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MRC Unit, The Gambia Leading scientific research to save lives and improve health across the developing world

The challenges of malaria

elimination/eradication

Umberto D’Alessandro

Medical Research Council

London School of Hygiene and Tropical Medicine

(Institute of Tropical Medicine, Antwerp)


October

2007


The three components of the global strategy


Gates and malaria eradication

• Davos 2013 • Malaria Can Be Eradicated

• Tools for eradication not available yet

• Funding for new drugs and vaccines

• ASTMH 2014-keynote speech • Malaria eradication in my lifetime


Zanzibar - hospitalizations and malaria deaths 1999-2008


The Gambia - slide positivity rates 2003-2009


Farafenni demographic surveillance, 1989 – 2008

<5yrs mortality from 159/1000 live births in 1990 to 45/1000 lb in 2008


Non-thyphoid Salmonella and malaria (Mackenzie et al, 2010)


Crude mortality rates before and after the eradication programme in Sri Lanka (Molineaux 1985)

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5

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25

30

35

40

-10 10 30 50 70

Cru

de

mo

rta

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ra

te (1

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00

)

Spleen index 1938-1941

Decrease of overall mortality

was related to the level of malaria

endemicity before the campaign

r²= 0,938

1930-1945

1946-1960

Malaria control vs. malaria elimination

GOAL

Reduction of the malaria burden to a level that it is no longer a major public health problem

Interruption of local mosquito-borne malaria transmission in a defined geographical area

Area of Operations

Malaria endemic areas: Universal coverage of prevention and treatment (SUFI)

Foci identified through epidemiological intelligence

Surveillance

May not be the best but is sufficient

Must be rapid and highly efficient

CONTROL ELIMINATION

Adapted from WHO, 2007

Elimination: A Paradigm Shift for Surveillance

For elimination purposes, a malaria case is a person in whom, regardless of the presence or absence of clinical symptoms, malaria parasites have been confirmed by quality-controlled laboratory diagnosis.

Clinical Cases Infections

Interventions during elimination programs are based on the concept of a malaria focus, assuming that transmission is focalized and no longer homogeneous across the country.

Universal Coverage Targeting Foci


Final parasite prevalence after 15 years of sustained intervention (Griffin et al, PLoS

Medicine, 2010)

EIR 3 43 46 81 586 675

Elimination achievable with current methods only in areas with extremely low transmission


The hidden reservoir of malaria infection

Modified from Breman, AJTMH 2001

Clinical cases

Patent infections

Sub-patent infections


Hollow: microscopy Filled: PCR

Diamonds:Asia Triangles: LA Squares: Africa

Lindblade et al, 2013


Lin et al,

Trends in

Parasitology,

2014


Submicroscopic gametocytaemia and mosquito infectivity threshold

Lin et al,

Trends in

Parasitology,

2014


Higher carriage than suspected

• Blood volume for PCR assay about 5μl

• Detection threshold about 1,000 parasites/ml

• Use of ≥200μl of blood increases sensitivity (Imwong et al, 2014)

• Are these carriers important in maintaining transmission?


Asymptomatic malaria infections

• About half infections undetected by microscopy

• Difference is greatest in low transmission settings

• Many asymptomatic infections can persist for significant periods of time;

• P. falciparum gametocytes positively associated with no symptoms and low asexual parasite densities;

• Mosquitoes infected with gametocyte densities as low as 5 gametocytes/μl

• Children with undetectable gametocytaemia by molecular methods could still transmit to mosquitoes;

• Gametocyte carriers may be more attractive to mosquitoes than both uninfected individuals and individuals with only asexual parasites.


Extreme heterogeneity- school survey (Takem et al, 2011)

Heterogeneity

•Apparent geographically homogeneous area with similar villages

•Major differences in the prevalence of malaria

•Genetic factors

•Haemoglobin abnormalities

•Immune responsiveness

•Environmental factors

•Vector breeding and survival

•Exposure to vector mosquitoes


Bed net and indoor residual spraying coverage, malaria

prevalence by study sites (Mwesigwa et al, submitted)


Heterogeneity of risk and transmission

• Kilifi, Kenya (Mwangi et al, 2008)

– 21% of the children categorized as ‘more susceptible’ and experienced 55% of total clinical malaria episodes (contributed only 23% of the person-time of follow-up)

• Smith et al, 2005: Heterogeneous biting or heterogeneous susceptibility to infection are important and pervasive factors determining the prevalence of infection: 20% of people receive 80% of all infections


Questions

• Who are the people initiating/maintaining transmission?

• How can we identify them?

• If identified, can we stop transmission by treatment and/or vaccination?

• When these interventions should be implemented and for how long?


Two broad different approaches

Active case detection (ACD)

• Reactive – Screening people around a

passively detected clinical case

– No studies on impact on transmission

• Proactive – Screening of high risk

populations

– Low sensitivity of diagnostic tests

Presumptive treatment

• Mass drug administration (MDA) – Whole population

– Targeted to high risk groups

• IPT/SMC


Combined impact of MDA and vector control (Okell et al, 2010)

1,000 people

10,000 people

500,000 people

MDA 2 rounds I year


MDA (1 yearly round for 2 years) plus RTS,S/AS01

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2011 2016 2021 2026

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Control - LLIN plus IRS

MDA Only

Vaccine only

MDA plus vaccine

VE=30% VE=50%


Conclusions

• Eradicating P. falciparum malaria may be much harder than anticipated

• P. vivax malaria would be even harder

• Most if not all new interventions, e.g. MDA, require a huge investment of the health services and involvement of the local populations

• Different approaches poorly defined and evaluated

• Factors affecting effectiveness not well understood but human/social factors are extremely important - Risk of embarking in large interventions without the required information

• Social scientists should be involved in any attempt of elimination from the very beginning

Thank you for your attention

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