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 are increasingly being rolled out in lower-income countries with Gavi support. However, they are typically expensive to manufacture, and there is an ongoing need for low-cost candidates targeting LMIC serotypes, as gains from existing PCVs are threatened by serotype replacement. Non-conjugate protein- and whole-cell based vaccines are two potential approaches offering broad protection and cheaper costs, while in 2019 WHO prequalified PNEUMOSIL, a 10-valent PCV candidate for $2/dose. Since the introduction of the MenAfriVac monovalent conjugate meningitis A vaccine, meningitis A infection rates have plummeted across the African continent. Other serogroups have become more prominent however, creating the need for low-cost polyvalent vaccine candidates such as PATH/SII’s NmCV-5. Diagnostics are also needed, including RDTs that can detect serogroups to guide vaccine response, as well as multi-pathogen point-of-care tests to guide case management in both epidemic and endemic settings.
Pipeline spotlight
Following the successful prequalification of their affordable 10-valent pneumococcal conjugate vaccine (PNEUMOSIL) in December 2019, PATH and the Serum Institute of India have just completed a Phase III trial of their low-cost pentavalent meningitis conjugate vaccine, NmCV-5. Phase II results suggest it could be effective as a single dose.
Disease burden
- Deaths 2017 1.2M
- DALYs 2017 65M
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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
Current diagnostics are costly, complex and unsuitable for the point of care in endemic areas. There is a need for simple rapid diagnostic tests to allow prompt diagnosis at the community level. Several tests are currently under development, including the BU-MYCOLAC Rapid Test and Aptagen’s point-of-care diagnostic based on RNA aptamers. Recent research calls for ongoing monitoring to detect any emerging drug-resistant strains, highlighting the need for new drugs that can be given in an intermittent or shorter period. One recent study demonstrated that an 8-week all-oral drug regimen was non-inferior to the traditional oral/injectable treatment, while Telacebec, an investigational TB drug, shows promise as a single-dose candidate with the potential of reducing treatment period to 2 weeks. There is currently no approved vaccine for Buruli ulcer. The (anti-TB) BCG vaccine provides short-term protection, but is not an adequate substitute for a specifically targeted vaccine; current vaccine development efforts are in the very early preclinical phase.
Pipeline spotlight
Funded by GHIT, FIND and collaborating partners are conducting field evaluation of the first mycolactone-specific prototype rapid diagnostic test (BU-MYCOLAC RDT). Meanwhile, the US FDA has granted orphan and fast track status to Qurient’s Telacebec drug for Buruli ulcer, with planning underway for a global Phase II trial.
Disease burden
- Cases 2020 1.2K
- DALYs and Deaths Unknown
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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 requires careful blood monitoring. As a result, most developing countries resort to fluconazole use, which is only partially effective. Notwithstanding the AMBITION-cm findings, there remains a need for affordable, efficacious drugs that are adapted for resource poor settings. New antifungal agents, repurposed drugs and immunotherapies targeting various biochemical processes are in different stages of development, with many candidates showing promising activity against cryptococcal meningitis. Two such candidates are Mycovia Pharmaceutical’s VT-1129 and VT 1598, which have both progressed to clinical stages of development. Clinical trials are also being conducted on new oral formulations of amphotericin B (MAT2203). Monoclonal antibodies and immunomodulators alone or in combination with antifungal agents have been investigated, but there are currently no biological candidates in clinical trials.
Pipeline spotlight
Results from the Phase III AMBITION-cm trial showed that a single, high-dose of AmBisome (liposomal amphotericin B) combined with seven days of oral flucytosine and fluconazole was non-inferior to – and safer than – the current WHO recommended standard of care, providing an easier to use and better tolerated treatment regimen for developing countries.
Disease burden
- Deaths 2014 181K
- DALYs Unknown
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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
Point-of-care antigen and antibody serological tests are available, but cannot distinguish between serotypes, lack optimal sensitivity and specificity and exhibit serotype-specific performance discrepancies. There is a pressing need for diagnostics that can distinguish between current and previous infection, and distinguish dengue from other causes of fever, as well as RDTs for serostatus screening. Effective therapeutic options are also needed, although most curative candidates – including direct acting antivirals and broadly neutralising monoclonal antibodies –are still in the preclinical phase. Finally, there is a need for new and improved vector control products targeting the Aedes mosquito, including adulticidal oviposition traps and space spray insecticides, as well as biological control tools such as Wolbachia and genetic manipulation (with field experiments currently ongoing across Asia and Latin America). Dengue’s prevalence in high- and upper-middle-income countries has been sufficient to attract commercially focused industry investment in vaccine R&D; this category has therefore been excluded from the G-FINDER scope.
Pipeline spotlight
A biological control tool – Wolbachia (wMel)-infected Aedes aegypti became the first intervention targeting dengue-carrying mosquitoes to receive a positive assessment of public health value by the WHO advisory committee. The CDC’s Trioplex qPCR – a real-time multiplex PCR capable of detecting dengue, Zika and Chikungunya simultaneously – has been shown to have high sensitivity and specificity in a geographic area with a current dengue outbreak. Meanwhile, the monoclonal antibody candidate HUMab 3G9 exhibited neutralising properties against all dengue serotypes.
Disease burden
- Deaths 2019 36K
- DALYs 2019 2.4M
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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
Available vaccines against diarrhoeal diseases are mostly oral, live attenuated candidates, which are sometimes ineffective, and may be unsuitable for infants. Novel multivalent vaccines are needed, which confer longer-term protection in high-burden settings and are suitable for infants. Such next-generation candidates for rotavirus include non-replicating parenteral vaccines, the most advanced being PATH’s trivalent NRRV (P2-VP8) candidate, currently in Phase III trials. Others including CureVac’s mRNA rotavirus vaccine remain in preclinical development. Supportive therapy including oral rehydration therapy and zinc supplementation remain the mainstay of management in LMICs but are insufficient in many cases. Safe, affordable, and effective pathogen-specific drugs are needed to improve treatment options for these diseases. The therapeutic pipeline currently includes both small molecule drugs and biologics, which remain in preclinical development. Likewise, multiplex rapid diagnostic tests able to diagnose multiple diarrhoeal diseases as well as differentiate between them are needed, however, no candidate is in late-stage development.
Pipeline spotlight
ShigETEC, the novel live attenuated combined Shigella and ETEC oral vaccine candidate developed by Eveliqure Biotechnologies, was found to be safe and induced robust immune response in a recently concluded Phase I clinical trial. The company also recently received NIH funding to advance the candidate into Phase II human challenge studies.
Disease burden
- Deaths 2019 1.0M
- DALYs 2019 46M
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Helminth infections
Helminth infections
Helminths are parasitic worms and flukes that can cause disease in humans. The most common mode of transmission to humans is through ingesting or coming into contact with contaminated food, water, or soil. Helminth infections transmitted in this manner include ancylostomiasis and necatoriasis (hookworm), ascariasis (roundworm), trichuriasis (whipworm) and strongyloidiasis (intestinal roundworms) – collectively referred to as soil-transmitted helminths – as well as taeniasis/cysticercosis (tapeworm) and schistosomiasis (bilharziasis, also known as snail fever). Other helminth infections are transmitted by bites of blood-sucking arthropods: these include lymphatic filariasis, which is transmitted by mosquitoes, and river blindness (onchocerciasis), which is transmitted by the black fly.
Adult worms can reside in the intestines and other organs, causing malnutrition and impaired cognitive development (hookworms), or progressive damage to the bladder, ureter and kidneys (schistosomiasis). Onchocerciasis is a major cause of blindness in many African and some Latin American countries, while lymphatic filariasis can cause painful, disfiguring swelling of the scrotum (hydrocele) and limbs (elephantiasis).
R&D needs
With no vaccines, disease control efforts currently rely on mass-drug administration. Variable drug efficacy and the need to control transmission mean that treatment programmes must continue for many years, increasing the risk of drug resistance. New and more effective drugs are needed, as are paediatric formulations of existing drugs. Moxidectin, the first new onchocerciasis treatment in 20 years received FDA approval in 2018. Promising clinical candidates include emodepside and oxfendazole for onchocerciasis, tribendimidine for hookworm, and TylAMac for filarial diseases. Vaccine development has proved a challenge: for schistosomiasis, the most advanced vaccine candidate, rSh28GST showed insufficient efficacy in a Phase III trial. Clinical development of the most promising candidate antigen, Sm-p80 is currently underway. Other promising candidate antigens for multiple helminth infections are in preclinical/Phase I stages of development. Current diagnostic products are outdated or complex. As such, new and effective diagnostics that can measure infection intensity and detect drug resistance are urgently needed.
Pipeline spotlight
In 2021, Merck KGaA and the Pediatric Praziquantel Consortium successfully completed a pivotal Phase III trial for an orally dispersible form of arpraziquantel in preschool-aged children, which achieved clinical cure while showing favourable safety, tolerability and improved palatability. They plan to apply for a scientific opinion by EMA under the EU-M4all scheme.
Disease burden
- Deaths 2019 15K
- DALYs 2019 7.7M
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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
A highly effective vaccine against HBV exists, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal. Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis, however their sensitivity is significantly compromised by HIV/HCV co-infection, low HbsAG titres, and S gene mutations/variants. Available drugs are generally safe and well tolerated, however lifelong treatment is generally required; as a result there is significant interest in development of a functional cure. There is also a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load, for confirmation of diagnosis, treatment monitoring and detection of drug resistance. Finally, there is a need for additional basic research to inform approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs.
Pipeline spotlight
Multiple drug and biologic candidates aimed at functional cure are currently in clinical development, with new approaches including combined siRNA/mAb regimens recently entering Phase II trials. A therapeutic vaccine candidate (TherVacB) has been successfully tested preclinically, and will commence a Phase I/II clinical trial in 2022.
Disease burden
- Deaths 2019 510K
- DALYs 2019 17M
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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 women. Despite extensive research efforts, development of a protective vaccine has not been achieved. In a recent study, vaccine candidate AdCh3NSmut1 and MVA-NSmut applied in a prime/boost regimen, failed to prevent chronic infection with HCV in a high-risk population of IV drug users, while other vaccine candidates, containing E1/E2 glycoproteins, have not matured beyond the stage of preclinical/early clinical development. There is also a need for HCV diagnostic tests that are affordable and simple to use in developing country contexts, especially tests for treatment monitoring, screening and tests of cure.
Pipeline spotlight
In June 2021, Malaysia approved ravidasvir, a low-cost, pan-genotypic direct-acting antiviral (DAA) for use in combination with sofosbovir, an existing DAA. Developed in partnership by DNDi and two LMIC-based pharmaceutical companies, the regimen is intended to provide a much more affordable treatment option than the currently available regimens on the market.
There is no vaccine against HCV, although there are some pan-genotypic candidates in early-stage development, such as the Burnet Institute’s HepSeeVaxDelta3 candidate. Only two candidates have reached clinical development and both have been unsuccessful: GSK’s GSK3378455A and NIAID’s AdCh3NSmut1/MVA-NSmut.
Disease burden
- Deaths 2019 412K
- DALYs 2019 12M
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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 initiation of treatment are critical for histoplasmosis management, as untreated or delayed disseminated histoplasmosis is often fatal. Conventional methods of diagnosis are laboratory based, making them unsuitable in low-resource settings. There is a need for highly sensitive and specific point-of-care diagnostic tests for Histoplasma diagnosis. MiraVista Diagnostics’ recently launched antigen-based lateral flow assay is one such test. Other similar test kits are needed to drive commercial availability, particularly in LMICs. Clinical guidelines for histoplasmosis management recommends a year-long treatment with liposomal amphotericin B and itraconazole. Though effective, liposomal amphotericin is a parenteral drug that is not heat stable, while itraconazole has drug-drug interactions with anti-tubercular and anti-retroviral medications, necessitating monitoring of its blood concentrations, thus limiting their use in LMICs. Thus, there is a need for new treatment regimens, preferably oral, with shorter duration, that are safe in combination with other drugs. Most investigational agents including are in early-stage development.
Pipeline spotlight
In 2020, MiraVista Diagnostics launched the world’s first lateral flow assay for Histoplasma antigen detection in serum and urine samples. This point of care test has subsequently been validated by several clinical studies with positive results.
Disease burden
- DEATHS Unknown
- DALYS Unknown
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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, and the rapid mutation of the virus poses a significant challenge to development. Currently, only one large HIV vaccine efficacy trial is underway: a global Phase III HVTN 706. Two other large HIV vaccine efficacy studies, HVTN 705 and HVTN 702 have both ceased due to non-efficacy. Despite advances in HIV therapeutics, R&D gaps for HIV drugs persist in LMICs, including paediatric formulations or long-acting injectable drugs for PrEP, with promising progress underway, including both small molecule and broadly neutralising anti-HIV antibody (bNAb) based approaches. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially early infant diagnosis. However, there is progress towards robust, point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates.
Pipeline spotlight
Following EMA approval and WHO prequalification in 2020, the International Partnership for Microbicides’ dapivirine vaginal ring (DPV-VR) was recommended by WHO and approved by the South African regulator as an additional prevention choice for women at substantial risk of HIV. A newly developed AIOD-CRISPR assay system was able to successfully detect nucleic acids of both SARS-CoV-2 and HIV.
Disease burden
- Deaths 2019 849K
- DALYs 2019 47M
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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
No human vaccine exists for any of the three kinetoplastid diseases (Chagas’ disease, leishmaniasis and HAT), and current development efforts are relatively early stage, with all current candidates still in the preclinical or early clinical phases. There is a need for new diagnostic tests – particularly point of care tests – for all three diseases, including tests for cure, and for monitoring chronic or second stage disease. In leishmaniasis, HIV co-infection constitutes a diagnostic challenge, as most existing RDTs exhibit reduced sensitivity in co-infected patients. Simplification of diagnosis is also needed, with appropriate role for different tests currently being evaluated in operational studies. There is a need for improved, preferably oral, drug formulations for leishmaniasis, and safer, more effective drugs for Chagas’, which are suitable for children and pregnant and breastfeeding women. Biologics and therapeutic vaccines may also have a role to play, particularly for Chagas’ disease.
Pipeline spotlight
The BENDITA trial showed no benefit from fosravuconazole in treating Chagas’ disease, but showed a two week regimen of benzidazole is just as effective as the current eight week course. Acoziborole is being tested in a Phase II/III trial as a single dose cure against HAT caused by T.b. gambiense.
Disease burden
- Deaths 2019 16K
- DALYs 2019 1.0M
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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
Current drug regimens used for leprosy treatment, though effective, require prolonged treatment of 6-24 months. There is an ongoing need for new drugs with simpler regimens, shorter treatment duration and which provide nerve function improvement. BCG represents the best available preventive vaccine for leprosy, but has only a modest ability to prevent leprosy (26% in observational studies, 41% in experimental studies), and post-exposure BCG immunisation may cause paucibacillary disease in some individuals. Modern vaccines are needed that confer both pre- and post-exposure immunoprophylaxis against leprosy without exacerbating nerve damage. LepVax is one such candidate currently in Phase Ib/IIa clinical development. Leprosy diagnosis is primarily based on identifying key clinical features, leading to late diagnosis of asymptomatic cases and continued disease transmission. New and improved diagnostics are needed capable of identifying both asymptomatic and symptomatic cases of all forms. Leiden University recently prototyped a multi-biomarker finger prick point-of-care lateral flow diagnostic test, currently in pilot testing.
Pipeline spotlight
Following successful Phase Ia clinical trials, leprosy vaccine candidate LepVax is due to start Phase Ib/IIa trials in Brazil in early 2022. Meanwhile, AMG 634, a drug candidate initially developed by AMGEN and Leprosy Mission Nepal, was licensed to the Medicines Development for Global Health in 2020 for further clinical development.
Disease burden
- Deaths 2019 0
- DALYs 2019 29K
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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
Effective, appropriate drugs exist for leptospirosis, meaning that infection can be successfully treated if diagnosed. However, diagnosing leptospirosis can be challenging due to the non-specific symptoms of early infection as well as asymptomatic infection in some affected individuals. Accurate diagnosis of leptospirosis during the acute phase of the disease is currently only possible with sophisticated laboratory tests, which are unsuitable for remote settings. There is a real need for new, easy-to-use tests that can quickly and accurately diagnose acute infection in the field. Several rapid point-of-care tests are available on the market, but none of these are widely approved due to their lack of specificity and sensitivity. The promising diagnostic LEPkit assay has demonstrated higher sensitivity and specificity than existing rapid diagnostic tests, but its development status has not been updated since 2017.
Pipeline spotlight
A novel Onsite Leptospira IgG/IgM Combo Rapid Test has been developed by CTK Biotech to be used for the simultaneous detection and differentiation of IgG and IgM antibodies to Leptospira interrogans in human samples – serum, plasma or whole blood – aiding in the early diagnosis of leptospirosis in resource-limited settings.
Disease burden
- Deaths 2015 59K
- DALYs 2015 2.9M
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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, as well as vaccines that can provide protection against P. vivax, and/or block transmission. New drugs are needed in response to emerging resistance and to meet the needs of key populations, as well as for chemoprotection, and – ideally – to meet the goal of a single-dose treatment. In addition to small molecule drugs, monoclonal antibodies (mAbs) are being investigated. There is an urgent need to develop new rapid diagnostic tests in response to emerging pfhrp2/3 gene deletion in malaria parasites, as well as a need for more sensitive diagnostics to identify non-falciparum species, distinguish malaria from other febrile illnesses, detect asymptomatic cases, and diagnose G6PD enzyme deficiency. Next-generation vector control products are needed in response to emerging pyrethroid resistance, including genetic approaches to reduce mosquito populations or block parasite transmission, as well as endectocides for malaria transmission control.
Pipeline spotlight
In October 2021, based on pilot programmes in Malawi, Kenya and Ghana – and following shortly after a Phase III trial showed its effectiveness in significantly reducing malaria mortality when combined with chemoprevention – WHO recommended the use of RTS,S/AS01E for children in areas with moderate to high P. falciparum malaria transmission.
Disease burden
- Deaths 2019 643K
- DALYs 2019 46M
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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
Despite the availability of several drugs for mycetoma treatment, including the antifungals ketoconazole and itraconazole, and antibiotics amikacin and co-trimoxazole, significant R&D gaps still exist in Mycetoma treatment. Antifungals targeting eumycetoma are only 25-35% effective, are costly, and require year-long administration with serious side effects. There is a need for more efficacious drug regimens, with shorter duration, lower costs and fewer side effects, for use in high-burden settings. Recently, the DNDi-supported MycetOS project identified at least 287 compounds active against mycetoma, with fenarimol being the most potent in vitro, while niclosamide was also shown to have good activity in preclinical studies. Existing mycetoma diagnostic tools are invasive, time-consuming, and laboratory-based, and are thus inappropriate for LMIC use. There is a need for cheap, rapid and accurate point-of-care diagnostics to facilitate early mycetoma diagnosis. In 2020, the Global Health Innovative Technology Fund supported the MycEXomics project, which aims to develop field-friendly point-of-care diagnostic tests for mycetoma.
Pipeline spotlight
Niclosamide, a broad-spectrum anthelmintic on the WHO Essential Medicines List, was recently shown to be active in vitro against Madurella mycetomatis, the main causative agent of eumycetoma in Sudan, and Acinetomadura spp., the causative agent of actinomycetoma.
Disease burden
- Deaths Unknown
- DALYs Unknown
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Rheumatic fever
Rheumatic fever
Rheumatic fever is a bacterial infection caused by Streptococcus pyogenes (also known as Group A streptococcus, GAS) that most commonly affects children aged 5-14 years. It usually follows untreated bacterial throat infections, and without treatment can lead to complications such as rheumatic heart disease, in which the heart valves are permanently damaged. It may also progress to heart failure and stroke.
R&D needs
Acute rheumatic fever can be treated using currently available drugs (although post-infection prophylaxis requires multiple doses of antibiotics), however, treatment of rheumatic heart disease often requires surgery. The main R&D required is therefore the development of a vaccine. Progress to date has been slow, with only four candidates progressing to clinical stages of development. There have been no recent updates identified for two of these candidates: StreptAvax, a 26-valent vaccine whose immunogenicity and safety was first confirmed in a Phase II clinical trial in 2004; and MJ8VAX(J8), where a 2018 Phase I clinical trial indicated the need for additional investigations to optimise its immunogenicity and improve dosing. A planned Phase I clinical trial for StreptInCor, another GAS vaccine candidate that showed promising results in diverse animal models, was withdrawn in February 2021. Positive Phase I results for StreptAnova, a 30-valent vaccine (which completed Phase I in 2017) were published in 2020.
Pipeline spotlight
A research collaboration led by the Murdoch Children’s Research Institute (MCRI) has developed the first controlled human infection model for Group A streptococcus (GAS). It will shortly be used to evaluate a GAS vaccine being developed by the Australian Strep A Vaccine Initiative (ASAVI), a partnership between MCRI and the Telethon Kids Institute.
Disease burden
- Deaths 2019 274K
- DALYs 2019 10M
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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
The rise of antimicrobial resistant S. typhi strains linked to the H58 clade is threatening the efficacy of existing drugs. There is a need for better surveillance of these resistant strains, and the development of novel, efficacious drugs, especially those suitable for children. The WHO recommends typhoid conjugate vaccines (TCVs) as the preferred vaccine for use in high-burden countries, and in 2018, Typbar TCV became the first TCV to achieve WHO prequalification, followed by TYPHIBEV in 2020, both of which are effective in children, and in high burden settings. There are however no approved bivalent vaccines targeting both typhoid and paratyphoid fever, nor any monovalent vaccines targeting paratyphoid fever specifically. Phase II trial results were recently published for the most advanced candidate CVS 1902. There are also no approved NTS vaccines, with all candidates in early-stage development. Given the threat of drug resistance, biologic R&D remains a need, with several monoclonal antibody cocktails in preclinical development.
Pipeline spotlight
TYPHIBEV, the Vi-polysaccharide typhoid conjugate vaccine (TCV) developed by Biological E, received WHO prequalification in 2020, becoming the second TCV to achieve this since 2018. Two other TCVs – edaTyph (Bio-Med) and ZyVac TCV (Cadila Healthcare) have been licensed for use in India, but have not been submitted for WHO prequalification.
Disease burden
- Deaths 2019 212K
- DALYs 2019 16M
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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 high price and limited availability of the most efficacious scabicide (permethrin 5% cream), many LMICs often rely on less effective and less well-tolerated alternatives, such as benzyl benzoate and sulphur ointments. Oral ivermectin is highly effective against scabies but does not kill scabies eggs, necessitating repeat doses and increasing the difficulty of mass drug administration (MDA) interventions. Additionally, ivermectin’s use is contraindicated for children weighing less than 15kg, and pregnant and breastfeeding women. New oral drugs are urgently needed that have prolonged skin activity, thereby effectively killing newly hatched eggs, and a proven safety profile in children and pregnant women. Moxidectin, a US FDA-approved antiparasitic agent related to ivermectin, is currently undergoing Phase II clinical trials. There is also a need for a low-cost point-of-care test for individual level diagnosis and management, to facilitate mapping and surveillance at the population level and monitor potential mites’ resistance towards ivermectin-based mass drug administration.
Pipeline spotlight
Following positive results from two Phase III trials, a new topical treatment (spinosad 0.9%) received US FDA approval in 2021. Medicines Development for Global Health is currently evaluating the oral drug candidate moxidectin in dose-finding trials in France, Austria and Australia. A Phase IIb trial is planned for 2022.
Disease burden
- Deaths 2019 0
- DALYs 2019 4.8M
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Snakebite envenoming
Snakebite envenoming
Snakebite envenoming results from the bite of a venomous snake, and if not treated quickly and effectively can result in life-long disability, or lead to amputation or death. Snakebite envenoming is prevalent in tropical and sub-tropical regions in Africa, Asia, Oceania and Latin America. Snakebite envenoming was included in the G-FINDER report for the first time in the 2019 report.
R&D needs
Antivenoms can be highly effective against snakebite envenomation if given at the right time, at the right dose, and for the right snake. However, they are expensive to manufacture, can be complex to administer and store, and carry the risk of adverse reactions. There is a need for R&D to support the approval and introduction of safe, effective, high-quality and geographically appropriate antivenoms, as well as to deliver next generation antivenoms that are more effective, more affordable, safer and heat stable. In low-resource settings, heat-stable venom-agnostic oral drugs are also needed as a first-line therapeutic to slow down neurotoxicity and prolong the window for victims to receive antivenom. Broad-spectrum small molecule inhibitors could help bridge this gap: varespladib has progressed to Phase II clinical trials and shows promise as therapy against venom-induced myonecrosis and haemorrhagic toxicity. Affordable, rapid, point-of-care diagnostics capable of identifying common species in high-burden areas, with low to no cross reactivity between venoms are also needed.
Pipeline spotlight
Indriyam Biologics Pvt. Ltd. has designed a ‘V-sens’ snake venom detection biosensor capable of identifying species-specific venom within minutes. The EC is funding the MABSTER project with the aim of discovering therapeutic human monoclonal antibodies that are recyclable, broadly cross-reactive, and capable of doing both simultaneously.
Disease burden
- Deaths 63K
- DALYs Unknown
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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 major development, given the challenges associated with successful implementation (and sustainability) of the SAFE (surgery; antibiotics; facial cleanliness; environmental improvement) strategy, which is the only currently available tool to reduce trachoma transmission. The most advanced trachoma vaccine candidate is NIAID’s live-attenuated (plasmid-deficient) trachoma vaccine which is still in preclinical development. Clinical diagnosis of trachoma is not always reliable, and current diagnostic tests are expensive and complex to use. Studies have shown that an antibody-based multiplex assay could be used to diagnose trachoma in low-prevalence settings. One candidate, the Pgp3 LFA-cassette, has been evaluated in field studies in Nepal, showing high specificity (99%) but low sensitivity (40%).
Pipeline spotlight
DjinniChip, a novel, rapid, low-cost molecular assay for diagnosing ocular C. trachomatis has demonstrated promising results during clinical testing, particularly in its ability to detect low concentrations of C. trachomatis and its usability in poorly resourced field conditions. This device was developed by the Fraunhofer IZI MicroDiagnostics Unit in Germany.
Disease burden
- Deaths 2019 0
- DALYs 2019 0.2M
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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
Despite recent improvements in diagnostic tools, TB is still lacking a reliable and accessible point-of-care test. There is also a need for improved tests to diagnose TB in children, and to test for drug resistance and susceptibility. The existing TB vaccine (BCG) is still in widespread use, but provides limited protection against pulmonary disease in adults. A vaccine which provides protection against all forms of TB in all age groups is needed; current efforts target one or more of prevention of infection, prevention of disease, or prevention of recurrence. New drugs are needed that can shorten treatment, work against both drug-sensitive and drug-resistant TB, are suitable for all age groups, are safe to use in conjunction with HIV treatments, and can be used in new treatment paradigms, including treatment of latent TB and MDR-TB prophylaxis. Therapeutic vaccines and other biologics are also a potential tool to simplify and shorten TB treatment.
Pipeline spotlight
In the TB Practecal Phase II/III trial, a new shorter, all oral regimen containing the new chemical entity pretomanid proved to be superior to the current standard of care for DR-TB. More than 14 preventive vaccine candidates are under development, with Immuvac and VPM1002 being currently tested in a large Phase III trial in India.
Disease burden
- Deaths 2019 1.2M
- DALYs 2019 47M
Emerging infectious diseases
Policy Cures Research began gathering data on R&D targeting emerging infectious diseases in response to the 2014 West African Ebola epidemic. In our 2015 G-FINDER survey and report (looking at investments made in 2014), this focused exclusively on Ebola R&D. Since then, we have adopted a progressively broader scope in each subsequent year, determined in consultation with the G-FINDER Advisory Committee and a separate emerging infectious diseases Expert Advisory Group.
Our current definition of emerging infectious diseases closely follows the list of priority diseases endorsed by the 2018 World Health Organization research and development Blueprint for action to prevent epidemics (the Blueprint), including its expansion in early 2020 to include COVID-19. The survey also gathers data on emerging infectious diseases and disease groups not included in the Blueprint priority list, including several pathogens which have been considered for inclusion.
Compared to our neglected disease definition, our definition of emerging infectious diseases has very few restrictions. R&D for almost all product development categories (drugs, vaccines, biologics, and diagnostics) is included without further restrictions for all priority emerging infectious diseases pathogens, as is basic research. R&D for vector control products is included where relevant.
A comprehensive explanation of all current inclusions, exclusions and restrictions, as well as changes to the scope over time, is provided by the emerging infectious disease scope document.
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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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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
A highly effective vaccine against HBV exists, and has been included in the national infant immunisation schedule of 185 countries. However, tools to diagnose and treat HBV are sub-optimal. Serological assays detecting HBV surface antigen (HBsAg) have been the mainstay of HBV screening and diagnosis, however their sensitivity is significantly compromised by HIV/HCV co-infection, low HbsAG titres, and S gene mutations/variants. Available drugs are generally safe and well tolerated, however lifelong treatment is generally required; as a result there is significant interest in development of a functional cure. There is also a need for robust, low-cost, point-of-care molecular diagnostics that can quantify HBV viral load, for confirmation of diagnosis, treatment monitoring and detection of drug resistance. Finally, there is a need for additional basic research to inform approaches to HBV screening, monitoring and treatment in LMICs, such as studies on the epidemiology of HBV drug and vaccine escape mutations in LMICs.
Pipeline spotlight
Multiple drug and biologic candidates aimed at functional cure are currently in clinical development, with new approaches including combined siRNA/mAb regimens recently entering Phase II trials. A therapeutic vaccine candidate (TherVacB) has been successfully tested preclinically, and will commence a Phase I/II clinical trial in 2022.
Disease burden
- Deaths 2019 510K
- DALYs 2019 17M
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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, and the rapid mutation of the virus poses a significant challenge to development. Currently, only one large HIV vaccine efficacy trial is underway: a global Phase III HVTN 706. Two other large HIV vaccine efficacy studies, HVTN 705 and HVTN 702 have both ceased due to non-efficacy. Despite advances in HIV therapeutics, R&D gaps for HIV drugs persist in LMICs, including paediatric formulations or long-acting injectable drugs for PrEP, with promising progress underway, including both small molecule and broadly neutralising anti-HIV antibody (bNAb) based approaches. In addition, microbicides – preventive tools designed to block transmission of HIV through the vaginal or rectal mucosa – have shown promise as a complementary tool. Current methods for early diagnosis are often not adapted to, or suitable for, developing countries, especially early infant diagnosis. However, there is progress towards robust, point-of-care diagnostics, culminating in the recent WHO prequalification of several promising candidates.
Pipeline spotlight
Following EMA approval and WHO prequalification in 2020, the International Partnership for Microbicides’ dapivirine vaginal ring (DPV-VR) was recommended by WHO and approved by the South African regulator as an additional prevention choice for women at substantial risk of HIV. A newly developed AIOD-CRISPR assay system was able to successfully detect nucleic acids of both SARS-CoV-2 and HIV.
Disease burden
- Deaths 2019 849K
- DALYs 2019 47M
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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