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 are increasingly being rolled out in lower-income countries with Gavi support. However, they are typically expensive to manufacture, and there is an ongoing need for low-cost candidates targeting LMIC serotypes, as gains from existing PCVs are threatened by serotype replacement. Non-conjugate protein- and whole-cell based vaccines are two potential approaches offering broad protection and cheaper costs, while in 2019 WHO prequalified PNEUMOSIL, a 10-valent PCV candidate for $2/dose. Since the introduction of  the MenAfriVac monovalent conjugate meningitis A vaccine, meningitis A infection rates have plummeted across the African continent. Other serogroups have become more prominent however, creating the need for low-cost polyvalent vaccine candidates such as PATH/SII’s NmCV-5. Diagnostics are also needed, including RDTs that can detect serogroups to guide vaccine response, as well as multi-pathogen point-of-care tests to guide case management in both epidemic and endemic settings.

  Pipeline spotlight

  Following the successful prequalification of their affordable 10-valent pneumococcal conjugate vaccine (PNEUMOSIL) in December 2019, PATH and the Serum Institute of India have just completed a Phase III trial of their low-cost pentavalent meningitis conjugate vaccine, NmCV-5. Phase II results suggest it could be effective as a single dose.

  Disease burden

  • Deaths 2017 1.2M
  • DALYs 2017 65M

  This information was last updated in April 2022

• 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

  Current diagnostics are costly, complex and unsuitable for the point of care in endemic areas. There is a need for simple rapid diagnostic tests to allow prompt diagnosis at the community level. Several tests are currently under development, including the BU-MYCOLAC Rapid Test and Aptagen’s point-of-care diagnostic based on RNA aptamers. Recent research calls for ongoing monitoring to detect any emerging drug-resistant strains, highlighting the need for new drugs that can be given in an intermittent or shorter period. One recent study demonstrated that an 8-week all-oral drug regimen was non-inferior to the traditional oral/injectable treatment, while Telacebec, an investigational TB drug, shows promise as a single-dose candidate with the potential of reducing treatment period to 2 weeks. There is currently no approved vaccine for Buruli ulcer. The (anti-TB) BCG vaccine provides short-term protection, but is not an adequate substitute for a specifically targeted vaccine; current vaccine development efforts are in the very early preclinical phase.

  Pipeline spotlight

  Funded by GHIT, FIND and collaborating partners are conducting field evaluation of the first mycolactone-specific prototype rapid diagnostic test (BU-MYCOLAC RDT). Meanwhile, the US FDA has granted orphan and fast track status to Qurient’s Telacebec drug for Buruli ulcer, with planning underway for a global Phase II trial.

  Disease burden

  • Cases 2020 1.2K
  • DALYs and Deaths Unknown

  This information was last updated in April 2022

• 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 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 drugs that are 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. Two such candidates are Mycovia Pharmaceutical’s VT-1129  and VT 1598,  which have both progressed to clinical stages of development. Clinical trials are also being conducted on new oral formulations of amphotericin B (MAT2203). 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

  Results from the Phase III AMBITION-cm trial showed that a single, high-dose of AmBisome (liposomal amphotericin B) combined with seven days of oral flucytosine and fluconazole was non-inferior to – and safer than – the current WHO recommended standard of care, providing an easier to use and better tolerated treatment regimen for developing countries.

  Disease burden

  • Deaths 2014 181K
  • DALYs Unknown

  This information was last updated in April 2022

• 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

  Point-of-care antigen and antibody serological tests are available, but cannot distinguish between serotypes, lack optimal sensitivity and specificity and exhibit serotype-specific performance discrepancies. There is a pressing need for diagnostics that can distinguish between current and previous infection, and distinguish dengue from other causes of fever, as well as RDTs for serostatus screening. Effective therapeutic options are also needed, although most curative candidates – including direct acting antivirals and broadly neutralising monoclonal antibodies –are still in the preclinical phase. Finally, there is a need for new and improved vector control products targeting the Aedes mosquito, including adulticidal oviposition traps and space spray insecticides, 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 been sufficient to attract commercially focused industry investment in vaccine R&D; this category has therefore been excluded from the G-FINDER scope.

  Pipeline spotlight

  A biological control tool – Wolbachia (wMel)-infected Aedes aegypti became the first intervention targeting dengue-carrying mosquitoes to receive a positive assessment of public health value by the WHO advisory committee. The CDC’s Trioplex qPCR – a real-time multiplex PCR capable of detecting dengue, Zika and Chikungunya simultaneously – has been shown to have high sensitivity and specificity in a geographic area with a current dengue outbreak. Meanwhile, the monoclonal antibody candidate HUMab 3G9 exhibited neutralising properties against all dengue serotypes.

  Disease burden

  • Deaths 2019 36K
  • DALYs 2019 2.4M

  This information was last updated in April 2022

• 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

  Available vaccines against diarrhoeal diseases are mostly oral, live attenuated candidates, which are sometimes ineffective, and may be unsuitable for infants. Novel multivalent vaccines are needed, which confer longer-term protection in high-burden settings and are suitable for infants. Such next-generation candidates for rotavirus include non-replicating parenteral vaccines, the most advanced being PATH’s trivalent NRRV (P2-VP8) candidate, currently in Phase III trials. Others including CureVac’s mRNA rotavirus vaccine remain in preclinical development. Supportive therapy including oral rehydration therapy and zinc supplementation remain the mainstay of management in LMICs but are insufficient in many cases. Safe, affordable, and effective pathogen-specific drugs are needed to improve treatment options for these diseases. The therapeutic pipeline currently includes both small molecule drugs and biologics, which remain in preclinical development. Likewise, multiplex rapid diagnostic tests able to diagnose multiple diarrhoeal diseases as well as differentiate between them are needed, however, no candidate is in late-stage development.

  Pipeline spotlight

  ShigETEC, the novel live attenuated combined Shigella and ETEC oral vaccine candidate developed by Eveliqure Biotechnologies, was found to be safe and induced robust immune response in a recently concluded Phase I clinical trial. The company also recently received NIH funding to advance the candidate into Phase II human challenge studies.

  Disease burden

  • Deaths 2019 1.0M
  • DALYs 2019 46M

  This information was last updated in April 2022

• 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 currently 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, as are paediatric formulations of existing drugs. Moxidectin, the first new onchocerciasis treatment in 20 years received FDA approval in 2018. Promising clinical candidates include emodepside and oxfendazole for onchocerciasis, tribendimidine for hookworm, and TylAMac for filarial diseases. Vaccine development has proved a challenge: for schistosomiasis, the most advanced vaccine candidate, rSh28GST showed insufficient efficacy in a Phase III trial. Clinical development of the most promising candidate antigen, Sm-p80 is currently underway. Other promising candidate antigens for multiple helminth infections are in preclinical/Phase I stages of development. Current diagnostic products are outdated or complex. As such, new and effective diagnostics that can measure infection intensity and detect drug resistance are urgently needed.

  Pipeline spotlight

  In 2021, Merck KGaA and the Pediatric Praziquantel Consortium successfully completed a pivotal Phase III trial for an orally dispersible form of arpraziquantel in preschool-aged children, which achieved clinical cure while showing favourable safety, tolerability and improved palatability. They plan to apply for a scientific opinion by EMA under the EU-M4all scheme.

  Disease burden

  • Deaths 2019 15K
  • DALYs 2019 7.7M

  This information was last updated in April 2022

• 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

  A highly effective vaccine against HBV exists, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal. Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis, however their sensitivity is significantly compromised by HIV/HCV co-infection, low HbsAG titres, and S gene mutations/variants. Available drugs are generally safe and well tolerated, however lifelong treatment is generally required; as a result there is significant interest in development of a functional cure. There is also a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load, for confirmation of diagnosis, treatment monitoring and detection of drug resistance. Finally, there is a need for additional basic research to inform approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs.

  Pipeline spotlight

  Multiple drug and biologic candidates aimed at functional cure are currently in clinical development, with new approaches including combined siRNA/mAb regimens recently entering Phase II trials. A therapeutic vaccine candidate (TherVacB) has been successfully tested preclinically, and will commence a Phase I/II clinical trial in 2022.

  Disease burden

  • Deaths 2019 510K
  • DALYs 2019 17M

  This information was last updated in April 2022

• 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 women. Despite extensive research efforts, development of a protective vaccine has not been achieved. In a recent study, vaccine candidate AdCh3NSmut1 and MVA-NSmut applied in a prime/boost regimen, failed to prevent chronic infection with HCV in a high-risk population of IV drug users, while other vaccine candidates, containing E1/E2 glycoproteins, have not matured beyond the stage of preclinical/early clinical development. 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

  In June 2021, Malaysia approved ravidasvir, a low-cost, pan-genotypic direct-acting antiviral (DAA) for use in combination with sofosbovir, an existing DAA. Developed in partnership by DNDi and two LMIC-based pharmaceutical companies, the regimen is intended to provide a much more affordable treatment option than the currently available regimens on the market.

  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 2019 412K
  • DALYs 2019 12M

  This information was last updated in April 2022

• 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 for histoplasmosis management, as untreated or delayed disseminated histoplasmosis is often fatal. Conventional methods of diagnosis are laboratory based, making them unsuitable in low-resource settings. There is a need for highly sensitive and specific point-of-care diagnostic tests for Histoplasma diagnosis. MiraVista Diagnostics’ recently launched antigen-based lateral flow assay is one such test. Other similar test kits are needed to drive commercial availability, particularly in LMICs. Clinical guidelines for histoplasmosis management recommends a year-long treatment with liposomal amphotericin B and itraconazole. Though effective, liposomal amphotericin is a parenteral drug that is not heat stable, while itraconazole has drug-drug interactions with anti-tubercular and anti-retroviral medications, necessitating monitoring of its blood concentrations, thus limiting their use in LMICs. Thus, there is a need for new treatment regimens, preferably oral, with shorter duration, that are safe in combination with other drugs. Most investigational agents including are in early-stage development.

  Pipeline spotlight

  In 2020, MiraVista Diagnostics launched the world’s first lateral flow assay for Histoplasma antigen detection in serum and urine samples. This point of care test has subsequently been validated by several clinical studies with positive results.

  Disease burden

  • DEATHS Unknown
  • DALYS Unknown

  This information was last updated in April 2022

• 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, and the rapid mutation of the virus poses a significant challenge to development. Currently, only one large HIV vaccine efficacy trial is underway: a global Phase III HVTN 706. Two other large HIV vaccine efficacy studies, HVTN 705 and HVTN 702 have both ceased due to non-efficacy. 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, including both small molecule and broadly neutralising anti-HIV antibody (bNAb) based approaches. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially 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

  Following EMA approval and WHO prequalification in 2020, the International Partnership for Microbicides’ dapivirine vaginal ring (DPV-VR) was recommended by WHO and approved by the South African regulator as an additional prevention choice for women at substantial risk of HIV. A newly developed AIOD-CRISPR assay system was able to successfully detect nucleic acids of both SARS-CoV-2 and HIV.

  Disease burden

  • Deaths 2019 849K
  • DALYs 2019 47M

  This information was last updated in April 2022

• 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

  No human vaccine exists for any of the three kinetoplastid diseases (Chagas’ disease, leishmaniasis and HAT), and current development efforts are relatively early stage, with all current candidates still in the preclinical or early clinical phases. There is a need for new diagnostic tests – particularly point of care tests – for all three diseases, including tests for cure, and for monitoring chronic or second stage disease.  In leishmaniasis, HIV co-infection constitutes a diagnostic challenge, as most existing RDTs exhibit reduced sensitivity in co-infected patients. Simplification of diagnosis is also needed, with appropriate role for different tests currently being evaluated in operational studies. There is a need for improved, preferably oral, drug formulations for leishmaniasis, and safer, more effective drugs for Chagas’, which are suitable for children and pregnant and breastfeeding women. Biologics and therapeutic vaccines may also have a role to play, particularly for Chagas’ disease.

  Pipeline spotlight

  The BENDITA trial showed no benefit from fosravuconazole in treating Chagas’ disease, but showed a two week regimen of benzidazole is just as effective as the current eight week course. Acoziborole is being tested in a Phase II/III trial as a single dose cure against HAT caused by T.b. gambiense.

  Disease burden

  • Deaths 2019 16K
  • DALYs 2019 1.0M

  This information was last updated in April 2022

• 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

  Current drug regimens used for leprosy treatment, though effective, require prolonged treatment of 6-24 months. There is an ongoing need for new drugs with simpler regimens, shorter treatment duration and which provide nerve function improvement.  BCG represents the best available preventive vaccine for leprosy, but 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. Modern vaccines are needed that confer both pre- and post-exposure immunoprophylaxis against leprosy without exacerbating nerve damage. LepVax is one such candidate currently in Phase Ib/IIa clinical development. Leprosy diagnosis is primarily based on identifying key clinical features, leading to late diagnosis of asymptomatic cases and continued disease transmission. New and improved diagnostics are needed capable of identifying both asymptomatic and symptomatic cases of all forms. Leiden University recently prototyped a multi-biomarker finger prick point-of-care lateral flow diagnostic test, currently in pilot testing.

  Pipeline spotlight

  Following successful Phase Ia clinical trials, leprosy vaccine candidate LepVax is due to start Phase Ib/IIa trials in Brazil in early 2022. Meanwhile, AMG 634, a drug candidate initially developed by AMGEN and Leprosy Mission Nepal, was licensed to the Medicines Development for Global Health in 2020 for further clinical development.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 29K

  This information was last updated in April 2022

• 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

  Effective, appropriate drugs exist for leptospirosis, meaning that infection can be successfully treated if diagnosed. However, diagnosing leptospirosis can be challenging due to the non-specific symptoms of early infection as well as asymptomatic infection in some affected individuals. 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.

  Pipeline spotlight

  A novel Onsite Leptospira IgG/IgM Combo Rapid Test has been developed by CTK Biotech to be used for the simultaneous detection and differentiation of IgG and IgM antibodies to Leptospira interrogans in human samples – serum, plasma or whole blood – aiding in the early diagnosis of leptospirosis in resource-limited settings.

  Disease burden

  • Deaths 2015 59K
  • DALYs 2015 2.9M

  This information was last updated in April 2022

• 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, as well as vaccines that can provide protection against P. vivax, 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. 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 a need for 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, as well as endectocides for malaria transmission control.

  Pipeline spotlight

  In October 2021, based on pilot programmes in Malawi, Kenya and Ghana – and following shortly after a Phase III trial showed its effectiveness in significantly reducing malaria mortality when combined with chemoprevention – WHO recommended the use of RTS,S/AS01E for children in areas with moderate to high P. falciparum malaria transmission.

  Disease burden

  • Deaths 2019 643K
  • DALYs 2019 46M

  This information was last updated in April 2022

• 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

  Despite the availability of several drugs for mycetoma treatment, including the antifungals ketoconazole and itraconazole, and antibiotics amikacin and co-trimoxazole, significant R&D gaps still exist in Mycetoma treatment. Antifungals targeting eumycetoma are only 25-35% effective, are costly, and require year-long administration with serious side effects. There is a need for more efficacious drug regimens, with shorter duration, lower costs and fewer side effects, for use in high-burden settings. Recently, the DNDi-supported MycetOS project identified at least 287 compounds active against mycetoma, with fenarimol being the most potent in vitro, while niclosamide was also shown to have good activity in preclinical studies. Existing mycetoma diagnostic tools are invasive, time-consuming, and laboratory-based, and are thus inappropriate for LMIC use. There is a need for cheap, rapid and accurate point-of-care diagnostics to facilitate early mycetoma diagnosis. In 2020, the Global Health Innovative Technology Fund supported the MycEXomics project, which aims to develop field-friendly point-of-care diagnostic tests for mycetoma.

  Pipeline spotlight

  Niclosamide, a broad-spectrum anthelmintic on the WHO Essential Medicines List, was recently shown to be active in vitro against Madurella mycetomatis, the main causative agent of eumycetoma in Sudan, and Acinetomadura spp., the causative agent of actinomycetoma.

  Disease burden

  • Deaths Unknown
  • DALYs Unknown

  This information was last updated in April 2022

• 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. Progress to date has been slow, with only four candidates progressing to clinical stages of development. There have been no recent updates identified for two of these candidates: StreptAvax, a 26-valent vaccine whose immunogenicity and safety was first confirmed in a Phase II clinical trial in 2004; and MJ8VAX(J8), where a 2018 Phase I clinical trial indicated the need for additional investigations to optimise its immunogenicity and improve dosing. A planned Phase I clinical trial for StreptInCor, another GAS vaccine candidate that showed promising results in diverse animal models, was withdrawn in February 2021. Positive Phase I results for StreptAnova, a 30-valent vaccine (which completed Phase I in 2017) were published in 2020.

  Pipeline spotlight

  A research collaboration led by the Murdoch Children’s Research Institute (MCRI) has developed the first controlled human infection model for Group A streptococcus (GAS). It will shortly be used to evaluate a GAS vaccine being developed by the Australian Strep A Vaccine Initiative (ASAVI), a partnership between MCRI and the Telethon Kids Institute.

  Disease burden

  • Deaths 2019 274K
  • DALYs 2019 10M

  This information was last updated in April 2022

• 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

  The rise of antimicrobial resistant S. typhi strains linked to the H58 clade is threatening the efficacy of existing drugs. There is a need for better surveillance of these resistant strains, and the development of novel, efficacious drugs, especially those suitable for children. The WHO recommends typhoid conjugate vaccines (TCVs) as the preferred vaccine for use in high-burden countries, and in 2018, Typbar TCV became the first TCV to achieve WHO prequalification, followed by TYPHIBEV in 2020, both of which are effective in children, and in high burden settings. There are however no approved bivalent vaccines targeting both typhoid and paratyphoid fever, nor any monovalent vaccines targeting paratyphoid fever specifically. Phase II trial results were recently published for the most advanced candidate CVS 1902. There are also no approved NTS vaccines, with all candidates in early-stage development. Given the threat of drug resistance, biologic R&D remains a need, with several monoclonal antibody cocktails in preclinical development.

  Pipeline spotlight

  TYPHIBEV, the Vi-polysaccharide typhoid conjugate vaccine (TCV) developed by Biological E, received WHO prequalification in 2020, becoming the second TCV to achieve this since 2018. Two other TCVs – edaTyph (Bio-Med) and ZyVac TCV (Cadila Healthcare) have been licensed for use in India, but have not been submitted for WHO prequalification.

  Disease burden

  • Deaths 2019 212K
  • DALYs 2019 16M

  This information was last updated in April 2022

• 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 high price and limited availability of the most efficacious scabicide (permethrin 5% cream), many 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 but does not kill scabies eggs, necessitating repeat doses and increasing the difficulty of mass drug administration (MDA) interventions. Additionally, ivermectin’s use is contraindicated for children weighing less than 15kg, and pregnant and breastfeeding women. New oral drugs are urgently needed that have prolonged skin activity, thereby effectively killing newly hatched eggs, and a proven safety profile in children and pregnant women. Moxidectin, a US FDA-approved antiparasitic agent related to ivermectin, is currently undergoing Phase II clinical trials. There is also a need for a low-cost point-of-care test for individual level diagnosis and management, to facilitate mapping and surveillance at the population level and monitor potential mites’ resistance towards ivermectin-based mass drug administration.

  Pipeline spotlight

  Following positive results from two Phase III trials, a new topical treatment (spinosad 0.9%) received US FDA approval in 2021. Medicines Development for Global Health is currently evaluating the oral drug candidate moxidectin in dose-finding trials in France, Austria and Australia. A Phase IIb trial is planned for 2022.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 4.8M

  This information was last updated in April 2022

• 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 can be highly effective against snakebite envenomation if given at the right time, at the right dose, and for the right snake. However, they are expensive to manufacture, can be complex to administer and store, and carry the risk of adverse reactions. There is a need for R&D to support the approval and introduction of safe, effective, high-quality and geographically appropriate antivenoms, as well as to deliver next generation antivenoms that are more effective, more affordable, safer and heat stable. In low-resource settings, 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. Broad-spectrum small molecule inhibitors could help bridge this gap: varespladib has progressed to Phase II clinical trials and shows promise as therapy against venom-induced myonecrosis and haemorrhagic toxicity. Affordable, rapid, point-of-care diagnostics capable of identifying common species in high-burden areas, with low to no cross reactivity between venoms are also needed.

  Pipeline spotlight

  Indriyam Biologics Pvt. Ltd. has designed a ‘V-sens’ snake venom detection biosensor capable of identifying species-specific venom within minutes. The EC is funding the MABSTER project with the aim of discovering therapeutic human monoclonal antibodies that are recyclable, broadly cross-reactive, and capable of doing both simultaneously.

  Disease burden

  • Deaths 63K
  • DALYs Unknown

  This information was last updated in April 2022

• 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 major development, given the challenges associated with successful implementation (and sustainability) of the SAFE (surgery; antibiotics; facial cleanliness; environmental improvement) strategy, which is the only currently available tool to reduce trachoma transmission. The most advanced trachoma vaccine candidate is NIAID’s live-attenuated (plasmid-deficient) trachoma vaccine which is still in preclinical development. Clinical diagnosis of trachoma is not always reliable, and current diagnostic tests are expensive and complex to use. 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%).

  Pipeline spotlight

  DjinniChip, a novel, rapid, low-cost molecular assay for diagnosing ocular C. trachomatis has demonstrated promising results during clinical testing, particularly in its ability to detect low concentrations of C. trachomatis and its usability in poorly resourced field conditions. This device was developed by the Fraunhofer IZI MicroDiagnostics Unit in Germany.

  Disease burden

  • Deaths 2019 0
  • DALYs 2019 0.2M

  This information was last updated in April 2022

• 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

  Despite recent improvements in diagnostic tools, TB is still lacking a reliable and accessible point-of-care test. There is also a need for improved tests to diagnose TB in children, and to test for drug resistance and susceptibility. The existing TB vaccine (BCG) is still in widespread use, but provides limited protection against pulmonary disease in adults. A vaccine which provides protection against all forms of TB in all age groups is needed; current efforts target one or more of prevention of infection, prevention of disease, or prevention of recurrence. New drugs are needed that can shorten treatment, work against both drug-sensitive and drug-resistant 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. Therapeutic vaccines and other biologics are also a potential tool to simplify and shorten TB treatment.

  Pipeline spotlight

  In the TB Practecal Phase II/III trial, a new shorter, all oral regimen containing the new chemical entity pretomanid proved to be superior to the current standard of care for DR-TB. More than 14 preventive vaccine candidates are under development, with Immuvac and VPM1002 being currently tested in a large Phase III trial in India.

  Disease burden

  • Deaths 2019 1.2M
  • DALYs 2019 47M

  This information was last updated in April 2022