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. See also Bio303 Facebook page

1. Global Health and Emerging Infections 1
The Global Burden of Infection and an old foe Malaria
Professor Mark Pallen
Bio303

2. Global Health and Emerging Infections
1. 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 2011
4. Operation Eradication. In this lecture, I will celebrate the global eradication of smallpox,
from the campaign's 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.

3. http://www.facebook.com/pages/Bio303-
Module/159615697415445

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

5. http://www.who.int/healthinfo/global_burden_disease/en/

8. 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

9. 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

10. Malaria in the Headlines
"It was the day after my birthday when the
symptoms first started. I put it down to that I'd
been drinking vodka the night before, because
I'm 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 couldn't 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 I'm dying'? Well, I actually felt
like I was dying. I asked the nurse outright – was
I going to die? She said, 'There's a possibility.' "

11. http://en.wikipedia.org/wiki/File:Plasmodium_lifecycle_PHIL_3405_lores.jpg

12. 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 http://en.wikipedia.org/wiki/File:Malaria.jpg
bloodstream with saliva when
mosquito feeds

13. http://upload.wikimedia.org/wikipedia/commons/7/7c/MalariacycleBig.jpg

14. 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

15. 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
http://en.wikipedia.org/wiki/File:IEcycle.PNG

16. 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

17. 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

20. 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

21. 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 mosquito's
salivary glands
 Awarded 1902 Nobel Prize

22. 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?"

23. 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

24. 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

25. 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

26. 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!

27. 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

28. Roll Back Malaria
 Initiative instigated by WHO's 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!

29. 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

30. International funding for malaria control up from ~US$0.3bn in 2003 to
US$1.7bn in 2009 due largely to the emergence of the Global Fund and
greater commitments by the US President’s Malaria Initiative, the World
Bank and other agencies.
This increase in funding is resulting in dramatic scale-up of malaria control
interventions in many settings and measurable reductions in malaria
burden

31. 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

32. Malaria Control: Intervention Points
Early and Effective Treatment Prevent Transmission with
Kill asexual forms (ACT) Genetic Manipulation?
Cure disease
Kill sexual forms (primaquine)
Prevent spread to mosquito
Prevent Breeding
Release sterile males
Early Diagnosis
Remove breeding sites
rDT
PARASITE Larvicides
Prevent Disease with
Vaccine?
Prevent Bites
HOST Nets
Repellents
Close doors/windows
Kill adult mosquitoes
Chemoprophylaxis
VECTOR
for travellers

33. 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

34. 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 http://www.flickr.com/photos/dfid/2944998010/
DFID Some rights reserved
2006 and 2008

35. 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 http://www.flickr.com/photos/27337026@N03/2589248767/
used some rights reserved

36. 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?

37. 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

38. 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

39. 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
http://www.flickr.com/photos/hdptcar/2530914336/
Some rights reserved hdptcar

40. 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

41. 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

42. 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

43. New Drugs Against Malaria?
Medicines for Malaria
Venture (MMV)
http://www.nature.com/clpt/journal/v85/n6/full/clpt200951a.html

44. 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

45. 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

47. Are we winning?

49. 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!

50. Will we eradicate malaria?
 In my lifetime?
 No 
 In your
lifetimes or
your children’s
lifetimes?
 Maybe, with
your help?
http://www.youtube.com/watch?v=5LdXy7nZXY4
“Death by mosquito bite? No! Not in the 21st Century,
we are not having that!” Bono

51. Any Questions?