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Bio303 Lecture 1 The Global Burden of Infection and an Old Enemy, Malaria


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The Global Burden of Infection and an Old Enemy, Malaria. In this lecture I will survey the global burden of infection, including its human and economic costs, and examine the problem of neglected tropical diseases before focusing on one of the most serious infectious threats to humanity: malaria, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection.
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Bio303 Lecture 1 The Global Burden of Infection and an Old Enemy, Malaria

  1. 1. Global Health and Emerging Infections 1The Global Burden of Infection and an old foe Malaria Professor Mark Pallen Bio303
  2. 2. Global Health and Emerging Infections1. The Global Burden of Infection and an Old Enemy, Malaria. In this lecture I will survey the global burden of infection, including its human and economic costs, and examine the problem of neglected tropical diseases before focusing on one of the most serious infectious threats to humanity: malaria, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection.2. Two Old Enemies, TB and Leprosy. In this lecture I will focusing on another of the most serious infectious threats to humanity, tuberculosis, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection. I will also discuss a related mycobacterial infection, leprosy and recent progress in its control.3. New foes. In this lecture I will describe emerging infections, their epidemiology and ecology and the threats that they pose. I will focus on three case studies: SARS, pandemic flu and the German STEC outbreak of May-June 20114. Operation Eradication. In this lecture, I will celebrate the global eradication of smallpox, from the campaigns beginnings in Gloucestershire to the last tragic cases here in Birmingham. I will discuss what is required for an infectious disease to be eradicated and summarise progress on disease eradication, focusing on poliomyelitis and guinea worm.5. Lab Diagnosis of Infectious Disease. Here I will provide an overview of how infections are diagnosed in the clinical microbiology lab, focusing not just on technologies, old and new, but on practical issues and workflows crucial to optimal use of the lab.
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  4. 4. Infection: the Global Challenge In most developed countries infectious diseases cause far fewer deaths than non-infectious diseases  Worldwide, infectious disease accounts for >15% of all deaths Even in developed countries new diseases are emerging  e.g. West Nile fever, SARS, German STEC Effective control of infectious disease remains a challenge
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  6. 6. Malaria Complex and deadly mosquito-borne infectious disease caused by a eukaryotic apicomplexanprotists from genus Plasmodium  most serious forms caused by P. falciparum  P. vivax, P. ovale, P. malariaecause milder, usually non- fatal disease in humans naturally transmitted by the bite of a female Anopheles mosquito
  7. 7. Malaria Leading cause of morbidity and mortality world-wide, especially in pregnant women and children >40% of world population, 3.3 billion people at risk in 109 countries ~250m cases worldwide in 2008  ~1m deaths in children (≥80% in tropical Africa) Economic burden highest in Africa  ≥ US$12 bn per year in direct losses (illness, treatment, premature death)  much more in lost economic growth
  8. 8. Malaria in the Headlines "It was the day after my birthday when the symptoms first started. I put it down to that Id been drinking vodka the night before, because Im not a regular drinker. I put it down to just a big hangover. It got gradually worse and worse." "I was exhausted and having flushes, goose bumps one minute – blue lips, blue fingertips, blue toes – to then being boiling hot. My skin was wet. I couldnt breathe properly.” “I had no liver function, no kidney function, I was swollen with the fluid, I had no oxygen in my blood, I literally had 24 hours to get fluid out of my body, otherwise my insides were going to pack in. You know how sometimes you feel ill and say, I feel like Im dying? Well, I actually felt like I was dying. I asked the nurse outright – was I going to die? She said, Theres a possibility. "
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  10. 10. Life Cycle in Mosquito Primary host and transmission vector is female Anopheles  young mosquitoes bite humans and ingest gametocytes in blood meal  gametocytes differentiate into male or female gametes  gametes fuse in gut into ookinete  penetrates gut lining to produce oocyst in gut wall  oocyst ruptures, releases sporozoites that migrate to salivary glands  sporozoites injected into human bloodstream with saliva when mosquito feeds
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  12. 12. Life cycle in Humans: Exoerythrocytic Phase sporozoitesenter bloodstream within 30 mins infect hepatocytes in liver multiply asexually and asymptomatically for 6–15 days differentiate into thousands of merozoites rupture hepatocytes and escape into blood
  13. 13. Life cycle in humans: erythrocytic phase merozoites infect erythrocytes then multiple rounds of  asexual reproduction (ring forms, trophozoites, schizonts, merozoites)  cell lysis and reinfection (hence cyclical fever) some merozoites differentiate into male and female gametocytes
  14. 14. species-specific features P. vivaxand P. ovale  hypnozoites remain dormant in liver for months-years, then reactivate and produce merozoites P. falciparum  adhesins on erythrocyte surface stick to walls of small vessels  responsible for haemorrhage and infarction in placental and cerebral malaria
  15. 15. Malaria and History co-evolved with anthropoid lineages in Africa  controversies as to source of human infection  carried by “out of Africa” migration to Old World periodic fevers recorded throughout history  China in 2700 BCE; 2nd C BCE describe Qinghao plant (Artemisia annua) as remedy  Hippocrates in the 5th C BCE carried to New World by explorers, missionaries, slaves  Jesuits bring back Peruvian Cinchonabark (source of quinine) historically associated with miasmas rising from marshes
  16. 16. Malaria and History 1880: parasites first seen in blood in by French army surgeon, Alphonse Laveran awarded 1907 Nobel Prize mosquito as vector suspected by Laveran and by Patrick Manson
  17. 17. Malaria and History 20 August 1897, Secunderabad, India Ronald Ross, an Indian army surgeon, spies oocysts of P. falciparumin stomach tissue of mosquito artificially fed on malaria patient, Hussain Khan By July 1898, Ross has confirmed mosquito link with bird malaria, revealing parasite entire life cycle including presence in mosquitos salivary glands Awarded 1902 Nobel Prize
  18. 18. Malaria and History "This day relenting God Hath placed within my hand A wondrous thing; and God Be praised. At his command, Seeking his secret deeds With tears and toiling breath, I find thy cunning seeds, O million-murdering Death. I know this little thing A myriad men will save, O Death, where is thy sting? Thy victory, O Grave?"
  19. 19. Malaria and History 1898: Grassi, BignamiBastianelli describe developmental stages of human malaria parasites in anopheline mosquitoes 1899: mosquitoes fed on a patient in Rome sent to London, fed on two volunteers; both develop malaria 1930s: de Meillon in South Africa shows that malaria controlled by frequent spraying of walls and ceilings of dwellings with pyrethrins
  20. 20. Malaria and History 1934: chloroquine discovered by Hans Andersag, at Bayer IG Farben  established as effective and safe antimalarial in 1946 1939: insecticidal properties of DDT discovered by Paul Müller in Switzerland  Müller wins 1948 Nobel Prize 1947: Henry Shortt and Cyril Garnham, working in London, show phase of division in liver precedes development of parasites in blood  With American clinician, WojciechKrotoski, later showed P. vivax could remain dormant in liver for several months
  21. 21. Control of Malaria: History In 1900, >77% of world population (1.6bn) in 140 countries at risk of malaria  3.1m deaths, ~90% outside sub-Saharan Africa National Malaria Eradication Program, 1947-52  eradicated malaria from USA  >4.6M houses sprayed: 1947 15,000 cases; 1950 2,000 cases Sardinia 1947-51  75,000 to 9 cases
  22. 22. Global Malaria Eradication Campaign 1950s–1970s Spearheaded by WHO and US epidemiologist Fred Soper and involved ≥50 countries  Heavy use of of DDT to spray houses twinned with case finding and treatment in four successive steps: preparation, attack, consolidation, and maintenance Reduced world population at risk of malaria to ~50% by 1975  Countries with temperate climates and seasonal transmission eradicated malaria Sri Lanka, >2m cases in 1958 to 17 in 1963  Then bounced back to 500,000! Negligible progress in e.g. Indonesia, Afghanistan, Haiti, and Nicaragua  most of Sub-Saharan Africa excluded!
  23. 23. Global Malaria Eradication Campaign 1950s–1970s Failure due to  Darwinian evolution of resistance to DDT and drugs  wars and massive population movements  lack of sustained funding from donor countries  lack of community participation WHA abandoned eradication in 1967  Focus on control  No mention of “E word” for decades Now ~40% of world population at risk
  24. 24. Roll Back Malaria Initiative instigated by WHOs Director General in 1998, launched by WHO, UNICEF, UNDP and the World Bank 2006 RBM Change Initiative to strengthen response to emerging challenges in global malaria control 2007: Gates calls for eradication!
  25. 25. Global Malaria Action Plan (2008)  Universal coverage for all populations at risk with locally appropriate interventions for prevention and case management by 2010  Reduce global malaria cases from 2000 levels by 50% in 2010 and by 75% in 2015  Reduce global malaria deaths from 2000 levels by 50% in 2010 and to near zero preventable deaths in 2015  Eliminate malaria in 8-10 countries by 2015 and afterwards in all countries in the pre-elimination phase today
  26. 26. International funding for malaria control up from ~US$0.3bn in 2003 toUS$1.7bn in 2009 due largely to the emergence of the Global Fund andgreater commitments by the US President’s Malaria Initiative, the WorldBank and other agencies.This increase in funding is resulting in dramatic scale-up of malaria controlinterventions in many settings and measurable reductions in malariaburden
  27. 27. Control of Malaria Effective medicines and relatively inexpensive preventive measures available  But these reach only a small proportion of those in need, mainly because of poverty Last decade: new medicines and approaches developed for  case management  selective vector control  epidemic detection and control challenge of producing widely available vaccine that provides high level of protection for sustained period yet to be met
  28. 28. Malaria Control: Intervention PointsEarly and Effective Treatment Prevent Transmission withKill asexual forms (ACT) Genetic Manipulation? Cure diseaseKill sexual forms (primaquine) Prevent spread to mosquito Prevent Breeding Release sterile malesEarly Diagnosis Remove breeding sitesrDT PARASITE LarvicidesPrevent Disease withVaccine? Prevent Bites HOST Nets Repellents Close doors/windows Kill adult mosquitoes Chemoprophylaxis VECTOR for travellers
  29. 29. Vector Control Measures AIM: to protect individuals against infective mosquito bites and at community level to reduce intensity of local malaria transmission Nets and Sprays
  30. 30. Insecticide-Treated Nets (ITN) Long-Lasting Insecticidal Nets (llins)  Do not require retreatment  Maintain biological efficacy against vector for ≥3 years  In Africa alone, 140 million nets were distributed between DFID Some rights reserved 2006 and 2008
  31. 31. Indoor Residual Spraying (irS) Insecticides are sprayed on walls of homes  DDT back in fashion  “weapon of mass survival” If breeding sites are few, fixed and easy to findlarviciding and environmental management can be used some rights reserved
  32. 32. Vector Control: alternative approaches Sterile insect technique  method of biological control: millions of radiation-sterilised male insects released, compete with wild males for female insects  successfully been used to eradicate screw-worm fly in areas of North America  suitable for mosquitoes in Africa? Transgenic parasite-resistant mosquitoes?
  33. 33. Malaria Case Management: Diagnosis Malaria confirmed by parasitological diagnosis with either microscopy or a rapid diagnostic test (rDT) Microscopy  Giemsa staining of thick and thin films: cheap and low(ish) tech  BUT requires well-trained, competent microscopists and rigorous maintenance of functional infrastructure and QC
  34. 34. MalariaRapid Diagnostic Tests immunochromatographicassa ys detect malaria antigens in 5–15 µL blood with mAb impregnated on a test strip; coloured test line obtained in 5–20 min; “pregnancy test for malaria”. require no capital investment or electricity, simple to perform and easy to interpret BUTexpensive
  35. 35. Malaria Case Management: iPTp intermittent preventive treatment for pregnant women (iPTp) to prevent malaria infection in high transmission settings  give ≥ 2 doses of sulphadoxine-pyrimethamine (SP)  regardless of presence of parasites  given from 2nd trimester, preferably 1 month apart Some rights reserved hdptcar
  36. 36. Malaria Case Management: Treatment AIMS to reduce morbidity and mortality by  ensuring rapid, complete cure  preventing progression to severe, potentially fatal disease  preventing malaria-related anaemia and negative impact of malaria on foetus to curtail transmission of malaria by reducing parasite reservoir
  37. 37. Malaria Case Management: Treatment Artemisinin-based combination therapies (ACTs) now recommended treatment against P. falciparummalaria Chloroquine and primaquine against P. vivaxmalaria. Prophylaxis to prevent malaria in travellers to malaria-endemic countries
  38. 38. Malaria Case Management: Threats Early evidence of resistance to artemisinins Continued use of artemisininmonotherapy major factor in parasite resistance Surveillance of therapeutic efficacy over time is an essential component of malaria control Genotyping to distinguish relapse from reinfection
  39. 39. New Drugs Against Malaria? Medicines for Malaria Venture (MMV)
  40. 40. Developing a Vaccine? Anti-blood-stage vaccine difficult because of  Antigenic diversity in parasite  Parasite mechanisms that evade host responses  Huge biomass of parasites  BUT we know that in endemic areas repeated infection results in control of blood-stage parasitaemia and effective immunity
  41. 41. Developing a Vaccine? Vaccines Against Pre-Erythrocytic Parasite Stages?  Some success with whole-cell irradiated and genetically attenuated parasites  Subunit vaccines targeting circumsporozoite antigen: RTS,S vaccine in phase III trials Transmission Blocking Vaccines (TBVs)?  BUT would not protect the vaccinated individual
  42. 42. Are we winning?
  43. 43. Will we win? Complete interruption of malaria transmission is likely to require additional, novel tools, especially in high-transmission situations Malaria control today relies heavily on limited number of tools, in particular artemisinin derivatives and pyrethroids which could be lost to resistance at any time Development of new tools for vector control and other preventive measures, diagnosis, treatment and surveillance remains a priority We need world peace and development!
  44. 44. Will we eradicate malaria? In my lifetime?  No  In your lifetimes or your children’s lifetimes?  Maybe, with your help? “Death by mosquito bite? No! Not in the 21st Century, we are not having that!” Bono
  45. 45. Any Questions?