R&D needs for global health

Neglected diseases

Find out how our definition of neglected diseases differs from the WHO neglected tropical disease list

Prior to the commencement of the G-FINDER project, there was no generally accepted definition of ‘neglected diseases’ and, for many diseases, no agreement on which new products were needed. Before the start of the survey in 2008, in order to reach a consensus position on these questions, a list was created of all diseases classified by major health bodies or publications as a ‘neglected disease’. This list was then assessed by an international Advisory Committee of 17 experts in neglected disease and R&D, who filtered candidates against

• The burden of the disease or condition disproportionately affects people in low- and middle-income countries;
• There is no existing product to treat / prevent the disease or condition, OR a product exists but is poorly suited for use in low- and middle-income countries; AND
• There is no commercial market to stimulate R&D by industry.

We maintain ongoing consultation with the Advisory Committee for advice on applying this definition in response to changes in the R&D or pathogenic landscape. Where the Advisory Committee does not reach a consensus, their views are supplemented by advice from further technical and R&D experts.

The result of this consultation is that not all areas of research are judged as meeting our definition of ‘neglected’ in relation to every disease, and some are included only with restrictions. For example, investments in pneumonia drug R&D are excluded because a sufficient commercial market exists; while pneumonia vaccine R&D investments are only included if they meet specific requirements for strain, vaccine type and target age group.

A comprehensive explanation of all current inclusions, exclusions and restrictions, as well as changes to the scope over time, is provided by the neglected disease scope document.

• Bacterial pneumonia & meningitis

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  Bacterial pneumonia & meningitis

  Pneumonia is an infection of the lungs that is transmitted when infected individuals cough or sneeze. Symptoms include coughing, fever, chest pain and shortness of breath. The illness can be deadly, especially for young children and elderly patients. Although pneumonia can be caused by a range of pathogens, pneumococcal pneumonia caused by the bacterium Streptococcus pneumoniae is by far the most common in developing countries.

  Bacterial meningitis is an infection of the fluid that surrounds the brain and spinal cord, most commonly caused by S. pneumoniae or Neisseria meningitidis. Symptoms of bacterial meningitis can include severe headaches, fever, chills, a stiff neck, nausea and vomiting, sensitivity to light, and an altered mental state. Bacterial meningitis is also often transmitted from person to person through coughing or sneezing. Even with early diagnosis and treatment, 5-10% of infected individuals die within 48 hours of showing symptoms.

  R&D needs

  Pneumococcal conjugate vaccines (PCVs) are highly effective and widely used in high-income countries, but until recently, the most common PCVs did not offer protection against serotypes most prevalent in developing countries. The WHO-prequalified PCV10 and PCV13 vaccines, which offer broader protection, have been rolled out in developing countries with positive results. However, PCVs are expensive to make and do not protect against all pneumococcal serotypes. Gains from PCVs with limited serotype coverage may be threatened by serotype replacement of vaccine-cleared serotypes with non-vaccine serotypes. New vaccines are needed that are more affordable, while still providing specific protection for children against all serotypes, or those predominant in developing countries. Non-conjugate protein- and whole-cell-based vaccines are two potential approaches, offering broad protection and cheaper manufacture; however Sanofi’s trivalent vaccine candidate PPrV and PATH’s whole-cell candidate PATH-wSP are the only non-PCV candidates currently in active clinical development. An affordable 10-valent PCV (PNEUMOSIL) was WHO prequalified in December 2019.

  Historically, most epidemic and endemic bacterial meningitis in the meningitis belt of sub-Saharan Africa has been caused by serogroup A meningococci. MenAfriVac, a 50c-per-dose monovalent conjugate meningitis A vaccine developed by the Meningitis Vaccine Project, has been rolled out across the meningitis belt since 2010, with much success. An infant version of MenAfriVac was prequalified by the WHO in early 2015. But as rates of meningitis A have fallen, other serogroups have become increasingly prominent. Two multivalent conjugate vaccines are currently available, but, at between $12 and $40 per dose, are too expensive for developing countries. There is an ongoing need for cheaper polyvalent conjugate vaccines, with one candidate – PATH and SII’s pentavalent meningococcal conjugate vaccine (A, C, Y, W-135, X) – entering Phase III trials in August 2019. Diagnostics are also needed, including an RDT for use at the peripheral level that can detect serogroups to guide vaccine response, as well as multi-pathogen point-of-care tests for use at either peripheral or hospital levels to guide case management in both epidemic and endemic settings. BioSpeedia’s MeningoSpeed RDT is currently undergoing clinical evaluations for the detection of serogroups A, C, W, Y, X.

  Disease burden

  • Deaths 2017 1,220,742
  • DALYs 2017 64,535,085

  This information was last updated in December 2019

• Buruli ulcer

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  Buruli ulcer

  Buruli ulcer, also known as Bairnsdale ulcer, is a chronic disease caused by Mycobacterium ulcerans. In developing countries, children under the age of 15 are at greatest risk. While the exact transmission mode is unknown, living around marshy areas with stagnant or slow-moving water can be a risk factor in endemic regions. Buruli ulcer usually appears as a painless lump or nodule that can later develop into an ulcer, usually on the arms or legs. M. ulcerans produces a toxin known as mycolactone, which causes tissue damage and can depress the immune response. As a result, coinfection with HIV can make Buruli ulcer more complex to address. If left undiagnosed or untreated, infection with M. ulcerans can lead to skin, tissue or bone damage, with surgery or amputation sometimes required.

  R&D needs

  Treatment options, including antibiotics and surgery, are effective if the disease is diagnosed early, however current diagnostics are both costly and complex. FIND is developing several Buruli ulcer diagnostics in collaboration with the WHO and other partners. These include an instrument-free point-of-care test as well as tools that can be used at peripheral health centres. Aptagen is also in the early stages of developing a point-of-care diagnostic based on RNA aptamers.

  Drug treatment is with a combination of two antibiotics given daily (or twice-daily) for eight weeks. The most commonly used regimen in sub-Saharan Africa combines one oral and one injectable antibiotic, but recent evidence suggests that all-oral regimens may be equally effective. Recent research calls for ongoing monitoring to detect any emerging drug-resistant strains, highlighting the need for new drugs that are less complicated to administer or can be given for a shorter period. Although there are few new drug candidates currently in development specifically for Buruli ulcer, two investigational tuberculosis drugs – telacebec (Q203) and TB47 – have demonstrated efficacy against Buruli ulcer in pre-clinical studies.

  The BCG vaccine (designed for TB) provides short-term protection, but is not an adequate substitute for a specifically targeted vaccine. Buruli ulcer vaccine development is in the very early stages of research. A recombinant Mycobacterium marinum strain expressing MU-Ag85A – the only candidate in the pre-clinical pipeline – has demonstrated superior immunogenicity and protection over the BCG vaccine.

  Disease burden

  • Deaths N/A
  • DALYs N/A

  This information was last updated in December 2019

• Cryptococcal meningitis

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  Cryptococcal meningitis

  Cryptococcal meningitis is an opportunistic infection that causes inflammation of the tissue covering the brain and spinal cord. It is caused primarily by Cryptococcus neoformans, a microscopic and easily inhaled fungus found throughout the world. In healthy individuals, inhalation of the fungal spores rarely leads to serious illness; but for immunocompromised individuals, such as those with HIV/AIDS, cryptococcal infection (cryptococcosis) can be serious and even deadly. Cryptococcosis can affect multiple organs, but the primary site of infection is usually the lungs. Cryptococcal meningitis occurs when the infection spreads to the brain and central nervous system, with symptoms including headaches, fever, neck pain, light sensitivity and altered mental state (ranging from confusion to coma). Mortality rates for cryptococcal meningitis can be as high as 70%.

  R&D needs

  Cryptococcal meningitis can be effectively treated with medicines such as amphotericin B and flucytosine, but these are poorly suited to developing country use. Amphotericin B is expensive and requires administration at a hospital, and flucytosine requires careful blood monitoring. As a result, cryptococcal meningitis in developing countries is usually treated with fluconazole, which is only partially effective. There is a need for affordable, efficacious drugs that are adapted for resource poor settings. New antifungal agents, repurposed drugs and immunotherapies are all being investigated. Several new antifungal agents targeting various biochemical processes are in the early stages of development and show promising activity against cryptococcal meningitis. One such candidate is the new long-acting azole-like compound VT-1129 – currently in pre-clinical development – which received Fast Track designation from the US FDA in 2016. Clinical trials are also being conducted on new oral formulations of amphotericin B (MAT2203). A number of repurposed drugs are under investigation for their efficacy against cryptococcal species alone or in conjunction with the current amphotericin B and fluconazole therapies, including the anti-cancer drug tamoxifen, which is in Phase II trials for a short-course combination therapy with amphotericin B and fluconazole. Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have demonstrated success in treating cryptococcal meningitis and cryptococcosis more generally. There are currently no late-stage candidates in the drug or biologic pipeline.

  Accurate rapid diagnostic tests for cryptococcal infection are available and appropriate for use in developing country settings, meaning that diagnostics are excluded from the G-FINDER scope.

  Disease burden

  • Deaths 2014 181,100
  • DALYs N/A

  This information was last updated in December 2019

• Dengue

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  Dengue

  Dengue is a viral infection transmitted to humans by the female Aedes mosquito – most often Aedes aegypti (common in urban environments) and Aedes albopictus (common in rural environments). The dengue virus has four serotypes, each with multiple genotypes. First time infection rarely results in anything more serious than a severe flu-like illness; subsequent infections with a different serotype (or even genotype) can result in severe disease, and are more likely to lead to dengue haemorrhagic fever. For children in affected regions, dengue is a leading cause of serious illness and death. Dengue outbreaks often occur in Asia, Central America and South America; the disease is now present in more than 100 countries, up from only nine in 1970.

  R&D needs

  Dengue’s prevalence in high- and upper-middle-income countries across Asia and Latin America and demand from travellers and the military has created a potential dengue vaccine commercial market large enough to attract industry investment in vaccine R&D. Dengue vaccine R&D investment has thus been excluded from the G-FINDER scope.

  No curative treatment is available, so management is focused on supportive therapy and the control of onward transmission. Despite the unmet need, there is little advanced dengue drug research. Drug candidates in clinical development include repurposed drugs, such as celgosivir, while other direct-acting antivirals such as DengueCide and JNJ-1A are in pre-clinical development. Biologic R&D – included in the G-FINDER scope for the first time this year – is currently centred on the pre-clinical development of monoclonal antibody (mAb) therapeutic candidates, including DENV mAb and AB513, both of which can neutralise all four dengue serotypes.

  There is a pressing need for diagnostics that work across the full spectrum of disease, and can distinguish dengue from other causes of fever. The first reverse transcription polymerase chain reaction (RT-PCR) diagnostic test capable of detecting all four serotypes was approved by the US FDA in 2012 (CDC DENV-1-4), but has shown a lower clinical sensitivity in practice. Several advanced tests are being adapted for dengue virus detection, including isothermal molecular technologies such as the DENV RT-LAMP and DENV NASBA assays, both from the US NMRC; US CDC’s DENV TMA assay; and DENV RT-RPA from TwistDx. Point-of-care serological tests based on antigen or antibody detection (such as the SD Bioline Dengue Duo RDT) are already available. Unfortunately, these tests cannot distinguish between serotypes, and may lack sensitivity and specificity.

  Several new vector controls targeting the Aedes mosquito are in development, including adulticidal oviposition traps and space spray insecticides. Field experiments for biological control tools are ongoing across Asia and South America for the Wolbachia bacteria method, including a large cluster-randomised controlled trial in Indonesia; trials in China and Thailand which combine the sterile insect technique with Wolbachia-based incompatible insect technique (SIT/IIT); and a trial in Brazil of the second generation genetically manipulated ‘Friendly’ Ae. Aegypti (OX5034).

  Disease burden

  • Deaths 2017 40,407
  • DALYs 2017 2,910,652

  This information was last updated in December 2019

• Diarrhoeal diseases

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  Diarrhoeal diseases

  Diarrhoeal diseases are a group of illnesses caused by viruses, bacteria and protozoan parasites that spread through contaminated food or water. Without treatment, diarrhoeal diseases can cause severe illness and death. Children under the age of five and immunocompromised individuals are most at risk. Rotavirus is the leading cause of severe diarrhoeal disease in young children worldwide, causing fever, vomiting and watery diarrhoea. Other diarrhoeal diseases include enteroaggregative E. coli (EAEC) and enterotoxigenic E. coli (ETEC), both of which can also cause fever and watery diarrhoea. For some people, cholera (caused by Vibrio cholerae) is asymptomatic but for others, infection can lead to severe diarrhoea and vomiting, and even kill within hours if left untreated. Shigellosis, caused by the Shigella bacterium, is highly contagious. Giardiasis is caused by the Giardia protozoan parasite found in soil, food and water contaminated by faeces. Cryptosporidium is a protozoan parasite that can survive in soil, food and water, causing cryptosporidiosis primarily in people who work with animals or live in overcrowded settings.

  R&D needs

  Current vaccines against diarrhoeal diseases are sometimes ineffective and not always suitable for infants. New bivalent and multivalent vaccines that are suitable for infants and that have long durations of protection are needed for most diarrhoeal diseases. Paxvax’s Vaxchora, a cholera vaccine, received US FDA approval in 2016 for use in adults travelling to cholera-affected areas. While it is currently being evaluated for use in children over two years of age, it has not be approved for, or tested in, endemic areas. There are currently four WHO prequalified rotavirus vaccines, with ROTASIIL receiving prequalification in September 2018. As of late 2018, 101 countries had introduced a rotavirus vaccine as part of their routine immunisation schedule. However these current-generation live attenuated oral vaccines are not optimally effective in high-burden settings, and coverage is lower than with comparable injectable vaccines on the routine schedule. The next generation of rotavirus vaccine candidates are non-replicating parenteral vaccines, the most advanced of which – NRRV (P2-VP8) – is in Phase III trials. Several vaccine candidates for other diarrhoeal diseases are in Phase II trials, including ETVAX to address ETEC; and GSK3536852A and Flexyn2a for Shigella. A combined Shigella and ETEC vaccine candidate, ShigETEC is also in pre-clinical development.

  Oral rehydration therapy in conjunction with zinc supplementation is the mainstay of diarrhoeal disease management in LMICs, but supportive therapy alone is not sufficient in all types of diarrhoea. Safe, effective and affordable pathogen-specific drugs are needed to target V. cholerae, Cryptosporidium, and Shigella. The current therapeutic pipeline of both small molecule drugs and biologics for these pathogens is in the early stages of development, with no candidates in clinical development. New rapid diagnostic tests capable of distinguishing between different diarrhoeal diseases are also required, however there are currently no late-stage candidates in the diagnostic pipeline.

  Disease burden

  • Deaths 2017 1,157,938
  • DALYs 2017 54,608,364

  This information was last updated in December 2019

• Helminth infections

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  Helminth infections

  Helminths are parasitic worms and flukes that can cause disease in humans. The most common mode of transmission to humans is through ingesting or coming into contact with contaminated food, water, or soil. Helminth infections transmitted in this manner include ancylostomiasis and necatoriasis (hookworm), ascariasis (roundworm), trichuriasis (whipworm) and strongyloidiasis (intestinal roundworms) – collectively referred to as soil-transmitted helminths – as well as taeniasis/cysticercosis (tapeworm) and schistosomiasis (bilharziasis, also known as snail fever). Other helminth infections are transmitted by bites of blood-sucking arthropods: these include lymphatic filariasis, which is transmitted by mosquitoes, and river blindness (onchocerciasis), which is transmitted by the black fly.

  Adult worms can reside in the intestines and other organs, causing malnutrition and impaired cognitive development (hookworms), or progressive damage to the bladder, ureter and kidneys (schistosomiasis). Onchocerciasis is a major cause of blindness in many African and some Latin American countries, while lymphatic filariasis can cause painful, disfiguring swelling of the scrotum (hydrocele) and limbs (elephantiasis).

  R&D needs

  With no vaccines, disease control efforts rely on mass-drug administration. Variable drug efficacy and the need to control transmission mean that treatment programmes must continue for many years, increasing the risk of drug resistance. New and more effective drugs are needed for many helminth infections, as are paediatric formulations of existing drugs. Current diagnostic products for detection of some helminths are outdated or complex; new and effective diagnostics that can measure infection intensity and detect drug resistance are needed.

  In 2018, the US FDA approved moxidectin, the first new onchocerciasis treatment in 20 years. Candidates in clinical development include oxfendazole and emodepside for onchocerciasis (both in Phase I), tribendimidine for hookworm (Phase II), an orodispersible praziquantel tablet for schistosomiasis in children (Phase III) and TylAMac for filarial diseases (Phase I). Among the schistosomiasis vaccines in development is Sm14, which has completed a Phase IIa trial, and Sm-TSP-2, which recently commenced Phase I/II trials in Uganda. Therapeutic vaccines and antibody immunotherapy against adult worms, included in the G-FINDER scope under the heading of ‘biologics’ for the first time in the 2019n report, are also being explored for schistosomiasis. Sm-p80, the only schistosomiasis vaccine with promising therapeutic potential, has completed pre-clinical evaluation and is currently in preparation for human clinical trials. Two candidate vaccines against human hookworm infection are in clinical development. Na-GST-1 – the most advanced candidate – entered 2018 Phase II trials using a controlled human hookworm infection model. All of the current vaccine candidates against onchocerciasis are in pre-clinical development.

  There are several diagnostic tests in development for helminth infections, including the SD BIOLINE Oncho/LF IgG4 biplex rapid test – a dual detection point-of-care test for onchocerciasis and lymphatic filariasis currently in field evaluation – and the UCP-LF CAA assay to diagnose schistosomiasis in low-prevalence settings, which is in clinical development. A lateral flow point-of-care test from the US CDC that can simultaneously detect taeniasis and neurocysticercosis is currently undergoing field evaluation in Tanzania and Zambia.

  Disease burden

  • Deaths 2017 12,765
  • DALYs 2017 7,512,706

  This information was last updated in December 2019

• Hepatitis B

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  Hepatitis B

  Hepatitis B is a disease of the liver caused by infection with the hepatitis B virus (HBV), and can be either acute or chronic. Acute infection is more common and more severe in adults and adolescents, but the likelihood of developing chronic disease is dramatically higher in infants and children under five. As many as 80-90% of children infected during the first year of life will progress to chronic disease, but this falls to less than 5% for otherwise healthy adults. Almost all of the burden of HBV-related disease is due to chronic hepatitis B – largely due to cirrhosis or liver cancer – following infection transmitted from mother to child at birth or acquired in early infancy. Although HBV is prevalent worldwide, the burden of hepatitis B is disproportionately high in low- and middle-income countries, and co-infection with HIV is not uncommon. Hepatitis B product R&D was added to the G-FINDER scope in the 2019 report, restricted to LMIC use and applicability.

  R&D needs

  An effective vaccine against HBV exists, with the current HBV preventive vaccine series (a dose at birth followed by two subsequent booster doses) providing protection in more than 95% of vaccinated infants. Vaccination against HBV remains the main strategy for the control and elimination of hepatitis B, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal.

  There is also a lack of data that could be used to inform population approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs, suggesting a need for additional basic research.

  Oral therapy with recommended first-line HBV treatments such as entecavir or tenofovir alafenamide is generally safe and well tolerated, and can result in virological suppression in more than 95% of patients. Long-term treatment and viral suppression is associated with regression of cirrhosis and reduced incidence of hepatocellular carcinoma, but seroclearance is uncommon and lifelong drug treatment is required for most patients. At least two candidates are in clinical development for functional cure of hepatitis B – defined by sustained undetectable surface antigen levels, regardless of seroconversion – including inarigivir in Phase II, and HS-10234  in Phase III. Novel therapies aimed at achieving HBV seroclearance are also in development, including immune stimulators, and other host-targeting bio-therapeutics.

  Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis; rapid diagnostic tests (RDTs) are available as cheap and generally accurate alternatives to laboratory-based immunoassays, although both may fail to identify low HBsAg concentrations, for example in HIV co-infection. However, for confirmation of diagnosis, treatment monitoring and detection of drug resistance, there is a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load. Two assays have recently been developed for POC molecular platforms – Cepheid’s Xpert HBV VL and Molbio Diagnostics’ Truenat HBV VL – but neither is currently WHO-prequalified and cost may remain a barrier to access.^,  Another molecular test designed explicitly for low-resource settings, DRW’s SAMBA POC platform, has HBV qualitative and semi-quantitative assays in early-stage development.

  Disease burden

  • Deaths 2017 741,267
  • DALYs 2017 23,752,066

  This information was last updated in July 2020

• Hepatitis C

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  Hepatitis C

  Hepatitis C is a blood-borne infectious disease caused by the hepatitis C virus (HCV), primarily affecting the liver. HCV causes both acute and chronic infection­­, with symptoms in the acute phase including fever, fatigue and jaundice. However, up to 80% of acute cases are asymptomatic, meaning that many HCV infections will go undetected until chronic disease develops, sometimes decades later. Although 20-40% of acute infections resolve spontaneously without treatment, the remaining 60-80% of cases will progress to chronic infection.¹⁴⁵ Without treatment, chronic hepatitis C is a lifelong disease which can lead to life threating liver damage (cirrhosis and fibrosis) and hepatocellular carcinoma (liver cancer).

  There are six main genotypes of HCV, with genotypes 4, 5 and 6 disproportionately affect developing countries, while having a low prevalence in high-income countries. Since R&D efforts have moved from genotypic-specific to pan-genetypic products, in the 2019 report we replaced the genotype restriction for inclusion in G-FINDER with more detailed restrictions on LMIC applicability and use.

  R&D needs

  There are 15 direct-acting antiviral (DAA) drugs available on the market, including four pan-genotype combinations. DAA-based regimens are more effective, require a shorter duration of treatment, are appropriate for most patients and have fewer side effects than previous interferon- and ribavirin-based treatments. Due to these advancements, in 2018 the WHO recommended that persons over the age of 12 years should be treated with DAAs. However, DAA-based regimens are expensive, and access remains limited in LMICs. The Medicines Patent Pool licenced a pan-genotype, fixed-dose combination DAA (glecaprevir/pibrentasvir) in 96 LMICs, but has not reached agreements for its generic production. More research is also needed to assess DAA-based regimens in developing country populations, adolescents, children under 12, and pregnant women. Several other multi- or pan-genotypic DAA-based regimens are undergoing trials, including ravidasvir/sofosbuvir – the only pan-gentoypic regimen in late-stage development – and two paediatric regimens, sofosbuvir/velpatasvir in Phase II trials and glecaprevir/pibrentasvir in expanded access Phase III trials.

  There is also a need for HCV diagnostic tests that are affordable and simple to use in developing country contexts, especially tests usable for treatment monitoring, screening and tests of cure. The WHO has prequalified nine HCV diagnostic tests, including three RDTs and one viral load test. Future diagnostic R&D needs to validate the use of dried blood spots for serological and molecular assays, validate core antigen-based assays as the gold standard for confirmatory tests and test of cure, and develop a true point-of-care nucleic acid test. Two diagnostics are in late stages of development: the Genedrive HCV ID Kit for confirmatory diagnosis/treatment monitoring and test of cure, and the STANDARD Q HCV Ab test as a point-of-care antibody assay.

  There is no vaccine against HCV, although there are some pan-genotypic candidates in early-stage development, such as the Burnet Institute’s HepSeeVaxDelta3 candidate. Only two candidates have reached clinical development and both have been unsuccessful: GSK’s GSK3378455A and NIAID’s AdCh3NSmut1/MVA-NSmut.

  Disease burden

  • Deaths 2017 449,333
  • DALYs 2017 12,743,817

  This information was last updated in December 2019

• Histoplasmosis

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  Histoplasmosis

  Histoplasmosis is a fungal infection caused by the dimorphic fungi Histoplasma capsulatum, transmitted via inhalation of spores from contaminated soil. In most cases, histoplasmosis presents as an asymptomatic infection or self-limited flu-like illness. Individuals with a compromised T-cell immune response, such as those with HIV, can develop more serious disease, including chronic pulmonary histoplasmosis or disseminated histoplasmosis – conditions which have a striking similarity with the pulmonary and miliary forms of tuberculosis, respectively, making clinical differentiation difficult.

  Histoplasma is mostly found in the Americas but has been reported in most countries, including in Africa and Asia. The HIV/AIDS pandemic resulted in an increased incidence of the more severe disseminated form of histoplasmosis in endemic regions of the Americas, and particularly in Latin America, where over 15,000 new cases and 4,500 deaths from disseminated histoplasmosis are reported each year among people living with HIV/AIDS (PLWHA). Recent estimates suggest that there is a higher incidence of histoplasmosis than of TB among PLWHA in Latin America, and that histoplasmosis causes more deaths.

  R&D needs

  Timely diagnosis and early initiation of treatment are critical, as untreated or delayed disseminated histoplasmosis management is often fatal. Laboratory diagnosis using conventional techniques such as culture and histopathology have several drawbacks, including the need for complex infrastructure and varied sensitivity. Detecting circulating Histoplasma antigens in urine by ELISA has been shown to be highly sensitive (95%), but lack of commercial availability hampers its use. An antigen-based lateral flow assay has recently become commercially available, but still requires additional research, including evaluation under programmatic conditions.

  WHO guidelines for managing disseminated histoplasmosis recommend an induction phase with liposomal amphotericin B for two weeks, followed by maintenance therapy with itraconazole for 12 months. Although highly efficacious, liposomal amphotericin B is a parenteral drug that is not temperature stable, limiting its utility in resource-limited settings. In addition, itraconazole has drug-drug interactions with anti-tubercular and anti-retroviral medicines; monitoring blood concentration levels is therefore recommended, making its use in LMICs challenging. New treatment regimens are needed, that are preferably oral, with a shorter duration, and safe in combination with anti-tubercular and anti-retroviral medicines.

  Current data on the burden of histoplasmosis is primarily generated from Latin America. However, considering the global distribution of Histoplasma, fundamental research investigating the incidence and prevalence in other high-risk LMICs in critical.

  Disease burden

  • DEATHS N/A
  • DALYS N/A

  This information was last updated in May 2021

• HIV/AIDS

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  HIV/AIDS

  HIV continues to be a major public health issue, with almost 40 million people living with the virus as of 2018, the majority in LMICs. The virus attacks and destroys CD4 cells in the human immune system; without treatment, infected individuals become increasingly susceptible to other diseases, and eventually develop acquired immune deficiency syndrome (AIDS). People with AIDS often die from opportunistic infections like tuberculosis or cryptococcal meningitis, or cancers like Kaposi’s sarcoma.

  R&D needs

  There is currently no vaccine against HIV, and the rapid mutation of the virus poses a significant challenge to development. To date no vaccine candidate has proved able to match even the 31% efficacy achieved in the 2009 RV144 Thai Phase III clinical trials. There are currently two large HIV vaccine efficacy trials underway: HVTN 706, a global Phase III HIV vaccine efficacy trial of mosaic immunogens; and HVTN 705, a Phase IIb trial of Janssen’s prime-boost-based regimen. A third vaccine trial – HVTN 702, a Phase IIb/III trial investigating a modified version of the RV144 vaccine regimen – was halted in early 2020 due to non-efficacy. Several other candidates are currently in Phase I and II trials, including NIAID’s broadly neutralising anti-HIV antibody (bNAb) candidate, VRC01, which is in Phase IIb.

  Therapeutic vaccines – including bNAb-based approaches, which are designed to control HIV infection by boosting the body’s natural immunity – are also being investigated for immunotherapy, including VRC01LS/10-1074, a dual long-acting bNAb currently in Phase II. Plasmid and viral vectored DNA vaccines are also among the therapeutic vaccine candidates currently in Phase I and II clinical trials.

  Despite advances in HIV therapeutics, R&D gaps for HIV drugs persist in LMICs, including paediatric formulations or long-acting injectable drugs for PrEP, with promising progress underway. The Drugs for Neglected Diseases initiative (DNDi) is developing Quadrimune – a ‘4-in-1’ LPV/r-based taste-masked and heat-stable fixed-dose formulation designed specifically for children, which is currently under review by the FDA, with a Phase I/II trial ongoing in Uganda to generate evidence for worldwide scale-up. One long-acting injectable PrEP candidate, cabotegravir, is also in Phase IIb/III and III trials, and has demonstrated high efficacy when administered every eight weeks, with the blinded part of the study subsequently stopped as a result of this success. Following a Phase III trial, the long-acting injectable treatment regimen cabotegravir/rilpivirine was also granted approval by Health Canada in early 2020. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise. The International Partnership for Microbicides (IPM)’s monthly dapivirine ring has completed Phase III trials, and in July 2020 received a positive scientific opinion from the European Medicines Agency for use in women over 18 in LMICs.

  Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially early infant diagnosis. There is progress towards robust, rapid point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates. These include early infant diagnostic tests (Alere’s q HIV-1/2 Detect and Cepheid’s Xpert HIV-1 Qual Assay), an assay for viral load monitoring (Hologic’s Aptima HIV-1 Quant Assay) and the first true point-of-care molecular test for resource limited settings (Abbott’s m-PIMA HIV-1/2 VL).

  Disease burden

  • Deaths 2017 938,891
  • DALYs 2017 53,567,471

  This information was last updated in July 2020

• Kinetoplastid diseases

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  Kinetoplastid diseases

  Kinetoplastid infections include three diseases: leishmaniasis; Chagas’ disease (also known as American trypanosomiasis); and sleeping sickness (human African trypanosomiasis). Leishmaniasis – caused by Leishmania parasites and spread by phlebotomine sand flies – has three forms: visceral (the most severe form, often fatal without treatment); cutaneous (the most common); and mucocutaneous. Chagas’ disease – caused by Trypanosoma cruzi and predominantly spread by the blood-sucking triatomine bug – has two stages. Symptoms in the acute stage are often mild or absent, resulting in under-diagnosis. Left untreated, infected individuals will progress to the chronic second stage, and 20-30% will develop life-threatening complications. Sleeping sickness is caused by the parasite Trypanosoma brucei and spread by tsetse flies. It also has two stages, with early-stage disease symptoms difficult to distinguish from other viral illnesses. In late-stage disease, the parasite infects the brain and central nervous system, causing confusion and – without treatment – coma and death.

  R&D needs

  Leishmaniasis needs a preventive vaccine; biologic treatments; improved, preferably oral, drug formulations; and diagnostic tests for general disease diagnosis, cure, and a specific test for post-kala-azar dermal leishmaniasis (PKDL). Two visceral leishmaniasis candidates – a vaccine and a biologic therapy – are in active clinical development. Three novel leishmaniasis drugs being developed by GSK and DNDi have entered Phase I trials while a topical formulation of an existing drug (amphotericin B) is in clinical trials for the treatment of cutaneous leishmaniasis. Diagnostics for resource-limited settings in development include: VL Sero K-SeT (in late-stage development) for rapid monitoring of cure and diagnosis of PKDL; a VL ELISA test (in late-stage development); and a LAMP-based test for visceral and cutaneous leishmaniasis currently undergoing demonstration studies.

  Chagas’ disease needs a preventive vaccine; biologic treatments; safer, more effective drugs suitable for children and effective against the chronic form of the disease; and diagnostics that can reliably detect chronic disease and monitor treatment. All Chagas’ disease vaccine and biological therapeutic candidates are in the pre-clinical stage or earlier. A paediatric benznidazole formulation has been approved in Brazil, the US and Argentina, while a combination of benznidazole and fosravuconazole has completed Phase II trials, showing effectiveness as a two-week treatment course. A Phase II trial of short-course and low-dose regimens of fexinidazole is ongoing in Spain. Several new diagnostic tools to detect congenital Chagas’ disease are in development, including two immunoassays in early-stage development and two LAMP-based molecular tests in late-stage development.

  Fexinidazole, the first all-oral treatment active against both stages of sleeping sickness, was registered in 2019 in the DRC, following the 2018 EMA positive scientific opinion. It could potentially replace the current nifurtimox-eflornithine combination injectable treatments with an all-oral treatment which can be completed in just ten days. A second oral treatment, acoziborole, is in Phase II/III clinical trials. There is little active research into sleeping sickness vaccines or biologics, with no candidates currently in the pipeline. Two point-of-care serological tests are in late-stage development: Coris BioConcept’s second generation HAT RDT and ITM Antwerp’s iELISA.

  Disease burden

  • Deaths 2017 16,641
  • DALYs 2017 1,076,053

  This information was last updated in December 2019

• Leprosy

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  Leprosy

  Leprosy, also known as Hansen’s disease, is caused by Mycobacterium leprae and is transmitted via air droplets from the nose or mouth of infected people. Leprosy mainly affects the skin and nerves and has an incubation period that can be as long as 20 years. The disease is curable with multidrug therapy using a combination of rifampicin, clofazimine and dapsone (for multibacillary leprosy), or rifampicin and dapsone (for paucibacillary leprosy). However, if left untreated, leprosy can cause nerve damage, muscle weakness and permanent impairments.

  R&D needs

  The current drug regimen for leprosy has been standard treatment for 30 years and, although highly effective, it requires between six and 24 months of treatment. Further research is needed to improve and simplify drug regimens, and to provide products for nerve function management. Bedaquiline, an antibiotic approved for the treatment of MDR-TB and found to be effective in the treatment of leprosy in animal models, is currently undergoing Phase II clinical trials.

  Leprosy vaccine and biologic R&D was included in the G-FINDER scope for the first time in the 2019 report given the absence of effective preventive or therapeutic vaccines. Immunisation with BCG has only a modest ability to prevent leprosy (26% in observational studies, 41% in experimental studies) and post-exposure BCG immunisation may cause paucibacillary disease in some individuals. Preventive and therapeutic vaccine R&D for leprosy is currently underway to identify antigens that can offer post-exposure immunoprophylaxis or confer protection without exacerbating nerve damage, most notably LEP-F1/GLA-SE (LepVax), which is currently in Phase Ib/IIa clinical trials.

  Diagnosis of leprosy is primarily based on identifying key clinical features of infection, meaning that asymptomatic early-stage cases are often missed or diagnosed late, leading to continued disease transmission. Elimination of leprosy will likely require new and improved diagnostics capable of identifying asymptomatic cases, as well as all symptomatic forms (paucibacillary, borderline tuberculoid, borderline, borderline lepromatous or multibacillary) of the disease. The Infectious Disease Research Institute (IDRI) is one organisation currently developing rapid diagnostic tests for leprosy, including co-development of NDO-LID, which to date has been limited by very low capacity to detect true positives in both paucibacillary (14.9%) and multibacillary (47.9%) Brazilian patients. Additional immuno-diagnostic tests include Leiden University’s Field-friendly lateral flow assays (LFAs), currently in late-stage development.

  Disease burden

  • Deaths 2017 -
  • DALYs 2017 31,397

  This information was last updated in December 2019

• Leptospirosis

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  Leptospirosis

  Leptospirosis is an infection caused by bacteria of the genus Leptospira, which affects both humans and animals. The infection is transmitted to humans through contact with the urine or blood of infected animals, either directly or via contaminated water, food or soil. People who live in tropical climates, who work in flooded areas such as rice paddies and sugar cane plantations, or who work with animals are most at risk. The bacteria can survive for several weeks in water or soil, and outbreaks often occur after flooding.

  R&D needs

  Diagnosing leptospirosis can be challenging due to the non-specific symptoms of early infection, which are shared with a number of other diseases, such as dengue and malaria, as well as the fact that some infected individuals may remain asymptomatic. Without treatment, the infection can progress to a more severe second phase, causing meningitis, kidney and liver failure, respiratory distress, and sometimes death.

  Effective, appropriate drugs exist for leptospirosis, meaning that infection can be successfully treated if it is diagnosed. However, accurate diagnosis of leptospirosis during the acute phase of the disease is currently only possible with sophisticated laboratory tests, which are unsuitable for remote settings. There is a real need for new, easy-to-use tests that can quickly and accurately diagnose acute infection in the field. Several rapid point-of-care tests are available on the market, but none of these are widely approved due to their lack of specificity and sensitivity. The promising diagnostic LEPkit assay has demonstrated higher sensitivity and specificity than existing rapid diagnostic tests, but its development status has not been updated since 2017.

  Disease burden

  • Deaths 2015 58,900
  • DALYs 2015 2,900,000

  This information was last updated in December 2019

• Malaria

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  Malaria

  Malaria is a parasitic disease transmitted through the bite of an infected female Anopheles mosquito. The two most common types of malaria are caused by Plasmodium falciparum and Plasmodium vivax. Left untreated, malaria can cause severe illness and death. Children and pregnant women are among the most vulnerable, with more than 70% of all malaria deaths occurring in children under five years of age.

  R&D needs

  The most advanced malaria vaccine candidate, RTS,S, commenced large-scale pilot implementation in 2019 in Malawi, Ghana and Kenya under the auspices of the WHO-coordinated Malaria Vaccine Implementation Programme. There remains a need for new vaccines which have greater efficacy; provide protection against both P. falciparum and P. vivax; and can block transmission. The next most advanced vaccine candidate, Sanaria’s PfSPZ, is now in Phase II trials.

  Eleven new malaria drugs have been approved since 2007, including tafenoquine, a single-dose treatment for relapsing P. vivax malaria approved in 2018, and two paediatric artemisinin-based combination therapy (ACT) formulations. New drugs are still needed in response to emerging resistance to ACTs, and to meet the goal of a single-dose cure. Several promising novel drugs are in late-stage development, including artefenomel/ferroquine and ganaplacide/lumefantrine. Both candidates are undergoing Phase IIb trials for safety, efficacy and their potential as a single-encounter radical cure. Biologics were included in scope for the first time this year, with monoclonal antibodies (mAbs) being investigated as a new approach for malaria prophylaxis, treatment or blocking transmission. At least one transmission blocking biologic, mAb TB31F, is currently in pre-clinical development.

  Cheap, sensitive rapid diagnostic tests (RDTs) exist, although heat stability can be an issue. The emergence of parasites with deletions in the pfhrp2/3 gene – which codes for the most common RDT target for detecting P. falciparum – is concerning. Improved, more sensitive diagnostics are needed to identify non-falciparum species, distinguish malaria from other febrile illnesses, detect asymptomatic cases, and diagnose G6PD enzyme deficiency. PATH’s RDT to diagnose G6PD deficiency is currently in late-stage development, while Alere’s Malaria Ag P.f, a new generation highly-sensitive RDT which can detect asymptomatic infections, was prequalified in 2019.

  Next-generation vector control products are urgently needed in response to emerging pyrethroid resistance. Novel non-pyrethroid-based products that received WHO prequalification in 2017 include Sumitomo’s SumiShield 50WG, a clothianidin indoor residual spray (IRS) formulation and BASF’s Interceptor G2, a chlorfenapyr-based, dual-ingredient long-lasting insecticide-treated bed net (LLIN). Chemical control products in development include Sylando 240SC – a chlorfenapyr-based IRS formulation – currently undergoing final phases of WHO prequalification review, and Olyset Duo – a dual LLIN with permethrin plus pyriproxyfen – which recently completed field evaluations. Vector manipulation approaches to reduce mosquito populations or block parasite transmission are also being investigated, with field experiments of CRISPR/Cas9-based gene drive approaches starting this year in Burkina Faso. New approaches to vector control are being explored, including use of ivermectin mass drug administrations for malaria transmission control, as well as spatial repellents and insecticide-treated baits.

  Disease burden

  • Deaths 2017 619,685
  • DALYs 2017 45,005,406

  This information was last updated in December 2019

• Mycetoma

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  Mycetoma

  Mycetoma is a chronic infection of the skin and soft tissue caused by either flesh-eating fungi (eumycetoma) or bacteria (actinomycetoma). When left untreated, it can affect deeper tissues and lead to amputation. Although the true global incidence and prevalence of mycetoma is still not fully known, it most often occurs across the so-called mycetoma belt, which includes Sudan, Chad, Ethiopia, Senegal, Somalia, Yemen, Mauritania, Venezuela, Mexico and India. Mycetoma has been included in the G-FINDER scope for the first time.

  R&D needs

  There is a need for new tools to address the ongoing challenge of mycetoma in endemic countries, including new drugs and diagnostics, as well as basic research to fill critical information gaps.

  Despite the availability of several drugs for the treatment of mycetoma, including the antifungals ketoconazole and itraconazole, and the antibiotics amikacin and co-trimoxazole, significant R&D gaps still exist. Antifungals targeting eumycetoma are only 25-35% effective, are costly, require extended treatment and can cause serious side effects. DNDi is currently supporting a Phase II trial of fosravuconazole in Sudan to assess whether it is superior to these existing antifungals. While antibiotics used for the treatment of actinomycetoma have a cure rate of 90%, the global rise of antimicrobial resistance threatens their long term effectiveness.

  Existing tools for diagnosing mycetoma are often inappropriate for use in LMICs, as they are invasive, time-consuming and require a well-equipped laboratory. There is a need for cheap, rapid and accurate point-of-care diagnostics for patients with early lesions.

   

  More basic research is needed in order to accurately estimate the burden of mycetoma, to understand its epidemiology and mode of transmission, and to facilitate the development and use of new drugs and diagnostics.

  Disease burden

  • Deaths N/A
  • DALYs N/A

  This information was last updated in December 2019

• Rheumatic fever

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  Rheumatic fever

  Rheumatic fever is a bacterial infection caused by Streptococcus pyogenes (also known as Group A streptococcus, GAS) that most commonly affects children aged 5-14 years. It usually follows untreated bacterial throat infections, and without treatment can lead to complications such as rheumatic heart disease, in which the heart valves are permanently damaged. It may also progress to heart failure and stroke.

  R&D needs

  Acute rheumatic fever can be treated using currently available drugs (although post-infection prophylaxis requires multiple doses of antibiotics); however, treatment of rheumatic heart disease often requires surgery. The main R&D required is therefore the development of a vaccine. Several GAS vaccines are in development, with only two candidates in clinical trials: StreptAnova, which completed a Phase I trial in December 2017, and MJ8VAX, whose Phase I clinical trial indicated the need for additional investigations to optimise its immunogenicity and improve dosing. Phase I/IIa trials are planned for StreptInCor, the most advanced pre-clinical candidate.

  Disease burden

  • Deaths 2017 245,372
  • DALYs 2017 8,814,192

  This information was last updated in December 2019

• Salmonella infections

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  Salmonella infections

  Salmonella infections are a group of diseases caused by the Salmonella enterica bacteria, and transmitted through contaminated food or drink. These include: typhoid (caused by Salmonella Typhi); paratyphoid fever (caused by Salmonella Paratyphi A, B or C) – collectively referred to as enteric fever; and thousands of non-typhoidal serotypes, referred to as non-typhoidal Salmonella (NTS). Enteric fevers affect only humans, while NTS affects both humans and animals.

  Salmonella infections are more common where there is dirty water and poor sanitation or hygiene. Symptoms can include fever, malaise, headache, constipation or diarrhoea, and an enlarged spleen and liver. Occasionally rose-coloured spots appear on the chest. In the case of typhoid fever, a small proportion of people can recover but still carry and spread the bacteria for as long as a year after infection. Diagnosis of Salmonella infections may require a blood, stool or bone marrow sample.

  R&D needs

  Medicines exist to treat enteric fever; however data from endemic regions show antimicrobial resistance linked to S. Typhi H58 clade is increasing, including the first ever reported outbreak of ceftriaxone-resistant S. Typhi in Pakistan in 2016. Therefore, there is a need for more efficacious drugs, including ones suitable for children. There are currently three safe and effective typhoid vaccines available, with the latest to receive WHO prequalification being the world’s first typhoid conjugate vaccine (TCV), Typbar TCV. The WHO recommends TCVs as the preferred vaccine in high-burden countries and Gavi funding for the introduction of this vaccine has been available for eligible countries since April 2018, with Zimbabwe as the first beneficiary. Given the threat of antibiotic resistance, biologic R&D remains a need and was included in the G-FINDER scope for the first time in the 2019 report. Pathogen-specific antibody-based therapeutics, such as monoclonal antibodies (targeting the typhoid toxin) and bacteriophages, are also being considered as an alternative modality for the treatment of typhoid fever.

  Paratyphoid fever is an increasingly common cause of enteric fever throughout Asia, but there are no registered vaccines specifically targeting it, nor any bivalent vaccines that target both typhoid and paratyphoid fever. There are at least two vaccine candidates targeting serovar Paratyphi A currently in clinical development: a glycoconjugate vaccine candidate O:2-TT (Phase II) and a live oral vaccine strain CVD 1902 (Phase I).

  There is no vaccine available for NTS, and treatment with antibiotics is only recommended for high-risk individuals such as young children, elderly people and immunocompromised patients. Several NTS vaccine candidates are in development, although they are all in the pre-clinical stage or earlier, including two candidates already set to transition to early clinical development: iNTS-GMMA, and the trivalent typhoid/iNTS glycoconjugate vaccine formulation (S. Enteritidis COPS:FliC/S. Typhimurium COPS:FliC/Typbar-TCV).

  Disease burden

  • Deaths 2017 193,943
  • DALYs 2017 14,023,086

  This information was last updated in December 2019

• Scabies

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  Scabies

  Scabies is a parasitic infection of the skin caused by infestation with the microscopic mite Sarcoptes scabiei var. hominis. It is a highly contagious disease, transmitted through close skin-to-skin contact, with the highest rates of infestation occurring in resource-limited settings, particularly associated with tropical climates and overcrowded living conditions. The infestation triggers an immune response causing intense itching and rash, which can be severe enough to disrupt day-to-day activities. Secondary effects result from bacterial skin infection (impetigo), which can progress to severe skin and soft tissue infections and sepsis, or  rheumatic fever and glomerulonephritis (leading in turn to rheumatic heart disease and chronic kidney disease).

  Scabies is one of the most common illnesses globally, with 565 million incident cases and 4.8 million DALYs in 2019. Although prevalent in most of the world, Asia, including Oceania, accounted for three-quarters (76%) of all new cases in 2019. Due to the high prevalence and greater vulnerability among socio-economically marginalised populations, WHO declared scabies a neglected tropical disease in 2017.

  R&D needs

  Permethrin 5% cream is the most efficacious topical scabicide for treating individual cases but its high price and lack of availability means LMICs often rely on less effective and less well-tolerated alternatives, such as benzyl benzoate and sulphur ointments. Oral ivermectin is highly effective against scabies however does not kill scabies eggs, meaning a second dose is required, increasing the difficulty of mass drug administration (MDA) interventions. Additionally, it is not recommended for pregnant and breastfeeding women, or in children weighing less than 15 kg. Moxidectin, a US FDA-approved antiparasitic agent related to ivermectin, is currently undergoing clinical trials for scabies. New oral drugs are needed that have prolonged skin activity, thereby effectively killing newly hatched eggs, and a proven safety profile in children and pregnant women.

  Visual identification of mites and eggs by microscopy is the gold standard tool for diagnosis but is operator dependent and can be insensitive, making it only suited for screening and diagnosing at an individual level. There is a need for a low-cost point-of-care test for both individual level diagnosis and management, and to facilitate mapping and surveillance at the population level.

  Better prevalence data are needed to guide the MDA intervention, especially critical in the regions phasing out ivermectin for helminth control. Monitoring mites’ resistance towards ivermectin will be necessary where it is currently used or expected to be used.

  Disease burden

  • DEATHS N/A
  • DALYS N/A

  This information was last updated in May 2021

• Snakebite envenoming

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  Snakebite envenoming

  Snakebite envenoming results from the bite of a venomous snake, and if not treated quickly and effectively can result in life-long disability, or lead to amputation or death. Snakebite envenoming is prevalent in tropical and sub-tropical regions in Africa, Asia, Oceania and Latin America. Snakebite envenoming was included in the G-FINDER report for the first time in the 2019 report.

  R&D needs

  Antivenoms – biological immunotherapeutics – have been used to treat snakebite envenomation for more than a century, and can be highly effective if given at the right time, at the right dose, and for the right snake.  However there is a critical lack of high-quality, safe and effective region-specific antivenoms appropriate for use in LMICs, particularly in sub-Saharan Africa and Asia.  Even the best currently-available antivenoms – all of which are based on animal-derived antibodies – are expensive to manufacture, can be complex to administer and store, and carry the risk of adverse reactions including anaphylaxis and serum sickness; they are also unable to neutralise all of the toxic effects of envenomation. There is a need for R&D to support the approval and introduction of safe, effective, high-quality antivenoms that are appropriate for the regions in which they are used, as well as to deliver next generation antivenoms that are more effective, more affordable, safer and heat-stable. Next generation antivenoms in preclinical development include single domain antibodies such as camelid-derived V_HH and human scFv, as well as several types of non-antibody-based molecules, such as nanoparticles, peptides and oligonucleotide aptamers.

  More basic research is needed to accurately estimate the burden of snakebite envenoming, and to understand the natural history and pathogenesis of disease, and the structure and properties of toxins and their variability between regions and species.

  In low-resource settings where immediate treatment may be impossible, heat-stable venom-agnostic oral drugs are also needed as a first-line therapeutic to slow down neurotoxicity and prolong the window for victims to receive antivenom. The development of broad-spectrum small molecule inhibitors could help bridge this gap; the repurposed phospholipase A₂ inhibitor varespladib is currently in pre-clinical trials and shows promise as a first line and combination therapy against venom-induced myonecrosis and haemorrhagic toxicity.

  There is also a need for affordable, rapid, point-of-care diagnostics capable of identifying the common species in high-burden areas, with low to no cross reactivity between venoms. The only existing point-of-care diagnostic is only available in Australia and is specific to Australian snake species. Two lateral flow assays for Taiwanese and Indian snakes are currently in clinical development.

  Disease burden

  • Deaths N/A
  • DALYs N/A

  This information was last updated in December 2019

• Trachoma

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  Trachoma

  Trachoma is an infectious eye disease caused by the bacterium Chlamydia trachomatis. The infection can be spread by contact with infected eyes or nasal discharge, including via contact from flies and shared use of clothing and towels. Trachoma is common among children and in areas where there is unclean water and poor sanitation. After repeat infection and without medical treatment, the eyelid can turn inwards, causing the eyelashes to rub against the eyeball, resulting in scarring, visual impairment or irreversible blindness.

  R&D needs

  WHO recommends a combination of interventions known as the SAFE strategy for the elimination of trachoma, which is an acronym for surgery (which has low acceptance and high recurrence rates); antibiotics (including treatment with azithromycin, though over-reliance on a single drug therapy can increase the risk of drug resistance); facial cleanliness; and environmental improvement to reduce transmission.

  Because of the challenges associated with successful implementation (and sustainability) of the SAFE strategy, a vaccine is needed. The most advanced trachoma vaccine candidate is NIAID’s live-attenuated (plasmid-deficient) trachoma vaccine, which is currently in pre-clinical development.

  Clinical diagnosis of trachoma is not always reliable, and current diagnostic tests are expensive and complex. Studies have shown that an antibody-based multiplex assay could be used to diagnose trachoma in low-prevalence settings. One candidate, the Pgp3 LFA-cassette, has been evaluated in field studies in Nepal, showing high specificity (99%) but low sensitivity (40%).

  Disease burden

  • Deaths 2017 -
  • DALYs 2017 301,761

  This information was last updated in December 2019

• Tuberculosis

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  Tuberculosis

  Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an airborne disease that most commonly affects the lungs, and is the leading cause of death of any single infectious pathogen. Almost a quarter of the world’s population is estimated to be infected, but most TB cases are latent and non-infectious; around 5-15% will progress to active TB if left untreated. Active TB usually causes coughing, fever and weight loss, and is highly infectious. TB is especially dangerous for people with low immunity, and is a leading cause of death among people with HIV/AIDS. There is also growing resistance to existing treatments.

  R&D needs

  Current TB drug regimens are complex and can require up to two years of daily treatment, leading to poor compliance, drug resistance and treatment failure. New drugs are needed that can shorten the duration of treatment, are effective not only against drug-sensitive TB but also against multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB), are suitable for all age groups, are safe to use in conjunction with HIV treatments, and can be used in new treatment paradigms, including treatment of latent TB and MDR-TB prophylaxis.

  The world’s first fixed-dose combination treatment specifically designed for children, HRZ/HR, received WHO prequalification in 2017 and has since been rolled out in over 80 countries, while in 2019 the FDA approved the all-oral, once daily BPaL regimen (including the novel drug pretomanid in combination with bedaquiline and linezolid), which promises to dramatically shorten the duration of treatment for XDR-TB and treatment-tolerant or non-responsive MDR-TB. TB Alliance is also preparing clinical trials for paediatric formulations of pretomanid. There are several ongoing Phase III trials of various regimens for the treatment of drug resistant TB based on new and approved drugs, including NeXT, SimpliciTB, TB PRACTECAL and endTB; and a further Phase III clinical trial (PHOENIx MDR-TB) evaluating the effectiveness of prophylactic delamanid in protecting household contacts from contracting MDR-TB. There are also two Phase III trials (SimpliciTB and TBTC Study 31) currently examining shorter duration regimens for drug-sensitive TB.

  The existing TB vaccine (BCG) provides limited protection against pulmonary disease in adults. A vaccine which provides protection against all forms of TB in all age groups is needed. Results from two recent TB vaccine efficacy trials were mixed: M72/AS01E showed an efficacy of 54% among TB-infected adults, and even higher levels in participants 25 years of age or younger, while H4:IC31 showed no statistically significant protection. A recombinant vaccine, VPM1002, has completed Phase II trials to assess safety and immunogenicity in neonates (including those exposed to HIV), and is in Phase II/III trials for prevention of TB recurrence in adults. Therapeutic vaccines (which now fall under the expanded ‘biologics’ category in this year’s G-FINDER report), are a potential tool to simplify and shorten TB treatment; at least one such candidate (RUTI) targeting MDR-TB is currently in Phase II clinical trials.

  There is a need for more effective and appropriate point-of-care TB tests, tests to diagnose TB in children, and tests for drug resistance and susceptibility. Cepheid’s next generation molecular test, Xpert MTB/RIF Ultra, showed significantly better performance than its predecessor, and the WHO is expected to provide a policy update on its use. Two new types of diagnostic technology – genotypic drug resistance testing and centralised high-throughput testing platforms – are currently under development.

  Disease burden

  • Deaths 2017 1,167,623
  • DALYs 2017 44,666,899

  This information was last updated in December 2019