Global Health and Emerging Infections 1The Global Burden of Infection and an old foe Malaria

Professor Mark Pallen

Bio303

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 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.

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

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

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

Malaria Complex and deadly mosquito-borne

infectious disease caused by a eukaryotic apicomplexan protists from genus Plasmodium most serious forms caused by P. falciparum P. vivax, P. ovale, P. malariae cause milder, usually

non-fatal disease in humans naturally transmitted by the bite of a female

Anopheles mosquito

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

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.' "

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

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

http://en.wikipedia.org/wiki/File:Malaria.jpg

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

Life cycle in Humans: Exoerythrocytic Phase sporozoites enter 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

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

species-specific features P. vivax and 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

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 Cinchona bark (source

of quinine) historically associated with miasmas rising

from marshes malaria=“bad air”

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

Malaria and History 20 August 1897, Secunderabad,

India Ronald Ross, an Indian army surgeon, spies oocysts of P. falciparum in 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

Malaria and History

"This day relenting GodHath placed within my

handA 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?"

Malaria and History 1898: Grassi, Bignami Bastianelli 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

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, Wojciech Krotoski, later

showed P. vivax could remain dormant in liver for several months

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

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!

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

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!

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

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

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

Malaria Control: Intervention Points

Kill asexual forms (ACT)Cure disease

Kill sexual forms (primaquine)Prevent spread to

mosquito

Early DiagnosisrDT

Prevent BitesNetsRepellentsClose doors/windowsKill adult mosquitoes

Prevent Disease with Vaccine?

Prevent Transmission with Genetic Manipulation?

Prevent BreedingRelease sterile malesRemove breeding sitesLarvicidesPARASITE

VECTOR

HOST

Chemoprophylaxis for travellers

Early and Effective Treatment

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

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 2006 and 2008

http://www.flickr.com/photos/dfid/2944998010/DFID Some rights reserved

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 find larviciding and environmental management can be used

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

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?

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

Malaria Rapid Diagnostic Tests immunochromatographic

assays 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

BUT expensive

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

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

Malaria Case Management: Treatment Artemisinin-based combination therapies

(ACTs) now recommended treatment against P. falciparum malaria

Chloroquine and primaquine against P. vivax malaria.

Prophylaxis to prevent malaria in travellers to malaria-endemic countries

Malaria Case Management: Threats Early evidence of resistance to artemisinins Continued use of artemisinin monotherapy

major factor in parasite resistance Surveillance of therapeutic efficacy over time

is an essential component of malaria control Genotyping to distinguish relapse from

reinfection

New Drugs Against Malaria?

Medicines for Malaria Venture (MMV)

http://www.nature.com/clpt/journal/v85/n6/full/clpt200951a.html

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

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

Are we winning?

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!

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

Any Questions?