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 have been rolled out in LMICs with favourable results with support from Gavi. However, they are typically expensive to manufacture. There is a need for low-cost candidates that offer broader protection for children against serotypes predominant in LMICs, as gains from existing PCVs are threatened by serotype replacement. Two potential approaches – non-conjugate protein-and whole-cell-based vaccines, both potentially offering broader protection and cheaper manufacturing cost, are being explored; but majority of candidates remain in preclinical development. The introduction of the MenAfriVac monovalent conjugate meningitis A vaccine culminated in a drastic reduction in meningitis A infection across the African continent, but other serogroups have become more prominent, creating the need for low-cost polyvalent vaccine candidates. Rapid diagnostic tests that can detect serogroups to guide vaccine response and multi-pathogen point-of-care tests to guide case management in both epidemic and endemic settings are also needed.

  Pipeline spotlight

  NmCV-5, a pentavalent meningococcal vaccine co-developed by PATH and Serum Institute of India, already proven to be safe, well-tolerated, and capable of producing strong immune responses to all five serogroups has entered a pivotal Phase III trial, specifically designed to generate optimal evidence for a WHO pre-qualification.

  Disease burden

  • Deaths 2017 1.2M
  • DALYs 2017 65M

  This information was last updated in May 2023

• Buruli ulcer

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  Buruli ulcer

  Buruli ulcer, also known as Bairnsdale ulcer, is a chronic necrotizing skin 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. Early case detection and antibiotic treatment remain the cornerstones of the control strategy for Buruli ulcer to reduce morbidity, treatment costs and prevent long-term disabilities. 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

  Adoption of IS2404 PCR by national Buruli ulcer (BU) programs has dramatically improved diagnostic and epidemiological accuracy in endemic countries. However, there remains a need for simpler diagnostic tools allowing prompt and accurate diagnosis at the community level. BU-MYCOLAC, the first RDT designed to detect mycolactone, still needs clinical evaluation in endemic settings, while other point-of-care molecular methods like BUD-LAMP require field evaluation. Treatment of BU remains cumbersome – often complicated by paradoxical reactions – and lengthy, making development of new drugs a key priority. Τelacebec, Clofazamine and TB47 are stand-alone or combination pipeline candidates – all still in preclinical or early clinical phases, highlighting the need for acceleration and diversification of drug R&D. Tools for immunization against BU remain underdeveloped. All vaccine candidates are in early preclinical stages, while the widely available repurposed TB vaccine, BCG vaccine, provides only short-term protection and is no substitute for a targeted BU vaccine.

  Pipeline spotlight

  A Phase II clinical trial of reducing treatment duration via expansion of the standard regimen to include amoxicillin/clavulanate is underway in Benin. A larger study of f-TCL diagnosis conducted in Ghana showed over 80% diagnostic accuracy, suggesting its potential to become an ideal tool for diagnosing Buruli ulcer.

  Disease burden

  • Cases 2020 1.2K
  • DALYs and Deaths Unknown

  This information was last updated in May 2023

• 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

  Antifungal medications used for treating cryptococcal meningitis are effective, but poorly suited for use in developing countries. Amphotericin B is expensive and requires administration at a hospital, and flucytosine – another repurposed antifungal – requires careful blood monitoring. As a result, most developing countries resort to fluconazole use, which is only partially effective. Notwithstanding the AMBITION-cm findings, there remains a need for affordable, efficacious oral drugs, adapted for resource-poor settings. New antifungal agents, repurposed drugs and immunotherapies targeting various biochemical processes are in different stages of development, with many candidates showing promising activity against cryptococcal meningitis. One such candidate, Mycovia Pharmaceutical’s VT 1598, is in an ongoing Phase I trial. Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have been investigated, but there are currently no biological candidates in clinical trials.

  Pipeline spotlight

  A pivotal Phase III trial of Matinas BioPharma’s MAT2203, an orally administered lipid-crystal nano-particle formulation of amphotericin B – with support from the US NIH – is expected to start in early 2023 following the drug meeting all its endpoints in the EnACT Phase II trial.

  Disease burden

  • Deaths 2014 181K
  • DALYs Unknown

  This information was last updated in May 2023

• Dengue

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  Dengue

  Dengue is a viral infection transmitted to humans by the female Aedes mosquito – most often Aedes aegypti and Aedes albopictus. The dengue virus has four serotypes, each with multiple genotypes. First time infection results mostly in a 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. In analogy, Dengue naïve persons getting vaccinated with Dengvaxia, the only currently licensed Dengue vaccine, run the risk of developing severe dengue disease through antibody-dependent enhancement.  Dengue outbreaks often occur in Asia, Central America and South America, while the first autochtonous cases of Dengue have been recently registered in southern Europe in the recent past years; the disease is now present in more than 100 countries, up from only nine in 1970.

  R&D needs

  Currently, no curative therapy is available for managing dengue fever. Effective therapeutic options are needed, including direct-acting antivirals and mAbs. Several such candidates are currently in early-stage clinical development, including Novartis’ EYU 688 and Atea’s AT-752. Point-of-care serological tests are already available but have many drawbacks. There is a pressing need for diagnostics that can function across the entire disease spectrum, distinguish dengue from other febrile illnesses, and for RDTs for serostatus screening. New and improved vector control products targeting the Aedes mosquito, including adulticidal oviposition traps and space spray insecticides, are needed, as well as biological control tools such as Wolbachia and genetic manipulation (with field experiments currently ongoing across Asia and Latin America). Dengue’s prevalence in high- and upper-middle-income countries has attracted commercially focused industry investment in vaccine R&D; this category has therefore been excluded from the G-FINDER scope.

  Pipeline spotlight

  VIS 513, a broadly neutralising monoclonal antibody (mAb) developed by Visterra that targets the E protein, present across all dengue serotypes, has progressed to Phase II clinical development and has been sub-licenced for further development by Serum Institute of India. Janssen’s JNJ-1802, a direct-acting antiviral, commenced a Phase II human challenge study in collaboration with NIAID.

  Disease burden

  • Deaths 2019 36K
  • DALYs 2019 2.4M

  This information was last updated in May 2023

• 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

  Approved vaccines against diarrhoeal diseases are sometimes ineffective or unsuitable for infants. New multivalent vaccines suitable for infants and with longer-term protection in high-burden settings are urgently needed. Such next-generation candidates for rotavirus include non-replicating parenteral vaccines, the most advanced being PATH’s trivalent NRRV (P2-VP8) candidate, undergoing Phase III trials. Other potential candidates remain in preclinical development, except for Mitsubishi Tanabe’s VLP rotavirus vaccine, MT 5625, which has progressed to Phase I development. Oral rehydration therapy and zinc supplementation are the mainstay of management in LMICs but are insufficient in many cases. Safe, effective, and affordable pathogen-specific drugs are also needed. The therapeutic pipeline currently includes both small molecule drugs and biologics, with only a few candidates in early-stage clinical development. Likewise, rapid diagnostic tests capable of differentiating between different diarrhoeal diseases, as well as diagnosing multiple diseases, are required; however, only one candidate, RLDT, is in late-stage development.

  Pipeline spotlight

  Beijing Zhifei Lvzhu’s live attenuated Shigella vaccine entered a Phase III trial in December 2021. NIAID initiated a Phase II Shigella human challenge study of another live attenuated candidate, WRSs2. In November 2022, Maxvax Biotechnology began Phase II trials of its trivalent rotavirus vaccine, only the second sub-unit vaccine to reach late-stage development.

  Disease burden

  • Deaths 2019 1.0M
  • DALYs 2019 46M

  This information was last updated in May 2023

• 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

  Preventive chemotherapy in the form of mass drug administration or targeting specific groups such as preschool and school-aged children is the only medical countermeasure available for the control and elimination of helminthic diseases. Only one vaccine candidate, rSh28GST/Alhydrogel, targeting schistosomiasis, has ever reached an efficacy trial. Current vaccine development efforts are concentrated on hookworm, onchocerciasis and schistosomiasis, with most candidates either in pre-clinical development or human safety studies. The heavy reliance on preventive therapeutic agents, often as a monotherapy, has the potential to cause drug resistance. New therapies are urgently needed to counteract the future threat of resistance and overcome the shortcomings of current therapies, including child-friendly formulations and macrofilaricidal agents for onchocerciasis. The current therapeutic pipeline includes emodepside and oxfendazole for onchocerciasis, oxantel pamoate for trichuriasis, tribendimidine for hookworm and TylAMac for filariasis. Diagnosis remains reliant on stool/urine microscopy, underlining the need for rapid, point-of-care, molecular diagnostic tests which can detect resistance.

  Pipeline spotlight

  In May 2022, NIAID initiated a Phase I trial of SchistoShield®, a schistosomiasis investigational vaccine based on a new, never before trialled antigen, Sm-p80. The Paediatric Praziquantel Consortium reported successful results from a pivotal Phase III trial of oro-dispersible praziquantel and has submitted a Letter of Intent to the EMA.

  Disease burden

  • Deaths 2019 15K
  • DALYs 2019 7.7M

  This information was last updated in May 2023

• 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 and has been included in 185 countries’ national infant immunisation schedules. Current nucleos(t)ide analogues are safe, well tolerated and halt transmission; but life-long treatment is needed to avoid relapse. New therapies are aimed at a functional cure – sustained undetectable viraemia with or without antibody production – with multiple drugs and biologic combinations in clinical development. Tools to diagnose and treat HBV remain sub-optimal as standard serological assays detecting HBV surface antigen (HBsAg) are compromised by HIV/HCV co-infection, low HBsAG titres, and S gene mutations/variants. None of the available molecular tests are pre-qualified by WHO, and there is a need for low-cost, point-of-care molecular diagnostics that can quantify viral load, for confirmation of diagnosis, treatment monitoring, detection of drug resistance, and treatment initiation to prevent mother-to-child transmission. Epidemiological research in LMICs is needed to inform approaches to screening, monitoring and treatment, and advance understanding of drug and vaccine escape mutations.

  Pipeline spotlight

  Vir Biotechnology’s VIR-2218 (a small interfering ribonucleic acid) and VIR-3434 (a monoclonal antibody) in combination with pegylated interferon-α and GSK’s bepirovirsen (an antisense oligonucleotide) recently showed promising results for seroclearance and hepatitis B surface antibody production, a feature not observed in current treatments. Both treatments belong to the novel post-transcription inhibitor class.

  Disease burden

  • Deaths 2019 510K
  • DALYs 2019 17M

  This information was last updated in May 2023

• 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

  Direct-acting antiviral (DAA) drugs are more effective, require a shorter duration of treatment, and have fewer side effects than previous interferon- and ribavirin-based treatments, and have revolutionised the treatment of hepatitis C. However, DAA-based regimens are expensive, and access remains limited in LMICs. More research is also needed to assess DAA-based regimens in developing country populations, adolescents, children under 12, and pregnant or breastfeeding women. Despite extensive research efforts, the virus’ genetic diversity and limited infection models have meant that no protective vaccine yet exists, with many candidates not maturing beyond preclinical and early clinical development. A broadly reactive vaccine would prevent incidence of new infections and ideally elicit an antibody and cross-reactive T-cell response. There is also a need for HCV diagnostic tests that are affordable and simple to use in developing country contexts, especially tests for treatment monitoring, screening and tests of cure.

  Pipeline spotlight

  A preventive vaccine based on E1/E2 glycoproteins induced broadly neutralising antibodies against all HCV genotypes in mice. Glecaprevir and pibrentasvir combinations are currently in Phase III trials for acute hepatitis C infections and for paediatric populations.

  Disease burden

  • Deaths 2019 412K
  • DALYs 2019 12M

  This information was last updated in May 2023

• 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 start of treatment are critical for histoplasmosis management, as disseminated histoplasmosis is often fatal if left untreated. Clinical guidelines for managing histoplasmosis recommend a year-long treatment with liposomal amphotericin B and itraconazole. Though highly efficacious, the parenteral liposomal amphotericin B is heat unstable, and itraconazole presents significant drug-drug interaction with anti-tubercular and anti-retroviral medications, thus requiring monitoring of its blood concentrations, limiting LMIC use. There is a need for new treatments, preferably oral, with shorter duration, that are safe in combination with other therapies. Most new investigational agents are in early-stage development, with only the triterpenoid antifungal by Scynexis Inc., Ibrexafungerp, undergoing a Phase III trial for histoplasmosis. Current techniques for diagnosing Histoplasma are mainly laboratory-based with inconsistent sensitivity, making them unsuitable in poor-resource settings. Highly sensitive and specific point-of-care tests, which are appropriate for LMIC settings are urgently needed – such as antigen-based RDT from MiraVista diagnostics.

  Pipeline spotlight

  To improve the sensitivity of existing real-time quantitative PCR (qPCR) assays, the French Mycoses Study Group has developed a novel assay that amplifies whole nucleic acids of Histoplasma spp. Clinical validation showed the test as highly sensitive, and able to perform Histoplasma detection from blood and bronchoalveolar lavage fluid.

  Disease burden

  • DEATHS Unknown
  • DALYS Unknown

  This information was last updated in May 2023

• 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 2020, 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, due to the challenge posed by the virus’ genetic elasticity. All Phase III candidates so far have failed to demonstrate efficacy, with the most recent Phase III trial (Mosaico) discontinued in January 2023 after disappointing interim results. Passive immunisation with biologics such as monoclonal antibodies (mAbs) remain promising, with WHO and IAVI publishing preferred product characteristics to guide R&D. AMP mAb trials demonstrated proof of concept, though revealed that one monoclonal antibody alone is insufficient. Microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool, with the dapivirine vaginal ring included in WHO’s prequalification list in 2020. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially for early infant diagnosis. However, there is progress towards robust, point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates.

  Pipeline spotlight

  The South African Health Products Regulatory Authority was the first to approve a ‘4-in-1’ fixed-dose combination for paediatric HIV in June 2022. The single, easy-to-use granule-filled capsule is taste-masked and can be sprinkled into the child’s food. IAVI, NIAID and Moderna commenced Phase I trials in March 2022 of three mRNA-based vaccines leveraging COVID-19-tested technologies.

  Disease burden

  • Deaths 2019 849K
  • DALYs 2019 47M

  This information was last updated in May 2023

• 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

  Kinetoplastid diseases (Chagas’ disease, leishmaniasis and HAT) lack approved vaccines, and current development efforts are in their early stages. Chagas’, however, has a relatively full preclinical pipeline and leishmaniasis a candidate in Phase II trials. Many gaps remain with respect to diagnosis: HAT requires a point-of-care test for T.b. rhodesiense (r-HAT), simpler confirmatory tests, tests of cure and high-volume testing on dried blood samples as endemic countries move towards surveillance and/or post-elimination maintenance. The existing cutaneous leishmaniasis diagnostic, CL Detect, failed to demonstrate satisfactory standalone accuracy in various endemic settings including Morocco, Afghanistan and Ethiopia, underlining the importance of novel diagnostic tools, while Chagas’ needs tests of cure and for congenital infection. Improved and safer drugs are needed, particularly for r-HAT, pregnant women infected with Chagas’, and oral drug regimens in leishmaniasis. Biologics and therapeutic vaccines are of particular interest for Chagas’, but still lack either a mature candidate or approved product.

  Pipeline spotlight

  In November 2022, DNDi and Novartis initiated a Phase II safety and efficacy trial of oral LXE408 as a monotherapy for treating visceral leishmaniasis. A Phase II/III trial of acoziborole as a single dose cure for adult Human African trypanosomiasis (HAT) completed recruitment, while the paediatric trial launched in July 2022.

  Disease burden

  • Deaths 2019 16K
  • DALYs 2019 1.0M

  This information was last updated in May 2023

• 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

  Drug regimens used for leprosy treatment, though effective, require 6-24 months of treatment. With surveillance data suggesting emergence of resistance to first-line drugs in high-endemic countries, there is a growing need for drugs with simpler regimens and shorter treatments. WHO’s recommendation of single-dose rifampicin as post-exposure prophylaxis constitutes major progress in disease prevention, though we still lack an effective preventive vaccine, with all but one candidate in early-stage development. Leprosy diagnosis is primarily based on clinical criteria and/ or positive microscopy of skin slit specimens. As both methods exhibit suboptimal sensitivity and specificity and rely on individual expertise, novel diagnostic tools are needed. The WHO Diagnostic Technical Advisory Group notes that gaps in the detection of infection, nerve loss function and prediction of future disease need to be addressed. In a proof-of-concept study, a multi-biomarker finger prick point-of-care test showed encouraging results in detecting infection and early-stage disease.

  Pipeline spotlight

  Phase II clinical evaluation of Bedaquline for therapy and post-exposure prophylaxis is ongoing, while development of the vaccine candidate LepVax has transitioned from Phase Ia to Ib/IIa. AMG 634, a compound for the treatment of Erythema Nodosum Leprosum, is being tested for efficacy and safety in a Phase II clinical trial in Nepal.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 29K

  This information was last updated in May 2023

• 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

  Leptospirosis can be effectively treated with antibiotics if diagnosed accurately and timely. Gold standard leptospirosis diagnosis during the acute phase of infection currently involves polymerase chain reaction (PCR) techniques, which require sophisticated laboratory equipment and technical expertise, making it inappropriate for resource-limited settings. There are several leptospirosis diagnostic test kits commercially available. However, the marketed tests have questionable sensitivity and specificity. The recently published Thai-Lepto AKI study revealed that the five Leptospirosis RDTs commercially available in Thailand had overall sensitivity ranging from 1.8% to 75% and specificity ranging from 52.3% to 97.7%. This highlights the need for novel, easy-to-use, rapid diagnostic tests to accurately detect leptospirosis infection in LMIC settings.

  Pipeline spotlight

  Researchers from Thailand recently reported that a CRISPR-based leptospiral rapid diagnostic assay targeting the lipL32 gene demonstrated acceptable sensitivity and excellent accuracy. The overall performance of the CRISPR-based molecular test was better than the commercial rapid diagnostic test.

  Disease burden

  • Deaths 2015 59K
  • DALYs 2015 2.9M

  This information was last updated in May 2023

• 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

  There remains a clear need for a more efficacious vaccine and vaccines that can protect against P. vivax and placental malaria, and/or block transmission. New drugs are needed in response to emerging resistance and to meet the needs of key populations, as well as for chemoprotection, and – ideally – to meet the goal of a single-dose treatment. In addition to small molecule drugs, monoclonal antibodies (mAbs) are being investigated, though large-scale administration is not yet suited to low-resource settings. There is an urgent need to develop new rapid diagnostic tests in response to emerging pfhrp2/3 gene deletion in malaria parasites, as well as more sensitive diagnostics to identify non-falciparum species, distinguish malaria from other febrile illnesses, detect asymptomatic cases, and diagnose G6PD enzyme deficiency. Next-generation vector control products are needed in response to emerging pyrethroid resistance, including genetic approaches to reduce mosquito populations or block parasite transmission, and endectocides for malaria transmission control.

  Pipeline spotlight

  Mosquirix, the first approved vaccine, received WHO prequalification in July 2022. R21/Matrix-M vaccine, developed by University of Oxford and manufactured by Serum Institute of India, was approved by Ghana’s FDA and Nigeria’s NAFDAC in April 2023. Phase II results for US NIH’s CIS43LS monoclonal antibody demonstrated six month’s protection against Plasmodium falciparum after a single dose. MMV and Novartis announced a Phase III efficacy trial of ganaplacide/lumefantrine-SDF combination for 2023, the first novel non-artemisinin-based therapy to enter regulatory trials.

  Disease burden

  • Deaths 2019 643K
  • DALYs 2019 46M

  This information was last updated in May 2023

• 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 was included in the G-FINDER scope for the first time in 2019.

  R&D needs

  The current standard treatment for mycetoma has a cure rate of around 30% and comes with serious side effects. More effective, less toxic drugs with shorter duration of treatment are urgently needed. Aside from fosravuconazole, mycetoma drug R&D efforts are at a very early stage, such as DNDi’s MycetOs, a screening project to identify new leads, and niclosamide, a repurposed drug which showed potential in in-vitro studies. At present, mycetoma is diagnosed clinically, with identification of causative agents via histology and culture, techniques which require laboratory infrastructure and skilled practitioners. Specific diagnostics, such as PCR-based tests, are available only for research purposes. In 2022, the WHO published a target product profile (TPP) for a rapid test for diagnosis of mycetoma at the primary healthcare level. The TPP aims to facilitate the development of point-of-care tests that diagnose mycetoma and differentiate actinomycetoma and eumycetoma to allow initiation of appropriate treatments.

  Pipeline spotlight

  A clinical trial investigating fosravuconazole, the only drug ever to undergo an efficacy trial for mycetoma treatment, was completed in late 2021. DNDi and its partners have established a strategy for registering fosravuconazole in Sudan for compassionate use in advance of full approval.

  Disease burden

  • Deaths Unknown
  • DALYs Unknown

  This information was last updated in May 2023

• 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

  Prophylactic use of antibiotics is the only preventive measure currently available for preventing rheumatic fever and its associated complications, such as rheumatic heart disease. Such widespread use of antibiotics is potentially vulnerable to and causative of antimicrobial resistance, meaning that a vaccine to prevent rheumatic fever is a much-needed medical countermeasure. Currently, the vaccine development pipeline is mostly at the stage of pre-clinical testing, and only a handful of candidates have undergone human safety trials. These include StreptAnova, the most advanced candidate, which successfully completed a Phase I trial in 2020.

  Pipeline spotlight

  Two conjugated peptide vaccines, p*17-CRM + K4S2-CRM and J8-CRM + K4S2-CRM, commenced a Phase I clinical trial in November 2022 after having successfully completed preclinical studies. The Phase I trial is designed to automatically transition to Phase II if no serious adverse effects are observed.

  Disease burden

  • Deaths 2019 274K
  • DALYs 2019 10M

  This information was last updated in May 2023

• 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

  Typhoid can be successfully treated with available antibiotics. However, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of S. typhi, the causative agent of typhoid, have emerged and are spreading rapidly. The emergence of the XDR strain is especially alarming as it is resistant to almost all the available therapeutic options. There is an urgent need for a next generation of antibiotics that are effective against resistant strains. Current pipeline candidates include several broad-spectrum antibiotics with the potential to be effective against drug-resistant strains of S. typhi, but most are in the pre-clinical stage of development. The WHO recommends typhoid conjugate vaccines (TCVs) as the preferred vaccine for use in Salmonella prophylaxis in endemic regions. Two such TCVs – Typbar TCV and TYPHIBEV are currently pre-qualified by the WHO.

  Pipeline spotlight

  A new typhoid conjugate vaccine (Vi-DT) completed a Phase III trial in 2021. Vi-DT was found to be immunologically non-inferior to the control, Typbar TCV. Three new vaccine candidates entered clinical trials in 2022; two combination vaccines targeting NTS and typhoid (TSCV and iNTS-TCV), and a first-in-human trial of typhoid and paratyphoid bivalent vaccine (TYP03/04).

  Disease burden

  • Deaths 2019 212K
  • DALYs 2019 16M

  This information was last updated in May 2023

• 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

  Due to the cost and limited availability of the most efficacious scabicide (permethrin 5% cream), many LMICs rely on less effective and less well-tolerated alternatives, such as benzyl benzoate and sulphur ointments. Topical treatments often suffer from acceptability and compliance issues. Oral ivermectin, approved in many countries for the treatment of scabies, is highly effective but does not kill scabies eggs, necessitating repeat doses and increasing the difficulty of mass drug administration (MDA). Ivermectin is also contraindicated for children less than 15kg and for pregnant and breastfeeding women. Thus, new oral drugs exhibiting prolonged skin activity, effective against newly hatched eggs, and usable by children and pregnant women are urgently needed. Novel diagnostics, such as molecular tests are at an early stage of development. There is an urgent need to develop point–of–care tests as an alternative to existing clinical examination and as a tool to guide ivermectin-based MDA.

  Pipeline spotlight

  In January 2022, Medicines Development for Global Health completed a Phase II proof-of-concept study investigating the effectiveness of moxidectin in eliminating the scabies parasite. Data from the completed trial will inform the dose-confirmatory Phase IIb trial, which is expected to start enrolling its first patient early in 2023.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 4.8M

  This information was last updated in May 2023

• 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

  Antibody-based antivenoms are the mainstay of snakebite envenomation treatment. These are effective, life-saving products if administered at the right time, in the correct dose, and for the right species. However, manufacturing immunobiologicals is expensive and complex, requiring harvesting and purifying immune-rich plasma from hyper-immunised large animals. The production of quality antivenom is hampered by the lack of a universal regulatory framework and appropriate reference standards, and geographical variations in the venom pool. Conventional anti-venoms are liquid or freeze-dried formulations requiring skilled professionals for administration, making them inappropriate in resource-limited settings. There is an urgent need to develop next-generation antivenom products that are safe, effective, geography-appropriate or polyvalent, and affordable for the low-income settings where they are most needed. The current research efforts include recombinantly expressed human antibodies and antibody fragments and small molecule therapeutics (SMT), including oral formulations. One such SMT – varespladib-methyl, is currently in a Phase II clinical trial.

  Pipeline spotlight

  In early 2022, researchers from the Liverpool School of Tropical Medicine and Kenya Medical Research Institute, with funding from the Wellcome Trust, initiated a Phase I clinical trial of Unithiol – a chelating agent which is routinely used to treat heavy metal poisoning – repurposed for treatment of snakebite.

  Disease burden

  • Deaths 63K
  • DALYs Unknown

  This information was last updated in May 2023

• 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

  An effective vaccine would be a breakthrough development, given that the goal of eliminating Trachoma as a public health problem is unlikely to be reached solely through the implementation of the existing SAFE (surgery; antibiotics; facial cleanliness; environmental improvement) strategy. The trachoma vaccine pipeline is at an early stage of development. Only a few candidates have reached beyond the concept stage, such as VD1-MOMP (‘TracVac’), designed to target ocular and genital serovars, which was found to be immunogenic in pre-clinical studies.

  Pipeline spotlight

  In a study examining samples from different epidemiological settings, two rapid lateral flow assays LFA-latex and LFA-gold, demonstrated promising and comparable results to ELISA immunoassays. Their low cost, lack of instrument requirements, and ease of training and use make these rapid diagnostic tests an appealing option for post-validation surveillance.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 0.2M

  This information was last updated in May 2023

• 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 a chronic cough, fever and weight loss. 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

  A new TB vaccine, which is effective across all ages and safe for pregnant and lactating women, is critical for achieving targets set by the WHO’s End TB Strategy. However, TB vaccine R&D is lagging on most fronts – the number of candidates in late clinical development is unchanged, and most are non-inactivated/attenuated vaccines targeting the same antigen, no new evidence on efficacy since the publication of M72/AS01E’s clinical trial results in 2019 and the exclusion of pregnant women, a high-risk group, from clinical trials. A more diverse early-stage pipeline is urgently needed to safeguard against the potential failure of the current clinical candidates. In recent years, the WHO has endorsed several new tools, including molecular tests for diagnosing TB. However, research gaps still exist, including non-sputum-based tests for diagnosing paediatric TB, true point-of-care molecular tests and tools for screening and triage.

  Pipeline spotlight

  BioNTech’s BNT164, the first mRNA-based TB vaccine, entered clinical trials in December 2022 – testimony to the flow-on benefits of the unprecedented technological innovations during the development of COVID-19 vaccines. A Phase II trial for drug-sensitive TB is investigating an all-new regimen of Otsuka’s investigational compound, OPC-167832, with recently approved bedaquiline and delamanid.

  Disease burden

  • Deaths 2019 1.2M
  • DALYs 2019 47M

  This information was last updated in May 2023

• Yaws

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  Yaws

  Yaws is a chronic skin infection caused by the spirochaete, Treponema pallidum subspecies pertenue, which is closely related to the bacteria that causes syphilis and other endemic treponematoses – pinta and benjel. The disease is endemic in 15 countries, with endemicity still unknown in more than 70 countries worldwide. In 2021, over 120,000 suspected yaws cases were reported from 13 countries, with 1,102 confirmed cases from 9 countries. More than 80% of suspected cases were from the West Pacific region.

  It is a highly contagious disease primarily affecting children under 15 years of age and those residing in poor communities in low- and middle-income countries. Transmission from person to person occurs through skin-to-skin contact with infectious skin lesions. Like syphilis, yaws is characterized by chronic relapsing skin manifestations, which is often associated with stigma and significant socioeconomic implications. Yaws is typically responsive to a single dose of azithromycin which is currently used in both mass treatment campaigns and targeted treatment of individual identified cases. Additionally, benzathine benzylpenicillin is a widely available safe and efficacious second line treatment for azithromycin-resistant cases. If left untreated, the lesions can progress to affect cartilages, joints, and bones, resulting in disfigurement and disability. Yaws is classified as a neglected tropical disease (NTD) of the skin by WHO and is targeted in the latest Roadmap for eradication by 2030.

   

  R&D needs

  Historically, laboratory-based serological tests have been widely used in diagnosing treponemal infections, but these are unable to distinguish yaws from syphilis infection. These tests are expensive, resource-intensive, require highly skilled personnel, and are associated with a long wait-time for results, leading to delays in initiating treatment. Multiple affordable treponemal rapid point-of-care tests are available. However, these tests cannot distinguish between past and present infection, limiting their use in monitoring the interruption of yaws transmission. Chembio’s novel Dual Path Platform Syphilis Screen and Confirm assay is capable of distinguishing active and past infection but its high cost makes it unsuitable for low resource settings.  A by the WHO Diagnostic Technical Advisory Group (DTAG) for NTDs suggests the sensitivity and specificity of the currently used point-of-care tests are suboptimal for disease surveillance and eradication. DTAG has endorsed a target product profile (TPP) for the development of new diagnostic tools for case detection and identification of azithromycin-resistant cases, owing to reports of a small number of azithromycin resistant cases. DTAG is also developing a TPP for affordable, sensitive, rapid point-of-care molecular tests for diagnosing single yaws cases. With the global distribution of yaws undefined, improving understanding of yaws epidemiology is critical to guide its eradication. Research into non-human primates as potential reservoirs also remains a priority

  Pipeline spotlight

  The EDCTP-funded project, LAMP4yaws, is conducting real-life evaluation of a novel diagnostic test – the combined Treponema pallidum, Haemophilus ducreyi loop mediated isothermal test (TPHD-LAMP) for yaws in three endemic West African countries. The project will also assess its acceptability, feasibility and cost-effectiveness in comparison to the reference standard, qPCR.

  Disease burden

  • Deaths N/A
  • DALYs N/A

  This information was last updated in May 2023