Tropical Health Matters

Leading off our news update are findings from eastern Kenya about a genetic blood grouping that may help prevent malaria. While government leaders in the Asia-Pacific region committed to eliminating malaria, a report from the Gates Foundation explains how COVID-19 has set progress back and without new tools it may take more than 25 years to rid the world of the disease. In that light, Novartis is staking its finances on being able to make medicines that will be accessible and fight malaria. More details and the Gates video can be seen by clicking the links below.

How Dantu Blood Group protects against malaria

The secret of how the Dantu genetic blood variant helps to protect against malaria has been revealed for the first time by scientists at the Wellcome Sanger Institute, the University of Cambridge and the KEMRI-Wellcome Trust Research Programme, Kenya. The team found that red blood cells in people with the rare Dantu blood variant have a higher surface tension that prevents them from being invaded by the world’s deadliest malaria parasite, Plasmodium falciparum. The findings were published in Nature and could be significant in the wider battle against malaria.

In 2017, researchers discovered that the rare Dantu blood variant, which is found regularly only in parts of East Africa, provides some degree of protection against severe malaria. The intention behind this new study was to explain why. Red blood cell samples were collected from 42 healthy children in Kilifi, Kenya, who had either one, two or zero copies of the Dantu gene. The Dantu variant created cells with a higher surface tension—like a drum with a tighter skin. At a certain tension, malaria parasites were no longer able to enter the cell.

Novartis ties bond sale to malaria treatment access in sustainability push

Novartis raised 1.85 billion euros on Wednesday from the sale of a bond on which interest payments will rise if the drugmaker fails to expand access to medicines and programmes to combat malaria and leprosy in a number of developing countries.

Investors are increasingly pushing companies to improve their track record on environmental, social and governance (ESG) issues while sustainable investing grows in popularity, spurring an increase in sustainable debt issuance year after year. Novartis’ bond is only the third issue to date to link payments to creditors to company-wide sustainable development targets. By Yoruk Bahceli

Commitment to make Asia Pacific a malaria free region

Government officials from across Asia Pacific have come together during virtual Malaria Week 2020, to reaffirm their commitment to eliminating malaria and strengthening health systems to keep the region safe from health threats. Embracing the theme of “Inclusion. Integration. Innovation.”, officials called for increased collaboration and action to accelerate towards the goal of ending malaria in the region by 2030, at a time when major gains and regional progress are under threat due to disruptions caused by Covid-19.

It could take up to 25 years to eradicate malaria from Africa – Bill Gates

Bill Gates said: “Moving to malaria which is a very awful disease not just to the kids it kills but many kids whose brains are permanently damaged, the economic effects you have with malaria. If we don’t have new tools like vaccines or new ways of killing mosquitoes, it would probably take more than 25 years to get rid of malaria. If we get the new tools and they work, we think it can be done in under 20 years. So the malaria field is both trying to keep the number of deaths down, and we have to deal with the resistance that comes up, that the mosquitoes develop.”

Gates Foundation Report notes that, “We’ve been set back about 25 years in about 25 weeks.” Extreme poverty increased 7% because of COVID-19. In a video included in the Foundation’s report, Bill Gates explains how COVID-19 disrupts the fight against malaria.

Malaria Journal released three articles ranging from the relation between malaria and agricultural irrigation, artemisinin resistance on the Myanmar-China border, and efforts at costing malaria elimination interventions. PLoS Medicine examined the quality of malaria clinical management in children. Finally, Frontiers in Cellular and Infection Microbiology reported on a new drug against malaria and toxoplasmosis. Click on links to read more details.

Minimal tillage and intermittent flooding farming systems show a potential reduction in the proliferation of Anopheles mosquito larvae in a rice field in Malanville, Northern Benin

Irrigation systems have been identified as one of the factors promoting malaria disease around agricultural farms in sub-Saharan Africa. However, if improved water management strategy is adopted during rice cultivation, it may help to reduce malaria cases among human population living around rice fields.

A clear reduction of larva density was observed with both intermittent flooding systems applied to minimal tillage (MT?+?IF?+?NL) and intermittent flooding applied to deep tillage (DT?+?IF?+?AL), showing that intermittent flooding could reduce the abundance of malaria vector in rice fields. Recommending intermittent flooding technology for rice cultivation may not only be useful for water management but could also be an intentional strategy to control mosquitoes vector-borne diseases around rice farms.

No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China’s plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China–Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance.

DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China–Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.

Costing malaria interventions from pilots to elimination programmes

Malaria programmes in countries with low transmission levels require evidence to optimize deployment of current and new tools to reach elimination with limited resources. Recent pilots of elimination strategies in Ethiopia, Senegal, and Zambia produced evidence of their epidemiological impacts and costs. There is a need to generalize these findings to different epidemiological and health systems contexts. Drawing on experience of implementing partners, operational documents and costing studies from these pilots, reference scenarios were defined for rapid reporting (RR), reactive case detection (RACD), mass drug administration (MDA), and in-door residual spraying (IRS). These generalized interventions from their trial implementation to one typical of programmatic delivery. In doing so, resource use due to interventions was isolated from research activities and was related to the pilot setting. Costing models developed around this reference implementation, standardized the scope of resources costed, the valuation of resource use, and the setting in which interventions were evaluated. Sensitivity analyses were used to inform generalizability of the estimates and model assumptions.

Populated with local prices and resource use from the pilots, the models yielded an average annual economic cost per capita of $0.18 for RR, $0.75 for RACD, $4.28 for MDA (two rounds), and $1.79 for IRS (one round, 50% households). Intervention design and resource use at service delivery were key drivers of variation in costs of RR, MDA, and RACD. Scale was the most important parameter for IRS. Overall price level was a minor contributor, except for MDA where drugs accounted for 70% of the cost. The analyses showed that at implementation scales comparable to health facility catchment area, systematic correlations between model inputs characterizing implementation and setting produce large gradients in costs. Prospective costing models are powerful tools to explore resource and cost implications of policy alternatives. By formalizing translation of operational data into an estimate of intervention cost, these models provide the methodological infrastructure to strengthen capacity gap for economic evaluation in endemic countries. The value of this approach for decision-making is enhanced when primary cost data collection is designed to enable analysis of the efficiency of operational inputs in relation to features of the trial or the setting, thus facilitating transferability.

Quality of clinical management of children diagnosed with malaria: A cross-sectional assessment in 9 sub-Saharan African countries between 2007–2018

Appropriate clinical management of malaria in children is critical for preventing progression to severe disease and for reducing the continued high burden of malaria mortality. This study aimed to assess the quality of care provided to children under 5 diagnosed with malaria across 9 sub-Saharan African countries. We used data from the Service Provision Assessment (SPA) survey. SPAs are nationally representative facility surveys capturing quality of sick-child care, facility readiness, and provider and patient characteristics across 9 countries, including Uganda (2007), Rwanda (2007), Namibia (2009), Kenya (2010), Malawi (2013), Senegal (2013–2017), Ethiopia (2014), Tanzania (2015), and Democratic Republic of the Congo (2018).

In this study, we found that a majority of children diagnosed with malaria across the 9 surveyed sub-Saharan African countries did not receive recommended care. Clinical management is positively correlated with the stocking of essential commodities and is somewhat improved in more recent years, but important quality gaps remain in the countries studied. Continued reductions in malaria mortality will require a bigger push toward quality improvements in clinical care. Despite increases in the distribution of malaria tests and effective antimalarial medications, significant gaps in the quality of care for pediatric malaria are present in these 9 countries. Further improvements in quality of malaria care may require a better understanding of remaining barriers and facilitators to appropriate management.

Novel drug could be a powerful weapon in the fight against malaria and toxoplasmosis

Princeton researchers are making key contributions toward developing a promising new treatment for the widespread and devastating diseases toxoplasmosis and malaria.
The Princeton scientists specialize in preparing the drug compound into a medicine that is both safe and effective for humans and able to reach its intended sites of action in the body in sufficient doses. An international team of scientists found the new drug—designated JAG21—to be highly effective against parasites in cell-based studies in the lab. After the discovery, team representatives contacted Princeton’s Robert Prud’homme for help in translating the JAG21 compound into a deliverable medication. Prud’homme is a co-author of a study, published in June 2020 in Frontiers in Cellular and Infection Microbiology, that describes the compound and its excellent preliminary results in mice.

May 31st marks World No Tobacco Day. The Theme for 2017 is “Tobacco – a threat to development.” According to WHO, “Tobacco control has been enshrined in the Sustainable Development Agenda. It is seen as one of the most effective means to help achieve SDG target 3.4 of a one-third reduction globally, by 2030, of premature deaths from  noncommunicable diseases (NCDs).” Control is also associated with positive environmental and anti-poverty outcomes.

It is ironic then that the tobacco plant itself may be modified to produce life saving anti-malarial medicines. Nature reported that because Artemisia annua produces a precursor of the compound, artemisinic acid, only in low quantities, it is expensive to grow.  Consequently, “a team led by Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam-Golm, Germany, inserted genes for artemisinic acid synthesis into tobacco plants’ chloroplasts — abundant organelles that have their own DNA. By adding ‘accessory genes’ that make artemisinic acid production more efficient, they created a line that pumps out 120 milligrams of artemisinic acid per kilogram of biomass.”

Science magazine followed up to report that although “several years ago researchers transplanted the drugmaking genes into yeast, allowing them to collect the compound from a microbial brew, the fermentation process is still relatively expensive.” Tobacco, on the other hand, is an “inexpensive, high-volume crop.” Inserting the right genes into tobacco, they noted, would enable “harvesting artemisinic acid from a plot of land 200 square kilometers—less area than a city the size of Boston—would provide enough artemisinin to meet the entire worldwide demand.”

Malhotra et al. discovered another novel approach that found that, “Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants.”

Another approach looks at malaria vaccines. Beiss et al. note that malaria “transmission blocking vaccine (TBVs) need to be produced in large quantities at low cost.” They found a high level  transient expression in fresh leaves of Nicotiana benthamiana of an effective TBV candidate. Likewise Jones et al. demonstrated the potential of the new malaria vaccine candidate and also support feasibility of expressing Plasmodium antigens in Nicotiana benthamiana.

The American Cancer Society observed that most African Countries are in the early stages of the tobacco epidemic. This may be a good time to switch the production of tobacco on the continent from purveyor of cancer and NCDs to a ‘factory’ for producing malaria medicines. The sooner this can be done, the better since artemisinin  resistance is a growing threat.

Many tropical diseases are co-endemic in a given country and environment. Therefore, it only makes sense to learn whether there can be common strategies and synergies in disease control and elimination efforts. Onchocerciasis or River Blindness is carried by the black fly (simulium damnosum) that breeds along the banks of fast flowing rivers and malaria are examples.

Onchocerciasis was eliminated in many settings in the Sahel through the process or aerial spraying of these riverbanks to kill the black fly larvae. Though the insecticide used was often the same as used for malaria larviciding, the habitats differed and no synergies were achieved then.

Merck donates ivermectin to achieve control and elimination of onchocerciasis

Through subsequent programs using community directed treatment with ivermectin (Mectizan ®) interventions sponsored by the African Program for Onchocerciasis Control (APOC) it was learned that ivermectin also had beneficial effects on malaria transmission.

Ivermectin had been used in agriculture not only for internal parasites of animals. The agricultural community has long known that ivermectin kills both internal parasites (worms) but is also effective against some external parasites (lice and ticks).

Around 2010 scientists began to consider the anti-mosquito effects ivermectin might have when humans consumed it. It turns out that after a mass distribution in a community of ivermectin for onchocerciasis that mosquitoes feeding on people who had recently swallowed ivermectin would die. This was demonstrated when mosquitoes bit volunteers who took ivermectin of the first few days after consumption died there was no effect in the group not taking the drug.

Ivermectin distribution sessions in a Cameroonian village

Of particular interest was the fact that people who had consumed ivermectin would contribute to mosquito mortality even when they were outdoors. While the effect was not long lasting, the onchocerciasis control programs in the Americas have shown that it is safe to administer the drug two or four times a year.

Research that looks at the malaria parasite concluded that, “it is likely that ivermectin treatment is arresting parasite growth.” The researchers note that, “given the prior use of ivermectin and its safety record in humans and animals, it can be considered in combination therapy with other antimalarials.” The issue of dosage would need to be tested further.  Ivermectin at sub-lethal concentrations even inhibits the sporogony of P. falciparum in An. Gambiae.

Because of the need to find new and complementary tools to eliminate malaria the Malaria Policy Advisory Committee (MPAC) of the World Health Organization’s Global Malaria Program considered at its recent meeting the role of endectocides including ivermectin in the future of malaria control and elimination and the importance of further research.

The future of malaria elimination requires finding new tools to integrate with and the strengthening of existing tools. If these efforts also benefit the control and elimination of other diseases, the public’s health will benefit.

… and Dealing with it Should Resistance Occur

Professor Joseph Ana, Africa Centre for Clinical Governance Research & Patient Safety in Calabar, Nigeria shares his experiences and concerns in this blog.

Drug resistance is one of the biggest challenges facing health care systems in the world today. Around 25,000 people die each year from resistant viral and bacterial infections in Europe, but no new classes of antibiotics have come on the market for more than 25 years. The figures are difficult to obtain for Africa and other developing countries.

Medicine shops may sell inappropriate malaria medicines, thus contributing to resistance

Drug resistance is considered important in the failure of control and treatment of diseases its consequences, and it is considered to be one of the causes of emergence of new strains of infective organisms and re-emergence of once-controlled diseases. The occurrence and impact of the phenomenon is worse in Africa and parts of Asia for malaria according to WHO and the US CDC. Viral and bacterial diseases are also affected in this region.

Therefore, there is urgent need for global sustained action to prevent drug resistance from happening, and to control it, if it happens. The causes of Drug resistance are varied including lack of or poor implementation of the control of access to drugs, population migration and movement, misdiagnosis, under-treatment and irrational drug prescription and use.

To prevent drug resistance, countries need to legislate and implement adequate control of access to drugs, sustain public education on the dangers of drug resistance, educate health workers on and enforce rational drug prescribing and use. Effective monitoring of treatment outcomes is also important to know when drug resistance is occurring. With the global and country by country best efforts drug resistance may still occur because of mutation and adaptation of infective organisms.

For diseases like Malaria for which resistance to the most effective drug today, artemisinin-combination drugs, is being reported from Southeast Asia, the development of new drugs alongside vector control is essential by all countries, particularly in Africa.

Professor Joseph Ana – BM.BCh (UNN), FRCSEd, FRSPH, JtCertRCGP-UK, DFFP (RCOG)-UK, DipUrology-UK, Cert.ClinGov.UK; Lead Consultant Trainer / CEO; joseph ana <jneana@yahoo.co.uk>; Contact: Africa Centre for Clinical Governance Research & Patient Safety; @Health Resources International (HRI WA); Consultants in Clinical Governance & Patient Safety (MDCN Accredited CPD Provider); 8 Amaku Street State Housing  (& 20 Eta Agbor Road UNICAL Road),  Calabar, Nigeria.

Visit Website: www.hriwestafrica.com; email: hriwestafrica@gmail.com    Tel: +2348063600642

World Pneumonia Day (WPD) helps us focus on the major killers of children globally. While Pneumonia is responsible for more child mortality across the world, in tropical malaria endemic areas both create nearly equal damage (see WPD graphic showing Nigeria and DRC which are both have the highest burden for pneumonia, but also malaria). Of particular concern is case management at the clinic and community level where there is great need to differentiate between these two forms of febrile illness so that the right care is given and lives are saved.

Diagnostics are a particular challenge. While we now have malaria rapid diagnostic test kits that can be used at the community level, we must rely on breath counting for malaria. The Pneumonia Diagnostics Project (see video) “is working to identify the most accurate and acceptable devices for use by frontline health workers in remote settings in Cambodia, Ethiopia, South Sudan and Uganda.”

Ease of use at low cost must be achieved. One approach to solve the pneumonia diagnostics challenge at community and front line clinic level is to find “mobile phone applications or alternative energy for pulse oximetry,” to test low oxygen levels.

Vaccine development for both diseases is underway. The challenge for malaria results from the different stages of the parasites life-cycle. Lack of affordable vaccines for pneumonia limits at present widespread preventive action, though public-private partnerships offer hope.

Dispersable and correct dose for age prepackaged malaria drugs are already available. Now more child-friendly medicines for pneumonia are being developed. In low resource settings, “amoxicillin dispersible tablets are a better option, particularly for children who can’t swallow pills. They have a longer shelf-life, are cost-effective, don’t need refrigeration, and are easy to administer.”

Similarities in the problems and solutions to control these two diseases require that interventions must continue to be developed and implemented jointly in order to benefit children the most. As can be seen again from the WPD graphics (right), many children do not get needed treatment. Integrated case management at all levels is the answer.

Malaria Journal has launched a new series on malaria elimination in which the Journal’s editorial notes that, “The challenges remain formidable, but efforts must focus at all levels from developing better tools to how existing and future tools can be strategically combined for maximum synergistic effectiveness when integrated into different health and social systems prevailing in endemic areas.”

GlaxoSmithKline (GSK)yesterday annnounced one way to help develop better malaria control tools. At the Council on Foreign Relations Andrew Witty announced the ‘open innovation’ strategy focusing on neglected diseases and malaria and explained that …

…we have spent the last 12 months screening two million molecules in our compound library for reactions to the malaria parasite P. falciparum, the deadliest form of malaria found primarily in sub-Saharan Africa. This exercise has yielded more than 13,500 ‘hits’ that inhibited the parasite.

Apparently GSK itself has 5 or 6 in advanced phases of development. With this open sourcing, researchers, NGOs, governments and manufacturers in endemic countries can continue the work of drug development on the many other open source chemicals.  For HIV drugs GSK already has local manufacturers producing its products without charging royalties.

These activities build on GSK’s commitment, announced in February 2009, “to searching for new treatments for many of the diseases that affect millions of people in some of the world’s least well off nations. We have a heritage and expertise in researching and developing new medicines and vaccines, and we are directing our scientific resources into this important area.”

Hopefully such openness will spur local and appropriate solutions to disease control. Andrew Witty also encouraged other pharmaceutical companies to join in this process. With the early signs of artemisinin resistance on the horizon, new malaria drug research and development will always be needed until eradication is finally certified in the future.

PS – GSK contributes Albendazole for free to compliment donations of Mectizan by Merck for the lymphatic filariasis elimination program.