Pathogens
About Tuberculosis (TB)
Tuberculosis (TB) is a disease caused by a bacterium, Mycobacterium tuberculosis (M.tb), and is found worldwide. In 2015 10.4 million people developed TB and 1.8 million died, making TB the greatest global infectious disease cause of death, killing more people every year than HIV or malaria.
Aside from causing death TB impairs general health, resulting in reduced economic productivity and increased social and medical burdens on families. The World Health Organisation estimates 100 million disability adjusted life years are lost due to TB in India alone. The average total cost to a patient with TB in a low/middle-income country is US$538-1268, which is equivalent to a year’s wages for many sufferers. Furthermore, animal disease such as bovine (cow) TB also has a very significant effect on people’s livelihoods and the economic development of low and middle-income countries.
Where is TB found?
TB occurs in every part of the world. In the UK, where TB used to kill 1 in 4 people in Victorian times, only around 6,000 people now develop TB each year. TB is a disease of poverty. The highest rates today are in sub-Saharan Africa, in countries such as South Africa (world map of TB disease).
Around one-third of the world’s population is latently infected with M.tb, which means they have been infected but do not yet have active TB disease. Latently infected people have a 10% chance of developing active TB during their lifetime, and becoming ill. This risk increases if they are also infected with HIV.
Mycobacterium tuberculosis (credit: CDC)
How is TB spread?
TB is spread by inhaling bacteria that have been coughed, sneezed or spat into the air.
What are the symptoms of TB?
TB usually affects the lungs causing symptoms such as coughing, fever, tiredness and weight loss, but it can also affect other parts of the body such as the spine and brain (NHS symptoms page). Eventually TB leads to death.
Is TB curable?
TB is curable but drug-resistant strains of the bacteria are increasing (map). Treatment takes six months, is very costly, and can have unpleasant side effects, while treatment of drug resistant strains of M.tb can take up to two years. So developing a vaccine that could prevent TB infection is an important global public health goal - reducing global TB rates by 90% by 2030 is UN Sustainable Development Goal #3.
Vaccines against TB
The current TB vaccine is called BCG (Bacille Calmette-Guérin). BCG has been administered globally to several billion people, but it is over 90 years old and does not protect well against pulmonary (lung) TB. Pulmonary TB has the highest mortality and morbidity rates, so an improved vaccine is essential.
VALIDATE
At the VALIDATE Network, by bringing together TB researchers from around the world we hope to speed up progress towards an improved vaccine against this deadly disease.
Further Information:
‘Exposed: The Race Against TB’ – informative and interesting short films about TB and TB research
Medicins Sans Frontieres (MSF) - information and videos
World Health Organisation – Status of the Global TB Epidemic and Response infographic
World Health Organisation - End TB Strategy document
Mycobacterium tuberculosis (M.tb) is a pathogen with worldwide preponderance, which infects humans causing tuberculosis (TB), a transmissible disease resulting in very high mortality and morbidity. M.tb can also infect cattle and cause bovine TB and is very closely related to Mycobacterium bovis, which causes most bovine TB.
It is estimated that a third of the world’s population is latently infected with M.tb, and these people carry a 10% lifetime risk of developing active life-threatening disease (Dye 1999). In 2015, there were 10.4 million new cases worldwide and 1.8 million people died of TB (WHO 2015). Co-infection with human immunodeficiency virus (HIV) greatly increases risk of TB reactivation and death (Corbett 2006, Colditz 1994). The emergence of drug resistant strains of M.tb has further compounded the problem. The diagnosis of TB is challenging and drug treatment can be prolonged, harmful, costly and complex. For these reasons an effective vaccine is a global public health priority. An effective vaccine could revolutionise TB control (McShane 2011).
The challenges of developing a TB vaccine
Developing an effective TB vaccine is not easy. We already have a vaccine, BCG, which is one of the world’s most widely used vaccines. BCG was first developed in 1921. When given at birth, BCG is good at protecting against severe disease in childhood. However the protection it confers against lung disease, particularly in adults, is highly variable. We urgently need a more effective vaccine.
Some of the scientific challenges in TB vaccine development are:
Lack of immune correlates
For some vaccines, we know exactly the level of a particular kind of immune response that is needed for the vaccine to work – i.e. to stop someone getting disease. For TB, we do not know what kind of immune response is needed, let alone what level of response is required. This means we can only test if a vaccine works in humans by doing large, expensive and time consuming human efficacy trials. This limits the number of vaccines that can be tested in humans.
Fluorescent acid-fast stained smithwick photomicrograph of Mycobacterium tuberculosis (credit: CDC)
Uncertain predictive value of animal models
It is not possible to test a vaccine in humans without testing it first in animals. However we do not know which if any of the animal models best predicts efficacy in humans. Again, this means we can only determine if a vaccine will work in humans by testing it in large, expensive, human efficacy trials.
Difficulty of working with TB in the lab
M.tb is a highly infectious pathogen, which means we can only safely work with it in the lab using special containment measures (called Category or BSL 3). This limits the number of laboratories that can work on M.tb.
The variable efficacy of BCG
The currently available vaccine, BCG, works very well in the UK but does not work in India, Africa or other countries where TB remains endemic. We do not fully understand the reason for this but it is important that any new vaccine works well across the world, including in the high burden countries most in need of an effective vaccine.
How VALIDATE will help
By bringing together researchers working on different (but similar) pathogens, discoveries in one field can be more quickly taken advantage of in research against another pathogen. Bringing together researchers from different disciplines and institutes in new collaborations means knowledge can be exchanged and new research ideas for the field can be generated and investigated. Bringing new researchers into this field, and progressing the careers of early career researchers, will aid with new ideas and the continuation of the field into the future.
Further reading
- Scriba TJ, Coussens AK, Fletcher HA. Human Immunology of Tuberculosis.Microbiol Spectr. 2017 Jan;5(1). doi: 10.1128/microbiolspec.TBTB2-0016-2016. PMID:28155806
- Hatherill M, Tait D, McShane H. Clinical Testing of Tuberculosis Vaccine Candidates. Microbiol Spectr. 2016 Oct;4(5). doi: 10.1128/microbiolspec.TBTB2-0015-2016. PMID:28087924
- Raviglione M, Sulis G. Tuberculosis 2015: Burden, Challenges and Strategy for Control and Elimination. Infect Dis Rep. 2016 Jun 24;8(2):6570. doi: 10.4081/idr.2016.6570. eCollection 2016 Jun 24. PMID:27403269
- Cardona PJ, Williams A. Experimental animal modelling for TB vaccine development. Int J Infect Dis. 2017 Mar;56:268-273. doi: 10.1016/j.ijid.2017.01.030. Epub 2017 Feb 3. PMID:28163168
- World Health Organisation - End TB Strategy document
References
1. Dye, C., et al., Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA, 1999. 282(7): p. 677-86.
2. WHO, Global tuberculosis report 2015. (accessed 20/06/17).
3. Corbett, E.L., et al., Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet, 2006. 367(9514): p. 926-37.
4. Colditz, G.A., et al., Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA, 1994. 271(9): p. 698-702.
5. McShane, H., Tuberculosis vaccines: beyond bacille Calmette-Guerin. Philos Trans R Soc Lond B Biol Sci, 2011. 366(1579): p. 2782-9.
Natural variation of the bovine lymph node microenvironment and its possible effect on BCG immunogenicity
Led by Dr Lucia Biffar (University of Oxford, UK), with Dr Bernardo Villarreal-Ramos (APHA, UK) and Prof Tracy Hussell (University of Manchester, UK)
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Enhancing BCG efficacy: the Social Technology Lab Initiative
Led by Assist Prof Delia Boccia (LSHTM, UK), with Dr Jenn Dowd (KCL, UK), and Prof Helen Fletcher (LSHTM, UK)
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Establishment of a functional assay panel to evaluate the role of antibodies in defence against melioidosis and tuberculosis
Led by Dr Panjaporn Chaichana (MORU, Thailand), with Prof Susanna Dunachie (University of Oxford, UK), and Prof Helen Fletcher (LSHTM, UK)
Read more here
Overcoming innate immune tolerance in the respiratory tract for optimal vaccine design
Led by Dr Rajko Reljic (SGUL, UK) with Prof Tracy Hussell (University of Manchester, UK)
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How do functional and metabolic characteristics of trained monocytes affect their anti-bacterial activity?
Led by Asst Prof Steven Smith (LSHTM, UK), with Dr Javier Sanchez-Garcia (Instituto Politécnico Nacional, Mexico), Prof Jo Prior (dstl, UK), and Prof Gregory Bancroft (LSHTM, UK)
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Vaccines to target people with diabetes: characterising the pathways of immune response to M. tuberculosis and B. pseudomallei in people with diabetes compared to non-diabetics
Led by Prof Susanna Dunachie (University of Oxford, UK), with Assistant Prof Jacqueline Cliff (LSHTM, UK), and Prof Gregory Bancroft (LSHTM, UK)
Read more here
Identification of Leishmania donovani and Mycobacterium tuberculosis- derived proteins on the surface of infected macrophages that are associated with ADCC induction
Led by Dr Mohamed Osman (University of York, UK), with Prof Paul Kaye (University of York, UK), Dr John Pearl (University of Leicester, UK) and Prof Andrea Cooper (University of Leicester, UK)
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Identification of latency associated antigens and biosignatures associated with Mycobacterium tuberculosis
Dr Jomien Mouton (University of Stellenbosch, South Africa) - VALIDATE Fellowship
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Characterising the BCG-induced antibody response to inform the design of improved vaccines against M.tuberculosis, M.leprae and M.bovis
Dr Rachel Tanner (University of Oxford, UK) - VALIDATE Fellowship
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Metabolic reprogramming of skin microenvironment for improved BCG vaccine efficacy
Led by Titular Prof Francisco Javier Sánchez-García (Instituto Politécnico Nacional, Mexico), with Dr Steven Smith (LSHTM, UK), Dr Barbara Kronsteiner-Dobramysl (University of Oxford, UK) and Prof Hazel Dockrell (LSHTM, UK)
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Development of an RNA based vaccine against Mycobacterium tuberculosis
Led by Dr Rhea Coler (IDRI, USA), with Prof Helen Fletcher (LSHTM, UK)
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Developing a mouse model of diabetes to evaluate vaccines for TB and melioidosis
Led by Dr Elena Stylianou (University of Oxford, UK), with Prof Helen McShane (University of Oxford, UK), Assoc Prof Susanna Dunachie (University of Oxford, UK), Assoc Prof Paul Brett (University of Nevada, USA), Dr Barbara Kronsteiner-Dobramysl (University of Oxford, UK) and Dr Panjaporn Chaichana (MORU, Thailand)
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Cross protection against TB by attenuated Mycobacterium ulcerans strain 5114
Led by Dr Justice Boakye-Appiah (SGUL, UK), with Dr Rajko Reljic (SGUL, UK) and Dr Tufária Mussá (Eduardo Mondlane University, Mozambique)
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Characterising the cellular immunity and metabolic response to Mycobacterium tuberculosis and Burkholderia pseudomallei in Indian patients for vaccine design
Led by Prof Chiranjay Mukhopadhyay (Manipal Academy of Higher Education, India), with Prof Susanna Dunachie (University of Oxford, UK) and Prof Mitali Chatterjee (IPGMER, India)
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T cell receptor sequencing to identify correlates of protection in human tuberculosis vaccine studies
Led by Dr Gabriele Pollara (UCL, UK), with Prof Mahdad Noursadeghi (UCL, UK), Assoc Prof Susanna Brighenti (Karolinska Institutet, Sweden), Assoc Prof Senait Ashenafi (Addis Ababa University, Ethiopia) and Prof Benny Chain (UCL, UK)
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An ex vivo model for understanding the impact of vaccination on Mycobacterial persister populations
Led by Prof Samantha Sampson (Stellenbosch University, South Africa), with Asst Prof Andrea Zelmer (LSHTM, UK) and Dr Jomien Mouton (Stellenbosch University, South Africa)
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Investigating the BCG-induced Natural Killer (NK) cell response in cattle and humans
Led by Dr Iman Satti (University of Oxford, UK), with Asst Prof Stephen Cose (UVRI, Uganda), Prof Helen McShane (University of Oxford, UK), Prof Alison Elliott (UVRI, Uganda) and Prof Jayne Hope (University of Edinburgh, UK)
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Cytomegalovirus as a risk factor for TB and leishmaniasis
Led by Dr Lisa Stockdale (University of Oxford, UK), with Dr Robindra Basu Roy (LSHTM, UK), Dr Vivian Tamietti Martins (Federal University of Minas Gerais, Brazil), Assoc Prof Eduardo Coelho (Federal University of Minas Gerais, Brazil), and Prof Helen Fletcher (LSHTM, UK)
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Innovative tools to measure mycobacterial antigen expression in tissue
Led by Dr Simon Waddell (University of Sussex, UK), with Dr Javier Salguero Bodes (PHE, UK), Prof Gobena Ameni (Addis Ababa University, Ethiopia), Dr Sally Sharpe (PHE, UK) and Dr Ann Rawkins (PHE, UK)
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Leishmaniasis refers to a diverse group of diseases, all caused by single-celled parasites called Leishmania. About 150m people worldwide have leishmaniasis at any given time, and the disease is recognized by the World Health Organisation (WHO) as a major neglected disease of poverty that disproportionately affects populations in low and middle-income countries.
Where is Leishmaniasis found?
Leishmaniasis is found in 98 countries worldwide. The majority of cases of visceral leishmaniasis are found in five countries (India, Nepal, Bangladesh, Sudan and Brazil), whereas cutaneous leishmaniasis is found in most parts of the Middle East as well as South, Central and Latin America. Although the major impact of the disease is found in developing countries, leishmaniasis transmission also occurs in European countries bordering the Mediterranean, where clinical disease is often associated with immune deficiency (e.g. due to HIV infection). Leishmaniasis in refugees fleeing conflict is an increasing problem, although in the absence of the sand fly vector, they are unlikely to spread disease in northern Europe. Leishmaniasis has been reported in the US, likely due to the northern spread of sand flies from Central and Latin America.
How is Leishmaniasis spread?
Leishmaniasis is spread by the bite of female sand flies. Sand flies are much smaller than mosquitoes, making bed nets less effective for preventing leishmaniasis than malaria.
Sandfly that spreads Leishmaniasis (credit: CDC)
What are the symptoms of Leishmaniasis?
The symptoms of leishmaniasis are variable, and depend on the type of parasite you are infected with. In some forms of leishmaniasis, a nodule develops at the site of the sand fly bite and this may or may not ulcerate into an open lesion with a crater-like appearance. This is often referred to as simple cutaneous leishmaniasis and the lesions typically self-heal after several months, leaving a scar. If the lesion is on soft tissue, e.g. the ear lobe, there may be significant tissue destruction.
In some cases, parasites may spread from the primary lesion and invade the mucosal tissues of the mouth, upper palate and nose. Although the primary skin lesion may heal successfully, mucosal tissue may be significantly damaged, leading to disfigurement and difficulty in eating. This form of disease is called mucosal or mucocutaneous leishmaniasis. Collectively, these different types of cutaneous leishmaniasis impact quality of life for millions of people.
Some Leishmania parasites are able to invade deep tissues like the spleen, liver and bone marrow causing visceral leishmaniasis or kala azar. This is usually fatal if not treated and visceral leishmaniasis results in >20,000 deaths annually, making it the second most important parasitic disease in terms of mortality after malaria. Some patients who are successfully treated for visceral leishmaniasis may go on to develop a chronic skin disease with nodules, papules or hypo-pigmented macules on the face and upper body (called post kala azar dermal leishmaniasis or PKDL).
Is Leishmaniasis curable?
Yes, but treatment is often long, painful and may have serious side effects, particularly when started late. AmbiSome has revolutionised the treatment of visceral leishmanaisis in South Asia, but it is less effective elsewhere. Treatment for cutaneous leishmaniasis has changed little in >50 years. Like other microbes, the Leishmania parasites can develop drug resistance.
Skin ulcer caused by Leishmaniasis (credit: CDC)
Vaccines against Leishmaniasis
There is no vaccine against human leishmaniasis at the moment. A veterinary vaccine is available to protect dogs from contracting visceral leishmaniasis.
VALIDATE
At the VALIDATE Network, by bringing together Leishmaniasis researchers from around the world we hope to speed up progress towards developing vaccines against this disease.
Further Information:
WHO Leishmaniasis factsheet:
WHO endemicity maps:
Videos about Leishmaniasis:
Leishmania are protozoan parasites that are transmitted between mammalian hosts by biting Phlebotomine sand flies. Approx. 15 species of Leishmania infect humans and cause a spectrum of clinical diseases that affect the skin and mucosa (tegumentary leishmaniasis) or systemic tissues (visceral leishmaniasis). Although the type of leishmaniasis is often closely associated with parasite species, this is not always the case, and varying clinical presentations may occur e.g. due to malnutrition or host genetic diversity.
Found in 98 countries worldwide, leishmaniasis affects over 150m people, with approx. 20,000 deaths annually due to visceral leishmaniasis (VL). Most forms of leishmaniasis are zoonotic diseases, infecting a range of hosts including rodents and canids, but in some cases transmission may be restricted to humans (anthroponotic VL). Canine VL is an important veterinary disease and an important target for controlling disease in humans.
Leishmania donovani (credit: CDC)
Latest estimates of the worldwide prevalence of the different forms of leishmaniasis can be found in (1). Importantly, many people exposed to these parasites do not develop clinical leishmaniasis, indicating the ability of the human immune system to control infection in most cases. However, suppression of the immune system by co-infection with human immunodeficiency virus (HIV) or by elective therapy (e.g. for autoimmune disease) may lead to clinical leishmaniasis (2). Drug resistance is of increasing concern in leishmaniasis. Diagnosis of the disease is by looking for the parasites in biopsies, by antibody-based tests or by clinical exam. Developing drugs for leishmaniasis is complicated as these are eukaryotic parasites and share much of their biochemistry with human cells. Most anti-leishmanials, therefore, have narrow therapeutic windows; one contains a heavy metal (antimony), whilst another is teratogenic. The most effective drug, liposomal Amphotericin B (AmbiSome) has revolutionised treatment for VL in South Asia, but is much less effective in other parts of the world. Drugs for CL have changed little in >50 years. Many treatment courses are protracted, painful and have significant side effects. An effective vaccine could revolutionise leishmaniasis control (3, 4).
The challenges of developing a leishmaniasis vaccine
Developing an effective vaccine for leishmaniasis is not easy, but epidemiological, clinical and experimental data suggests it should be possible (3, 4). It is known that deliberate infection with live Leishmania can prevent against re-infection (this practice of “leishmanisation” was once widespread in the Middle East) and vaccines have been developed for use in dogs. Vaccines for leishmaniasis could be used to prevent disease (prophylactic vaccines) or to treat patients by stimulating their immune system (therapeutic vaccines).
Some of the scientific challenges in leishmaniasis vaccine development are highlighted below:
Lack of immune correlates
For some vaccines, we know exactly the level of a particular kind of immune response that is needed for the vaccine to work – i.e. to stop someone getting disease. For leishmaniasis, we do not know what kind of immune response is needed, or what level of response is required. This means we can only test if a vaccine works in humans by doing large, expensive and time consuming human efficacy trials. This limits the number of vaccines that can be tested in humans.
Uncertain predictive value of animal models
It is not possible to test a vaccine in humans without testing it first in animals. However we do not know which if any of the animal models best predicts efficacy in humans. Again, this means we can only determine if a vaccine will work in humans by testing it in large, expensive, human efficacy trials.
Importance of the vector
Unlike some diseases, such as TB, where transmission occurs directly between people, leishmaniasis is a vector-borne disease. It is now known that during the taking of a blood meal, sand flies introduce a variety of proteins into the mammalian host that affect local immune function. The effects of these proteins have to be taken into account in developing a vaccine for leishmaniasis. Indeed, some have been proposed as candidates to include in a vaccine (5)!
Difficulty of working with leishmania
Some forms of leishmaniasis (VL, mucocutaneous leishmaniasis) are particularly serious once contracted and difficult to treat, and so in some countries (including the UK) they can only be studied in laboratories using special containment measures (called Category or BSL 3). To study natural transmission of disease, sand flies also need to be reared in captivity and once experimentally infected, these sand flies must be kept under BSL 3 containment to prevent their escape. This limits the number of laboratories that can work on the most serious forms of leishmaniasis.
How VALIDATE will help
By bringing together researchers working on different (but similar) pathogens, discoveries in one field can be more quickly taken advantage of in research against another pathogen. Bringing together researchers from different disciplines and institutes in new collaborations means knowledge can be exchanged and new research ideas for the field can be generated and investigated. Bringing new researchers into this field, and progressing the careers of early career researchers, will aid with new ideas and the continuation of the field into the future.
Further reading
http://www.who.int/mediacentre/factsheets/fs375/en/
References
1. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PloS one. 2012;7(5):e35671.
2. Fletcher K, Issa R, Lockwood DN. Visceral leishmaniasis and immunocompromise as a risk factor for the development of visceral leishmaniasis: a changing pattern at the hospital for tropical diseases, london. PloS one. 2015;10(4):e0121418.
3. Alvar J, Croft SL, Kaye P, Khamesipour A, Sundar S, Reed SG. Case study for a vaccine against leishmaniasis. Vaccine. 2013;31 Suppl 2:B244-9.
4. Gillespie PM, Beaumier CM, Strych U, Hayward T, Hotez PJ, Bottazzi ME. Status of vaccine research and development of vaccines for leishmaniasis. Vaccine. 2016;34(26):2992-5.
5. Reed SG, Coler RN, Mondal D, Kamhawi S, Valenzuela JG. Leishmania vaccine development: exploiting the host-vector-parasite interface. Expert review of vaccines. 2016;15(1):81-90.
The effect of BCG vaccination in immune responses against visceral leishmaniasis in a natural (canine) model of infection
Led by Dr Javier Salguero Bodes (Public Heath England, UK), with Dr Isadora dos Santos Lima (FIOCRUZ, Brazil), Assoc Prof Daniela Farias Larangeira (UFBA, Brazil), Dr Deborah Fraga (FIOCRUZ), Dr Geraldo Sá Oliveira (FIOCRUZ), Dr Washington dos-Santos (FIOCRUZ), and Prof Luiz Freitas (FIOCRUZ)
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Identification of Leishmania donovani and Mycobacterium tuberculosis- derived proteins on the surface of infected macrophages that are associated with ADCC induction
Led by Dr Mohamed Osman (University of York, UK), with Prof Paul Kaye (University of York, UK), Dr John Pearl (University of Leicester, UK) and Prof Andrea Cooper (University of Leicester, UK)
Read more here
Protective efficacy of conserved Leishmania hypothetical proteins against visceral leishmaniasis
Led by Prof Myron Christodoulides (University of Southampton, UK), with Assoc Prof Eduardo Coelho(Federal Unversity of Minas Gerais, Brazil)
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Cytomegalovirus as a risk factor for TB and leishmaniasis
Led by Dr Lisa Stockdale (University of Oxford, UK), with Dr Robindra Basu Roy (LSHTM, UK), Dr Vivian Tamietti Martins (Federal University of Minas Gerais, Brazil), Assoc Prof Eduardo Coelho (Federal University of Minas Gerais, Brazil), and Prof Helen Fletcher (LSHTM, UK)
Read more here
About Melioidosis
Melioidosis is a disease caused by a bacterium, Burkholderia pseudomallei, and is found across tropical and semi-tropical regions worldwide. It is estimated that 165,000 people develop melioidosis annually with 89,000 of these cases being fatal, making melioidosis a global health concern.
Treatment of melioidosis is difficult with 43% of people with the disease dying in NE Thailand (Limmathurotsakul D, et al 2010.) and 14% in N Australia (Currie BJ, Ward L, Cheng AC 2010.). The occurrence of melioidosis in the population is associated with some risk factors such as diabetes and generation of a vaccine and administration to at risk personnel has been demonstrated to be potentially cost effective (Peacock et al 2012).
Where is melioidosis found?
Melioidosis occurs in tropical and semi-tropical regions of the world, especially in rice farming regions. B. pseudomallei can survive in the environment for long periods of time, present in the soil and water in endemic areas. The melioidosis.info webpage provides maps showing distribution of the disease, cases diagnosed and mortality.
How is melioidosis contracted?
Infection is acquired through skin inoculation, contamination of wounds, inhalation or ingestion.
Burkholderia pseudomallei on blood agar plate (credit: CDC)
What are the symptoms of melioidosis?
Diagnosis of melioidosis is difficult with symptoms varying depending on route and stage of infection. Often initial symptoms resemble many other bacterial infections with fever, and severe septicaemia (blood poisoning) can develop.
Is melioidosis curable?
Melioidosis is curable but B. pseudomallei is naturally drug-resistant making treatment choices limited and sometimes ineffective.
Treatment takes about 4 months with 10-14 days intravenous therapy followed by 12 weeks of oral therapy. This is very costly, and can have unpleasant side effects. In addition there are a percentage of individuals who will enter a latent (dormant) infection even after the intensive antibiotic therapy. These people may go onto have a resurgence of infection weeks, months or even years later. This means developing a vaccine that could prevent melioidosis infection is an important global public health goal.
Vaccines against melioidosis
There is no vaccine for melioidosis. There are vaccine research programmes currently focusing on inactivated bacteria, live attenuated (altered) bacteria and subunits (parts of the bacteria).
VALIDATE
At the VALIDATE Network, by bringing together melioidosis researchers from around the world we hope to speed up progress towards a vaccine against this deadly disease.
Further Information
Limmathurotsakul D, et al 2010. Increasing incidence of human melioidosis in Northeast Thailand. Am J Trop Med Hyg 82: 1113–1117.
Currie BJ, Ward L, Cheng AC 2010. The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study. PLoS Negl Trop Dis 4: e900.
Peacock et al 2012. Melioidosis Vaccines: A Systematic Review and Appraisal of the Potential to Exploit Biodefense Vaccines for Public Health Purposes. PLOS Negl Trop Dis 6: e1488.
Limmathurotsakul et al 2016. Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis. Nature Microbiology 1, Article number: 15008.
Burkholderia pseudomallei is a pathogen that infects humans causing melioidosis, a non-transmissible disease resulting in high mortality and morbidity.
Evidence is evolving to suggest that B. pseudomallei is present in many tropical and sub-tropical regions of the world (Limmathurotsakul 2016, Currie 2008). Identification and diagnosis are problematic due to non-specific symptoms of infection and inaccurate identification because of cross reactivity with closely related environmental bacteria. Treatment of infection can be ineffective due to inherent antibiotic resistance of the pathogen resulting in lengthy treatment regimes with high rates of failure. B. pseudomallei is designated as a select agent by the centre for disease control because of its potential as a bioweapon and its ability to cause lethal disease in humans and animals.
The challenges of developing a Melioidosis vaccine
Developing an effective B. pseudomallei vaccine is a considerable challenge. There are several different types of vaccine in the research phase, demonstrating varying levels of efficacy in a number of animal models. Progress in the B. pseudomallei vaccine field of research is impeded by the lack of an agreed animal vaccine challenge model. This results in generation of data from a number of different laboratories that cannot be directly compared. There is a requirement for both a public health and military vaccine. In the public health case the vaccine would need to protect humans against infection from ingestion, aerosolisation or subcutaneous injection of the pathogen, whereas the most likely route of exposure in a military scenario would be by aerosolisation.
In order to progress a potential B. pseudomallei vaccine it may be that the ‘animal rule’ to obtain licensure would be used. This requires that animal efficacy data is compiled along with human safety data to progress a vaccine to licensure. This is because it may be difficult to generate sufficient data for a phase 3 trial in the disparate at risk human population.
Further challenges include:
Lack of immune correlates
For some vaccines, the level and particular kind of immune response that is needed for the vaccine to work – i.e. to stop someone getting disease, is known. For melioidosis, we do not know what kind of immune response is needed, let alone what level of response is required.
Uncertain predictive value of animal models
It is not possible to test a vaccine in humans without testing it first in animals. However, we do not know which, if any, of the animal models to assess B. pseudomallei vaccines best predicts efficacy in humans. This means we can only determine if a vaccine will evoke a potentially appropriate immune response in humans by immunogenicity testing.
Difficulty of working with B. pseudomallei in the lab
B. pseudomallei is a highly infectious pathogen, which means we can only safely work with it in the lab using special containment measures (called Category or BSL 3). This limits the number of laboratories that can work on B. pseudomallei.
How VALIDATE will help
By bringing together researchers working on different (but similar) pathogens, discoveries in one field can be more quickly taken advantage of in research against another pathogen. Bringing together researchers from different disciplines and institutes in new collaborations means knowledge can be exchanged and new research ideas for the field can be generated and investigated. Bringing new researchers into this field, and progressing the careers of early career researchers, will aid with new ideas and the continuation of the field into the future.
Further reading
There are several reviews available on the internet and the ‘Melioidosis.info’ webpages have a lot of useful information.
References
Limmathurotsakul D et al. Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis. Nat Microbiol 2016;1:15008.
Currie BJ, et al. The global distribution of Burkholderia pseudomallei and melioidosis: an update. Trans R Soc Trop Med Hyg 2008;102 (Suppl 1):S1–4.
Establishment of a functional assay panel to evaluate the role of antibodies in defence against melioidosis and tuberculosis
Led by Dr Panjaporn Chaichana (MORU, Thailand), with Prof Susanna Dunachie (University of Oxford, UK), and Prof Helen Fletcher (LSHTM, UK)
Read more here
In vivo protection studies of chimeric Burkholderia pseudomallei antigens presenting multiple epitopes on protein scaffolds and outer membrane vesicles
Led by Prof Gregory Bancroft (LSHTM, UK), with Asst Prof Louise Gourlay (University of Milan, Italy), Prof Martino Bolognesi (University of Milan, Italy), Prof Giorgio Colombo (University of Pavia, Italy), and Asst Prof Ganjana Lertmemongkolchai (Khon Kaen University, Thailand)
Read more here
Vaccines to target people with diabetes: characterising the pathways of immune response to M. tuberculosis and B. pseudomallei in people with diabetes compared to non-diabetics
Led by Prof Susanna Dunachie (University of Oxford, UK), with Asst Prof Jacqueline Cliff (LSHTM, UK), and Prof Gregory Bancroft (LSHTM, UK)
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Developing a mouse model of diabetes to evaluate vaccines for TB and melioidosis
Led by Dr Elena Stylianou (University of Oxford, UK), with Prof Helen McShane (University of Oxford, UK), Assoc Prof Susanna Dunachie (University of Oxford, UK), Assoc Prof Paul Brett (University of Nevada, USA), Dr Barbara Kronsteiner-Dobramysl (University of Oxford, UK) and Dr Panjaporn Chaichana (MORU, Thailand)
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Elucidating the T-cell epitopes and T-cells responses of two B. pseudomallei vaccine antigens
Led by Dr Julen Tomás Cortázar (University College Dublin, Ireland), with Prof Susanna Dunachie(University of Oxford, UK), Asst Prof Louise Gourlay (University of Milan, Italy), Prof Giorgio Colombo(University of Pavia, Italy), and Dr Siobhán McClean (University College Dublin, Ireland)
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Characterising the cellular immunity and metabolic response to Mycobacterium tuberculosis and Burkholderia pseudomallei in Indian patients for vaccine design
Led by Prof Chiranjay Mukhopadhyay (Manipal Academy of Higher Education, India), with Prof Susanna Dunachie (University of Oxford, UK) and Prof Mitali Chatterjee (IPGMER, India)
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About leprosy
Leprosy (also known as Hansen’s Disease) is a chronic neglected tropical disease associated with poverty. It is caused by the bacterium Mycobacterium leprae. Leprosy symptoms can take 20 years or more to occur. Leprosy infection damages the peripheral nerves in the skin’s surface, resulting in loss of sensation. Without the feedback of pain, sufferers more easily damage their hands and feet with burns and ulcers. The nerve damage can then grow to elbows, wrists, knees and ankles and, if not treated, eventually lead to limb deformities, paralysis and limb loss, as well as blindness. However, leprosy is treatable with antibiotics and, if caught early, can be cured and these serious issues avoided.
Over 200,000 new cases of leprosy are diagnosed every year – this is one every two minutes - however, leprosy is likely to be under-reported due to its stigma and link to those living in poverty. It is estimated that around three million people worldwide are living with irreversible damage caused by leprosy.
Leprosy can have a profound effect on those infected as they often also suffer from severe social stigma and discrimination, loneliness and isolation – fear and misunderstanding of the disease means that, even today, sometimes the sufferer’s whole family can be ostracised. Worldwide, 146 laws are still in place that discriminate against people affected by leprosy, including some that segregate and isolate people from their communities and even their families.
Where is leprosy found?
Historically, leprosy was found worldwide; today it is mainly found in 14 countries: Bangladesh, Brazil, DR Congo, Ethiopia, India, Indonesia, Madagascar, Mozambique, Myanmar, Nepal, Nigeria, Philipppines, Sri Lanka and Tanzania. More than half of all leprosy cases are diagnosed in India.
How is leprosy spread?
Leprosy is only mildly infectious. How a person acquires Mycobacterium leprae and develops the disease remains uncertain, although it is currently thought likely that it is spread when healthy individuals inhale water droplets coughed or sneezed by infected people. Prolonged, close contact with someone suffering from leprosy is needed to catch the disease, and more than 95% of people have natural immunity to the disease.
Currently, leprosy has to be diagnosed using clinical symptoms as there is no diagnostic laboratory screening test.
Is leprosy curable?
Leprosy is curable with antibiotic treatment for 6-12 months. Unfortunately, for many people living in poverty around the world, diagnosis is too late to avoid limb damage or blindness, and the stigma associated with these injuries and a leprosy diagnosis.
Vaccines against leprosy
There is currently no vaccine specifically for leprosy. BCG was developed as a vaccine against tuberculosis (TB), and it also affords some protection against leprosy because Mycobacterium tuberculosis and Mycobacterium leprae are highly related. However, BCG is protective against leprosy to very varying degrees and only in some populations, and even where protection is observed it drops off over time. Leprosy remains endemic in some countries where BCG vaccination is widespread, so we clearly need to improve on BCG.
There are few leprosy vaccines in development, although three are currently in Phase 3 clinical trials which means they have shown promise and are now being tested on a large scale in many hundreds of subjects.
A successful leprosy vaccine would be a critical step in controlling the epidemic by preventing disease and transmission, and could be used in conjunction with other strategies, including better diagnostics, increased awareness, and the development of new drugs, to finally eradicate this disease.
How is VALIDATE helping?
At the VALIDATE Network, by bringing together leprosy researchers from around the world we hope to speed up progress towards an improved vaccine against this neglected disease.
Further information
How leprosy affects the body and the impact it can have on a person’s life – The Leprosy Mission
CDC Hansen's Disease webpage
International Leprosy Foundation (ILEP) Zero Discrimination campaign
Mycobacterium leprae
Mycobacterium leprae is an acid-fast, rod-shaped bacillus and is an intracellular pathogen causing leprosy in humans and armadillos. The genus Mycobacterium, also contains M.tuberculosis which causes TB (tuberculosis).
The challenges of developing a leprosy vaccine
Developing an effective vaccine against leprosy has proved challenging over the last decades. Mycobacterium leprae is an intracellular pathogen, which means it can ‘hide’ from the immune system inside our body's cells, which can make vaccine development more tricky. As is the case for TB as well as leprosy, we don’t understand which parts of the human immune system are important in protection from these infections, which makes it difficult to design a vaccine because we don’t know what it needs to do to be effective. It’s also unclear why BCG is effective against leprosy (and TB) in some populations and not others, and we don’t want a new vaccine to be subject to the same pitfalls.
M. leprae is notoriously difficult to work with in the lab, as it cannot be cultured in artificial medium (so making large amounts of vaccines based on M. leprae itself is challenging), and the only animal models available are nine-banded armadillos and mouse footpads. Funding is also a huge challenge; leprosy numbers are decreasing as sanitation and general health improve worldwide, meaning funders are less interested in funding research - but leprosy cases are likely underreported and unlikely to drop to zero without a vaccine. In addition, as leprosy is a disease not generally found in the developed world and therefore unlikely to make a profit for its developer or manufacturer, it is difficult to encourage large pharma and industry organisations to work on leprosy vaccine development.
How will VALIDATE help?
By bringing together researchers working on different (but similar) pathogens, discoveries in one field can be more quickly applied to research against another pathogen. Bringing together researchers from different disciplines and institutes in new collaborations means knowledge can be exchanged and new research ideas for the field can be generated and investigated. VALIDATE can provide invaluable funding for neglected disease vaccine research. Finally, bringing new researchers into this field, and progressing the careers of early career researchers, will aid with new ideas and the continuation of the field into the future.
Further reading
Vaccines for Leprosy and Tuberculosis: Opportunities for Shared Research, Development, and Application - M Coppola et al 2018 in Frontiers in Immunology 9:308
Characterising the BCG-induced antibody response to inform the design of improved vaccines against M.tuberculosis, M.leprae and M.bovis
Dr Rachel Tanner (University of Oxford, UK) - VALIDATE Fellowship
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These diseases are often associated
with poverty (credit: CDC)
