New Diagnostic Test for Malaria

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REEAD Malaria Diagnostics

The high sensitivity is achieved by performing the REEAD technology within droplets surrounded by oil. The malaria parasites are distributed in the pico-litre droplet, where they react effectively with the other components of the REEAD technology (Source: Sissel Juul and Birgitta Knudsen).

A new diagnostic test could revolutionize the treatment of malaria, one of the world’s most persistent and deadly diseases, making it possible to diagnose the illness from a single drop of blood or saliva.

The test, developed by researchers at Aarhus University in Denmark, detects very low levels of an enzyme produced by the Plasmodium parasite, the organism that causes malaria. This could allow intervention before an outbreak develops, researchers say. [Read more…]

G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries

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Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.

Methods and Findings

Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene’s X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd.

Conclusions

G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit.

Background

Malaria is a parasitic infection that is transmitted to people through the bites of infected mosquitoes. Of the four parasites that cause malaria, Plasmodium falciparum is the most deadly and P. vivax is the commonest and most widely distributed. Malaria parasites have a complex life cycle. Infected mosquitoes inject “sporozoites” into people, a form of the parasite that replicates inside human liver cells. After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting other red blood cells. This increase in the parasitic burden causes malaria’s characteristic fever and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite’s life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Treatment with effective antimalarial drugs also decreases malaria transmission.

Why Was This Study Done?

The Global Malaria Action Plan aims to reduce malaria deaths to zero by 2015 and to eradicate malaria in the long-term through its progressive elimination in malaria-endemic countries (countries where malaria is always present). Primaquine is a key drug for malaria elimination. It is the only treatment effective against the gametocytes that transmit malaria between people and mosquitoes and against P. vivax “hypnozoites,” which hibernate in the liver and cause malaria relapses. Unfortunately, primaquine induces mild to severe destruction of red blood cells (hemolysis) in people who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common in some ethnic groups but the global distribution of individuals at risk of primaquine-induced hemolysis is unknown and there is no practical field test for G6PDd. Consequently, it is hard to design and implement primaquine treatment practices that balance the benefits of malaria transmission reduction and relapse prevention against the risk of hemolysis. Here, the researchers use a geostatistical model to map the prevalence (frequency in a population) of G6PDd in malaria-endemic countries and to estimate how many people are affected in these countries. They also develop a national index of relative hemolytic risk.

What Did the Researchers Do and Find?

The researchers fed data from community surveys of the prevalence of phenotypic G6PDd (reduced enzyme activity) for 1,734 sites (including 1,289 sites in malaria-endemic countries) into a geostatistical model originally developed to map global malaria endemicity. The model predicted that G6PDd is widespread across malaria-endemic regions, with the lowest prevalences in the Americas and the highest in tropical Africa and the Arabian Peninsula, but that most G6PDd individuals live in Asian countries. The predicted prevalence of G6PDd varied considerably over relatively short distances in many areas but, averaged across malaria-endemic countries it was 8%, which corresponds to about 350 million affected individuals; averaged across countries that are currently planning for malaria elimination, the prevalence was 5.3% (nearly 100 million affected individuals). Finally, the researchers used data on the geographical occurrence of G6PD variants classified according to their enzyme activity levels as mild or severe to derive an index of hemolytic risk from G6PDd for each malaria-endemic country. The greatest risk was in the Arabian Peninsula and west Asia where the predicted prevalence of G6PDd and the occurrence of severe G6PD variants were both high.

What Do These Findings Mean?

These findings suggest that G6PDd is widespread and spatially heterogeneous across most of the malaria-endemic countries where primaquine would be valuable for malaria control and elimination. The accuracy of these findings is limited, however, by the assumptions made in the geostatistical model, by the accuracy of the data fed into the model, and by the lack of data for some malaria-endemic countries. Moreover, there is considerable uncertainty associated with the proposed index of hemolysis risk because it is based on phenotypic G6PDd enzyme activity classifications, which is presumed, but not widely demonstrated, to be a surrogate marker for hemolysis. Nevertheless, these findings pave the way for further data collection and for the refinement of G6PDd maps that, in the absence of non-toxic alternatives to primaquine, will guide the design of safe primaquine regimens for the elimination of malaria.

Citation: Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, et al. (2012) G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map. PLoS Med 9(11): e1001339. doi:10.1371/journal.pmed.1001339

Academic Editor: Lorenz von Seidlein, Menzies School of Health Research, Australia

Received: February 22, 2012; Accepted: October 4, 2012; Published: November 13, 2012

Funding: This work was supported by a Wellcome Trust Biomedical Resources Grant (#085406), which funded REH, FBP, OAN, and MMH; SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) that also supports PWG and KEB; APP was funded by a Biomedical Resources Grant from the Wellcome Trust (#091835). MD is funded by the Oxford University-Li Ka Shing Foundation Global Health Programme. This work forms part of the output of the Malaria Atlas Project (MAP), principally funded by the Wellcome Trust, UK. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: G6PDd, glucose-6-phosphate dehydrogenase deficiency; GRUMP, Global Rural-Urban Mapping Project; IQR, interquartile range; MEC, malaria endemic country; PPD, posterior predictive distribution; UN, United Nations; WHO, World Health Organization

Full Article: G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map (PDF)

Copyyight © 2012 Rosalind E. Howes, Frédéric B. Piel, Anand P. Patil, Oscar A. Nyangiri, Peter W. Gething, Mewahyu Dewi, Mariana M. Hogg, Katherine E. Battle, Carmencita D. Padilla, J. Kevin Baird, Simon I. Hay

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Phase III Trial of RTS,S Malaria Candidate Vaccine Reduces Malaria by One Third

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Results from a pivotal, large-scale Phase III trial, published online today in the New England Journal of Medicine, show that the RTS,S malaria vaccine candidate can help protect African infants against malaria. When compared to immunization with a control vaccine, infants (aged 6-12 weeks at first vaccination) vaccinated with RTS,S had one-third fewer episodes of both clinical and severe malaria and had similar reactions to the injection. In this trial, RTS,S demonstrated an acceptable safety and tolerability profile.

Eleven African research centres in seven African countries1 are conducting this trial, together with GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative (MVI), with grant funding from the Bill & Melinda Gates Foundation to MVI.

Dr. Salim Abdulla, a principal investigator for the trial from the Ifakara Health Institute, Tanzania, said: “We’ve made significant progress in recent years in our battle against malaria, but the disease still kills 655,000 people a year—mainly children under five in sub-Saharan Africa. An effective malaria vaccine would be a welcome addition to our tool kit, and we’ve been working toward this goal with this RTS,S trial. This study indicates that RTS,S can help to protect young babies against malaria. Importantly, we observed that it provided this protection in addition to the widespread use of bed nets by the trial participants.”

Efficacy
When administered along with standard childhood vaccines,2 the efficacy of RTS,S in infants aged 6 to 12 weeks (at first vaccination) against clinical and severe malaria was 31% and 37%,3 respectively, over 12 months of follow-up after the third vaccine dose.4 Insecticide-treated bed nets were used by 86% of the trial participants, which demonstrated that RTS,S provided protection beyond existing malaria control interventions. The efficacy observed with RTS,S last year in children aged 5-17 months of age against clinical and severe malaria was 56% and 47%, respectively. Follow-up in this Phase III trial will continue and is expected to provide more data for analyses to better understand the different findings between the age categories.

Dr. Abdulla added: “The efficacy is lower than what we saw last year with the older 5-17 month age category, which surprised some of us scientists at the African trial sites. It makes us even more eager to gather and analyze more data from the trial to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease. We were also glad to see that the study indicated that RTS,S could be administered to young infants along with standard childhood vaccines and that side effects were similar to what we would see with those vaccines.”

Safety
There was no increase in overall reporting of serious adverse events5 (SAEs) between the infants vaccinated with the RTS,S malaria vaccine candidate and infants in the control group, which received a comparator vaccine. Side effects primarily included local injection site reactions, which were less frequent following RTS,S vaccinations compared to the DTP-HepB/Hib vaccine. Fever was reported more frequently following RTS,S vaccinations than the control vaccine group (30.6% versus 21.1% of vaccine doses, respectively).

Two new cases of meningitis were reported in the 6-12 week-old infant age category in addition to the 9 reported last year; one in the RTS,S group and one in the control vaccine group. Further analysis revealed a bacterial cause of the meningitis in 7 of the 11 cases.

Sir Andrew Witty, CEO, GSK said: “While the efficacy seen is lower than last year, we believe these results confirm that RTS,S can help provide African babies and young children with meaningful protection against malaria. They take us another important step forward on the journey towards having a new intervention available against this disease, which is a huge burden on the health and economic growth of Africa. We remain convinced that RTS,S has a role to play in tackling malaria and we will continue to work with our partners and other stakeholders to better understand the data and to define how the vaccine could best be used to provide public health benefit to children in malaria endemic areas in Africa.”

David Kaslow, Director of the PATH Malaria Vaccine Initiative, said: “Determining the role of RTS,S in Africa will depend on analyses of additional data. We are now an important step closer to that day. Success in developing malaria vaccines depends on many factors: at the top of the list are partnerships and robust evidence, coupled with an understanding that different combinations of tools to fight malaria will be appropriate in different settings in malaria-endemic countries. My congratulations go out to the team at GSK and to the African research centres for their exemplary conduct of this trial.”

“This is an important scientific milestone and needs more study,” said Bill Gates, co-founder of the Bill & Melinda Gates Foundation. “The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do. The trial is continuing and we look forward to getting more data to help determine whether and how to deploy this vaccine.”

The vaccine is being developed in partnership by GSK and MVI, together with prominent African research centres1*. The collaborators are represented on the Clinical Trials Partnership Committee, which oversees the conduct of the trial. An extended team of organisations work on RTS,S, including scientists from across Africa, Europe, and North America. Major funding for clinical development of RTS,S comes from a grant by the Bill & Melinda Gates Foundation to MVI.

Looking ahead
Follow-up in this Phase III trial will continue to provide more data for analyses to better understand the different findings between the age categories. These data and analyses should also provide insights into the vaccine candidate’s efficacy in different malaria parasite transmission settings. More data on the longer-term efficacy of the vaccine during 30 months of follow-up after the third dose, and the impact of a booster dose are expected to be publicly available at the end of 2014.

The data and analyses will inform the regulatory submission strategy and, if the required regulatory approvals are obtained and public health information, including safety and efficacy data from the Phase III programme, is deemed satisfactory, the World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015, paving the way for decisions by African nations regarding large-scale implementation of the vaccine through their national immunisation programmes. An effective vaccine for use alongside other measures such as bed nets and anti-malarial medicines would represent a decisive advance in malaria control.

GSK and MVI are committed to making this vaccine available to those who need it most, should it be approved and recommended for use. In January 2010, GSK announced that the eventual price of RTS,S (also known as MosquirixTM) will cover the cost of manufacturing the vaccine together with a small return of around 5% that will be reinvested in research and development for second-generation malaria vaccines or vaccines against other neglected tropical diseases.

About RTS,S
RTS,S is a scientific name given to this malaria vaccine candidate6 and represents the composition of this vaccine candidate. RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms. In the Phase III efficacy trial, RTS,S is administered in three doses, one month apart. A booster dose administered 18 months after the third dose is also being studied in the trial.

The vaccine, based on a protein first identified in the laboratory of Drs Ruth and Victor Nussenzweig at New York University, was invented, developed, and manufactured in laboratories at GSK Vaccines in Belgium in the late 1980s and initially tested in US volunteers as part of a collaboration with the US Walter Reed Army Institute of Research.

In 2001, the MVI entered into partnership with GSK to study the vaccine candidate’s ability to protect young children in sub-Saharan Africa. Over time, the partnership expanded to include the 11 African research centres and, in some instances, associated scientific institutions from Europe and the United States.

With more than US$200 million in grant monies from the Bill & Melinda Gates Foundation, MVI contributes financial, scientific, managerial, and field expertise to the development of RTS,S. GSK takes the lead in the overall development of RTS,S and has invested more than $300 million to date and expects to invest more than $200 million before the completion of the project.

About the study
The first complete set of results in children aged 5 to 17 months and combined data for severe malaria in the first 250 cases from those aged 6 weeks to 17 months were published in the New England Journal of Medicine in November 2011. The Phase III trial has been designed in consultation with the appropriate regulatory authorities and the WHO. It is conducted in accordance with the highest international standards for safety, ethics, and clinical practices and is overseen by an independent data safety monitoring committee.

About GSK Vaccines
GlaxoSmithKline Vaccines is active in vaccine research and development. Headquartered in Belgium, GSK Vaccines has 14 manufacturing sites strategically positioned around the globe. Of the 1.1 billion doses of our vaccines we distributed in 2011, over 80% went to developing countries, which include the least developed, low- and middle-income countries.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information, please visit www.gsk.com.

The PATH Malaria Vaccine Initiative (MVI) is a global program established at PATH through an initial grant from the Bill & Melinda Gates Foundation. MVI’s mission is to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world. MVI’s vision is a world free from malaria. For more information, please visit www.malariavaccine.org.

PATH is an international nonprofit organization that transforms global health through innovation. PATH takes an entrepreneurial approach to developing and delivering high-impact, low-cost solutions, from lifesaving vaccines and devices to collaborative programs with communities. Through its work in more than 70 countries, PATH and its partners empower people to achieve their full potential. For more information, please visit www.path.org.

1  Burkina Faso – Nanoro, Institut de Recherche en Science de la Santé (IRSS) / Centre Muraz
Gabon – Lambaréné Albert Schweitzer Hospital, Medical Research Unit
Ghana – Agogo/Kumasi: School of Medical Sciences, Kwame Nkrumah University of Science and Technology; Kumasi Centre for Collaborative Research, Agogo Presbyterian Hospital
Ghana – Kintampo: Kintampo Health Research Centre, Ghana Health Service
Kenya – Kilifi, KEMRI-Wellcome Trust Research Program
Kenya – Kombewa (Kisumu), KEMRI-Walter Reed Project Kenya Medical Research Institute
Kenya – Siaya (Kisumu), KEMRI-CDC Research and Public Health Collaboration
Malawi – Lilongwe, University of North Carolina Project at the Tidziwe Centre
Mozambique – Manhica, Centro de Investigação em Saúde de Manhiça
Tanzania – Bagamoyo, Ifakara Health Institute
Tanzania – Korogwe, National Institute for Medical Research, Tanzania, Kilimanjaro Christian Medical Centre
2  Standard childhood vaccines used were the combined diphtheria-tetanus-whole-cell-pertussis, hepatitis B, and Haemophilus influenzae type b vaccine (DTPwHepB/Hib) and the oral polio virus vaccine (OPV).
3  Based on According To Protocol (ATP) statistical methodology.
4 Average risk for malaria in the control group was 0.9 clinical episodes per child per year and 2.3% of the children experienced at least one episode of severe malaria.
5  A serious adverse event refers to any medical event that occurs during the course of a clinical trial and that results in death, is life threatening, requires inpatient hospitalization, or results in a persistent or significant disability or incapacity needs, regardless of whether the event is considered by the investigator to be caused by the study vaccination. All SAEs are reported to regulatory authorities.
6  Contains QS-21 Stimulon® adjuvant licensed from Antigenics Inc, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes

Source: Malaria Vaccine Initiative. Reproduced from the Malaria Vaccine Initiative website at www.malariavaccine.org, Nov. 9, 2012

GlaxoSmithKline Malaria Vaccine Candidate Results Disappointing

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The latest clinical trial of the world’s leading malaria vaccine candidate produced disappointing results on Friday. The infants it was given to had only about a third fewer infections than a control group. Three shots of the vaccine, known as RTS, S or Mosquirix and produced by GlaxoSmithKline, gave babies fewer than 12 weeks old 31 percent protection against detectable malaria and 37 percent protection against severe malaria, according to an announcement by the company at a vaccines conference in Cape Town.

Read more, via The New York Times.

An Effective Fix for the Devastation of Malaria

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“Malaria made me and my family poor,” says Ngoy Kabulo, 52, of the Democratic Republic of the Congo. “Every day, we would wake up with swollen bodies because of mosquito bites,” he says. “Our two small children had anemia every month, and we were always spending money on the hospital.”

But a very simple item — a long-lasting insecticide-treated bed net — can help put a stop to this escalation. When coupled with malaria-fighting, awareness-raising efforts, it can reverse the trend and even end the threat posed by this totally preventable disease to families like Kabulo’s.

Read more via The Huffington Post.

Challenges in Malaria Research: 2012 Highlights

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Guest bloggers Rosalind Howes and Katherine Battle report from this month’s Challenges in Malaria Research Conference in Basel, Switzerland.

The fight against malaria has enjoyed unprecedented financial and research investment over the past decade, with ensuing successes including important drops in malaria mortality and morbidity, stories of national elimination and targets set for regional elimination. The flip side to this optimism, which would be naïve to ignore, is a raft of major threats to these current successes: financial, social, technical, pharmaceutical and biological. Interspersed with bratwurst and rösti in Basel, Switzerland, leading experts from a range of backgrounds and at least 40 countries discussed these issues, raising strong reminders of the very real Challenges still facing Malaria Research and control.

The conference saw the launch of the WHO Global Malaria Program/UCSF Global Health Group Case Studies on Malaria Elimination: four case studies documenting the ups and downs along the path to elimination experienced by Cape Verde, Sri Lanka, Turkmenistan and Mauritius. Presenting these, WHO’s Rob Newman particularly praised the “army of unsung heroes” carrying out the day-to-day work in the field which led to the achievements. While cause for celebration, these case studies must also be reminders of the major risks associated with complacency. The resounding message from each country was the fragility of control and elimination successes: in all cases, malaria has resurged, most alarmingly in Sri Lanka were 17 cases in 1963 exploded into ½ million cases four years later.

The importance of correctly focusing the problem was made evident: ‘one size does not fit all’. Endemic regions endure a spectrum of transmission intensity: from regions working to control malaria mortality through to those working to eliminate the parasite. Acknowledging the different challenges presented along this spectrum and adapting the toolkit to meet these goals is essential. Diagnostic strategies for effective surveillance differ between contexts. As transmission intensity drops, the relative significance of sub-microscopic infections increases and novel serological methods for detecting exposure, rather than symptoms, may be required to identify remaining reservoirs of infection. Methods for efficient targeting of interventions will also vary as the prevalence of infection decreases. For example, large-scale spatial mapping of global limits and endemicity (see maps) have wildly different applications from real-time monitoring of population movement for predicting transmission bottlenecks or hotspot populations (“hotpops”) at the household level and anticipating outbreaks. The integrated approach of using appropriate diagnostics and surveillance to inform control strategies and treatment was repeatedly highlighted. Much progress can be made from building a ‘common agenda’ among groups investigating various facets of the malaria problem, as stated by Philippe Guerin of WWARN.

P. Falciparum Malaria Maps

The maps above show the estimated levels of P. falciparum (top) and P. vivax (bottom) endemicity within the limits of stable transmission. The maps were originally published by Gething, et al. in the Malaria Journal and PLoS NTDs, respectively.

Further blurred definitions stall the much needed precision in surveillance. P. vivax presents a very different challenge from P. falciparum malaria, and the persistent neglect which P. vivax has suffered over the past century following its fallacious description as ‘benign’ was strongly condemned by Kevin Baird. The significance of P. vivax, both clinically and epidemiologically, was repeatedly emphasised, including by all presenters of the Elimination Case Studies: P. vivax is the ‘last man standing’. Primaquine is the only drug available against relapse. Furthermore, it targets mature sexual parasites and may block transmission: a bottleneck stage in the parasite lifecycle which will have disproportionate benefits if it can be successfully targeted. However, controversy and contradictory advice surround use of this potentially dangerous drug (a genetic vulnerability to haemolysis is common), as recently explained in a Speaking of Medicine Blog by Lorenz von Seidlein. The importance of blocking parasite transmission, particularly in areas where artemisinin resistance is emerging, forms the rationale to the WHO’s important announcement at this conference, that low doses of primaquine (0.25mg base/kg) are being recommended for P. falciparumpatients without prior safety screening.

A key message from this wide-ranging conference? To borrow from one of the conference organisers, Marcel Tanner, ‘Don’t give up!’ Ric Steketee’s sense of urgency encouraged us to learn as we go, striving to eliminate district by district, country by country. The Challenges in Malaria Research are very real, diverse, urgent and long-term. Research and financial commitments, combined with top-down engagement from political leaders to affected community members are crucial to prevent history repeating itself…

Rosalind E. Howes investigates the epidemiology of the human Duffy blood group and G6PD deficiency to support the evidence-base around Plasmodium vivax transmission and primaquine treatment risk. rosalind.howes@zoo.ox.ac.uk

Katherine E. Battle studies the geographical variation and burden of Plasmodium vivax malaria as a DPhil student at the University of Oxford. She has an MSc in the Control of Infectious Diseases from the LSHTM. katherine.battle@zoo.ox.ac.uk

Both authors are researchers of the Malaria Atlas Project.

The authors declare that they have no conflict of interest.

Copyyight © 2012 Rosalind Howes and Katherine Battle. This post was originally published on Speaking of Medicine.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

Mobile Phones Used to Help Fight Malaria

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Researchers are studying the use of mobile phones to document the spread of malaria. The study is part of an effort to stop or control the disease.

The World Health Organization says malaria mortality rates have fallen by twenty-five percent since two thousand. Yet the disease killed an estimated six hundred fifty-five thousand people in twenty-ten.

Scientists say malaria-carrying mosquitoes cannot travel far on their own. But the insects can, and do, catch rides in the belongings of people who travel. Malaria also can be spread by people who come from an area with large numbers of malaria cases. They may show no signs of having the disease themselves.

That is what Harvard University researchers discovered in Kenya. They found that the disease mainly spreads east from the country’s Lake Victoria area with people who travel to the capital, Nairobi.

Researchers with the Harvard School of Public Health reported the finding. It was based on the mobile phone records of fifteen million Kenyans.

Caroline Buckee is an assistant professor of epidemiology at the Harvard school. She says one of the first steps in stopping malaria is to learn how human travel might be adding to its spread. She says it has been difficult to follow large population movements with methods like government census records.

“But mobile phones offer a really unique way, on an unprecedented scale, to understand how a whole population is moving around.”

In Kenya, the researchers estimated the distance and length of each phone user’s trip away from home. This information was based on messages to and from the mobile phone carrier’s twelve thousand transmission towers.

The researchers then compared that information to a map showing reports of malaria in different parts of the country. The researchers estimated each user’s probability of being infected in a given area. They also estimated the likelihood that a visitor to that area would become infected.

The result was a picture showing malaria transmission routes starting in Lake Victoria. Caroline Buckee says such evidence could influence malaria control efforts.

“One thing that you could consider is sending text messages to people coming to high risk cell towers, for example, reminding them to use a bed net. And I think those types of approaches are simple but they would hopefully target people who are asymptomatic and unaware that they are carrying parasites.”

She says researchers are investigating using mobile phone records in other areas to help identify malaria transmission routes. A report on the study was published in the Journal Science.
—
Contributing: June Simms and Jessica Berman

Source: VOA News

How Mosquito Immune System Attacks Specific Infections, Including Malaria Parasite

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Researchers have determined a new mechanism by which the mosquitoes’ immune system can respond with specificity to infections with various pathogens, including the parasite that causes malaria in humans, using one single gene.

Unlike humans and other animals, insects do not make antibodies to target specific infections. According to researchers at the Johns Hopkins Bloomberg School of Public Health, mosquitoes use a mechanism known as alternative splicing to arrange different combinations of binding domains, encoded by the same AgDscam gene, into protein repertoires that are specific for different invading pathogens. The researchers’ findings were published October 18 in the journal Cell Host & Microbe and could lead to new ways to prevent the spread of a variety of mosquito born illnesses.

Mosquitoes and other insects use their primitive innate immune systems to successfully fight infections with a broad spectrum of viruses, bacteria, fungi and parasites, despite the lack of antibodies that are part of the more sophisticated human immune system. The effectiveness of the human immune system is to a large degree based on the ability to produce an enormous variety of antibodies containing different immunoglobulin domains that can specifically tag and label a pathogen for destruction. This great variety of pathogen-binding antibodies is achieved by combining different immunoglobulin gene segments and further mutate them through mechanisms called somatic recombination and hypermutation. While mosquitoes also have genes encoding immunoglobulin domains, they lack these specific mechanisms to achieve pathogen recognition diversity.

The Johns Hopkins researchers discovered a different way by which mosquitoes can combine immunoglobulin domains of a single gene called AgDscam (Anopheles gambiae Down Syndrome Cell Adhesion Molecule) to produce a variety of pathogen-binding proteins. The AgDscam gene is subjected to a mechanism called alternative splicing that combines different immunoglobulin domains into mature AgDscam proteins, depending on which pathogen has infected the mosquito. The researchers showed that this alternative splicing is guided by the immune signal transducing pathways (analogous to electrical circuits) that they previously demonstrated to activate defenses against different malaria parasites and other pathogens. While alternative splicing of the AgDscam gene does not nearly achieve the degree of pathogen recognition diversity of human antibodies, it does nevertheless vastly increase the variety of pathogen binding molecules.

“Using antibodies to fight infection is like fishing with a harpoon—it’s very targeted. The mosquito’s innate immune system is more like fishing with a net—it catches a bit of everything,” explained George Dimopoulos, PhD, senior investigator of the study and professor with the Johns Hopkins Malaria Research Institute. “However, we discovered that immune pathway-guided alternative splicing of the AgDscam gene renders the mosquito’s immune net, so to speak, more specific than previously suspected. The mosquito’s immune system can come up with approximately 32,000 AgDscam protein combinations to target infections with greater specificity.”

Dimopoulos and his group are developing a malaria control strategy based on mosquitoes that have been genetically modified to possess an enhanced immune defense against the malaria parasite Plasmodium. One obstacle to this approach is the great variety of Plasmodium strains that may interact somewhat differently with the mosquito’s immune system.

“Some of these strains may not be detected by the engineered immune system proteins that mediate their killing. Our new discovery may provide the means to create genetically modified mosquitoes that can target a broader variety of parasite strains, like casting a net rather than shooting with a harpoon,” said Dimopoulos.

Malaria kills more than 800,000 people worldwide each year. Many are children.

“Anopheles NF-kB –Regulated Splicing Factors Direct Pathogen-Specific Repertoires of the Hypervariable Pattern Recognition Receptor AgDscam” was written by Yuemei Dong, Chris M. Cirimotich, Andrew Pike, Ramesh Chandra and George Dimopoulos.

The research was supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Disease, the Calvin A. and Helen H. Lang Fellowship, and the Johns Hopkins Malaria Research Institute.

Sources: Johns Hopkins Bloomberg School of Public Health; Cell Host & Microbe

Mini Primaquine? Controversy and Uncertainty Surround WHO Guidelines for the Antimalarial Primaquine

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By Lorenz von Seidlein –
This year has seen a considerable increase in interest in primaquine, an antimalarial that has been around for more than 60 years. The answer to why the spotlight has recently intensified on this old drug lies in three key questions in malaria research and control:  How do we contain the spread of artemisinin resistance; how do we minimise the transmission of P.falciparum in regions of sub-Saharan Africa which have reached low malaria endemicity; and what is the optimal treatment to achieve radical cure of P. vivax? The answers to all three questions lead to primaquine, which is the only drug that can prevent both the transmission of falciparum malaria, by killing mature sexual stage parasites (gametocytes), and relapse of vivax malaria by eliminating dormant liver stage parasites (hypnozoites). Alternative drugs, such as methylene blue and tafenoquine, are in development but for the time being there is no alternative to primaquine.

While primaquine is set to play a key role in global efforts to control malaria, it is not a panacea and has considerable drawbacks. In particular, primaquine can cause the potentially severe side effect of haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a congenital anomaly which is not uncommon. The last few months in particular have led to much debate about what the optimal dose of primaquine should be given efforts to control malaria and concerns over primaquine’s safety:

First, in September a Cochrane analysis concluded, “In light of these doubts about safety, and lack of evidence of any benefit in reducing transmission, countries should question whether to continue to use [primaquine] routinely in primary treatment of malaria.”

Secondly, a group of experts was asked to review the WHO guidelines which currently recommend a single 0.75mg/kg dose of primaquine to kill gametocytes and thus prevent the transmission of falciparum malaria. The experts, some of whom had drafted the current and previous  WHO malaria treatment guidelines came to the conclusion that countries should continue to use single dose primaquine but reduce the dose by two thirds from 0.75 to 0.25 mg/kg.

Third, the recommendation of the experts was submitted to the WHO Global Malaria Programme’s malaria policy advisory committee where it triggered controversy. The final decision if and how to accept the recommendations is expected shortly.

What has happened? The Cochrane analysis is based on stringent and hence exclusive criteria. Only 1776 individuals enrolled in 11 randomised controlled trials were included in the Cochrane analysis. None of the trials assessed effects on malaria transmission hence no evidence for an impact on malaria transmission was demonstrated.

The WHO experts took a very different approach and looked for evidence that primaquine reduces gametocytaemia or more importantly prevents the infection of mosquitoes in feeding experiments i.e. it is assumed that a reduction in infectivity translates into lower transmission rates at least in low transmission areas. Secondly the WHO experts felt no constraint to look exclusively at evidence from randomised controlled trials and reviewed the extensive historical experience with primaquine. Single dose primaquine has been used as an addition to falciparum therapy and in mass drug administrations most recently in Tanzania. This last trial, which started in 2008 couldn’t detect any evidence in a reduction of transmission because there were no malaria cases in the intervention or in the control group. But the investigators detected high levels of haemolysis in study participants especially in study participants who had an underlying congenital deficiency of G6PD. The surprise was that a single dose of 0.75mg/kg primaquine could trigger acute haemolytic anaemia. But then again haemoglobin levels had not been routinely measured  after single dose primaquine administrations and none of the study participants had clinical signs associated with acute haemolytic anaemia. This experience in Tanzania put an end to the belief that the administration of a single dose of 0.75mg/kg primaquine is safe in individuals with G6PD deficiency.

Equally or even more important than the reported trials is the unreported experience with single dose primaquine. Trainloads of primaquine have been used in mass drug administrations in China, Russia and North Korea during the second half of the last century. These mass drug administration coincided with a nadir in individual rights when the benefit of the community had a higher priority than individual health risks. A safety assessment of these huge campaigns is difficult and the completeness of adverse events data is hard to assess. The WHO experts commissioned a safety review of all documents related to primaquine use archived by the League of Nations and its successor the WHO. The review found 13 deaths associated with primaquine administrations and estimated the risk of death around 1:700,000 with considerable uncertainty surrounding the denominator (Recht J, Ashley E, White NJ. unpublished). It is expected that the review will be made available with the revised WHO guidelines. Malaria has been eliminated from the former Soviet republics, and has reached very low levels in China, suggesting but not proving an effect of single dose primaquine on malaria transmission.

Evidence for the efficacy of small primaquine doses comes from the review of the historical literature. More recent, unpublished laboratory work in Jiangsu province, China suggests that a single primaquine dose of 0.125mg/kg or even less can reliably kill oocytes and gametocytes. Whether the large amounts of primaquine administered in the last century have resulted elsewhere in primaquine resistant P.falciparum strains has yet to be explored.

When asked why the experts felt an urgent need to change the treatment guidelines for single dose primaquine the emergence of artemisinin resistant P.falciparum strains and their spread in South East Asia was mentioned. This threat has triggered series of high level meetings yet no viable containment plan has so far emerged. Adding a single dose of primaquine to the treatment of falciparum malaria is recommended in many countries but in practice this is rarely done. Furthermore a substantial proportion of gametocyte carriers are subclinically infected and very low gametocyte densities can’t be detected by microscopy or PCR of dried blood spots. Eliminating this gametocyte reservoir will require mass drug administrations which will probably need to include primaquine. However, uncertain about the safety of primaquine, practitioners are reluctant to prescribe it and policy makers, well aware of the consequences of adverse events caused by public health measures, shy away from recommending the administration of primaquine.

Members of the WHO expert group believe that a reduced single dose primaquine will find wider acceptance than the previously recommended dose and will thus help to contain the spread of artemisinin resistance. They also feel that the spread of artemisinin resistance represents a sufficiently big threat not to wait for more current data. To retain credibility the WHO would be well advised to make without delay the data available on which the proposed changes in treatment guidelines are based. How the WHO identifies and selects their experts is not transparent and several emails to explore this selection process didn’t result in a satisfactory answer. Changes in guidelines may reach wider acceptance if they are the result of a transparent process. Time will tell whether a recommendation to reduce the dose of primaquine by two thirds has any impact on the spread of artemisinin resistance. A much more courageous strategy may be needed to prevent a health disaster.

Lorenz von Seidlein works for the Menzies School of Health Research, Australia and coordinates the vivax working group of the Asian Pacific Malaria Elimination Network (APMEN). He is a co-investigator in several primaquine trials and a member of the PLOS Medicine editorial board.

Copyyight © 2012 Lorenz von Seidlein.

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