R&D needs for global health
“Global health” can be defined in many ways. Policy Cures Research uses “global health” to capture three different health areas – neglected diseases, emerging infectious diseases, and sexual & reproductive health – with a specific focus on medical research and biomedical innovation within these historically neglected and underfunded areas.
Although all basic research and relevant product types are considered part of our definition of global health, not every combination of health issue and product type is included in our estimates of global R&D funding, and some combinations are included only with restrictions.
Appropriately targeted platform technologies (such as adjuvants, diagnostic platforms and delivery devices), multi-disease vector control products and multipurpose prevention technologies are also included in our definition of global health. Some of this R&D is targeted at diseases or issues from more than one global health area. We also include core funding to organisations focusing on more than one disease or issue from different global health areas.
Find out more about the products we cover here. Additional detail on inclusions and restrictions by global health area is provided below.
Drugs
Drugs are essential, chemically synthesised small molecules specifically designed to either manage medical illnesses or to address other important health issues (such as contraceptive drugs). Depending upon the profile of the candidate, an investigational drug can be a new chemical entity or an already approved drug repurposed for a new indication. A drug can either be used as a therapeutic agent or for prophylaxis. Drugs for a number of diseases or health issues are needed, including those with better efficacy and safety profiles.
Diagnostics
In-vitro diagnostics are medical devices that are used to diagnose or screen individuals for specific diseases, conditions or infections, as well as monitor treatment, cures, and distinguish vaccinated individuals from the sick. Diagnostic tests are essential for understanding, controlling and eliminating disease, but need to be appropriate for use in resource-limited settings, for example be affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free and easily deliverable to end-users.
Vaccines
Immunisation is a high-impact, low-cost public health strategy to drive down the burden of preventable infectious diseases. Vaccines can be used as either a preventive measure – such as through routine immunisation – or as a reactive tool to control a disease outbreak. For many diseases – including most neglected diseases, emerging infectious diseases and many sexually transmitted infections – vaccines are either missing, or if a vaccine is existing, it is suboptimal for use in low- and middle-income countries. New vaccines are needed, including those that are safe for all age groups, such as young children and pregnant women, that can provide long-term protection in as few doses as possible, and that are broadly efficacious where needed.
Biologics
Biological medicines are a class of large molecules that includes sugars, proteins, nucleic acids, and cell- and tissue-based products. Biologics are sourced from living organisms, and many are produced using recombinant DNA technology. They are still in a very early stage in neglected disease, emerging infectious disease and the sexually transmitted infection R&D landscape, with most of the research activity dominated by anti-HIV monoclonal antibodies for treatment or prevention.
Vector-control products
Vector-borne diseases account for 17% of the estimated global burden of communicable diseases Vector control interventions are mainly either chemical-based, such as indoor residual spraying and insecticide-treated nets, or biological-based, such as genetic manipulation of vectors and microbial control of pathogens in adult vectors. New vector control tools are needed in response to increasing resistance to pyrethroid-based insecticides, the current mainstay of vector control interventions. This includes next-generation non-pyrethroid-based insecticides and innovative non-chemical based techniques.
Devices and combination products
In the context of G-FINDER, a device is an instrument with no pharmaceutical element that by itself is intended to address specific health issues – for example a copper intrauterine device to prevent pregnancy or a tool to assist bimanual compression to control post-partum haemorrhage. A combination product combines an instrument with a pharmaceutical element that together address a specific health issue – for example a hormone-releasing vaginal ring. R&D gaps persist for devices and combination products to address a number of sexual and reproductive health issues, including contraceptives to meet people’s myriad needs and that are appropriate for use in low-resource settings (e.g. simple to administer, user-controlled or non-hormonal) and for devices to treat post-partum haemorrhage.
Neglected diseases
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.
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Bacterial pneumonia & meningitis
Bacterial pneumonia & meningitis
Pneumonia is an infection of the lungs that is transmitted when infected individuals cough or sneeze. Symptoms include coughing, fever, chest pain and shortness of breath. The illness can be deadly, especially for young children and elderly patients. Although pneumonia can be caused by a range of pathogens, pneumococcal pneumonia caused by the bacterium Streptococcus pneumoniae is by far the most common in developing countries.
Bacterial meningitis is an infection of the fluid that surrounds the brain and spinal cord, most commonly caused by S. pneumoniae or Neisseria meningitidis. Symptoms of bacterial meningitis can include severe headaches, fever, chills, a stiff neck, nausea and vomiting, sensitivity to light, and an altered mental state. Bacterial meningitis is also often transmitted from person to person through coughing or sneezing. Even with early diagnosis and treatment, 5-10% of infected individuals die within 48 hours of showing symptoms.
R&D needs
Pneumococcal conjugate vaccines (PCVs) are highly effective and widely used in high-income countries, but until recently, the most common PCVs did not offer protection against serotypes most prevalent in developing countries. The WHO-prequalified PCV10 and PCV13 vaccines, which offer broader protection, have been rolled out in developing countries with positive results. However, PCVs are expensive to make and do not protect against all pneumococcal serotypes. Gains from PCVs with limited serotype coverage may be threatened by serotype replacement of vaccine-cleared serotypes with non-vaccine serotypes. New vaccines are needed that are more affordable, while still providing specific protection for children against all serotypes, or those predominant in developing countries. Non-conjugate protein- and whole-cell-based vaccines are two potential approaches, offering broad protection and cheaper manufacture; however Sanofi’s trivalent vaccine candidate PPrV and PATH’s whole-cell candidate PATH-wSP are the only non-PCV candidates currently in active clinical development. An affordable 10-valent PCV (PNEUMOSIL) was WHO prequalified in December 2019.
Historically, most epidemic and endemic bacterial meningitis in the meningitis belt of sub-Saharan Africa has been caused by serogroup A meningococci. MenAfriVac, a 50c-per-dose monovalent conjugate meningitis A vaccine developed by the Meningitis Vaccine Project, has been rolled out across the meningitis belt since 2010, with much success. An infant version of MenAfriVac was prequalified by the WHO in early 2015. But as rates of meningitis A have fallen, other serogroups have become increasingly prominent. Two multivalent conjugate vaccines are currently available, but, at between $12 and $40 per dose, are too expensive for developing countries. There is an ongoing need for cheaper polyvalent conjugate vaccines, with one candidate – PATH and SII’s pentavalent meningococcal conjugate vaccine (A, C, Y, W-135, X) – entering Phase III trials in August 2019. Diagnostics are also needed, including an RDT for use at the peripheral level that can detect serogroups to guide vaccine response, as well as multi-pathogen point-of-care tests for use at either peripheral or hospital levels to guide case management in both epidemic and endemic settings. BioSpeedia’s MeningoSpeed RDT is currently undergoing clinical evaluations for the detection of serogroups A, C, W, Y, X.
Disease burden
- Deaths 2017 1,220,742
- DALYs 2017 64,535,085
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Buruli ulcer
Buruli ulcer
Buruli ulcer, also known as Bairnsdale ulcer, is a chronic disease caused by Mycobacterium ulcerans. In developing countries, children under the age of 15 are at greatest risk. While the exact transmission mode is unknown, living around marshy areas with stagnant or slow-moving water can be a risk factor in endemic regions. Buruli ulcer usually appears as a painless lump or nodule that can later develop into an ulcer, usually on the arms or legs. M. ulcerans produces a toxin known as mycolactone, which causes tissue damage and can depress the immune response. As a result, coinfection with HIV can make Buruli ulcer more complex to address. If left undiagnosed or untreated, infection with M. ulcerans can lead to skin, tissue or bone damage, with surgery or amputation sometimes required.
R&D needs
Treatment options, including antibiotics and surgery, are effective if the disease is diagnosed early, however current diagnostics are both costly and complex. FIND is developing several Buruli ulcer diagnostics in collaboration with the WHO and other partners. These include an instrument-free point-of-care test as well as tools that can be used at peripheral health centres. Aptagen is also in the early stages of developing a point-of-care diagnostic based on RNA aptamers.
Drug treatment is with a combination of two antibiotics given daily (or twice-daily) for eight weeks. The most commonly used regimen in sub-Saharan Africa combines one oral and one injectable antibiotic, but recent evidence suggests that all-oral regimens may be equally effective. Recent research calls for ongoing monitoring to detect any emerging drug-resistant strains, highlighting the need for new drugs that are less complicated to administer or can be given for a shorter period. Although there are few new drug candidates currently in development specifically for Buruli ulcer, two investigational tuberculosis drugs – telacebec (Q203) and TB47 – have demonstrated efficacy against Buruli ulcer in pre-clinical studies.
The BCG vaccine (designed for TB) provides short-term protection, but is not an adequate substitute for a specifically targeted vaccine. Buruli ulcer vaccine development is in the very early stages of research. A recombinant Mycobacterium marinum strain expressing MU-Ag85A – the only candidate in the pre-clinical pipeline – has demonstrated superior immunogenicity and protection over the BCG vaccine.
Disease burden
- Deaths N/A
- DALYs N/A
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Cryptococcal meningitis
Cryptococcal meningitis
Cryptococcal meningitis is an opportunistic infection that causes inflammation of the tissue covering the brain and spinal cord. It is caused primarily by Cryptococcus neoformans, a microscopic and easily inhaled fungus found throughout the world. In healthy individuals, inhalation of the fungal spores rarely leads to serious illness; but for immunocompromised individuals, such as those with HIV/AIDS, cryptococcal infection (cryptococcosis) can be serious and even deadly. Cryptococcosis can affect multiple organs, but the primary site of infection is usually the lungs. Cryptococcal meningitis occurs when the infection spreads to the brain and central nervous system, with symptoms including headaches, fever, neck pain, light sensitivity and altered mental state (ranging from confusion to coma). Mortality rates for cryptococcal meningitis can be as high as 70%.
R&D needs
Cryptococcal meningitis can be effectively treated with medicines such as amphotericin B and flucytosine, but these are poorly suited to developing country use. Amphotericin B is expensive and requires administration at a hospital, and flucytosine requires careful blood monitoring. As a result, cryptococcal meningitis in developing countries is usually treated with fluconazole, which is only partially effective. There is a need for affordable, efficacious drugs that are adapted for resource poor settings. New antifungal agents, repurposed drugs and immunotherapies are all being investigated. Several new antifungal agents targeting various biochemical processes are in the early stages of development and show promising activity against cryptococcal meningitis. One such candidate is the new long-acting azole-like compound VT-1129 – currently in pre-clinical development – which received Fast Track designation from the US FDA in 2016. Clinical trials are also being conducted on new oral formulations of amphotericin B (MAT2203). A number of repurposed drugs are under investigation for their efficacy against cryptococcal species alone or in conjunction with the current amphotericin B and fluconazole therapies, including the anti-cancer drug tamoxifen, which is in Phase II trials for a short-course combination therapy with amphotericin B and fluconazole. Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have demonstrated success in treating cryptococcal meningitis and cryptococcosis more generally. There are currently no late-stage candidates in the drug or biologic pipeline.
Accurate rapid diagnostic tests for cryptococcal infection are available and appropriate for use in developing country settings, meaning that diagnostics are excluded from the G-FINDER scope.
Disease burden
- Deaths 2014 181,100
- DALYs N/A
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Dengue
Dengue
Dengue is a viral infection transmitted to humans by the female Aedes mosquito – most often Aedes aegypti (common in urban environments) and Aedes albopictus (common in rural environments). The dengue virus has four serotypes, each with multiple genotypes. First time infection rarely results in anything more serious than a severe flu-like illness; subsequent infections with a different serotype (or even genotype) can result in severe disease, and are more likely to lead to dengue haemorrhagic fever. For children in affected regions, dengue is a leading cause of serious illness and death. Dengue outbreaks often occur in Asia, Central America and South America; the disease is now present in more than 100 countries, up from only nine in 1970.
R&D needs
Dengue’s prevalence in high- and upper-middle-income countries across Asia and Latin America and demand from travellers and the military has created a potential dengue vaccine commercial market large enough to attract industry investment in vaccine R&D. Dengue vaccine R&D investment has thus been excluded from the G-FINDER scope.
No curative treatment is available, so management is focused on supportive therapy and the control of onward transmission. Despite the unmet need, there is little advanced dengue drug research. Drug candidates in clinical development include repurposed drugs, such as celgosivir, while other direct-acting antivirals such as DengueCide and JNJ-1A are in pre-clinical development. Biologic R&D – included in the G-FINDER scope for the first time this year – is currently centred on the pre-clinical development of monoclonal antibody (mAb) therapeutic candidates, including DENV mAb and AB513, both of which can neutralise all four dengue serotypes.
There is a pressing need for diagnostics that work across the full spectrum of disease, and can distinguish dengue from other causes of fever. The first reverse transcription polymerase chain reaction (RT-PCR) diagnostic test capable of detecting all four serotypes was approved by the US FDA in 2012 (CDC DENV-1-4), but has shown a lower clinical sensitivity in practice. Several advanced tests are being adapted for dengue virus detection, including isothermal molecular technologies such as the DENV RT-LAMP and DENV NASBA assays, both from the US NMRC; US CDC’s DENV TMA assay; and DENV RT-RPA from TwistDx. Point-of-care serological tests based on antigen or antibody detection (such as the SD Bioline Dengue Duo RDT) are already available. Unfortunately, these tests cannot distinguish between serotypes, and may lack sensitivity and specificity.
Several new vector controls targeting the Aedes mosquito are in development, including adulticidal oviposition traps and space spray insecticides. Field experiments for biological control tools are ongoing across Asia and South America for the Wolbachia bacteria method, including a large cluster-randomised controlled trial in Indonesia; trials in China and Thailand which combine the sterile insect technique with Wolbachia-based incompatible insect technique (SIT/IIT); and a trial in Brazil of the second generation genetically manipulated ‘Friendly’ Ae. Aegypti (OX5034).
Disease burden
- Deaths 2017 40,407
- DALYs 2017 2,910,652
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Diarrhoeal diseases
Diarrhoeal diseases
Diarrhoeal diseases are a group of illnesses caused by viruses, bacteria and protozoan parasites that spread through contaminated food or water. Without treatment, diarrhoeal diseases can cause severe illness and death. Children under the age of five and immunocompromised individuals are most at risk. Rotavirus is the leading cause of severe diarrhoeal disease in young children worldwide, causing fever, vomiting and watery diarrhoea. Other diarrhoeal diseases include enteroaggregative E. coli (EAEC) and enterotoxigenic E. coli (ETEC), both of which can also cause fever and watery diarrhoea. For some people, cholera (caused by Vibrio cholerae) is asymptomatic but for others, infection can lead to severe diarrhoea and vomiting, and even kill within hours if left untreated. Shigellosis, caused by the Shigella bacterium, is highly contagious. Giardiasis is caused by the Giardia protozoan parasite found in soil, food and water contaminated by faeces. Cryptosporidium is a protozoan parasite that can survive in soil, food and water, causing cryptosporidiosis primarily in people who work with animals or live in overcrowded settings.
R&D needs
Current vaccines against diarrhoeal diseases are sometimes ineffective and not always suitable for infants. New bivalent and multivalent vaccines that are suitable for infants and that have long durations of protection are needed for most diarrhoeal diseases. Paxvax’s Vaxchora, a cholera vaccine, received US FDA approval in 2016 for use in adults travelling to cholera-affected areas. While it is currently being evaluated for use in children over two years of age, it has not be approved for, or tested in, endemic areas. There are currently four WHO prequalified rotavirus vaccines, with ROTASIIL receiving prequalification in September 2018. As of late 2018, 101 countries had introduced a rotavirus vaccine as part of their routine immunisation schedule. However these current-generation live attenuated oral vaccines are not optimally effective in high-burden settings, and coverage is lower than with comparable injectable vaccines on the routine schedule. The next generation of rotavirus vaccine candidates are non-replicating parenteral vaccines, the most advanced of which – NRRV (P2-VP8) – is in Phase III trials. Several vaccine candidates for other diarrhoeal diseases are in Phase II trials, including ETVAX to address ETEC; and GSK3536852A and Flexyn2a for Shigella. A combined Shigella and ETEC vaccine candidate, ShigETEC is also in pre-clinical development.
Oral rehydration therapy in conjunction with zinc supplementation is the mainstay of diarrhoeal disease management in LMICs, but supportive therapy alone is not sufficient in all types of diarrhoea. Safe, effective and affordable pathogen-specific drugs are needed to target V. cholerae, Cryptosporidium, and Shigella. The current therapeutic pipeline of both small molecule drugs and biologics for these pathogens is in the early stages of development, with no candidates in clinical development. New rapid diagnostic tests capable of distinguishing between different diarrhoeal diseases are also required, however there are currently no late-stage candidates in the diagnostic pipeline.
Disease burden
- Deaths 2017 1,157,938
- DALYs 2017 54,608,364
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Helminth infections
Helminth infections
Helminths are parasitic worms and flukes that can cause disease in humans. The most common mode of transmission to humans is through ingesting or coming into contact with contaminated food, water, or soil. Helminth infections transmitted in this manner include ancylostomiasis and necatoriasis (hookworm), ascariasis (roundworm), trichuriasis (whipworm) and strongyloidiasis (intestinal roundworms) collectively referred to as soil-transmitted helminths as well as taeniasis/cysticercosis (tapeworm) and schistosomiasis (bilharziasis, also known as snail fever). Other helminth infections are transmitted by bites of blood-sucking arthropods: these include lymphatic filariasis, which is transmitted by mosquitoes, and river blindness (onchocerciasis), which is transmitted by the black fly.
Adult worms can reside in the intestines and other organs, causing malnutrition and impaired cognitive development (hookworms), or progressive damage to the bladder, ureter and kidneys (schistosomiasis). Onchocerciasis is a major cause of blindness in many African and some Latin American countries, while lymphatic filariasis can cause painful, disfiguring swelling of the scrotum (hydrocele) and limbs (elephantiasis).
R&D needs
With no vaccines, disease control efforts rely on mass-drug administration. Variable drug efficacy and the need to control transmission mean that treatment programmes must continue for many years, increasing the risk of drug resistance. New and more effective drugs are needed for many helminth infections, as are paediatric formulations of existing drugs. Current diagnostic products for detection of some helminths are outdated or complex; new and effective diagnostics that can measure infection intensity and detect drug resistance are needed.
In 2018, the US FDA approved moxidectin, the first new onchocerciasis treatment in 20 years. Candidates in clinical development include oxfendazole and emodepside for onchocerciasis (both in Phase I), tribendimidine for hookworm (Phase II), an orodispersible praziquantel tablet for schistosomiasis in children (Phase III) and TylAMac for filarial diseases (Phase I). Among the schistosomiasis vaccines in development is Sm14, which has completed a Phase IIa trial, and Sm-TSP-2, which recently commenced Phase I/II trials in Uganda. Therapeutic vaccines and antibody immunotherapy against adult worms, included in the G-FINDER scope under the heading of biologics for the first time in the 2019n report, are also being explored for schistosomiasis. Sm-p80, the only schistosomiasis vaccine with promising therapeutic potential, has completed pre-clinical evaluation and is currently in preparation for human clinical trials. Two candidate vaccines against human hookworm infection are in clinical development. Na-GST-1 the most advanced candidate entered 2018 Phase II trials using a controlled human hookworm infection model. All of the current vaccine candidates against onchocerciasis are in pre-clinical development.
There are several diagnostic tests in development for helminth infections, including the SD BIOLINE Oncho/LF IgG4 biplex rapid test a dual detection point-of-care test for onchocerciasis and lymphatic filariasis currently in field evaluation and the UCP-LF CAA assay to diagnose schistosomiasis in low-prevalence settings, which is in clinical development. A lateral flow point-of-care test from the US CDC that can simultaneously detect taeniasis and neurocysticercosis is currently undergoing field evaluation in Tanzania and Zambia.
Disease burden
- Deaths 2017 12,765
- DALYs 2017 7,512,706
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Hepatitis B
Hepatitis B
Hepatitis B is a disease of the liver caused by infection with the hepatitis B virus (HBV), and can be either acute or chronic. Acute infection is more common and more severe in adults and adolescents, but the likelihood of developing chronic disease is dramatically higher in infants and children under five. As many as 80-90% of children infected during the first year of life will progress to chronic disease, but this falls to less than 5% for otherwise healthy adults. Almost all of the burden of HBV-related disease is due to chronic hepatitis B – largely due to cirrhosis or liver cancer – following infection transmitted from mother to child at birth or acquired in early infancy. Although HBV is prevalent worldwide, the burden of hepatitis B is disproportionately high in low- and middle-income countries, and co-infection with HIV is not uncommon. Hepatitis B product R&D was added to the G-FINDER scope in the 2019 report, restricted to LMIC use and applicability.
R&D needs
An effective vaccine against HBV exists, with the current HBV preventive vaccine series (a dose at birth followed by two subsequent booster doses) providing protection in more than 95% of vaccinated infants. Vaccination against HBV remains the main strategy for the control and elimination of hepatitis B, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal.
There is also a lack of data that could be used to inform population approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs, suggesting a need for additional basic research.
Oral therapy with recommended first-line HBV treatments such as entecavir or tenofovir alafenamide is generally safe and well tolerated, and can result in virological suppression in more than 95% of patients. Long-term treatment and viral suppression is associated with regression of cirrhosis and reduced incidence of hepatocellular carcinoma, but seroclearance is uncommon and lifelong drug treatment is required for most patients. At least two candidates are in clinical development for functional cure of hepatitis B – defined by sustained undetectable surface antigen levels, regardless of seroconversion – including inarigivir in Phase II, and HS-10234 in Phase III. Novel therapies aimed at achieving HBV seroclearance are also in development, including immune stimulators, and other host-targeting bio-therapeutics.
Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis; rapid diagnostic tests (RDTs) are available as cheap and generally accurate alternatives to laboratory-based immunoassays, although both may fail to identify low HBsAg concentrations, for example in HIV co-infection. However, for confirmation of diagnosis, treatment monitoring and detection of drug resistance, there is a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load. Two assays have recently been developed for POC molecular platforms – Cepheid’s Xpert HBV VL and Molbio Diagnostics’ Truenat HBV VL – but neither is currently WHO-prequalified and cost may remain a barrier to access., Another molecular test designed explicitly for low-resource settings, DRW’s SAMBA POC platform, has HBV qualitative and semi-quantitative assays in early-stage development.
Disease burden
- Deaths 2017 741,267
- DALYs 2017 23,752,066
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Hepatitis C
Hepatitis C
Hepatitis C is a blood-borne infectious disease caused by the hepatitis C virus (HCV), primarily affecting the liver. HCV causes both acute and chronic infection, with symptoms in the acute phase including fever, fatigue and jaundice. However, up to 80% of acute cases are asymptomatic, meaning that many HCV infections will go undetected until chronic disease develops, sometimes decades later. Although 20-40% of acute infections resolve spontaneously without treatment, the remaining 60-80% of cases will progress to chronic infection.145 Without treatment, chronic hepatitis C is a lifelong disease which can lead to life threating liver damage (cirrhosis and fibrosis) and hepatocellular carcinoma (liver cancer).
There are six main genotypes of HCV, with genotypes 4, 5 and 6 disproportionately affect developing countries, while having a low prevalence in high-income countries. Since R&D efforts have moved from genotypic-specific to pan-genetypic products, in the 2019 report we replaced the genotype restriction for inclusion in G-FINDER with more detailed restrictions on LMIC applicability and use.
R&D needs
There are 15 direct-acting antiviral (DAA) drugs available on the market, including four pan-genotype combinations. DAA-based regimens are more effective, require a shorter duration of treatment, are appropriate for most patients and have fewer side effects than previous interferon- and ribavirin-based treatments. Due to these advancements, in 2018 the WHO recommended that persons over the age of 12 years should be treated with DAAs. However, DAA-based regimens are expensive, and access remains limited in LMICs. The Medicines Patent Pool licenced a pan-genotype, fixed-dose combination DAA (glecaprevir/pibrentasvir) in 96 LMICs, but has not reached agreements for its generic production. More research is also needed to assess DAA-based regimens in developing country populations, adolescents, children under 12, and pregnant women. Several other multi- or pan-genotypic DAA-based regimens are undergoing trials, including ravidasvir/sofosbuvir – the only pan-gentoypic regimen in late-stage development – and two paediatric regimens, sofosbuvir/velpatasvir in Phase II trials and glecaprevir/pibrentasvir in expanded access Phase III trials.
There is also a need for HCV diagnostic tests that are affordable and simple to use in developing country contexts, especially tests usable for treatment monitoring, screening and tests of cure. The WHO has prequalified nine HCV diagnostic tests, including three RDTs and one viral load test. Future diagnostic R&D needs to validate the use of dried blood spots for serological and molecular assays, validate core antigen-based assays as the gold standard for confirmatory tests and test of cure, and develop a true point-of-care nucleic acid test. Two diagnostics are in late stages of development: the Genedrive HCV ID Kit for confirmatory diagnosis/treatment monitoring and test of cure, and the STANDARD Q HCV Ab test as a point-of-care antibody assay.
There is no vaccine against HCV, although there are some pan-genotypic candidates in early-stage development, such as the Burnet Institute’s HepSeeVaxDelta3 candidate. Only two candidates have reached clinical development and both have been unsuccessful: GSK’s GSK3378455A and NIAID’s AdCh3NSmut1/MVA-NSmut.
Disease burden
- Deaths 2017 449,333
- DALYs 2017 12,743,817
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HIV/AIDS
HIV/AIDS
HIV continues to be a major public health issue, with almost 40 million people living with the virus as of 2018, the majority in LMICs. The virus attacks and destroys CD4 cells in the human immune system; without treatment, infected individuals become increasingly susceptible to other diseases, and eventually develop acquired immune deficiency syndrome (AIDS). People with AIDS often die from opportunistic infections like tuberculosis or cryptococcal meningitis, or cancers like Kaposi’s sarcoma.
R&D needs
There is currently no vaccine against HIV, and the rapid mutation of the virus poses a significant challenge to development. To date no vaccine candidate has proved able to match even the 31% efficacy achieved in the 2009 RV144 Thai Phase III clinical trials. There are currently two large HIV vaccine efficacy trials underway: HVTN 706, a global Phase III HIV vaccine efficacy trial of mosaic immunogens; and HVTN 705, a Phase IIb trial of Janssen’s prime-boost-based regimen. A third vaccine trial – HVTN 702, a Phase IIb/III trial investigating a modified version of the RV144 vaccine regimen – was halted in early 2020 due to non-efficacy. Several other candidates are currently in Phase I and II trials, including NIAID’s broadly neutralising anti-HIV antibody (bNAb) candidate, VRC01, which is in Phase IIb.
Therapeutic vaccines – including bNAb-based approaches, which are designed to control HIV infection by boosting the body’s natural immunity – are also being investigated for immunotherapy, including VRC01LS/10-1074, a dual long-acting bNAb currently in Phase II. Plasmid and viral vectored DNA vaccines are also among the therapeutic vaccine candidates currently in Phase I and II clinical trials.
Despite advances in HIV therapeutics, R&D gaps for HIV drugs persist in LMICs, including paediatric formulations or long-acting injectable drugs for PrEP, with promising progress underway. The Drugs for Neglected Diseases initiative (DNDi) is developing Quadrimune – a ‘4-in-1’ LPV/r-based taste-masked and heat-stable fixed-dose formulation designed specifically for children, which is currently under review by the FDA, with a Phase I/II trial ongoing in Uganda to generate evidence for worldwide scale-up. One long-acting injectable PrEP candidate, cabotegravir, is also in Phase IIb/III and III trials, and has demonstrated high efficacy when administered every eight weeks, with the blinded part of the study subsequently stopped as a result of this success. Following a Phase III trial, the long-acting injectable treatment regimen cabotegravir/rilpivirine was also granted approval by Health Canada in early 2020. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise. The International Partnership for Microbicides (IPM)’s monthly dapivirine ring has completed Phase III trials, and in July 2020 received a positive scientific opinion from the European Medicines Agency for use in women over 18 in LMICs.
Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially early infant diagnosis. There is progress towards robust, rapid point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates. These include early infant diagnostic tests (Alere’s q HIV-1/2 Detect and Cepheid’s Xpert HIV-1 Qual Assay), an assay for viral load monitoring (Hologic’s Aptima HIV-1 Quant Assay) and the first true point-of-care molecular test for resource limited settings (Abbott’s m-PIMA HIV-1/2 VL).
Disease burden
- Deaths 2017 938,891
- DALYs 2017 53,567,471
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Kinetoplastid diseases
Kinetoplastid diseases
Kinetoplastid infections include three diseases: leishmaniasis; Chagas’ disease (also known as American trypanosomiasis); and sleeping sickness (human African trypanosomiasis). Leishmaniasis – caused by Leishmania parasites and spread by phlebotomine sand flies – has three forms: visceral (the most severe form, often fatal without treatment); cutaneous (the most common); and mucocutaneous. Chagas’ disease – caused by Trypanosoma cruzi and predominantly spread by the blood-sucking triatomine bug – has two stages. Symptoms in the acute stage are often mild or absent, resulting in under-diagnosis. Left untreated, infected individuals will progress to the chronic second stage, and 20-30% will develop life-threatening complications. Sleeping sickness is caused by the parasite Trypanosoma brucei and spread by tsetse flies. It also has two stages, with early-stage disease symptoms difficult to distinguish from other viral illnesses. In late-stage disease, the parasite infects the brain and central nervous system, causing confusion and – without treatment – coma and death.
R&D needs
Leishmaniasis needs a preventive vaccine; biologic treatments; improved, preferably oral, drug formulations; and diagnostic tests for general disease diagnosis, cure, and a specific test for post-kala-azar dermal leishmaniasis (PKDL). Two visceral leishmaniasis candidates – a vaccine and a biologic therapy – are in active clinical development. Three novel leishmaniasis drugs being developed by GSK and DNDi have entered Phase I trials while a topical formulation of an existing drug (amphotericin B) is in clinical trials for the treatment of cutaneous leishmaniasis. Diagnostics for resource-limited settings in development include: VL Sero K-SeT (in late-stage development) for rapid monitoring of cure and diagnosis of PKDL; a VL ELISA test (in late-stage development); and a LAMP-based test for visceral and cutaneous leishmaniasis currently undergoing demonstration studies.
Chagas’ disease needs a preventive vaccine; biologic treatments; safer, more effective drugs suitable for children and effective against the chronic form of the disease; and diagnostics that can reliably detect chronic disease and monitor treatment. All Chagas’ disease vaccine and biological therapeutic candidates are in the pre-clinical stage or earlier. A paediatric benznidazole formulation has been approved in Brazil, the US and Argentina, while a combination of benznidazole and fosravuconazole has completed Phase II trials, showing effectiveness as a two-week treatment course. A Phase II trial of short-course and low-dose regimens of fexinidazole is ongoing in Spain. Several new diagnostic tools to detect congenital Chagas’ disease are in development, including two immunoassays in early-stage development and two LAMP-based molecular tests in late-stage development.
Fexinidazole, the first all-oral treatment active against both stages of sleeping sickness, was registered in 2019 in the DRC, following the 2018 EMA positive scientific opinion. It could potentially replace the current nifurtimox-eflornithine combination injectable treatments with an all-oral treatment which can be completed in just ten days. A second oral treatment, acoziborole, is in Phase II/III clinical trials. There is little active research into sleeping sickness vaccines or biologics, with no candidates currently in the pipeline. Two point-of-care serological tests are in late-stage development: Coris BioConcept’s second generation HAT RDT and ITM Antwerp’s iELISA.
Disease burden
- Deaths 2017 16,641
- DALYs 2017 1,076,053
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Leprosy
Leprosy
Leprosy, also known as Hansen’s disease, is caused by Mycobacterium leprae and is transmitted via air droplets from the nose or mouth of infected people. Leprosy mainly affects the skin and nerves and has an incubation period that can be as long as 20 years. The disease is curable with multidrug therapy using a combination of rifampicin, clofazimine and dapsone (for multibacillary leprosy), or rifampicin and dapsone (for paucibacillary leprosy). However, if left untreated, leprosy can cause nerve damage, muscle weakness and permanent impairments.
R&D needs
The current drug regimen for leprosy has been standard treatment for 30 years and, although highly effective, it requires between six and 24 months of treatment. Further research is needed to improve and simplify drug regimens, and to provide products for nerve function management. Bedaquiline, an antibiotic approved for the treatment of MDR-TB and found to be effective in the treatment of leprosy in animal models, is currently undergoing Phase II clinical trials.
Leprosy vaccine and biologic R&D was included in the G-FINDER scope for the first time in the 2019 report given the absence of effective preventive or therapeutic vaccines. Immunisation with BCG has only a modest ability to prevent leprosy (26% in observational studies, 41% in experimental studies) and post-exposure BCG immunisation may cause paucibacillary disease in some individuals. Preventive and therapeutic vaccine R&D for leprosy is currently underway to identify antigens that can offer post-exposure immunoprophylaxis or confer protection without exacerbating nerve damage, most notably LEP-F1/GLA-SE (LepVax), which is currently in Phase Ib/IIa clinical trials.
Diagnosis of leprosy is primarily based on identifying key clinical features of infection, meaning that asymptomatic early-stage cases are often missed or diagnosed late, leading to continued disease transmission. Elimination of leprosy will likely require new and improved diagnostics capable of identifying asymptomatic cases, as well as all symptomatic forms (paucibacillary, borderline tuberculoid, borderline, borderline lepromatous or multibacillary) of the disease. The Infectious Disease Research Institute (IDRI) is one organisation currently developing rapid diagnostic tests for leprosy, including co-development of NDO-LID, which to date has been limited by very low capacity to detect true positives in both paucibacillary (14.9%) and multibacillary (47.9%) Brazilian patients. Additional immuno-diagnostic tests include Leiden University’s Field-friendly lateral flow assays (LFAs), currently in late-stage development.
Disease burden
- Deaths 2017 -
- DALYs 2017 31,397
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Leptospirosis
Leptospirosis
Leptospirosis is an infection caused by bacteria of the genus Leptospira, which affects both humans and animals. The infection is transmitted to humans through contact with the urine or blood of infected animals, either directly or via contaminated water, food or soil. People who live in tropical climates, who work in flooded areas such as rice paddies and sugar cane plantations, or who work with animals are most at risk. The bacteria can survive for several weeks in water or soil, and outbreaks often occur after flooding.
R&D needs
Diagnosing leptospirosis can be challenging due to the non-specific symptoms of early infection, which are shared with a number of other diseases, such as dengue and malaria, as well as the fact that some infected individuals may remain asymptomatic. Without treatment, the infection can progress to a more severe second phase, causing meningitis, kidney and liver failure, respiratory distress, and sometimes death.
Effective, appropriate drugs exist for leptospirosis, meaning that infection can be successfully treated if it is diagnosed. However, accurate diagnosis of leptospirosis during the acute phase of the disease is currently only possible with sophisticated laboratory tests, which are unsuitable for remote settings. There is a real need for new, easy-to-use tests that can quickly and accurately diagnose acute infection in the field. Several rapid point-of-care tests are available on the market, but none of these are widely approved due to their lack of specificity and sensitivity. The promising diagnostic LEPkit assay has demonstrated higher sensitivity and specificity than existing rapid diagnostic tests, but its development status has not been updated since 2017.
Disease burden
- Deaths 2015 58,900
- DALYs 2015 2,900,000
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Malaria
Malaria
Malaria is a parasitic disease transmitted through the bite of an infected female Anopheles mosquito. The two most common types of malaria are caused by Plasmodium falciparum and Plasmodium vivax. Left untreated, malaria can cause severe illness and death. Children and pregnant women are among the most vulnerable, with more than 70% of all malaria deaths occurring in children under five years of age.
R&D needs
The most advanced malaria vaccine candidate, RTS,S, commenced large-scale pilot implementation in 2019 in Malawi, Ghana and Kenya under the auspices of the WHO-coordinated Malaria Vaccine Implementation Programme. There remains a need for new vaccines which have greater efficacy; provide protection against both P. falciparum and P. vivax; and can block transmission. The next most advanced vaccine candidate, Sanaria’s PfSPZ, is now in Phase II trials.
Eleven new malaria drugs have been approved since 2007, including tafenoquine, a single-dose treatment for relapsing P. vivax malaria approved in 2018, and two paediatric artemisinin-based combination therapy (ACT) formulations. New drugs are still needed in response to emerging resistance to ACTs, and to meet the goal of a single-dose cure. Several promising novel drugs are in late-stage development, including artefenomel/ferroquine and ganaplacide/lumefantrine. Both candidates are undergoing Phase IIb trials for safety, efficacy and their potential as a single-encounter radical cure. Biologics were included in scope for the first time this year, with monoclonal antibodies (mAbs) being investigated as a new approach for malaria prophylaxis, treatment or blocking transmission. At least one transmission blocking biologic, mAb TB31F, is currently in pre-clinical development.
Cheap, sensitive rapid diagnostic tests (RDTs) exist, although heat stability can be an issue. The emergence of parasites with deletions in the pfhrp2/3 gene – which codes for the most common RDT target for detecting P. falciparum – is concerning. Improved, more sensitive diagnostics are needed to identify non-falciparum species, distinguish malaria from other febrile illnesses, detect asymptomatic cases, and diagnose G6PD enzyme deficiency. PATH’s RDT to diagnose G6PD deficiency is currently in late-stage development, while Alere’s Malaria Ag P.f, a new generation highly-sensitive RDT which can detect asymptomatic infections, was prequalified in 2019.
Next-generation vector control products are urgently needed in response to emerging pyrethroid resistance. Novel non-pyrethroid-based products that received WHO prequalification in 2017 include Sumitomo’s SumiShield 50WG, a clothianidin indoor residual spray (IRS) formulation and BASF’s Interceptor G2, a chlorfenapyr-based, dual-ingredient long-lasting insecticide-treated bed net (LLIN). Chemical control products in development include Sylando 240SC – a chlorfenapyr-based IRS formulation – currently undergoing final phases of WHO prequalification review, and Olyset Duo – a dual LLIN with permethrin plus pyriproxyfen – which recently completed field evaluations. Vector manipulation approaches to reduce mosquito populations or block parasite transmission are also being investigated, with field experiments of CRISPR/Cas9-based gene drive approaches starting this year in Burkina Faso. New approaches to vector control are being explored, including use of ivermectin mass drug administrations for malaria transmission control, as well as spatial repellents and insecticide-treated baits.
Disease burden
- Deaths 2017 619,685
- DALYs 2017 45,005,406
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Mycetoma
Mycetoma
Mycetoma is a chronic infection of the skin and soft tissue caused by either flesh-eating fungi (eumycetoma) or bacteria (actinomycetoma). When left untreated, it can affect deeper tissues and lead to amputation. Although the true global incidence and prevalence of mycetoma is still not fully known, it most often occurs across the so-called mycetoma belt, which includes Sudan, Chad, Ethiopia, Senegal, Somalia, Yemen, Mauritania, Venezuela, Mexico and India. Mycetoma has been included in the G-FINDER scope for the first time.
R&D needs
There is a need for new tools to address the ongoing challenge of mycetoma in endemic countries, including new drugs and diagnostics, as well as basic research to fill critical information gaps.
Despite the availability of several drugs for the treatment of mycetoma, including the antifungals ketoconazole and itraconazole, and the antibiotics amikacin and co-trimoxazole, significant R&D gaps still exist. Antifungals targeting eumycetoma are only 25-35% effective, are costly, require extended treatment and can cause serious side effects. DNDi is currently supporting a Phase II trial of fosravuconazole in Sudan to assess whether it is superior to these existing antifungals. While antibiotics used for the treatment of actinomycetoma have a cure rate of 90%, the global rise of antimicrobial resistance threatens their long term effectiveness.
Existing tools for diagnosing mycetoma are often inappropriate for use in LMICs, as they are invasive, time-consuming and require a well-equipped laboratory. There is a need for cheap, rapid and accurate point-of-care diagnostics for patients with early lesions.
More basic research is needed in order to accurately estimate the burden of mycetoma, to understand its epidemiology and mode of transmission, and to facilitate the development and use of new drugs and diagnostics.
Disease burden
- Deaths N/A
- DALYs N/A
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Rheumatic fever
Rheumatic fever
Rheumatic fever is a bacterial infection caused by Streptococcus pyogenes (also known as Group A streptococcus, GAS) that most commonly affects children aged 5-14 years. It usually follows untreated bacterial throat infections, and without treatment can lead to complications such as rheumatic heart disease, in which the heart valves are permanently damaged. It may also progress to heart failure and stroke.
R&D needs
Acute rheumatic fever can be treated using currently available drugs (although post-infection prophylaxis requires multiple doses of antibiotics); however, treatment of rheumatic heart disease often requires surgery. The main R&D required is therefore the development of a vaccine. Several GAS vaccines are in development, with only two candidates in clinical trials: StreptAnova, which completed a Phase I trial in December 2017, and MJ8VAX, whose Phase I clinical trial indicated the need for additional investigations to optimise its immunogenicity and improve dosing. Phase I/IIa trials are planned for StreptInCor, the most advanced pre-clinical candidate.
Disease burden
- Deaths 2017 245,372
- DALYs 2017 8,814,192
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Salmonella infections
Salmonella infections
Salmonella infections are a group of diseases caused by the Salmonella enterica bacteria, and transmitted through contaminated food or drink. These include: typhoid (caused by Salmonella Typhi); paratyphoid fever (caused by Salmonella Paratyphi A, B or C) – collectively referred to as enteric fever; and thousands of non-typhoidal serotypes, referred to as non-typhoidal Salmonella (NTS). Enteric fevers affect only humans, while NTS affects both humans and animals.
Salmonella infections are more common where there is dirty water and poor sanitation or hygiene. Symptoms can include fever, malaise, headache, constipation or diarrhoea, and an enlarged spleen and liver. Occasionally rose-coloured spots appear on the chest. In the case of typhoid fever, a small proportion of people can recover but still carry and spread the bacteria for as long as a year after infection. Diagnosis of Salmonella infections may require a blood, stool or bone marrow sample.
R&D needs
Medicines exist to treat enteric fever; however data from endemic regions show antimicrobial resistance linked to S. Typhi H58 clade is increasing, including the first ever reported outbreak of ceftriaxone-resistant S. Typhi in Pakistan in 2016. Therefore, there is a need for more efficacious drugs, including ones suitable for children. There are currently three safe and effective typhoid vaccines available, with the latest to receive WHO prequalification being the world’s first typhoid conjugate vaccine (TCV), Typbar TCV. The WHO recommends TCVs as the preferred vaccine in high-burden countries and Gavi funding for the introduction of this vaccine has been available for eligible countries since April 2018, with Zimbabwe as the first beneficiary. Given the threat of antibiotic resistance, biologic R&D remains a need and was included in the G-FINDER scope for the first time in the 2019 report. Pathogen-specific antibody-based therapeutics, such as monoclonal antibodies (targeting the typhoid toxin) and bacteriophages, are also being considered as an alternative modality for the treatment of typhoid fever.
Paratyphoid fever is an increasingly common cause of enteric fever throughout Asia, but there are no registered vaccines specifically targeting it, nor any bivalent vaccines that target both typhoid and paratyphoid fever. There are at least two vaccine candidates targeting serovar Paratyphi A currently in clinical development: a glycoconjugate vaccine candidate O:2-TT (Phase II) and a live oral vaccine strain CVD 1902 (Phase I).
There is no vaccine available for NTS, and treatment with antibiotics is only recommended for high-risk individuals such as young children, elderly people and immunocompromised patients. Several NTS vaccine candidates are in development, although they are all in the pre-clinical stage or earlier, including two candidates already set to transition to early clinical development: iNTS-GMMA, and the trivalent typhoid/iNTS glycoconjugate vaccine formulation (S. Enteritidis COPS:FliC/S. Typhimurium COPS:FliC/Typbar-TCV).
Disease burden
- Deaths 2017 193,943
- DALYs 2017 14,023,086
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Snakebite envenoming
Snakebite envenoming
Snakebite envenoming results from the bite of a venomous snake, and if not treated quickly and effectively can result in life-long disability, or lead to amputation or death. Snakebite envenoming is prevalent in tropical and sub-tropical regions in Africa, Asia, Oceania and Latin America. Snakebite envenoming was included in the G-FINDER report for the first time in the 2019 report.
R&D needs
Antivenoms – biological immunotherapeutics – have been used to treat snakebite envenomation for more than a century, and can be highly effective if given at the right time, at the right dose, and for the right snake. However there is a critical lack of high-quality, safe and effective region-specific antivenoms appropriate for use in LMICs, particularly in sub-Saharan Africa and Asia. Even the best currently-available antivenoms – all of which are based on animal-derived antibodies – are expensive to manufacture, can be complex to administer and store, and carry the risk of adverse reactions including anaphylaxis and serum sickness; they are also unable to neutralise all of the toxic effects of envenomation. There is a need for R&D to support the approval and introduction of safe, effective, high-quality antivenoms that are appropriate for the regions in which they are used, as well as to deliver next generation antivenoms that are more effective, more affordable, safer and heat-stable. Next generation antivenoms in preclinical development include single domain antibodies such as camelid-derived VHH and human scFv, as well as several types of non-antibody-based molecules, such as nanoparticles, peptides and oligonucleotide aptamers.
More basic research is needed to accurately estimate the burden of snakebite envenoming, and to understand the natural history and pathogenesis of disease, and the structure and properties of toxins and their variability between regions and species.
In low-resource settings where immediate treatment may be impossible, heat-stable venom-agnostic oral drugs are also needed as a first-line therapeutic to slow down neurotoxicity and prolong the window for victims to receive antivenom. The development of broad-spectrum small molecule inhibitors could help bridge this gap; the repurposed phospholipase A2 inhibitor varespladib is currently in pre-clinical trials and shows promise as a first line and combination therapy against venom-induced myonecrosis and haemorrhagic toxicity.
There is also a need for affordable, rapid, point-of-care diagnostics capable of identifying the common species in high-burden areas, with low to no cross reactivity between venoms. The only existing point-of-care diagnostic is only available in Australia and is specific to Australian snake species. Two lateral flow assays for Taiwanese and Indian snakes are currently in clinical development.
Disease burden
- Deaths N/A
- DALYs N/A
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Trachoma
Trachoma
Trachoma is an infectious eye disease caused by the bacterium Chlamydia trachomatis. The infection can be spread by contact with infected eyes or nasal discharge, including via contact from flies and shared use of clothing and towels. Trachoma is common among children and in areas where there is unclean water and poor sanitation. After repeat infection and without medical treatment, the eyelid can turn inwards, causing the eyelashes to rub against the eyeball, resulting in scarring, visual impairment or irreversible blindness.
R&D needs
WHO recommends a combination of interventions known as the SAFE strategy for the elimination of trachoma, which is an acronym for surgery (which has low acceptance and high recurrence rates); antibiotics (including treatment with azithromycin, though over-reliance on a single drug therapy can increase the risk of drug resistance); facial cleanliness; and environmental improvement to reduce transmission.
Because of the challenges associated with successful implementation (and sustainability) of the SAFE strategy, a vaccine is needed. The most advanced trachoma vaccine candidate is NIAID’s live-attenuated (plasmid-deficient) trachoma vaccine, which is currently in pre-clinical development.
Clinical diagnosis of trachoma is not always reliable, and current diagnostic tests are expensive and complex. Studies have shown that an antibody-based multiplex assay could be used to diagnose trachoma in low-prevalence settings. One candidate, the Pgp3 LFA-cassette, has been evaluated in field studies in Nepal, showing high specificity (99%) but low sensitivity (40%).
Disease burden
- Deaths 2017 -
- DALYs 2017 301,761
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Tuberculosis
Tuberculosis
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an airborne disease that most commonly affects the lungs, and is the leading cause of death of any single infectious pathogen. Almost a quarter of the world’s population is estimated to be infected, but most TB cases are latent and non-infectious; around 5-15% will progress to active TB if left untreated. Active TB usually causes coughing, fever and weight loss, and is highly infectious. TB is especially dangerous for people with low immunity, and is a leading cause of death among people with HIV/AIDS. There is also growing resistance to existing treatments.
R&D needs
Current TB drug regimens are complex and can require up to two years of daily treatment, leading to poor compliance, drug resistance and treatment failure. New drugs are needed that can shorten the duration of treatment, are effective not only against drug-sensitive TB but also against multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB), are suitable for all age groups, are safe to use in conjunction with HIV treatments, and can be used in new treatment paradigms, including treatment of latent TB and MDR-TB prophylaxis.
The world’s first fixed-dose combination treatment specifically designed for children, HRZ/HR, received WHO prequalification in 2017 and has since been rolled out in over 80 countries, while in 2019 the FDA approved the all-oral, once daily BPaL regimen (including the novel drug pretomanid in combination with bedaquiline and linezolid), which promises to dramatically shorten the duration of treatment for XDR-TB and treatment-tolerant or non-responsive MDR-TB. TB Alliance is also preparing clinical trials for paediatric formulations of pretomanid. There are several ongoing Phase III trials of various regimens for the treatment of drug resistant TB based on new and approved drugs, including NeXT, SimpliciTB, TB PRACTECAL and endTB; and a further Phase III clinical trial (PHOENIx MDR-TB) evaluating the effectiveness of prophylactic delamanid in protecting household contacts from contracting MDR-TB. There are also two Phase III trials (SimpliciTB and TBTC Study 31) currently examining shorter duration regimens for drug-sensitive TB.
The existing TB vaccine (BCG) provides limited protection against pulmonary disease in adults. A vaccine which provides protection against all forms of TB in all age groups is needed. Results from two recent TB vaccine efficacy trials were mixed: M72/AS01E showed an efficacy of 54% among TB-infected adults, and even higher levels in participants 25 years of age or younger, while H4:IC31 showed no statistically significant protection. A recombinant vaccine, VPM1002, has completed Phase II trials to assess safety and immunogenicity in neonates (including those exposed to HIV), and is in Phase II/III trials for prevention of TB recurrence in adults. Therapeutic vaccines (which now fall under the expanded ‘biologics’ category in this year’s G-FINDER report), are a potential tool to simplify and shorten TB treatment; at least one such candidate (RUTI) targeting MDR-TB is currently in Phase II clinical trials.
There is a need for more effective and appropriate point-of-care TB tests, tests to diagnose TB in children, and tests for drug resistance and susceptibility. Cepheid’s next generation molecular test, Xpert MTB/RIF Ultra, showed significantly better performance than its predecessor, and the WHO is expected to provide a policy update on its use. Two new types of diagnostic technology – genotypic drug resistance testing and centralised high-throughput testing platforms – are currently under development.
Disease burden
- Deaths 2017 1,167,623
- DALYs 2017 44,666,899
Emerging infectious diseases
Policy Cures Research began gathering data on R&D targeting emerging infectious diseases in response to the 2014 West African Ebola epidemic. In our 2015 G-FINDER survey and report (looking at investments made in 2014), this focused exclusively on Ebola R&D. Since then, we have adopted a progressively broader scope in each subsequent year, determined in consultation with the G-FINDER Advisory Committee and a separate emerging infectious diseases Expert Advisory Group.
Our current definition of emerging infectious diseases closely follows the list of priority diseases endorsed by the 2018 World Health Organization research and development Blueprint for action to prevent epidemics (the Blueprint), including its expansion in early 2020 to include COVID-19. The survey also gathers data on emerging infectious diseases and disease groups not included in the Blueprint priority list, including several pathogens which have been considered for inclusion.
Compared to our neglected disease definition, our definition of emerging infectious diseases has very few restrictions. R&D for almost all product development categories (drugs, vaccines, biologics, and diagnostics) is included without further restrictions for all priority emerging infectious diseases pathogens, as is basic research. R&D for vector control products is included where relevant.
A comprehensive explanation of all current inclusions, exclusions and restrictions, as well as changes to the scope over time, is provided by the emerging infectious disease scope document.
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Crimean-Congo haemorrhagic fever and Rift Valley fever
Crimean-Congo haemorrhagic fever and Rift Valley fever
Crimean-Congo haemorrhagic fever (CCHF) and Rift Valley fever (RVF) are caused by bunyaviruses, and are transmitted to humans via insect vectors (ticks of the genus Hyalomma and Aedes/Culex mosquitoes respectively), as well as zoonotic transmission from infected animal tissues. Reservoir hosts of the CCHF virus include a range of animals – such as cattle, sheep, goats and hares – which become infected by the bite of infected ticks but do not manifest the disease. Human-to-human transmission of CCHF can occur upon direct contact with virus-infected bodily fluids. In contrast, RVF can cause disease in livestock, with transmission to humans upon contact with virus-infected blood or organs. Human infection from bites of virus-infected mosquitoes is less common. There is no documented evidence of human-to-human transmission of RVF.
CCHF and RVF have similar symptoms to other viral haemorrhagic fevers, making early clinical diagnosis challenging, including fever, sensitivity to light, fatigue and dizziness, sometimes progressing to haemorrhage, organ failure and shock. Less than one in ten RVF cases progress to severe disease, manifesting as ocular, meningoencephalitis, and/or haemorrhagic fever.
CCHF is endemic everywhere its tick vector is located, including sub-Saharan Africa, South and Central Europe, the Middle East and Central Asia. In contrast, RVF is mainly limited to sub-Saharan Africa, and, since 2000, the Middle East. CCHF cases occur sporadically, primarily in rural areas, with a case fatality ratio of up to 40%. There have been more than a dozen RVF outbreaks since 2000, with an average case fatality ratio of 1%, although this can vary widely depending on the outbreak – reaching up to 50%. Given the central role of livestock in contributing to human disease, CCHF and RVF are both exemplars of the need for a One Health approach to developing new countermeasures.
CCHF and RVF have similar symptoms to other viral haemorrhagic fevers, making early clinical diagnosis challenging. Initial symptoms of both may include fever, fatigue, dizziness, and muscle aches with progression to severe disease with bruising, haemorrhage, organ failure and shock. Whereas most cases of RVF are asymptomatic or mild with only one in ten progressing to severe disease and haemorrhagic fever occurring in less than 1% of all cases, the case fatality rate from CCHF can range from 10% up to 40%.
CCHF is endemic in regions where the tick vector is located, including in sub-Saharan Africa, South and Central Europe, the Middle East and Central Asia. The geographic distribution of RVF is mainly limited to sub-Saharan Africa, however, since 2000 it has also spread to the Middle East. There have been more than a dozen RVF outbreaks since 2000, with 4,830 cases and 967 deaths recorded as of June 2018.
R&D needs
With no approved drugs, CCHF case management relies on supportive care. Ribavirin is widely prescribed based on in vitro testing, though the clinical evidence is inconclusive. The therapeutics pipeline is weak, with no CCHF candidates in the clinical phase. Broadly neutralising and non-neutralising mAbs are undergoing study, while favipiravir, a broad-spectrum RNA inhibitor has shown promising results in pre-clinical studies. Conclusive evidence on the efficacy of ribavirin and mAbs, along with the in vitro screening of new and existing antivirals is urgently needed.
A cell culture-based vaccine, KIRIM-KONGO-VAX, is the only CCHF investigational candidate currently in clinical development. Effective CCHF vaccines targeting humans and animal reservoirs are urgently needed.
Suspected CCHF samples are primarily processed by large laboratories, using in-house assays. Point-of-care molecular tests are not currently available, and there are no RDTs under development. The unreliability of using serological biomarkers in the initial phase of infection further complicates the development of an appropriate diagnostic tool. As with vaccines, diagnostics are also needed to monitor the spread of disease in animals.
RVF is typically a self-limiting febrile illness. In the absence of approved drugs, supportive therapy is the only option for managing patients with severe RVF. While no RVF drug candidates have reached clinical development, two broad-spectrum antivirals – a non-nucleoside inhibitor (favipiravir) and a nucleoside analogue (BCX4430) – are in pre-clinical development.
In late 2019, WHO published a draft RVF vaccine TPP calling for a trio of vaccines for control of RVF: a human vaccine for reactive/emergency use and one for long term protection for high risk people, and an animal vaccine for prevention of transmission. There are several veterinary vaccines in routine use to prevent RVF infection in livestock, albeit with concerns about safety, effectiveness and the potential for reassortment with wild strains. To date, only two RVF vaccine candidates, one inactivated (TSI GSD 200) and one live-attenuated (MP12), both developed by the US DOD, have undergone human testing. All candidates based on novel approaches such as DNA and viral-vectors remain in the pre-clinical stage.
There are currently no point-of-care molecular tests in late-stage of development and no validated commercial serology assay for human specimens.
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Ebola and Marburg
Ebola and Marburg
Ebola disease and Marburg disease are caused by the Ebola and Marburg filoviruses. Six species of the genus Ebolavirus have been identified: Zaire (EBOV), Bombali, Bundibugyo, Reston, Sudan, and Taï Forest; the genus Marburgvirus contains Marburg virus and Ravn virus. Bats are known reservoirs of the Marburg virus and suspected reservoirs of Ebola viruses. Human outbreaks begin following exposure to blood or secretions of infected animals, such as fruit bats, gorillas, and monkeys. Once introduced into the human population, human-to-human transmission primarily occurs through contact with virus-infected bodily fluids. Their symptoms are similar and may include fatigue, headache, dizziness, vomiting and diarrhoea, and, in severe cases, haemorrhage, organ failure and shock. Ebola’s average case fatality ratio is around 50%, but can vary between 25% and 90%.
Since 1976, there have been 27 known African Ebola outbreaks, 11 of which were in the Democratic Republic of Congo (DRC). The largest recorded outbreak of Ebola occurred in 2013-16 in West Africa, affecting Guinea, Sierra Leone, and Liberia, causing more than 28,000 infections and 11,000 deaths (a confirmed-case fatality ratio of 63%). Between August 2018 and June 2020, there was a further outbreak focused in North Kivu, DRC, which was declared a Public Health Emergency of International Concern by the WHO in July 2019. It represents the second-largest Ebola epidemic on record, with more than 3,400 infections and 2,200 deaths.
Since its discovery in 1967, there have been more than a dozen recorded outbreaks of Marburg, mostly in Central Africa, and most recently in Uganda in 2017. Average Marburg case fatality ratio is around 50%, varying between 24% and 88%. The largest recorded Marburg outbreak occurred in 2004-2005 in Angola (252 known cases with 227 deaths; 90% case fatality ratio).
R&D needs
Before 2014, almost all Ebola pipeline candidates were at the pre-clinical stage. Today, following a coordinated global effort, there are active pipelines for diagnostics, drugs and vaccines, with multiple candidates in late-stage clinical development.
In December 2019, ERVEBO became the first FDA-approved Ebola vaccine, and it is now licensed for use in four African countries. It was also a vital part of the outbreak response in the North Kivu, DRC Ebola epidemic – the first Ebola outbreak in which a vaccine was widely deployed – with approximately 300,000 people vaccinated. Also deployed during this outbreak was another candidate regimen, Ad26.ZEBOV/ MVA-BN-Filo, which was still under investigation at the time. Now known as Zabdeno and Mvabea, it was approved by the European Commission in July 2020. It is the only one of the advanced candidates to target multiple species of Ebolavirus and Marburgvirus.
During the 2014 Ebola outbreak, the absence of bench-top or point-of-care diagnostic tools meant that laboratory-designed tests were the only tool available for confirmatory diagnosis. Since then, the Ebola diagnostics pipeline has improved significantly, with multiple point-of-care molecular and rapid diagnostic tests now available. The increased speed at which field laboratories with molecular testing capabilities became functional (from months to days) in the 2018-2020 DRC outbreak is testimony to the remarkable progress made in the past five years.
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Lassa fever
Lassa fever
Lassa fever is caused by the Lassa virus (LASV), an arenavirus which primarily spreads to humans through contact with the urine or faeces of infected rodents (Mastomys natalensis). Human-to-human transmission can also occur through direct contact with LASV-infected bodily fluids. Symptoms of Lassa fever are non-specific, making it difficult to distinguish from other viral haemorrhagic fevers and febrile diseases such as malaria, typhoid fever and bacterial sepsis. While the majority of cases of Lassa fever are mild, in severe cases, it may cause facial swelling, fluid in the lung cavity, liver and kidney abnormalities, haemorrhage, and death. Lassa fever is endemic in parts of West Africa including Sierra Leone, Liberia, and Nigeria, where an estimated 100,000 to 300,000 infections and approximately 5,000 deaths occur annually.
Due to a lack of accurate diagnostic tests, Lassa fever often goes undetected. During the 2018 outbreak, for example, an investigation began after reports of a cluster of deaths among healthcare workers from a single facility, revealing nosocomial transmission of LASV as the cause of death – but not until more than two weeks had passed between the index case entering the facility and accurate diagnosis. For LASV, correct and timely detection can single-handedly change the course of an epidemic, especially since early treatment can significantly decrease fatality.
R&D needs
Easy-to-use diagnostic tests are needed to accurately detect LASV, ideally across the disease spectrum and for multiple lineages. Most currently available RDTs and immunoassays are limited to use in research, while the three existing CE-IVD marked molecular tests require a health facility with bio-containment capabilities. The recombinant Lassa virus (ReLASV®) Antigen Rapid Test underwent field evaluation in 2018, performing better than the most robust qPCR currently available and signalling a promising advancement in clinical management of Lassa fever patients. More recently, a CRISPR-based point-of-care test with the ability to capture 90% LASV diversity was successfully deployed during recent outbreaks in Sierra Leone and Nigeria.
Ribavirin, in conjunction with supportive therapy, is the current mainstay of LASV case management and pre-and post-exposure-prophylaxis (PrEP/PEP), although there is no conclusive evidence that ribavirin is effective for PEP. However, ribavirin is most effective when given intravenously and within the first six days of illness, so what is needed is a shelf-stable oral therapeutic agent, which is effective against multiple LASV lineages. In June 2020, LF-535, a novel entry inhibitor completed a first-in-human Phase I trial.
More study is also warranted to confirm the mechanism of action, indications and optimal routes of administration of the current ribavirin-based treatment, which is backed by only one non-randomised study. A better understanding of ribavirin could open up new avenues for discovering new therapies, including combination treatments.
There is currently no approved vaccine for Lassa fever, reflecting the challenges associated with its development: genetic diversity of the pathogen; poorly-understood correlates of protection; differences in safety profile between preventive and reactive use; observed potential for immune-mediated neurological complications; and necessity for both cell- and antibody-mediated response for optimal protection. Multiple candidates based on live-attenuated, VSV-vectored or DNA platforms are in pre-clinical development, and are mostly reliant on antigen derived from a single strain of LASV. Two candidates have also entered Phase I trials, including MV-LASV – a recombinant live attenuated viral vectored vaccine and a DNA vaccine – INO-4500.
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Coronaviruses (MERS, SARS and COVID-19)
Coronaviruses (MERS, SARS and COVID-19)
Coronaviruses (CoVs) are a large family of viruses that cause respiratory illness in humans, ranging from mild common cold symptoms to the potentially fatal Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and, of course, COVID-19. The intermediary hosts and zoonotic source of human infection by MERS-CoV are dromedary camels, while SARS-CoV is transmitted by palm civets; however, the natural reservoir for both CoVs is thought to be bats. MERS infection can occur either through contact with infected dromedaries or upon ingestion of camel products; nosocomial infection of MERS is also possible, although sustained human-to-human transmission is limited. SARS is spread from human-to-human through respiratory droplets. The symptoms of MERS and SARS are non-specific, and both may include headache, fatigue, fever, sore throat, runny nose, and diarrhoea; and, in severe cases, pneumonia, respiratory failure and death.
MERS-CoV was first detected in 2012 in the Kingdom of Saudi Arabia (KSA). Since 2012, there have been at least 2,499 confirmed MERS cases and 861 deaths (34% case fatality ratio) across 27 countries, the vast majority from the KSA. Outside of the Middle East, MERS has been detected in North America, Europe and Asia, where a 2015 nosocomial outbreak in South Korea resulted in 186 cases and 38 deaths.
SARS was first detected during the 2002-2003 epidemic in China – its first and last outbreak – which spread to 26 countries, resulting in 8,098 cases and 774 deaths (10% case fatality ratio).
SARS-CoV-2 – the virus which causes COVID-19 – was first detected in Wuhan, China in late 2019. Following its global spread in early 2020, it was recognised as as a pandemic by the WHO on 12 March 2020. As of the beginning of June, SARS-CoV-2 has been responsible for more than six million cases and 380,000 deaths worldwide.
R&D needs
Currently, there are no approved drugs or vaccines targeting MERS-CoV infection. An overarching challenge impeding all aspects of research is the weakness of the available animal models in accurately mimicking the disease in humans.
Drawing on the experience with SARS, initial therapies for MERS case management included the use of convalescent plasma and ribavirin in conjunction with various interferons (IFNs). Although the subsequent in-vitro studies of ribavirin in combination with IFNs appeared promising, in vivo studies showed no clear effect. Based on the current understanding of MERS pathogenesis, a combination antiviral and antibody therapy seems more appealing. Reflecting this view, a combination of a repurposed drug (lopinavir/ritonavir) and a biologic (IFN-β1b) completed Phase IIb/III trials in 2020. Additionally, a human polyclonal antibody (SAB-301) and a cocktail of human monoclonal antibodies (REGN3048-3051) have completed Phase I trials, while remdesivir, a novel broad-spectrum antiviral with a proven safety profile, is in pre-clinical evaluation.
Creation of an accurate, rapid test to diagnose MERS is rendered challenging by the need for specimens taken from the lower respiratory tract. Consequently, there are currently no point-of-care molecular tests or RDTs available for use outside of research, requiring that suspected samples be sent to a laboratory with biosafety capabilities.
R&D needs for COVID-19 will be added in 2021.
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Nipah and henipaviral diseases
Nipah and henipaviral diseases
Nipah virus encephalitis is a neurological and respiratory zoonotic disease caused by the Nipah virus (NiV). Along with Hendra virus (HeV), which causes respiratory illness in horses and humans, NiV belongs to the genus Henipavirus. Fruit bats belonging to the Pteropus genus are the natural hosts of both NiV and HeV, and have a broad geographic range. Transmission to humans can occur through contact with infected bats, food contaminated by bat secretions, as well as contact with infected intermediate hosts (e.g. pigs and horses) and other NiV/HeV-infected humans. Symptoms include fever, headache, drowsiness, disorientation, altered consciousness; severe cases may progress to encephalitis, seizures and coma.
The first recorded NiV outbreak occurred in 1998 among pig farmers in Malaysia and Singapore, leading to 265 cases and 105 deaths (40% case fatality ratio). Since the first outbreak, there have been more than 20 human outbreaks of NiV infection in Bangladesh and India, with at least 346 cases and 260 deaths overall. The most recent outbreak occurred in May 2018, in Kerala, India, with 18 confirmed cases and 16 deaths (89% case fatality ratio). In 1994 in Australia, HeV spilled over from bats to horses and later to humans; since then there have been at least seven human cases and four deaths. There is also serological evidence of NiV cross-neutralizing antibodies in both bat and human populations in sub-Saharan Africa. Despite no recorded henipaviral outbreaks in humans, this evidence suggests that spill-over events have indeed occurred in sub-Saharan Africa and increased surveillance efforts are warranted.
During the 2018 Indian outbreak, there was only a single episode of animal-to-human spill-over; the driver of the epidemic was human-to-human transmission, with the index case transmitting the disease in 19 out of the 22 cases. In such situations, timely detection and prompt utilisation of PEP are vital for outbreak control.
R&D needs
There are no approved therapies for managing NiV; treatment consists of supportive care, and, during one outbreak, off-label usage of ribavirin. Results from animal studies are not promising; NiV infects the central nervous system, making it challenging to generate the optimal therapeutic class able to cross the blood-brain barrier. During the 2018 outbreak in India, authorities deployed an experimental monoclonal antibody (m102.4) which had completed Phase I clinical trials and had previously been used in humans as a PEP for HeV exposure. Immunomodulation is another approach currently being explored; early results show poly-IC12U as effective in neutralising NiV but it needs further evaluation using an improved animal model.
Considering the lethal nature of NiV, the preferred vaccine development strategy is a live-vectored, rather than live-attenuated, approach, such as the adeno-associated virus, vaccinia-virus or VSV. In early 2020, HeV-sG-V became the first NiV vaccine candidate to enter human, Phase I trials. Delivering cross-protection against different strains of NiV though, remains a significant challenge. Other promising vaccine approaches for henipaviruses include sub-unit vaccines (shown to be protective against HeV in horses), as well as reservoir-targeted vaccines.
Misdiagnosis was a significant factor in the length of the 1998-99 Malaysian NiV outbreak. Even in the absence of an effective vaccine, timely and accurate pathogen detection can help in deploying effective countermeasures, such as Malaysia’s targeting of animal-to-human spill-over. Developing an appropriate diagnostic test is challenging due to poorly understood disease kinetics (in CSF, saliva and other fluids), cross-reactivity with different strains especially in animals, and high rates of false-negative results from IgM serology-based tests. Consequently, there are currently no accurate point-of-care molecular tests or RDTs available or in development, with only specialised laboratories handling the isolation of NiV in suspected samples.
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Zika
Zika
The Zika virus (ZIKV) is a mosquito-borne flavivirus related to dengue, yellow fever, Japanese encephalitis and West Nile viruses. ZIKV is primarily transmitted by Aedes mosquitoes, which can also transmit Chikungunya, dengue, yellow fever and West Nile viruses. Human-to-human transmission of ZIKV occurs through sexual contact, blood transfusion, as well as from mother to foetus during pregnancy. ZIKV infection is usually asymptomatic, with mild symptoms including fever, muscle and joint pain, rash, conjunctivitis, and headache. Severe complications arise due to ZIKV-inducing Guillain-Barré syndrome (GBS) – an autoimmune condition – in adults, or upon infection during pregnancy, resulting in congenital Zika syndromes (CZS), which include microcephaly, central nervous system malformations and a host of other neurological abnormalities in infants. Between 5% and 15% of infants born to ZIKV-infected women may present with CZS.
Aedes mosquitoes are widespread, with local transmission of ZIKV reported in Africa, South-East Asia, the Pacific region, the Americas and Europe. Although ZIKV was first reported in Uganda in 1947 and spread to Asia in the 1960s, the first significant outbreak was reported in Micronesia in 2007 (49 confirmed GBS cases and no deaths). In 2013, another outbreak began in French Polynesia, spreading to other Pacific Islands, with 30,000 suspected cases (coinciding with a spike in cases of GBS). In 2015, the largest ever Zika outbreak occurred in Brazil, and soon spread elsewhere in the Americas and beyond. At the end of this outbreak in late 2016, there were 128,793 confirmed cases of ZIKV infections reported, with 2,289 newborns confirmed with CZS.
R&D needs
There is no vaccine or specific treatment for ZIKV infection. Research is ongoing for potential therapies, for vaccines to prevent ZIKV infection or CZS, and for diagnostic tests.
The updated 2019 ZIKV vaccine development roadmap adds the requirement that an ideal prospective vaccine be appropriate for endemic as well as outbreak settings. Vaccines under consideration include both conventional (inactivated, live-attenuated and recombinant subunit) and more novel (DNA, messenger RNA, self-replicating RNA and viral-vectored) approaches. The most advanced candidates use these novel platforms, with a DNA vaccine candidate (VRC 705) having completed Phase II trials in October 2019. Multiple additional vaccine candidates are currently in Phase I trials. While the ZIKV vaccine pipeline has progressed significantly in the last three years, designing large scale trials remains challenging due to the broad-spectrum of clinical manifestations of the disease and the infeasibility of using CZS as the primary endpoint for measuring clinical efficacy. Alternative approaches, such as accelerated regulatory pathways with immune correlates or surrogates as endpoints are under consideration.
Therapeutic agents play a key role as a countermeasure for ZIKV. The indication includes both therapeutic use for treating intra-uterine infection and prophylactic use for pre- and post-exposure. Even with the licensure of a ZIKV vaccine, drugs can play a valuable preventive role in areas of low endemicity. Currently, two biologics – a human mAb (Tyzivumab) and an immunoglobulin (ZIKV-IG/NP-024) – are the only therapeutics in clinical development. The biggest challenge impeding ZIKV therapeutic R&D is developing medications for use during pregnancy. The diagnostic pipeline for ZIKV has improved considerably since 2015, with multiple point-of-care or near-POC molecular and serological assays already approved by the US FDA and WHO under both emergency use and standard pathways.
Aedes mosquito control programmes in ZIKV affected countries – including targeted residual spraying, larval control and space spraying – must overcome urban outdoor transmission and high levels of infestation, which render the techniques used against malaria, such as bed-nets and indoor residual spraying, ineffective. In 2016, the WHO Vector Control Advisory Group (VCAG) reviewed five new approaches: Wolbachia-based microbial control; genetic manipulation; sterile insect technique (SIT); radiation-based sterility; vector traps; and attractive toxic sugar baits. SIT is undergoing entomological efficacy trials, while the other four techniques are undergoing epidemiological efficacy trials alongside another new approach – a transfluthrin passive emanator (spatial repellent).
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Disease X
Disease X
Along with the six Blueprint disease groups, the WHO has prioritised R&D preparedness for ‘Disease X’, which “represents the knowledge that a serious international epidemic could be caused by a pathogen currently unknown to cause human disease”. Funding for Disease X in this report includes the categories outlined below.
R&D needs
Fundamental research covers cross-cutting studies to increase understanding of multiple EIDs, which is not yet directed towards a specific technology. It includes research on disease surveillance and epidemiology, animal-to-human spill-over events, and pathogen biology. Viral surveillance studies in bats, for example, led to the 2018 discovery of Bombali virus, a new species of Ebolavirus. Basic biology and pathogenesis studies using prototype viruses help define target antigens and develop technology assays; for example, understanding of molecular structures across the flavivirus family was instrumental in rapid translational research during the recent Zika outbreak. Almost all EIDs are epizootic in nature, making a ‘One-Health’ approach essential to understanding wildlife/animal-human interface and drivers of spill-over.
Vaccine platforms include technologies and processes that allow the generation and presentation of immunogens applicable to multiple pathogens. Pre-existing safety and immunogenicity data and validated manufacturing practices allow rapid production and testing of platform-based vaccines. During the ongoing COVID-19 outbreak, a vaccine candidate based on an mRNA platform was identified in just 42 days – a pharmaceutical industry record. Other leading technologies include viral vector- and nucleic acid-based (‘plug and play’) platforms. The most advanced platform-backed EID vaccine candidates include a prime/boost viral vector-based Ebola vaccine (Ad26.ZEBOV/MVA-BN-Filo) and a DNA-based ZIKV vaccine (VRC-ZKADNA090-00-VP).
Adjuvants and immunomodulators are compounds or structures formulated to improve efficacy or duration of vaccine immunogens. Adjuvants play a key role in sub-unit or purified antigen-based vaccines, which lack immunostimulant properties. Current adjuvants have several drawbacks, such as inability to induce a cellular immune response. Adjuvants in development include synthetic TLR agonists, nanoemulsions and synthetic DNA formulated with alum – such as the alum-adjuvanted purified inactivated Zika virus vaccine currently in development.
Therapeutic platforms are adaptable technologies used for developing gene- and immune-based drugs to prevent, cure or treat EIDs. Current therapeutics platforms in development include DNA- and RNA-based monoclonal antibody (mAb) platforms and human polyclonal antibodies (pAbs) from transchromosomic bovine systems.
New delivery technologies and devices simplify administration of vaccines or drugs. Appropriate delivery is vital to achieving the full therapeutic or prophylactic potential. Delivery technologies in development include a polymeric microneedle system for DNA vaccines and nanoparticle-based drug delivery systems.
General diagnostic platforms are rapidly adaptable tools for detecting pathogens for which commercial diagnostic tests are unavailable. During recent Ebola and Zika outbreaks, diagnostic platforms allowed rapid development of highly-sensitive field-appropriate tests. Technologies used for platform-based diagnostics include molecular (reference or point-of-care test), high-throughput testing based on real-time PCR and lateral flow rapid diagnostic assays. Diagnostic tests in development based on these technologies include real-time RT-PCR kits, RT-LAMP, antigen and antibody-based assays, and cartridge-based point-of-care molecular tests.
Broad-spectrum antivirals include small molecule compounds, which inhibit essential machinery of multiple virus families. The development pipeline includes favipiravir, an RNA-dependent RNA polymerase inhibitor, and UV-4B, an alpha-glucosidase inhibitor.
The multi-disease vector control product category captures funding targeting vectors capable of transmitting several different diseases or unspecified vectors. These include altering mosquito populations using genetic tools and sterile insect technique, chemical and genetic screens to identify molecules targeting Aedes aegypti mosquitoes, and Aedes-targeted Attractive Targeted Sugar Baits.
Sexual & reproductive health issues
After a one-off report on global funding for reproductive health published by Policy Cures in 2014, Policy Cures Research again began tracking annual funding for R&D for sexual & reproductive health issues in 2019 (when we collected 2018 data), this time with a broader scope. Our updated definition of sexual & reproductive health issues was determined through a multi-stage process, starting with an initial, broad stakeholder consultation with 46 of the world’s leading stakeholder organisations. Participants included major donors, NGOs, peak bodies and coalitions, and research and innovation organisations. An Expert Advisory Group comprising 23 global experts in sexual & reproductive health was then convened to refine our definition, which is reviewed annually with their input.
As with neglected diseases, our definition of sexual & reproductive health aims to capture R&D that is relevant to the sexual and reproductive health needs of people in low- and middle-income countries according to the following overarching criteria:
- The area is a significant health issue affecting people in low- and middle-income countries;
- There is a need for new products (i.e. there is no existing product, or improved or additional products are needed to meet the needs of people in low- and middle-income countries).
We maintain an ongoing consultation with the Expert Advisory Group for advice on how to apply our definition of sexual & reproductive health issues in particular contexts. Where there is disagreement between experts, their decisions are supplemented by advice from further technical and R&D experts.
Not all basic research and product types are included in our definition of sexual & reproductive health issues, and some are included only with restrictions. For example, chlamydia drugs are excluded because cheap and efficacious treatment with oral azithromycin already exists and is appropriate for use in low- and middle-income settings; while syphilis drugs are included but restricted only to those that target latent, tertiary, maternal or congenital syphilis, since drugs to treat early stage syphilis are effective and readily available.
We also include platform technologies, where the product could feasibly be used for both sexual & reproductive health issues or neglected diseases, such as general drug or vaccine delivery platforms. HIV and hepatitis B are part of both our neglected disease and our sexual & reproductive health definitions, and may therefore appear in our analysis covering either of these disease areas.
A comprehensive explanation of all current inclusions, exclusions and restrictions is provided by the sexual & reproductive health scope document.
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Contraception
Contraception
People everywhere have the right to access safe, effective contraception that fits their lifestyle, needs and preferences. Despite significant improvements in availability of modern methods, the greatest gaps remain in LMICs, where an estimated 218 million women of reproductive age still have an unmet need for modern contraception, contributing to 111 million unintended pregnancies each year. Fully meeting this need would avert 76 million unintended pregnancies, 46 million induced abortions – approximately half of which are unsafe – and 70,000 maternal deaths annually.
R&D needs
There are many reasons people in LMICs may not use contraception, only some of which relate to product gaps. Lack of awareness of modern methods; opposition to use; and an inability to source or afford contraception can all contribute. In other cases, an R&D gap is the problem. Real or perceived side-effects, health risks, or inconvenience of available methods are the most common reasons cited by women for not using contraception, despite wanting to space or limit pregnancy.
Currently available modern contraceptive methods are limited to options that have changed little over decades, are largely hormonal, and only a few of which are user-controlled. Short-acting methods (monthly pills, vaginal rings, and three-monthly DMPA injectables) offer effective short-term protection from pregnancy, and for pills and rings, are user-controlled. However, all are hormonal, require regular repeat actions to be effective, and some (rings) require cold-storage. In contrast, long-acting reversible methods of contraception (LARCs) offer long-term protection from pregnancy – up to five years for subcutaneous hormonal implants and levonorgestrel-releasing intra-uterine systems (LNG-IUS), and 10 years for copper intra-uterine devices (IUDs) – with minimal user interaction. However, they require skilled health workers to insert and remove, and can have untenable side-effects, particularly heavy menstrual bleeding associated with copper IUDs – currently the only highly effective reversible non-hormonal contraceptive available besides barrier methods. Permanent contraception requires skilled, surgical intervention, while on-demand methods are limited to condoms, diaphragms, or emergency contraception. For men, there are just two modern contraceptive options: condoms and vasectomy.
Several new contraceptives have recently become available or are in late-stage development, including Medicines360’s Liletta hormonal IUS (Avibela in LMICs), now with a six-year indication and in ongoing Phase III trials for use up to 10 years; Sayana Press, the three month, low-dose DMPA-SC self-injectable, now in implementation studies to support introduction; and Annovera, the first heat-stable vaginal ring with efficacy up to a year, approved by the US FDA in 2018. Although a smaller area of research, R&D for non-surgical permanent contraception for women exists, with some products in clinical trials, such as Femasys’ FemBloc Permanent Contraceptive System, a temporary biopolymer that causes scarring and permanent closure of fallopian tubes.
Male contraceptive R&D focuses on novel hormonal combinations to block sperm production and non-hormonal approaches to interrupt sperm production, transport, motility, or fertilisation. Some promising candidates include Contraline’s vas-occlusion product Adam, a polymer hydrogel injected into the vas deferens, with clinical trials anticipated for 2020, and the US NIH/NICHD and Population Council’s Nestorone and Testosterone (NES/T) gel, a daily transdermal gel in Phase II clinical trials.
In 2020, the scope for contraception was expanded to include biologics and vaccines. Details on unmet needs for his area will follow.
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Hepatitis B
Hepatitis B
Hepatitis B is a disease of the liver caused by infection with the hepatitis B virus (HBV), and can be either acute or chronic. Acute infection is more common and more severe in adults and adolescents, but the likelihood of developing chronic disease is dramatically higher in infants and children under five. As many as 80-90% of children infected during the first year of life will progress to chronic disease, but this falls to less than 5% for otherwise healthy adults. Almost all of the burden of HBV-related disease is due to chronic hepatitis B – largely due to cirrhosis or liver cancer – following infection transmitted from mother to child at birth or acquired in early infancy. Although HBV is prevalent worldwide, the burden of hepatitis B is disproportionately high in low- and middle-income countries, and co-infection with HIV is not uncommon. Hepatitis B product R&D was added to the G-FINDER scope in the 2019 report, restricted to LMIC use and applicability.
R&D needs
An effective vaccine against HBV exists, with the current HBV preventive vaccine series (a dose at birth followed by two subsequent booster doses) providing protection in more than 95% of vaccinated infants. Vaccination against HBV remains the main strategy for the control and elimination of hepatitis B, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal.
There is also a lack of data that could be used to inform population approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs, suggesting a need for additional basic research.
Oral therapy with recommended first-line HBV treatments such as entecavir or tenofovir alafenamide is generally safe and well tolerated, and can result in virological suppression in more than 95% of patients. Long-term treatment and viral suppression is associated with regression of cirrhosis and reduced incidence of hepatocellular carcinoma, but seroclearance is uncommon and lifelong drug treatment is required for most patients. At least two candidates are in clinical development for functional cure of hepatitis B – defined by sustained undetectable surface antigen levels, regardless of seroconversion – including inarigivir in Phase II, and HS-10234 in Phase III. Novel therapies aimed at achieving HBV seroclearance are also in development, including immune stimulators, and other host-targeting bio-therapeutics.
Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis; rapid diagnostic tests (RDTs) are available as cheap and generally accurate alternatives to laboratory-based immunoassays, although both may fail to identify low HBsAg concentrations, for example in HIV co-infection. However, for confirmation of diagnosis, treatment monitoring and detection of drug resistance, there is a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load. Two assays have recently been developed for POC molecular platforms – Cepheid’s Xpert HBV VL and Molbio Diagnostics’ Truenat HBV VL – but neither is currently WHO-prequalified and cost may remain a barrier to access., Another molecular test designed explicitly for low-resource settings, DRW’s SAMBA POC platform, has HBV qualitative and semi-quantitative assays in early-stage development.
Disease burden
- Deaths 2017 741,267
- DALYs 2017 23,752,066
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HIV/AIDS
HIV/AIDS
HIV continues to be a major public health issue, with almost 40 million people living with the virus as of 2018, the majority in LMICs. The virus attacks and destroys CD4 cells in the human immune system; without treatment, infected individuals become increasingly susceptible to other diseases, and eventually develop acquired immune deficiency syndrome (AIDS). People with AIDS often die from opportunistic infections like tuberculosis or cryptococcal meningitis, or cancers like Kaposi’s sarcoma.
R&D needs
There is currently no vaccine against HIV, and the rapid mutation of the virus poses a significant challenge to development. To date no vaccine candidate has proved able to match even the 31% efficacy achieved in the 2009 RV144 Thai Phase III clinical trials. There are currently two large HIV vaccine efficacy trials underway: HVTN 706, a global Phase III HIV vaccine efficacy trial of mosaic immunogens; and HVTN 705, a Phase IIb trial of Janssen’s prime-boost-based regimen. A third vaccine trial – HVTN 702, a Phase IIb/III trial investigating a modified version of the RV144 vaccine regimen – was halted in early 2020 due to non-efficacy. Several other candidates are currently in Phase I and II trials, including NIAID’s broadly neutralising anti-HIV antibody (bNAb) candidate, VRC01, which is in Phase IIb.
Therapeutic vaccines – including bNAb-based approaches, which are designed to control HIV infection by boosting the body’s natural immunity – are also being investigated for immunotherapy, including VRC01LS/10-1074, a dual long-acting bNAb currently in Phase II. Plasmid and viral vectored DNA vaccines are also among the therapeutic vaccine candidates currently in Phase I and II clinical trials.
Despite advances in HIV therapeutics, R&D gaps for HIV drugs persist in LMICs, including paediatric formulations or long-acting injectable drugs for PrEP, with promising progress underway. The Drugs for Neglected Diseases initiative (DNDi) is developing Quadrimune – a ‘4-in-1’ LPV/r-based taste-masked and heat-stable fixed-dose formulation designed specifically for children, which is currently under review by the FDA, with a Phase I/II trial ongoing in Uganda to generate evidence for worldwide scale-up. One long-acting injectable PrEP candidate, cabotegravir, is also in Phase IIb/III and III trials, and has demonstrated high efficacy when administered every eight weeks, with the blinded part of the study subsequently stopped as a result of this success. Following a Phase III trial, the long-acting injectable treatment regimen cabotegravir/rilpivirine was also granted approval by Health Canada in early 2020. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise. The International Partnership for Microbicides (IPM)’s monthly dapivirine ring has completed Phase III trials, and in July 2020 received a positive scientific opinion from the European Medicines Agency for use in women over 18 in LMICs.
Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially early infant diagnosis. There is progress towards robust, rapid point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates. These include early infant diagnostic tests (Alere’s q HIV-1/2 Detect and Cepheid’s Xpert HIV-1 Qual Assay), an assay for viral load monitoring (Hologic’s Aptima HIV-1 Quant Assay) and the first true point-of-care molecular test for resource limited settings (Abbott’s m-PIMA HIV-1/2 VL).
Disease burden
- Deaths 2017 938,891
- DALYs 2017 53,567,471
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HPV and HPV-related cervical cancer
HPV and HPV-related cervical cancer
Human papillomavirus (HPV) is the most common sexually transmitted infection, affecting more than one in ten women and one in five men worldwide. In sub-Saharan Africa, almost a quarter of women and more than three-quarters of men are infected. While most infections are asymptomatic and resolve spontaneously, infection with key HPV strains can result in pre-cancer and cancer. HPV infection is the causal agent in almost all cases of cervical cancer, which is the fourth most frequent cancer worldwide and a leading cause of cancer death in women. There were 570,000 new cases and 311,000 deaths from cervical cancer in 2018, with more than 85% of deaths occurring in LMICs. In the presence of HIV, HPV infection is also more likely to lead to earlier development of cervical cancer, taking as little as 5 years for invasive cervical cancer to develop.
R&D needs
In 2020 the WHO Executive Board recommended adoption of the first global strategy for elimination of cervical cancer as a public health problem. It recognises that primary prevention through HPV vaccination is highly effective, and that elimination is feasible with the three currently available (WHO prequalified) virus-like particle-based HPV vaccines – Gardasil, Cervarix and Gardasil 9 – with studies suggesting that effective implementation of HPV vaccine programs could prevent up to 90% of HPV-positive cancers of the cervix. To date, GAVI has played a leading role in facilitating low-cost access to these vaccines in 30 countries. However, these vaccines follow a 2-dose or 3-dose schedule, and do not protect against all high-risk HPV strains. They also do not eliminate pre-existing HPV infection, nor does any virus-specific drug treatment for HPV infection exist.
Current HPV vaccine research includes dose reduction and longer interval studies for existing HPV vaccines, as well as development of novel preventative vaccines with broader strain specificity. Therapeutic vaccines are also in development: the modified vaccinia virus Ankara (MVA)-based vaccine candidate TG4001 has reported histological clearance and promising efficacy while being well tolerated in Phase II trials, and is now being trialled in combination with a monoclonal antibody (avelumab) in Phase Ib/II; the EC’s IMMUNISA program, which is advancing Phase II CervISA-2 clinical trials of the synthetic long-peptide HPV therapeutic candidate ISA101b; and Inovio’s DNA-based vaccine candidate VGX-3100, progressing to Phase III.
While screening programs have shown huge benefit in HICs, current screening technologies reach only 5% of women in LMICs. Testing is costly and generally requires highly skilled technicians and laboratory infrastructure. Even current POC HPV DNA tests designed with LMIC needs in mind remain prohibitively expensive. Visual inspection with acetic acid for screening or diagnosis of cervical epithelial changes – the method used in most LMICs – is simple to use, but has poor specificity and high observer variability. A number of technologies are in development that aim to be simpler, more reliable and safe for POC use in LMICs, such as the POCKeT colposcope, TruScreen, and High-Resolution Micro-endoscopy. Automated Visual Examination (AVE) – which uses smartphone-based algorithms to improve visualisation approaches – and a one-hour HPV DNA test to speed-up high-specificity screening are being developed by Global Good.
In 2020, the scope for HPV was expanded to include devices to clear HPV infection or treat cervical lesions. Details on unmet needs for these areas will follow.
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Multipurpose prevention technologies (MPTs)
Multipurpose prevention technologies (MPTs)
Multipurpose prevention technologies (MPTs) are a class of biomedical intervention that simultaneously provide protection – in varied combinations – against pregnancy, STIs or HIV in a single product. MPTs can be preventative drugs (including microbicides) or devices in combination with a pharmaceutical element, offering protection for the following indications:
- Contraception + HIV prevention
- Contraception + STI prevention
- Contraception + STI + HIV prevention
- HIV + STI prevention
- Prevention from two or more non-HIV STIs (multiple STIs)
In LMICs, where the brunt of STIs, HIV and unintended pregnancies is felt, the prospective benefits of effective MPTs would be huge. The vast majority of all women with an unmet need for contraception are found in LMICs, while over two-thirds of all people living with HIV are found in sub-Saharan Africa alone. Over 90% of all STIs globally also occur outside of high-income countries.
MPTs that are appropriate for use in low-resource settings would allow sexually active people, particularly women and girls, the ability to protect themselves against multiple SRH issues with the convenience of one product, increasing efficiencies for users, as well as donors, procurers, and healthcare providers. Currently the only MPT available is the condom, and while highly effective, a diverse range of MPTs will be critical if the different needs of people in different circumstances and life stages are to be met, particularly women in LMICs.
R&D needs
An array of potential MPT products are possible, including intravaginal rings, vaginal or rectal gels or films, fast dissolving inserts, and barrier devices combined with drugs (hormonal or non-hormonal), with a number of these in pre-clinical and clinical development for various combined indications. These include IPM’s Phase I trial of the combined dapivirine and levonorgestrel vaginal ring, Orion Biotechnology OB-001 vaginal gel, PATH’s dissolving MPT Microarray Patch, and RTI’s biodegradable subcutaneous implant (SCHIELD), all offering dual protection from HIV and pregnancy. Evofem’s Multipurpose Vaginal pH Regulator candidate – an on-demand, non-hormonal vaginal gel previously known as Amphora – is in late-stage clinical development for protection from STIs (urogenital chlamydia and gonorrhoea) as EVO100, with the contraceptive indication recently approved by the US FDA under the brand name Phexxi; while Population Council’s vaginal and rectal gel PC-1005 (MIV-150 and zinc acetate in a carrageenan gel) is in Phase I for protection against HIV, HPV and HSV-2.
MPTs with combined action against all SRH indications within the MPT definition – HIV, STIs and pregnancy – include products such as CONRAD’s Phase II tenofovir and levonorgestrel vaginal ring for simultaneous protection from pregnancy, HIV and HSV-2, as well as Yaso Therapeutics vaginal gel Yaso-GEL, in advanced pre-clinical development offering protection from chlamydia, gonorrhoea, HIV, HPV, HSV-2 and pregnancy.
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Pre-eclampsia and eclampsia
Pre-eclampsia and eclampsia
Pre-eclampsia is a hypertensive disorder of pregnancy characterised by the onset of sustained high blood pressure and evidence of organ damage, most commonly proteinuria (kidney damage). By definition, it occurs after 20 weeks gestation, however the pathophysiological changes underpinning the disorder are known to start at very early stages of pregnancy. Pre-eclampsia presents along a spectrum of symptoms, but can result in severe morbidity, including stroke, cardiac arrest, kidney or liver failure, foetal growth restriction and preterm birth. It is one of the leading causes of maternal and neonatal mortality and morbidity, affecting 2%-8% of all pregnancies worldwide. Women in LMICs are seven times more likely to develop pre-eclampsia than women in HICs, with rates as high as 16.7% in parts of Africa.
R&D needs
The underlying causes of pre-eclampsia are only partially understood, and its screening, diagnosis, and management need improvement. Magnesium sulphate is used (and strongly recommended by WHO) for both prevention and treatment of eclampsia (seizures associated with severe pre-eclampsia). However, there are no currently available options to effectively prevent primary development of pre-eclampsia. Nor are there alternatives to manage it at early or late-stage beyond magnesium sulphate, which while effective, can have dosing limitations in LMICs where full (24 hour) regimens may not be feasible. Ultimately, the only definitive treatment is delivery. Current research on alternatives for prevention and management of pre-eclampsia focus largely on evaluation of re-purposed drugs, such as calcium supplementation, low-dose aspirin, as well as esomeprazole, the diabetic drug metformin, antihypertensives, and cholesterol-lowering statins. There is also some promising R&D into novel biologics to target the underlying causes or effects of pre-eclampsia, such as AMAG Pharmaceutical’s biologic AMAG-423, in Phase II clinical trials. Despite progress, there is a need for therapeutics to both prevent and manage pre-eclampsia at early onset, severe and eclamptic stages, particularly with LMIC needs in mind.
Diagnosis of pre-eclampsia is also challenging, historically reliant on symptomatic evaluation. The angiogenic factors PlGF and sFlt1 have performed well as markers to assist diagnosis of pre-eclampsia in clinical trials, with recent development of a number of PlGf-based tests for prediction of pre-eclampsia, including the DELFIA Xpress PlGF 1-2-3 test (Perkin Elmer), Triage PLGF test (Alere) and Elecsys immunoassay sFlt-1/PlGF ratio (Roche Diagnostics). The need for blood sampling, skilled personnel, and laboratory infrastructure however make them difficult for LMIC settings. Protein in urine is also a commonly used indicator to identify increased risk of pre-eclampsia. Current tests however are impractical for LMICs – being either lab-based (and requiring a 24-hour urine test) or inaccurate (protein-only dipsticks). The recent finding that the urine of women with pre-eclampsia contains proteins that are Congo Red Dot Paper Test positive, however, has opened potential for the creation of a simple, non-invasive, specific, POC diagnostic, with research in this area underway. PATH and Lifeassay’s collaboration on an innovative protein to creatine ratiometric urine dipstick test also offers a low cost-alternative highly suitable for LMICs.
In 2020, pre-eclampsia was expanded to include drugs and biologics to prevent and/or treat pre-eclampsia and/or eclampsia. Details on unmet needs for this area will follow.
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Post-partum haemorrhage (PPH)
Post-partum haemorrhage (PPH)
Post-partum haemorrhage (PPH) is defined as blood loss of 500mL or more within the first 24 hours after birth. It is the leading direct cause of maternal mortality globally, with almost a fifth of maternal deaths attributable to PPH. Each year there are an estimated 14 million cases of PPH, and approximately 120,000 deaths, with almost all of this burden falling on women living in LMICs.
R&D needs
Intravenous (IV) or intramuscular (IM) injection of oxytocin remains the accepted gold standard for both the prevention and treatment of PPH. The use of oxytocin is limited in LMICs however by its need for cold-chain transport and refrigeration, often unavailable in low-resource settings. While current formulations of oxytocin also require a skilled health worker to administer them, globally only 78% of births are assisted by a skilled birth attendant, down to as few as 59% of births in sub-Saharan Africa.
Intravenous (IV) or intramuscular (IM) injection of oxytocin remains the accepted gold standard for both the prevention and treatment of PPH. The use of oxytocin is limited in LMICs however by its need for cold-chain transport and refrigeration, often unavailable in low-resource settings. Current formulations of oxytocin also require a skilled health worker to administer them. Globally, however, only 78% of births are assisted by a skilled birth attendant – down to as few as 59% in sub-Saharan Africa – which places an additional limitation on access.
Alternative uterotonic drugs to oxytocin for the prevention and treatment of PPH exist or are in development but are not without challenges. Oral misoprostol, for example, is an established alternative for both the prevention and treatment of PPH, and is inexpensive, easy to administer, and heat stable. It is however less effective than oxytocin and its availability can be restricted due to its abortifacient properties. Promising alternatives to oxytocin include heat-stable carbetocin – an oxytocin analogue tested in one of largest global PPH prevention trials (the CHAMPION (Carbetocin Haemorrhage Prevention) trial) – which has been shown to maintain stability at high temperatures and relative humidity for up to 36 months, and appears comparable to oxytocin for the prevention of PPH, with a more favourable side-effect profile than other medication options. It is currently recommended by WHO as a second-line option for the prevention and treatment of PPH, and is listed on WHO’s Model List of Essential Medicines. Tranexamic acid – an antifibrinolytic drug – can also reduce incidence of death due to post-partum bleeding by nearly one third when administered IV within three hours of birth with no adverse effects or complication, as demonstrated in the WOMAN Trial. It is currently recommended by WHO for use when uterotonics fail to control bleeding.
Most alternatives still however require skilled personnel for administration. A dry powder, heat stable, inhaled oxytocin formulation, which would eliminate the need for refrigeration and increase ease of administration such that mothers could potentially even self-administer the product, has completed Phase I trials. Other innovative approaches include PATH’s research into sublingual oxytocin in heat-stable, fast dissolving tablets.
In cases where drugs are ineffective or unavailable, treatment is escalated, first using mechanical interventions, such as uterine balloon tamponades, then surgery and hysterectomy. In LMICs however, many devices are prohibitively expensive and surgical services often unavailable, leading to uncontrolled bleeding and often death. Low-tech products are in development, such as PATH and Sinapi Biomedical’s Ellavi uterine balloon tamponade device designed specifically for low-resource settings, which received regulatory approval in Ghana and Kenya in July 2020 and Alydia Health’s Jada System vacuum-induced uterine tamponade, which is currently being trialled in the US-based PEARLE study.
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Sexually transmitted infections (STIs)
Sexually transmitted infections (STIs)
Sexually transmitted infections (STIs) are a major global health issue. Although primary infection can be asymptomatic or cause manageable symptoms, it can also produce acute illness, and result in serious conditions including increased HIV acquisition and transmission; pelvic inflammatory disease, ectopic pregnancy and infertility; and congenital deformities, stillbirth, neonatal illness and death. In 2016, there were 376 million new cases of the four most common curable STIs: 156 million cases of trichomoniasis, 127 million of chlamydia, 87 million of gonorrhoea, and 6.3 million of syphilis – equating to transmission of more than 1 million STIs per day. Up to 10 million people worldwide are also infected with HTLV-1, arguably the most potent oncovirus, while more than 400 million people live with incurable HSV-2. The burden of STI infections is greatest in LMICs.
R&D needs
A significant challenge in STI control is accurate and timely diagnosis. For most STIs, current diagnostic testing involves laboratory-based platforms that are resource-intensive, skilled labour-dependent, and expensive, making them unsuitable for LMICs. Lengthy time for results can also lead to lost patient follow-up. Point-of-care (POC) diagnostics have several benefits over traditional laboratory-based tests, including the ability for administration by lower cadre health workers, and facilitation of same-session testing, diagnosis, counselling, and treatment. Multiple syphilis POC tests meeting WHO assured criteria are available, with one capable of distinguishing active and past infection. For other STIs however, there is a need for low-cost, rapid, reliable, easy-to-use, POC diagnostics, particularly tests able to diagnose multiple STIs. The GeneXpert platform, for example, is capable of screening for and diagnosing trichomoniasis, chlamydia and gonorrhoea simultaneously, but it is costly, requires electricity and specific training, and has a run-time of 60-90 minutes.
Rising antimicrobial resistance presents a serious challenge to effective drug treatment of many STIs, particularly gonorrhoea, a high-priority pathogen identified by WHO. Two advanced candidates are in the pipeline for drug-resistant gonorrhoea: zoliflodacin – being co-developed by the Global Antibiotic Research and Development Partnership (GARDP) – and gepotidacin, both of which have shown good efficacy in Phase II trials, with Phase III trials ongoing; other candidates are in preclinical development, such as Debiopharm’s candidate Debio 1453. Diagnostics capable of identifying drug resistance without time- and labour-intensive traditional culture methods are also needed. Additionally, no novel syphilis drugs are in development, despite the need for drugs to treat latent, tertiary or congenital syphilis, and a growing threat of global benzathine penicillin shortage.
Preventive and therapeutic vaccines for STIs are also sorely needed, with promising progress made since the development of the Global STI Vaccine Roadmap. This is especially true for HSV-2, where – despite limited success with prophylactic candidates – there are multiple therapeutic candidates (many with prophylactic potential) in development, such as the live-attenuated candidate HSV529 in Phase I. Efforts to map all proteins produced by gonorrhoea, chlamydia and syphilis have also opened up opportunities for identification of new vaccine candidates. Preclinical work has progressed, including research into the cross-protective potential of meningococcal group B vaccines for gonorrhoea.
Disease burden
- Deaths 2017 119,093
- DALYs 2017 11,473,757