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 have been rolled out in LMICs with favourable results with support from Gavi. However, they are typically expensive to manufacture. There is a need for low-cost candidates that offer broader protection for children against serotypes predominant in LMICs, as gains from existing PCVs are threatened by serotype replacement. Two potential approaches – non-conjugate protein-and whole-cell-based vaccines, both potentially offering broader protection and cheaper manufacturing cost, are being explored; but majority of candidates remain in preclinical development. The introduction of the MenAfriVac monovalent conjugate meningitis A vaccine culminated in a drastic reduction in meningitis A infection across the African continent, but other serogroups have become more prominent, creating the need for low-cost polyvalent vaccine candidates. Rapid diagnostic tests that can detect serogroups to guide vaccine response and multi-pathogen point-of-care tests to guide case management in both epidemic and endemic settings are also needed.
Pipeline spotlight
NmCV-5, a pentavalent meningococcal vaccine co-developed by PATH and Serum Institute of India, already proven to be safe, well-tolerated, and capable of producing strong immune responses to all five serogroups has entered a pivotal Phase III trial, specifically designed to generate optimal evidence for a WHO pre-qualification.
Disease burden
- Deaths 2017 1.2M
- DALYs 2017 65M
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Buruli ulcer
Buruli ulcer
Buruli ulcer, also known as Bairnsdale ulcer, is a chronic necrotizing skin disease caused by Mycobacterium ulcerans. In developing countries, children under the age of 15 are at greatest risk. While the exact transmission mode is unknown, living around marshy areas with stagnant or slow-moving water can be a risk factor in endemic regions. Buruli ulcer usually appears as a painless lump or nodule that can later develop into an ulcer, usually on the arms or legs. M. ulcerans produces a toxin known as mycolactone, which causes tissue damage and can depress the immune response. As a result, coinfection with HIV can make Buruli ulcer more complex to address. Early case detection and antibiotic treatment remain the cornerstones of the control strategy for Buruli ulcer to reduce morbidity, treatment costs and prevent long-term disabilities. If left undiagnosed or untreated, infection with M. ulcerans can lead to skin, tissue or bone damage, with surgery or amputation sometimes required.
R&D needs
Adoption of IS2404 PCR by national Buruli ulcer (BU) programs has dramatically improved diagnostic and epidemiological accuracy in endemic countries. However, there remains a need for simpler diagnostic tools allowing prompt and accurate diagnosis at the community level. BU-MYCOLAC, the first RDT designed to detect mycolactone, still needs clinical evaluation in endemic settings, while other point-of-care molecular methods like BUD-LAMP require field evaluation. Treatment of BU remains cumbersome – often complicated by paradoxical reactions – and lengthy, making development of new drugs a key priority. Τelacebec, Clofazamine and TB47 are stand-alone or combination pipeline candidates – all still in preclinical or early clinical phases, highlighting the need for acceleration and diversification of drug R&D. Tools for immunization against BU remain underdeveloped. All vaccine candidates are in early preclinical stages, while the widely available repurposed TB vaccine, BCG vaccine, provides only short-term protection and is no substitute for a targeted BU vaccine.
Pipeline spotlight
A Phase II clinical trial of reducing treatment duration via expansion of the standard regimen to include amoxicillin/clavulanate is underway in Benin. A larger study of f-TCL diagnosis conducted in Ghana showed over 80% diagnostic accuracy, suggesting its potential to become an ideal tool for diagnosing Buruli ulcer.
Disease burden
- Cases 2020 1.2K
- DALYs and Deaths Unknown
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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
Antifungal medications used for treating cryptococcal meningitis are effective, but poorly suited for use in developing countries. Amphotericin B is expensive and requires administration at a hospital, and flucytosine – another repurposed antifungal – requires careful blood monitoring. As a result, most developing countries resort to fluconazole use, which is only partially effective. Notwithstanding the AMBITION-cm findings, there remains a need for affordable, efficacious oral drugs, adapted for resource-poor settings. New antifungal agents, repurposed drugs and immunotherapies targeting various biochemical processes are in different stages of development, with many candidates showing promising activity against cryptococcal meningitis. One such candidate, Mycovia Pharmaceutical’s VT 1598, is in an ongoing Phase I trial. Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have been investigated, but there are currently no biological candidates in clinical trials.
Pipeline spotlight
A pivotal Phase III trial of Matinas BioPharma’s MAT2203, an orally administered lipid-crystal nano-particle formulation of amphotericin B – with support from the US NIH – is expected to start in early 2023 following the drug meeting all its endpoints in the EnACT Phase II trial.
Disease burden
- Deaths 2014 181K
- DALYs Unknown
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Dengue
Dengue
Dengue is a viral infection transmitted to humans by the female Aedes mosquito – most often Aedes aegypti and Aedes albopictus. The dengue virus has four serotypes, each with multiple genotypes. First time infection results mostly in a flu-like illness; subsequent infections with a different serotype (or even genotype) can result in severe disease, and are more likely to lead to dengue haemorrhagic fever. In analogy, Dengue naïve persons getting vaccinated with Dengvaxia, the only currently licensed Dengue vaccine, run the risk of developing severe dengue disease through antibody-dependent enhancement. Dengue outbreaks often occur in Asia, Central America and South America, while the first autochtonous cases of Dengue have been recently registered in southern Europe in the recent past years; the disease is now present in more than 100 countries, up from only nine in 1970.
R&D needs
Currently, no curative therapy is available for managing dengue fever. Effective therapeutic options are needed, including direct-acting antivirals and mAbs. Several such candidates are currently in early-stage clinical development, including Novartis’ EYU 688 and Atea’s AT-752. Point-of-care serological tests are already available but have many drawbacks. There is a pressing need for diagnostics that can function across the entire disease spectrum, distinguish dengue from other febrile illnesses, and for RDTs for serostatus screening. New and improved vector control products targeting the Aedes mosquito, including adulticidal oviposition traps and space spray insecticides, are needed, as well as biological control tools such as Wolbachia and genetic manipulation (with field experiments currently ongoing across Asia and Latin America). Dengue’s prevalence in high- and upper-middle-income countries has attracted commercially focused industry investment in vaccine R&D; this category has therefore been excluded from the G-FINDER scope.
Pipeline spotlight
VIS 513, a broadly neutralising monoclonal antibody (mAb) developed by Visterra that targets the E protein, present across all dengue serotypes, has progressed to Phase II clinical development and has been sub-licenced for further development by Serum Institute of India. Janssen’s JNJ-1802, a direct-acting antiviral, commenced a Phase II human challenge study in collaboration with NIAID.
Disease burden
- Deaths 2019 36K
- DALYs 2019 2.4M
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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
Approved vaccines against diarrhoeal diseases are sometimes ineffective or unsuitable for infants. New multivalent vaccines suitable for infants and with longer-term protection in high-burden settings are urgently needed. Such next-generation candidates for rotavirus include non-replicating parenteral vaccines, the most advanced being PATH’s trivalent NRRV (P2-VP8) candidate, undergoing Phase III trials. Other potential candidates remain in preclinical development, except for Mitsubishi Tanabe’s VLP rotavirus vaccine, MT 5625, which has progressed to Phase I development. Oral rehydration therapy and zinc supplementation are the mainstay of management in LMICs but are insufficient in many cases. Safe, effective, and affordable pathogen-specific drugs are also needed. The therapeutic pipeline currently includes both small molecule drugs and biologics, with only a few candidates in early-stage clinical development. Likewise, rapid diagnostic tests capable of differentiating between different diarrhoeal diseases, as well as diagnosing multiple diseases, are required; however, only one candidate, RLDT, is in late-stage development.
Pipeline spotlight
Beijing Zhifei Lvzhu’s live attenuated Shigella vaccine entered a Phase III trial in December 2021. NIAID initiated a Phase II Shigella human challenge study of another live attenuated candidate, WRSs2. In November 2022, Maxvax Biotechnology began Phase II trials of its trivalent rotavirus vaccine, only the second sub-unit vaccine to reach late-stage development.
Disease burden
- Deaths 2019 1.0M
- DALYs 2019 46M
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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
Preventive chemotherapy in the form of mass drug administration or targeting specific groups such as preschool and school-aged children is the only medical countermeasure available for the control and elimination of helminthic diseases. Only one vaccine candidate, rSh28GST/Alhydrogel, targeting schistosomiasis, has ever reached an efficacy trial. Current vaccine development efforts are concentrated on hookworm, onchocerciasis and schistosomiasis, with most candidates either in pre-clinical development or human safety studies. The heavy reliance on preventive therapeutic agents, often as a monotherapy, has the potential to cause drug resistance. New therapies are urgently needed to counteract the future threat of resistance and overcome the shortcomings of current therapies, including child-friendly formulations and macrofilaricidal agents for onchocerciasis. The current therapeutic pipeline includes emodepside and oxfendazole for onchocerciasis, oxantel pamoate for trichuriasis, tribendimidine for hookworm and TylAMac for filariasis. Diagnosis remains reliant on stool/urine microscopy, underlining the need for rapid, point-of-care, molecular diagnostic tests which can detect resistance.
Pipeline spotlight
In May 2022, NIAID initiated a Phase I trial of SchistoShield®, a schistosomiasis investigational vaccine based on a new, never before trialled antigen, Sm-p80. The Paediatric Praziquantel Consortium reported successful results from a pivotal Phase III trial of oro-dispersible praziquantel and has submitted a Letter of Intent to the EMA.
Disease burden
- Deaths 2019 15K
- DALYs 2019 7.7M
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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 and has been included in 185 countries’ national infant immunisation schedules. Current nucleos(t)ide analogues are safe, well tolerated and halt transmission; but life-long treatment is needed to avoid relapse. New therapies are aimed at a functional cure – sustained undetectable viraemia with or without antibody production – with multiple drugs and biologic combinations in clinical development. Tools to diagnose and treat HBV remain sub-optimal as standard serological assays detecting HBV surface antigen (HBsAg) are compromised by HIV/HCV co-infection, low HBsAG titres, and S gene mutations/variants. None of the available molecular tests are pre-qualified by WHO, and there is a need for low-cost, point-of-care molecular diagnostics that can quantify viral load, for confirmation of diagnosis, treatment monitoring, detection of drug resistance, and treatment initiation to prevent mother-to-child transmission. Epidemiological research in LMICs is needed to inform approaches to screening, monitoring and treatment, and advance understanding of drug and vaccine escape mutations.
Pipeline spotlight
Vir Biotechnology’s VIR-2218 (a small interfering ribonucleic acid) and VIR-3434 (a monoclonal antibody) in combination with pegylated interferon-α and GSK’s bepirovirsen (an antisense oligonucleotide) recently showed promising results for seroclearance and hepatitis B surface antibody production, a feature not observed in current treatments. Both treatments belong to the novel post-transcription inhibitor class.
Disease burden
- Deaths 2019 510K
- DALYs 2019 17M
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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
Direct-acting antiviral (DAA) drugs are more effective, require a shorter duration of treatment, and have fewer side effects than previous interferon- and ribavirin-based treatments, and have revolutionised the treatment of hepatitis C. However, DAA-based regimens are expensive, and access remains limited in LMICs. More research is also needed to assess DAA-based regimens in developing country populations, adolescents, children under 12, and pregnant or breastfeeding women. Despite extensive research efforts, the virus’ genetic diversity and limited infection models have meant that no protective vaccine yet exists, with many candidates not maturing beyond preclinical and early clinical development. A broadly reactive vaccine would prevent incidence of new infections and ideally elicit an antibody and cross-reactive T-cell response. There is also a need for HCV diagnostic tests that are affordable and simple to use in developing country contexts, especially tests for treatment monitoring, screening and tests of cure.
Pipeline spotlight
A preventive vaccine based on E1/E2 glycoproteins induced broadly neutralising antibodies against all HCV genotypes in mice. Glecaprevir and pibrentasvir combinations are currently in Phase III trials for acute hepatitis C infections and for paediatric populations.
Disease burden
- Deaths 2019 412K
- DALYs 2019 12M
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Histoplasmosis
Histoplasmosis
Histoplasmosis is a fungal infection caused by the dimorphic fungi Histoplasma capsulatum, transmitted via inhalation of spores from contaminated soil. In most cases, histoplasmosis presents as an asymptomatic infection or self-limited flu-like illness. Individuals with a compromised T-cell immune response, such as those with HIV, can develop more serious disease, including chronic pulmonary histoplasmosis or disseminated histoplasmosis – conditions which have a striking similarity with the pulmonary and miliary forms of tuberculosis, respectively, making clinical differentiation difficult.
Histoplasma is mostly found in the Americas but has been reported in most countries, including in Africa and Asia. The HIV/AIDS pandemic resulted in an increased incidence of the more severe disseminated form of histoplasmosis in endemic regions of the Americas, and particularly in Latin America, where over 15,000 new cases and 4,500 deaths from disseminated histoplasmosis are reported each year among people living with HIV/AIDS (PLWHA). Recent estimates suggest that there is a higher incidence of histoplasmosis than of TB among PLWHA in Latin America, and that histoplasmosis causes more deaths.
R&D needs
Timely diagnosis and early start of treatment are critical for histoplasmosis management, as disseminated histoplasmosis is often fatal if left untreated. Clinical guidelines for managing histoplasmosis recommend a year-long treatment with liposomal amphotericin B and itraconazole. Though highly efficacious, the parenteral liposomal amphotericin B is heat unstable, and itraconazole presents significant drug-drug interaction with anti-tubercular and anti-retroviral medications, thus requiring monitoring of its blood concentrations, limiting LMIC use. There is a need for new treatments, preferably oral, with shorter duration, that are safe in combination with other therapies. Most new investigational agents are in early-stage development, with only the triterpenoid antifungal by Scynexis Inc., Ibrexafungerp, undergoing a Phase III trial for histoplasmosis. Current techniques for diagnosing Histoplasma are mainly laboratory-based with inconsistent sensitivity, making them unsuitable in poor-resource settings. Highly sensitive and specific point-of-care tests, which are appropriate for LMIC settings are urgently needed – such as antigen-based RDT from MiraVista diagnostics.
Pipeline spotlight
To improve the sensitivity of existing real-time quantitative PCR (qPCR) assays, the French Mycoses Study Group has developed a novel assay that amplifies whole nucleic acids of Histoplasma spp. Clinical validation showed the test as highly sensitive, and able to perform Histoplasma detection from blood and bronchoalveolar lavage fluid.
Disease burden
- DEATHS Unknown
- DALYS Unknown
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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 2020, the majority in LMICs. The virus attacks and destroys CD4 cells in the human immune system; without treatment, infected individuals become increasingly susceptible to other diseases, and eventually develop acquired immune deficiency syndrome (AIDS). People with AIDS often die from opportunistic infections like tuberculosis or cryptococcal meningitis, or cancers like Kaposi’s sarcoma.
R&D needs
There is currently no vaccine against HIV, due to the challenge posed by the virus’ genetic elasticity. All Phase III candidates so far have failed to demonstrate efficacy, with the most recent Phase III trial (Mosaico) discontinued in January 2023 after disappointing interim results. Passive immunisation with biologics such as monoclonal antibodies (mAbs) remain promising, with WHO and IAVI publishing preferred product characteristics to guide R&D. AMP mAb trials demonstrated proof of concept, though revealed that one monoclonal antibody alone is insufficient. Microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool, with the dapivirine vaginal ring included in WHO’s prequalification list in 2020. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially for early infant diagnosis. However, there is progress towards robust, point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates.
Pipeline spotlight
The South African Health Products Regulatory Authority was the first to approve a ‘4-in-1’ fixed-dose combination for paediatric HIV in June 2022. The single, easy-to-use granule-filled capsule is taste-masked and can be sprinkled into the child’s food. IAVI, NIAID and Moderna commenced Phase I trials in March 2022 of three mRNA-based vaccines leveraging COVID-19-tested technologies.
Disease burden
- Deaths 2019 849K
- DALYs 2019 47M
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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
Kinetoplastid diseases (Chagas’ disease, leishmaniasis and HAT) lack approved vaccines, and current development efforts are in their early stages. Chagas’, however, has a relatively full preclinical pipeline and leishmaniasis a candidate in Phase II trials. Many gaps remain with respect to diagnosis: HAT requires a point-of-care test for T.b. rhodesiense (r-HAT), simpler confirmatory tests, tests of cure and high-volume testing on dried blood samples as endemic countries move towards surveillance and/or post-elimination maintenance. The existing cutaneous leishmaniasis diagnostic, CL Detect, failed to demonstrate satisfactory standalone accuracy in various endemic settings including Morocco, Afghanistan and Ethiopia, underlining the importance of novel diagnostic tools, while Chagas’ needs tests of cure and for congenital infection. Improved and safer drugs are needed, particularly for r-HAT, pregnant women infected with Chagas’, and oral drug regimens in leishmaniasis. Biologics and therapeutic vaccines are of particular interest for Chagas’, but still lack either a mature candidate or approved product.
Pipeline spotlight
In November 2022, DNDi and Novartis initiated a Phase II safety and efficacy trial of oral LXE408 as a monotherapy for treating visceral leishmaniasis. A Phase II/III trial of acoziborole as a single dose cure for adult Human African trypanosomiasis (HAT) completed recruitment, while the paediatric trial launched in July 2022.
Disease burden
- Deaths 2019 16K
- DALYs 2019 1.0M
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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
Drug regimens used for leprosy treatment, though effective, require 6-24 months of treatment. With surveillance data suggesting emergence of resistance to first-line drugs in high-endemic countries, there is a growing need for drugs with simpler regimens and shorter treatments. WHO’s recommendation of single-dose rifampicin as post-exposure prophylaxis constitutes major progress in disease prevention, though we still lack an effective preventive vaccine, with all but one candidate in early-stage development. Leprosy diagnosis is primarily based on clinical criteria and/ or positive microscopy of skin slit specimens. As both methods exhibit suboptimal sensitivity and specificity and rely on individual expertise, novel diagnostic tools are needed. The WHO Diagnostic Technical Advisory Group notes that gaps in the detection of infection, nerve loss function and prediction of future disease need to be addressed. In a proof-of-concept study, a multi-biomarker finger prick point-of-care test showed encouraging results in detecting infection and early-stage disease.
Pipeline spotlight
Phase II clinical evaluation of Bedaquline for therapy and post-exposure prophylaxis is ongoing, while development of the vaccine candidate LepVax has transitioned from Phase Ia to Ib/IIa. AMG 634, a compound for the treatment of Erythema Nodosum Leprosum, is being tested for efficacy and safety in a Phase II clinical trial in Nepal.
Disease burden
- Deaths 2019 0
- DALYs 2019 29K
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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
Leptospirosis can be effectively treated with antibiotics if diagnosed accurately and timely. Gold standard leptospirosis diagnosis during the acute phase of infection currently involves polymerase chain reaction (PCR) techniques, which require sophisticated laboratory equipment and technical expertise, making it inappropriate for resource-limited settings. There are several leptospirosis diagnostic test kits commercially available. However, the marketed tests have questionable sensitivity and specificity. The recently published Thai-Lepto AKI study revealed that the five Leptospirosis RDTs commercially available in Thailand had overall sensitivity ranging from 1.8% to 75% and specificity ranging from 52.3% to 97.7%. This highlights the need for novel, easy-to-use, rapid diagnostic tests to accurately detect leptospirosis infection in LMIC settings.
Pipeline spotlight
Researchers from Thailand recently reported that a CRISPR-based leptospiral rapid diagnostic assay targeting the lipL32 gene demonstrated acceptable sensitivity and excellent accuracy. The overall performance of the CRISPR-based molecular test was better than the commercial rapid diagnostic test.
Disease burden
- Deaths 2015 59K
- DALYs 2015 2.9M
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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
There remains a clear need for a more efficacious vaccine and vaccines that can protect against P. vivax and placental malaria, and/or block transmission. New drugs are needed in response to emerging resistance and to meet the needs of key populations, as well as for chemoprotection, and – ideally – to meet the goal of a single-dose treatment. In addition to small molecule drugs, monoclonal antibodies (mAbs) are being investigated, though large-scale administration is not yet suited to low-resource settings. There is an urgent need to develop new rapid diagnostic tests in response to emerging pfhrp2/3 gene deletion in malaria parasites, as well as more sensitive diagnostics to identify non-falciparum species, distinguish malaria from other febrile illnesses, detect asymptomatic cases, and diagnose G6PD enzyme deficiency. Next-generation vector control products are needed in response to emerging pyrethroid resistance, including genetic approaches to reduce mosquito populations or block parasite transmission, and endectocides for malaria transmission control.
Pipeline spotlight
Mosquirix, the first approved vaccine, received WHO prequalification in July 2022. R21/Matrix-M vaccine, developed by University of Oxford and manufactured by Serum Institute of India, was approved by Ghana’s FDA and Nigeria’s NAFDAC in April 2023. Phase II results for US NIH’s CIS43LS monoclonal antibody demonstrated six month’s protection against Plasmodium falciparum after a single dose. MMV and Novartis announced a Phase III efficacy trial of ganaplacide/lumefantrine-SDF combination for 2023, the first novel non-artemisinin-based therapy to enter regulatory trials.
Disease burden
- Deaths 2019 643K
- DALYs 2019 46M
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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 was included in the G-FINDER scope for the first time in 2019.
R&D needs
The current standard treatment for mycetoma has a cure rate of around 30% and comes with serious side effects. More effective, less toxic drugs with shorter duration of treatment are urgently needed. Aside from fosravuconazole, mycetoma drug R&D efforts are at a very early stage, such as DNDi’s MycetOs, a screening project to identify new leads, and niclosamide, a repurposed drug which showed potential in in-vitro studies. At present, mycetoma is diagnosed clinically, with identification of causative agents via histology and culture, techniques which require laboratory infrastructure and skilled practitioners. Specific diagnostics, such as PCR-based tests, are available only for research purposes. In 2022, the WHO published a target product profile (TPP) for a rapid test for diagnosis of mycetoma at the primary healthcare level. The TPP aims to facilitate the development of point-of-care tests that diagnose mycetoma and differentiate actinomycetoma and eumycetoma to allow initiation of appropriate treatments.
Pipeline spotlight
A clinical trial investigating fosravuconazole, the only drug ever to undergo an efficacy trial for mycetoma treatment, was completed in late 2021. DNDi and its partners have established a strategy for registering fosravuconazole in Sudan for compassionate use in advance of full approval.
Disease burden
- Deaths Unknown
- DALYs Unknown
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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
Prophylactic use of antibiotics is the only preventive measure currently available for preventing rheumatic fever and its associated complications, such as rheumatic heart disease. Such widespread use of antibiotics is potentially vulnerable to and causative of antimicrobial resistance, meaning that a vaccine to prevent rheumatic fever is a much-needed medical countermeasure. Currently, the vaccine development pipeline is mostly at the stage of pre-clinical testing, and only a handful of candidates have undergone human safety trials. These include StreptAnova, the most advanced candidate, which successfully completed a Phase I trial in 2020.
Pipeline spotlight
Two conjugated peptide vaccines, p*17-CRM + K4S2-CRM and J8-CRM + K4S2-CRM, commenced a Phase I clinical trial in November 2022 after having successfully completed preclinical studies. The Phase I trial is designed to automatically transition to Phase II if no serious adverse effects are observed.
Disease burden
- Deaths 2019 274K
- DALYs 2019 10M
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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
Typhoid can be successfully treated with available antibiotics. However, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of S. typhi, the causative agent of typhoid, have emerged and are spreading rapidly. The emergence of the XDR strain is especially alarming as it is resistant to almost all the available therapeutic options. There is an urgent need for a next generation of antibiotics that are effective against resistant strains. Current pipeline candidates include several broad-spectrum antibiotics with the potential to be effective against drug-resistant strains of S. typhi, but most are in the pre-clinical stage of development. The WHO recommends typhoid conjugate vaccines (TCVs) as the preferred vaccine for use in Salmonella prophylaxis in endemic regions. Two such TCVs – Typbar TCV and TYPHIBEV are currently pre-qualified by the WHO.
Pipeline spotlight
A new typhoid conjugate vaccine (Vi-DT) completed a Phase III trial in 2021. Vi-DT was found to be immunologically non-inferior to the control, Typbar TCV. Three new vaccine candidates entered clinical trials in 2022; two combination vaccines targeting NTS and typhoid (TSCV and iNTS-TCV), and a first-in-human trial of typhoid and paratyphoid bivalent vaccine (TYP03/04).
Disease burden
- Deaths 2019 212K
- DALYs 2019 16M
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Scabies
Scabies
Scabies is a parasitic infection of the skin caused by infestation with the microscopic mite Sarcoptes scabiei var. hominis. It is a highly contagious disease, transmitted through close skin-to-skin contact, with the highest rates of infestation occurring in resource-limited settings, particularly associated with tropical climates and overcrowded living conditions. The infestation triggers an immune response causing intense itching and rash, which can be severe enough to disrupt day-to-day activities. Secondary effects result from bacterial skin infection (impetigo), which can progress to severe skin and soft tissue infections and sepsis, or rheumatic fever and glomerulonephritis (leading in turn to rheumatic heart disease and chronic kidney disease).
Scabies is one of the most common illnesses globally, with 565 million incident cases and 4.8 million DALYs in 2019. Although prevalent in most of the world, Asia, including Oceania, accounted for three-quarters (76%) of all new cases in 2019. Due to the high prevalence and greater vulnerability among socio-economically marginalised populations, WHO declared scabies a neglected tropical disease in 2017.
R&D needs
Due to the cost and limited availability of the most efficacious scabicide (permethrin 5% cream), many LMICs rely on less effective and less well-tolerated alternatives, such as benzyl benzoate and sulphur ointments. Topical treatments often suffer from acceptability and compliance issues. Oral ivermectin, approved in many countries for the treatment of scabies, is highly effective but does not kill scabies eggs, necessitating repeat doses and increasing the difficulty of mass drug administration (MDA). Ivermectin is also contraindicated for children less than 15kg and for pregnant and breastfeeding women. Thus, new oral drugs exhibiting prolonged skin activity, effective against newly hatched eggs, and usable by children and pregnant women are urgently needed. Novel diagnostics, such as molecular tests are at an early stage of development. There is an urgent need to develop point–of–care tests as an alternative to existing clinical examination and as a tool to guide ivermectin-based MDA.
Pipeline spotlight
In January 2022, Medicines Development for Global Health completed a Phase II proof-of-concept study investigating the effectiveness of moxidectin in eliminating the scabies parasite. Data from the completed trial will inform the dose-confirmatory Phase IIb trial, which is expected to start enrolling its first patient early in 2023.
Disease burden
- Deaths 2019 0
- DALYs 2019 4.8M
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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
Antibody-based antivenoms are the mainstay of snakebite envenomation treatment. These are effective, life-saving products if administered at the right time, in the correct dose, and for the right species. However, manufacturing immunobiologicals is expensive and complex, requiring harvesting and purifying immune-rich plasma from hyper-immunised large animals. The production of quality antivenom is hampered by the lack of a universal regulatory framework and appropriate reference standards, and geographical variations in the venom pool. Conventional anti-venoms are liquid or freeze-dried formulations requiring skilled professionals for administration, making them inappropriate in resource-limited settings. There is an urgent need to develop next-generation antivenom products that are safe, effective, geography-appropriate or polyvalent, and affordable for the low-income settings where they are most needed. The current research efforts include recombinantly expressed human antibodies and antibody fragments and small molecule therapeutics (SMT), including oral formulations. One such SMT – varespladib-methyl, is currently in a Phase II clinical trial.
Pipeline spotlight
In early 2022, researchers from the Liverpool School of Tropical Medicine and Kenya Medical Research Institute, with funding from the Wellcome Trust, initiated a Phase I clinical trial of Unithiol – a chelating agent which is routinely used to treat heavy metal poisoning – repurposed for treatment of snakebite.
Disease burden
- Deaths 63K
- DALYs Unknown
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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
An effective vaccine would be a breakthrough development, given that the goal of eliminating Trachoma as a public health problem is unlikely to be reached solely through the implementation of the existing SAFE (surgery; antibiotics; facial cleanliness; environmental improvement) strategy. The trachoma vaccine pipeline is at an early stage of development. Only a few candidates have reached beyond the concept stage, such as VD1-MOMP (‘TracVac’), designed to target ocular and genital serovars, which was found to be immunogenic in pre-clinical studies.
Pipeline spotlight
In a study examining samples from different epidemiological settings, two rapid lateral flow assays LFA-latex and LFA-gold, demonstrated promising and comparable results to ELISA immunoassays. Their low cost, lack of instrument requirements, and ease of training and use make these rapid diagnostic tests an appealing option for post-validation surveillance.
Disease burden
- Deaths 2019 0
- DALYs 2019 0.2M
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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 a chronic cough, fever and weight loss. TB is especially dangerous for people with low immunity, and is a leading cause of death among people with HIV/AIDS. There is also growing resistance to existing treatments.
R&D needs
A new TB vaccine, which is effective across all ages and safe for pregnant and lactating women, is critical for achieving targets set by the WHO’s End TB Strategy. However, TB vaccine R&D is lagging on most fronts – the number of candidates in late clinical development is unchanged, and most are non-inactivated/attenuated vaccines targeting the same antigen, no new evidence on efficacy since the publication of M72/AS01E’s clinical trial results in 2019 and the exclusion of pregnant women, a high-risk group, from clinical trials. A more diverse early-stage pipeline is urgently needed to safeguard against the potential failure of the current clinical candidates. In recent years, the WHO has endorsed several new tools, including molecular tests for diagnosing TB. However, research gaps still exist, including non-sputum-based tests for diagnosing paediatric TB, true point-of-care molecular tests and tools for screening and triage.
Pipeline spotlight
BioNTech’s BNT164, the first mRNA-based TB vaccine, entered clinical trials in December 2022 – testimony to the flow-on benefits of the unprecedented technological innovations during the development of COVID-19 vaccines. A Phase II trial for drug-sensitive TB is investigating an all-new regimen of Otsuka’s investigational compound, OPC-167832, with recently approved bedaquiline and delamanid.
Disease burden
- Deaths 2019 1.2M
- DALYs 2019 47M
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Yaws
Yaws
Yaws is a chronic skin infection caused by the spirochaete, Treponema pallidum subspecies pertenue, which is closely related to the bacteria that causes syphilis and other endemic treponematoses – pinta and benjel. The disease is endemic in 15 countries, with endemicity still unknown in more than 70 countries worldwide. In 2021, over 120,000 suspected yaws cases were reported from 13 countries, with 1,102 confirmed cases from 9 countries. More than 80% of suspected cases were from the West Pacific region.
It is a highly contagious disease primarily affecting children under 15 years of age and those residing in poor communities in low- and middle-income countries. Transmission from person to person occurs through skin-to-skin contact with infectious skin lesions. Like syphilis, yaws is characterized by chronic relapsing skin manifestations, which is often associated with stigma and significant socioeconomic implications. Yaws is typically responsive to a single dose of azithromycin which is currently used in both mass treatment campaigns and targeted treatment of individual identified cases. Additionally, benzathine benzylpenicillin is a widely available safe and efficacious second line treatment for azithromycin-resistant cases. If left untreated, the lesions can progress to affect cartilages, joints, and bones, resulting in disfigurement and disability. Yaws is classified as a neglected tropical disease (NTD) of the skin by WHO and is targeted in the latest Roadmap for eradication by 2030.
R&D needs
Historically, laboratory-based serological tests have been widely used in diagnosing treponemal infections, but these are unable to distinguish yaws from syphilis infection. These tests are expensive, resource-intensive, require highly skilled personnel, and are associated with a long wait-time for results, leading to delays in initiating treatment. Multiple affordable treponemal rapid point-of-care tests are available. However, these tests cannot distinguish between past and present infection, limiting their use in monitoring the interruption of yaws transmission. Chembio’s novel Dual Path Platform Syphilis Screen and Confirm assay is capable of distinguishing active and past infection but its high cost makes it unsuitable for low resource settings. A by the WHO Diagnostic Technical Advisory Group (DTAG) for NTDs suggests the sensitivity and specificity of the currently used point-of-care tests are suboptimal for disease surveillance and eradication. DTAG has endorsed a target product profile (TPP) for the development of new diagnostic tools for case detection and identification of azithromycin-resistant cases, owing to reports of a small number of azithromycin resistant cases. DTAG is also developing a TPP for affordable, sensitive, rapid point-of-care molecular tests for diagnosing single yaws cases. With the global distribution of yaws undefined, improving understanding of yaws epidemiology is critical to guide its eradication. Research into non-human primates as potential reservoirs also remains a priority
Pipeline spotlight
The EDCTP-funded project, LAMP4yaws, is conducting real-life evaluation of a novel diagnostic test – the combined Treponema pallidum, Haemophilus ducreyi loop mediated isothermal test (TPHD-LAMP) for yaws in three endemic West African countries. The project will also assess its acceptability, feasibility and cost-effectiveness in comparison to the reference standard, qPCR.
Disease burden
- Deaths N/A
- DALYs N/A
Emerging infectious diseases
The first emerging infectious disease to be tracked by G-FINDER was Ebola, which was included by Policy Cures in the 2015 G-FINDER survey and report (looking at investments made in 2014), in response to the 2014 West African Ebola epidemic. From FY2016, the scope of our emerging infectious diseases tracking effort has been based on the list of priority diseases identified in the World Health Organization’s R&D Blueprint for action to prevent epidemics (the Blueprint), including its expansion in early 2020 to include COVID-19. The survey also gathers data on some emerging infectious diseases and disease groups not included in the Blueprint priority list, but which have been considered for inclusion and deemed to warrant ongoing review.
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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COVID-19
COVID-19
Coronavirus disease (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most infected individuals develop mild to moderate illness and recover without hospitalisation, although some proportion may go on to experience mid- and long-term effects, commonly referred to as ‘long COVID’. Symptoms of acute infection are variable but often include fever, cough, fatigue, and the distinctive loss of taste or smell. The elderly and those with multiple underlying medical conditions are at the greatest risk of severe disease, which can be fatal without medical intervention. As the virus is transmitted by aerosols, public health infection prevention and control measures are important. Most of these measures continue to be employed globally under more relaxed guidelines, alongside mass vaccination campaigns to prevent infection and/or severe illness.
SARS-CoV-2 was first identified in Wuhan, China in December 2019. The WHO declared the outbreak a Public Health Emergency of International Concern (PHEIC), WHO’s highest warning level, on 30 January 2020. As of mid-June 2022, there have been 535 million confirmed cases and 6.3 million deaths globally, though the true death toll is estimated to be more than double that due to under-reporting.
The emergence of virus variants associated with increased transmission and/or disease severity spurred the assessment and classification of variants of interest (VOI) and variants of concern (VOC). The Omicron variant and its sub-lineages remain a concern, partly due to its ability to reinfect those with either vaccine- or infection-derived immunity. The ability for variants to cause reinfection challenges herd immunity, shifting the focus of mass vaccination to booster doses and potentially seasonal immunisation.
R&D needs
As of April 2022, there were 35 vaccines approved for use by at least one national regulatory authority, ten of which have WHO Emergency Use Listing. Under the WHO’s recently-revised Target Product Profile (TPP), a need remains for vaccines which confer protection against severe disease for at least one year, and are active against other coronaviruses and/or potential future variants. Other key attributes of the TPP address LMIC needs, such as non-parenteral administration, higher thermostability, lower frequency of booster doses, and potential coadministration with other vaccines.
There is a need for therapeutics to reduce mortality in hospitalised symptomatic patients with COVID-19, including pregnant women and children under six; preferably a daily oral dose, or a short-course parenteral or inhaled therapy for those requiring ventilation. Only two antivirals have received WHO prequalification – Pfizer’s Paxlovid (nirmatrelvir/ritonavir) and Gilead Sciences’ Veklury (remdesivir) – both of which are for patients at high risk of hospitalisation. The WHO also conditionally recommends the use of the antiviral molnupiravir developed by MSD (Merck) and two monoclonal antibody therapies – Regeneron’s REGEN-COV (casirivimab/imdevimab) and GSK’s Xevudy (sotrovimab) – early in cases where there is elevated risk of severe disease or hospitalisation.
Two diagnostic TPPs remain unmet: point-of-care tests for prior infection with SAR-CoV-2, and test for prior infection with SAR-CoV-2 suitable for analysing a moderate to high volume of samples. Molecular diagnosis of SARS-CoV-2 is recommended by the WHO and is considered the gold standard for case confirmation. However, it is complicated, costly, and slow to execute and not readily accessible in low-resource settings. As of April 2022, 28 in vitro diagnostics have received WHO Emergency Use Listing, six of which are rapid antigen tests. Though less sensitive, antigen-detecting rapid diagnostic tests are quicker, cheaper and can be used outside of clinical and laboratory settings.
Pipeline spotlights
SK bioscience and GSK are seeking approval for their recombinant protein-based SKYCovione vaccine candidate with GSK pandemic adjuvant, after Phase III trials demonstrated its superiority to AstraZeneca’s Vaxzevria, one of the most widely used vaccines; they plan to make the vaccine available through COVAX for equitable access. Veru Inc. has applied for US FDA Emergency Use Authorization for sabizabulin, an anti-inflammatory and antiviral drug to treat hospitalised patients at high risk of acute respiratory distress syndrome – a patient group for which there are no antivirals currently recommended for use – following Phase III trials which demonstrated a 55% reduction in mortality.
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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
Standardised models of non-human primates susceptible to CCHFV infection are needed for a better understanding of disease pathogenesis and immunology while offering insights for developing therapeutics and vaccines.
In the absence of approved drugs, CCHF case management relies on supportive care. Off-label use of Ribavirin, a broad-spectrum antiviral, lacks sufficient supporting evidence. There are no CCHF therapeutic candidates in clinical development. Broadly neutralising and non-neutralising mAbs, along with favipiravir, a small molecule drug, have shown potential in pre-clinical studies. Randomised controlled trials of favipiravir and ribavirin, and further development of novel biologics are urgently needed.
An inactivated, mouse brain-derived CCHF vaccine has been used in Bulgaria since 1974; but safety concerns, instability and a lack of efficacy trials make it unsuitable for global use. KIRIM-KONGO-VAX, an inactivated vaccine, is the only candidate currently in clinical development. Effective CCHF vaccines targeting humans and animal reservoirs are urgently needed.
CCHF detection currently involves direct isolation or molecular tests, each requiring sophisticated facilities. The WHO highlights three urgent R&D needs: clinically validated and quality assured RT-PCR, ELISA Assay for reference laboratories, and RDTs for near-patient settings.
As with CCHF, supportive therapy is the only option for managing patients with severe RVF. While no RVF drug candidates have reached clinical development, a chemotherapeutic agent, mitoxantrone, and two broad-spectrum antivirals – a non-nucleoside inhibitor (favipiravir) and a nucleoside analogue (BCX4430) – are in pre-clinical development. As RVF can cause encephalitis and miscarriages, an ideal therapeutic candidate should cross the blood-brain barrier and be usable in pregnant women.
The WHO’s draft RVF Target Product Profile calls for three RVF vaccines: one for reactive/emergency use, one for long term protection for high-risk populations, and an animal vaccine for prevention of transmission. There are several veterinary vaccines in routine use, albeit with concerns about their 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. Candidates based on novel approaches such as DNA and viral vectors remain in the pre-clinical stage.
There are no validated point-of-care molecular tests in late-stage of development, and no validated commercial serology assays for use in humans.
Pipeline Spotlight
A team of researchers at CIRAD Réunion have developed the first specific rapid detection test for RVF virus. This first-line lateral flow immunochromatographic strip test is able to identify all strains of the RVF virus and has demonstrated high specificity and sensitivity during validation, offering a promising first-line, on-site diagnostic assay for use in resource-limited settings.
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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
In December 2019, ERVEBO became the first FDA-approved Ebola vaccine, and is now licensed 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. In 2020, EMA gave marketing authorisation to Janssen’s multivalent heterologous prime-boost vaccine. Although vital progress has been made in developing vaccines since the 2014 West African Ebola outbreak, neither approved vaccine meets the requirement of providing protection against multiple strains, including the Marburg virus, as set out in the WHO’s Ebola vaccine Target Product Profile (TPP).
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 (POC) molecular and rapid diagnostic tests (RDTs) 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 seven years. While these developments have indeed been life-saving, to date only one of the available POC diagnostic tests meet the WHO TPP requirements for sensitivity and specificity benchmarks of >98% and >99% respectively. There is therefore a need for continued product development efforts focused on improving existing diagnostic tools and designing novel approaches.
While no TPP for a Marburg virus diagnostic test currently exists, the WHO Ebola/Marburg Research and Development Roadmap points to the need for similar rapid and deployable multiplex POC diagnostic tests, effective against both Filoviruses, with rapid turnaround times and requiring minimal laboratory infrastructure.
Pipeline spotlight
A Phase I trial has been launched by the University of Oxford, for a new ChAdOx1 biEBOV vaccine candidate effective against both Zaire and Sudan Ebola virus species. It seeks to establish the safety and immunogenicity of the new candidate for subsequent studies. In October 2020, the US FDA approved Inmazeb (REGN-EB3), the first biologic candidate for treating Zaire Ebola virus. A second biologic – Ebanga (Ansuvimab-zykl) was approved in December of the same year.
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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
There is currently no approved vaccine for Lassa fever, resulting from the unique challenges Lassa poses: genetic heterogeneity, poorly-understood correlates of infection, the potential for immune-mediated neurological complications, and the requirement of simultaneous cell- and antibody-mediated response for optimal protection. WHO’s Lassa fever vaccine Target Product Profile for preventive use recommends a homologous vaccine which confers protection for at least three years, is safe for healthy adults and children, and provides coverage against Lassa virus lineages I to IV. Three investigational vaccines based on different platforms (DNA, measles virus vector and vesicular stomatitis virus vector) have progressed into clinical trials, but none which meet the requirement for protection across all four lineages.
Easy-to-use diagnostic tests are needed for accurate detection, ideally across the disease spectrum and for multiple lineages. Most available RDTs and immunoassays are limited to research use, while the three existing CE-IVD marked molecular tests require a laboratory with bio-containment capabilities. Zalgen’s commercially-available ReLASV® Antigen Rapid Test underwent field evaluation in 2018, performing better than currently available qPCR tests and signaling a promising advancement in Lassa diagnosis, though one that detects only three of the four known lineages. A novel, species-neutral, Double Antigen Binding Assay was recently found to have detection specificity of 83.3% from oral fluid samples.
Ribavirin, in conjunction with supportive therapy, is the current mainstay of Lassa pre- and post-exposure prophylaxis (PrEP/PEP) treatment, despite inconclusive evidence about its efficacy as PEP. Ribavirin is most effective when given intravenously and within the first six days of illness, leaving an unmet need for a stable oral therapeutic agent, effective against multiple lineages.
There is also a need for more studies on 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 with newer candidates.
Pipeline spotlight
In 2021, following positive Phase I trial results, the International AIDS Vaccine Initiative (IAVI) plans to advance its Lassa vaccine candidate, rVSV∆G-LASV-GPC LASV, which is based on FDA approved technology, into Phase IIb clinical trials, making it the most advanced vaccine candidate in the pipeline. In 2021, Kineta Inc also announced positive Phase I trial results for the world’s first oral Lassa virus entry inhibitor LHF-535.
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MERS, SARS & multiple coronaviruses
MERS, SARS & multiple coronaviruses
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-CoV-1 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).
R&D needs
Currently, there are no approved drugs or vaccines targeting MERS-CoV or SARS-CoV-1 infections. Research and development for SARS has largely stalled in the absence of further outbreaks and of Target Product Profiles (TPPs) to align R&D activities. An overarching challenge impeding all aspects of MERS research is the weakness of the available animal models in accurately mimicking the disease and severe infections in humans.
The WHO recommends the development of three MERS-CoV vaccine categories: a single dose vaccine for reactive use in outbreak settings, a two-dose vaccine for long-term protection for those at continual high risk (such as healthcare workers and camel handlers), and a reservoir-targeted vaccine for juvenile dromedaries to reduce or prevent viral shedding. Various candidates based on DNA and viral-vector are in the early stage of clinical development. Only two SARS vaccine candidates have ever been tested in humans and no candidate has yet passed Phase I trials.
Based on the current understanding of MERS pathogenesis, a combination antiviral and antibody therapy would help avoid viral escape, while enabling researchers to learn more about the virus’ evolution and immune response in survivors. Based on this approach, 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 suspected samples to be sent to a laboratory with biosafety capabilities. Development of a sensitive, specific, and easily administered diagnostic assay is needed for case confirmation as well as surveillance, epidemiological studies and efficacy assessments in clinical trials.
Pipeline spotlights
In 2021, Inovio commenced Phase II trials of their DNA vaccine INO-4700 in Jordan and Lebanon, supported with funding from CEPI. Ardis Pharmaceuticals announced preclinical efficacy of a pan-coronavirus mAb cocktail (AR-701) showing broad reactivity against COVID-19 variants, SARS and MERS in December 2021. A new ultra-rapid real-time RT-PCR test using a mobile PCR device demonstrated a similar sensitivity and specificity to conventional real-time PCR instruments, detecting MERS-CoV RNA within 20 minutes.
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Mpox
Mpox
Mpox disease (formerly known as monkeypox disease) is a viral zoonotic disease caused by the mpox virus; a member of the Orthopoxvirus genus that also includes variola virus, the causative agent of smallpox. The mpox virus has two distinct genetic clades – Clade I (previously called the Congo Basin (central African) clade and Clade II (the west African clade), the former being more transmissible and causing more severe disease. With the eradication of smallpox, mpox disease has emerged as the orthopoxvirus of global public health importance. The virus is predominately found in sub-Saharan Africa but spread to non-endemic countries in 2022, particularly the Americas and Europe, with more than 86 000 confirmed cases and 116 deaths as of April 2023. This recent clade IIb outbreak, primarily affecting men who have sex with men (MSM), represents the first occurrence of laboratory-confirmed cases and sustained transmission reported in countries without direct or immediate epidemiological links to the endemic West or Central Africa.
Human-to-human transmission results from . It is usually a self-limiting disease characterised by fever, headache, lymphadenopathy and skin lesions. Most infected persons recover within a few weeks without the need for treatment. However, the disease can be severe among dvanced (CD4 count <350 cells/mm3) or untreated HIV infection, young children and pregnant women leading to bronchopneumonia, sepsis, encephalitis, and keratitis with ensuing loss of vision.
R&D needs
There is no approved specific therapy for mpox. Clinical management is primarily targeted at alleviating symptoms, managing complications, and preventing long-term consequences. It has been shown that prior immunization with smallpox vaccines has a protective effect against mpox virus and improves clinical manifestations of the disease.
Detection of mpox viral DNA by PCR using skin lesion samples or a biopsy where feasible is the preferred diagnostic method given its high specificity and sensitivity. PCR blood tests are often inconclusive due to a short viraemia phase of infection in relation to timing of sample collection. Thus, limiting the use of blood specimen in the diagnosis of mpox. Orthopoxviruses are serologically cross-reactive, therefore, serological and antigen detection methods do not provide mpox-specific confirmation or distinguish active infection from prior smallpox vaccinations or other orthopoxvirus infections. As such, these tests are not recommended for use in resource-limited settings. The development of affordable, rapid mpox-specific serology and IgM assays is critical to enable a quick response during outbreaks.
Currently, two vaccines – both based on a live vaccinia virus – are available for use among high-risk adults. These are third generation JYNNEOS, a two-dose vaccine approved by US FDA in 2019 and a second-generation smallpox vaccine – ACAM2000. However, availability for both remains limited. ACAM2000’s use may be associated with unintended disease transmission, serious adverse events and is contraindicated in immunocompromised persons including populations that are at increased risk of unrecognized HIV infection. Thus, making it an unattractive option for use among high-risk populations for mpox disease. Higher generation (4th) mpox vaccines are being explored but these are still in early phase of development.
Therapeutics developed and approved for other poxviruses (mainly smallpox) have typically been repurposed and recommended for use by WHO during outbreaks. Recently, a repurposed antiviral agent, tecovirimat, has been licensed by the European Medicines Agency for mpox disease based on animal and small human safety studies. Chimerix’s Brincidofovir has also completed Phase III trials. However, these drugs are not widely available and large efficacy trials for mpox are still lacking. The recent 2022 outbreak has seen the proliferation of several preclinical and clinical candidates specifically targeted at mpox virus, with most candidates still in early development. Vaccinia immune globulin is the only biologic available and FDA-approved for vaccinia virus in adults and children. However, its use for mpox disease is under the US FDA’s expanded access protocol for orthopoxviruses through the US CDC. While a formal consensus is yet to be reached, WHO has published a draft target product profile (TPP) for mpox therapeutics highlighting the need for a stable, once daily/weekly oral or parenteral formulation effective against all stages of infection. Combination therapy for high-risk groups and antivirals as post exposure prophylaxis (PEP) among close contacts is being considered, for which a separate TPP for PEP has been suggested by WHO’s working group.
Pipeline spotlight
Seegene Inc’s Novaplex MPXV Assay, a real-time polymerase chain reaction (PCR) diagnostic kit, proved 100% specificity and 100% sensitivity in clinical evaluation conducted in Israel. The novel test specifically detects the mpox virus target gene and provides results in 90 minutes.
Disease burden
- Deaths N/A
- DALYs N/A
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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
In the absence of an approved drug, Nipah virus case management relies on supportive care and off-label use of ribavirin, an anti-viral. Nipah infection often involves the central nervous system; therefore, an ideal therapeutic agent should be capable of crossing the blood-brain barrier. Additionally, new drugs are needed for post-exposure prophylaxis. A few small-molecule and biological approaches have been explored; however, the evidence generation involving antivirals such as remdesivir and favipiravir so far is limited to early-stage research using animal models.
The WHO draft Nipah virus vaccine Target Product Profile recommends that an ideal vaccine should have a reactive use-case profile – rapid protection, single dose, high efficacy, thermostability and provision of protection against both strains of Nipah. The current vaccine pipeline is made up of mostly pre-clinical candidates, with only two candidates entering clinical trials. Almost all candidates are monovalent – utilising either the Bangladesh or Malaysia strain.
Even in the absence of an effective vaccine, timely and accurate detection can help in deploying effective non-pharmaceutical 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 cerebrospinal fluid, 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, with specialised laboratories required to handle the isolation of Nipah virus in suspected samples.
Pipeline Spotlight
A monoclonal antibody, m102.4, remains the only novel therapeutic to undergo human trials. Molbio Diagnostics received approval from the Indian regulators for a molecular test based on its TruNat platform to detect NIV has developed. In 2022, PHV02, a recombinant vesicular stomatitis virus based vaccine, became only the second candidate to enter clinical trials.
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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
Research is ongoing for potential therapies and vaccines to prevent Zika virus infection and Congenital Zika Syndromes (CZS). However, further investigation of epidemiology, clinical manifestations, and long-term sequelae of CZS is urgently needed.
The ideal prospective vaccine should be appropriate for both endemic and outbreak settings and have an excellent safety profile in pregnant and lactating women. The most advanced candidate is a DNA vaccine (VRC 705), which completed Phase II trials in October 2019. Multiple additional vaccine candidates are currently in Phase I trials. While the Zika vaccine pipeline has progressed significantly, the low incidence and unpredictable nature of the outbreaks, diversity of clinical manifestations and infeasibility of trials using CZS as the primary endpoint make it difficult to conduct late-stage efficacy trials. Alternative approaches, such as accelerated regulatory pathways with immune correlates or animal rule, Controlled Human Infection Models or surrogates as endpoints are under consideration.
Ideal treatments for Zika should be suitable for both therapeutic use for treating intra-uterine infection and prophylactic use, including prevention of mother to child infections. Even with the licensure of a Zika vaccine, drugs can play a valuable preventive role in areas of low endemicity. Currently, two biologics – a human monoclonal antibody (Tyzivumab) and an immunoglobulin (ZIKV-IG/NP-024) – are the only therapeutics in clinical development. The single biggest challenge in developing Zika therapeutics is the discovery of an agent which is not teratogenic but which can prevent congenital Zika infection.
The diagnostic pipeline for Zika has improved since 2015, with multiple point-of-care (POC) or near-POC molecular and serological assays already approved by the US FDA and WHO under both emergency use and standard pathways. However, none of the FDA approved PoC tests adequately addresses multiplexing with other co-endemic and cross-reacting flaviviruses, such as dengue and Chikungunya.
Aedes mosquito control programmes in Zika-affected countries must overcome urban outdoor transmission and high levels of infestation. Several recent field studies have confirmed reduced incidence of arboviral diseases after implementation of Wolbachia-based microbial control, while as-yet-unvalidated modelling studies suggest high efficacy of genetic manipulation.
Pipeline spotlights
Two repurposed drugs, Asunaprevir and Simeprevir, have exhibited potent antiviral activities in in vitro studies while another broad-spectrum antiviral, Galidesivir, is undergoing preclinical evaluation in macaque apes. Biologics Tyzivumab and ZIKV-IG/NP-024 have successfully completed Phase I trials and are under further clinical development. In 2021, an RNA vaccine, mRNA-1893, entered Phase II trials.
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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 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. Pathogenesis studies using prototype viruses help define target antigens and develop assays; for example, understanding of molecular structures across the flavivirus family was instrumental in rapid translational research during the recent Zika outbreak.
Vaccine platforms include technologies and processes that allow the generation 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. In 2020, a COVID-19 vaccine candidate based on an mRNA platform was identified in just 42 days – an industry record. Other technologies include viral vector- and nucleic acid-based (‘plug and play’) platforms. Self-amplifying mRNA (SAM) technology is being investigated in early-stage clinical trials for the development of second generation COVID-19 vaccines, while a pan-coronavirus vaccine technology based on the Ferritin platform has been developed and is entering Phase I clinical trials. The most advanced platform-based EID vaccine candidates include a prime/boost viral vector-based Ebola vaccine (Ad26.ZEBOV/MVA-BN-Filo) and several COVID-19 vaccines.
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 MATRIX-M, which has been successfully combined with the R21 malaria vaccine candidate and is currently undergoing Phase III trials, and GLA-SE, a TLR4 agonist which has been combined with ID93 TB vaccine candidate in a successful Phase IIa trial.
Biologics- and drug-related platforms are adaptable technologies used for developing gene- and immune-based therapies. Current therapeutics platforms in development include DNA- and RNA-based monoclonal antibody (mAb) platforms and human polyclonal antibodies from transchromosomic bovine systems. This category also includes new delivery drug technologies and devices to simplify administration. Delivery technologies in development include nanoparticle-based drug delivery systems and controlled release formulation technologies such as PLGA micro- and nanoparticles, in situ gelling and liquid crystal formulations.
Broad-spectrum antivirals, which are also included here, are small molecule compounds which inhibit essential machinery of multiple virus families. The pipeline includes favipiravir, an RNA-dependent RNA polymerase inhibitor, UV-4B, an alpha-glucosidase inhibitor and nitazoxanide, an antiprotozoal agent recently investigated in late-stage clinical studies for use in treatment of COVID-19 and influenza.
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 field-appropriate tests. 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. Most recently, eRapid – a low-cost, affinity-based electrochemical sensing platform able to detect and quantify a broad range of viral biomarkers, has been developed and licensed for use in COVID-19 diagnosis.
The multi-disease vector control category captures funding targeting vectors capable of transmitting several different diseases. 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 and has been included in 185 countries’ national infant immunisation schedules. Current nucleos(t)ide analogues are safe, well tolerated and halt transmission; but life-long treatment is needed to avoid relapse. New therapies are aimed at a functional cure – sustained undetectable viraemia with or without antibody production – with multiple drugs and biologic combinations in clinical development. Tools to diagnose and treat HBV remain sub-optimal as standard serological assays detecting HBV surface antigen (HBsAg) are compromised by HIV/HCV co-infection, low HBsAG titres, and S gene mutations/variants. None of the available molecular tests are pre-qualified by WHO, and there is a need for low-cost, point-of-care molecular diagnostics that can quantify viral load, for confirmation of diagnosis, treatment monitoring, detection of drug resistance, and treatment initiation to prevent mother-to-child transmission. Epidemiological research in LMICs is needed to inform approaches to screening, monitoring and treatment, and advance understanding of drug and vaccine escape mutations.
Pipeline spotlight
Vir Biotechnology’s VIR-2218 (a small interfering ribonucleic acid) and VIR-3434 (a monoclonal antibody) in combination with pegylated interferon-α and GSK’s bepirovirsen (an antisense oligonucleotide) recently showed promising results for seroclearance and hepatitis B surface antibody production, a feature not observed in current treatments. Both treatments belong to the novel post-transcription inhibitor class.
Disease burden
- Deaths 2019 510K
- DALYs 2019 17M
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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 2020, the majority in LMICs. The virus attacks and destroys CD4 cells in the human immune system; without treatment, infected individuals become increasingly susceptible to other diseases, and eventually develop acquired immune deficiency syndrome (AIDS). People with AIDS often die from opportunistic infections like tuberculosis or cryptococcal meningitis, or cancers like Kaposi’s sarcoma.
R&D needs
There is currently no vaccine against HIV, due to the challenge posed by the virus’ genetic elasticity. All Phase III candidates so far have failed to demonstrate efficacy, with the most recent Phase III trial (Mosaico) discontinued in January 2023 after disappointing interim results. Passive immunisation with biologics such as monoclonal antibodies (mAbs) remain promising, with WHO and IAVI publishing preferred product characteristics to guide R&D. AMP mAb trials demonstrated proof of concept, though revealed that one monoclonal antibody alone is insufficient. Microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool, with the dapivirine vaginal ring included in WHO’s prequalification list in 2020. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially for early infant diagnosis. However, there is progress towards robust, point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates.
Pipeline spotlight
The South African Health Products Regulatory Authority was the first to approve a ‘4-in-1’ fixed-dose combination for paediatric HIV in June 2022. The single, easy-to-use granule-filled capsule is taste-masked and can be sprinkled into the child’s food. IAVI, NIAID and Moderna commenced Phase I trials in March 2022 of three mRNA-based vaccines leveraging COVID-19-tested technologies.
Disease burden
- Deaths 2019 849K
- DALYs 2019 47M
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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