019), it was still 684 million US$ in 2020, which is the second most funded disease behind HIV/AIDS (1368 million US$ in 2020) and just ahead of malaria (618 million US$ in 2020). This sum is twice as much as the total funding that all other NTDs receive (328 million US$ in 2020, Table 1.2). Neither the G-FINDER report, which covers funding from basic research right through to post-registration studies of new products, nor a systematic review on NTD funding between 2000 and 2017 [9] have data on the investments made in melioidosis research and development. A recent review from Savelkoel et al. [10] cites the most recent figure for global investment for melioidosis non-biodefence research and development to have been less than 4 million US$ in 2016 [11], and it is unlikely to be any greater today. Thus, the total funding on the VALIDATE-specific diseases of leishmaniasis, leprosy and melioidosis can be estimated as ~57 million US$ in 2020, which is a mere 8% of the funding that was received for tuberculosis. Thus, tuberculosis certainly is not neglected in terms of funding, and rightly so given the global burden of disease. In 2020, an estimated 5.6 million men, 3.3 million women and 1.1 million children fell ill with tuberculosis, with 1.5 million people dying. Only deaths from COVID-19 surpassed tuberculosis as the leading infectious killer in 2020. However, with the continual rollout of COVID-19 vaccines globally, tuberculosis is set to return as the leading cause of death from any infectious disease, even above HIV/AIDS-related illnesses (680,000 in 2020) (https://repository.gheli.harvard.edu/repository/12559/).

Table 1.2 Research and development funding into NTDs 2020 (in USD, millions)

Analysis of funding over the past decade (2011–2020) shows that it has been concentrated largely in tuberculosis research and development (Fig. 1.1, Table 1.3), which accounted for 65% of all funding. This was followed by the kinetoplastid diseases at 15%, with only 1% provided for leprosy, and no data available for melioidosis. What is clear from the data is that funding has been remarkably consistent over the years for each of the disease or disease groups (Fig. 1.1). Analysis of published research into the four VALIDATE NTDs demonstrates that tuberculosis predominates with over 33,000 articles published just in the past decade, followed by over 12,000 articles on Leishmania (all forms), with less than 2000 articles each for leprosy and melioidosis (Table 1.4). A paltry 1344 articles have been published on Mycobacterium ulcerans over the past 70 years (Table 1.4). To put this literature into perspective, in the past decade over 41,000 articles have been published into malaria, and over 153,000 into HIV and of course, these are dwarfed by the output on COVID-19, which stands at an astonishing 330,343 articles published from 2020!

Fig. 1.1

Cumulative spending on NTD research and development for the period 2011–2020. Data are collated from the ‘Neglected disease research and development: new perspectives’ G-FINDER report (2021). Policy Cures Research, G-FINDER data portal, https://gfinderdata.policycuresresearch.org

Table 1.3 Cumulative funding for NTD research and development from 2011 to 2020

Table 1.4 Number of articles in PubMed for each of the VALIDATE NTD pathogens

1.2 Book Synopsis

The overall focus of the book is vaccines for NTDs caused by the organisms studied by the VALIDATE network. The book begins with an introductory chapter on the creation of the VALIDATE network and its expansion into a global network of academic and clinical investigators, public health scientists, administrators, and policy makers. Diversity of the network is its strongest feature, and enables scientific collaboration between individuals from LDC, LMIC and developed countries. Indeed, a strength of the book is that many of the chapters are written by researchers from LDC/LMIC countries, where these diseases are endemic.

The introductory chapter is followed by contributions that cover mycobacterial diseases. There are two chapters on leprosy, the first providing a current perspective on Hansen’s disease and the second discussing the challenges that Mycobacterium leprae presents to vaccine developers. Next, we have chapters that focus on Mycobacterium tuberculosis and cover correlates of protection for tuberculosis, animal models, and Bacillus Calmette-Guérin (BCG) vaccine and fermentation strategies for BCG vaccine development. The final chapter in this part focuses on Buruli ulcer, which is caused by Mycobacterium ulcerans. Our next section explores leishmaniasis, with chapters that describe the plethora of diseases caused by Leishmania spp. and the development of canine Leishmania vaccines (CVL) and efforts to develop human Leishmania vaccines (HVL). A chapter on the human challenge model for Leishmania research explains how studying human infection under controlled conditions provides a meaningful model to test vaccines. The book closes with a chapter on Burkholderia pseudomallei (melioidosis) vaccine development.