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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)

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

    October

    2007

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

    The three components of the global strategy

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

    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

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

    Zanzibar - hospitalizations and malaria deaths 1999-2008

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

    The Gambia - slide positivity rates 2003-2009

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

    Farafenni demographic surveillance, 1989 – 2008

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

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

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

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

    0

    5

    10

    15

    20

    25

    30

    35

    40

    -10 10 30 50 70

    C r u

    d e

    m o

    r ta

    li ty

    r a

    te ( 1

    /1 0

    0 0

    )

    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

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

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

    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

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

    The hidden reservoir of malaria infection

    Modified from Breman, AJTMH 2001

    Clinical cases

    Patent infections

    Sub-patent infections

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

    Hollow: microscopy Filled: PCR

    Diamonds:Asia Triangles: LA Squares: Africa

    Lindblade et al, 2013

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

    Lin et al,

    Trends in

    Parasitology,

    2014

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

    Submicroscopic gametocytaemia and mosquito infectivity threshold

    Lin et al,

    Trends in

    Parasitology,

    2014

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

    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?

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

    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.

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

    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

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

    Bed net and indoor residual spraying coverage, malaria

    prevalence by study sites (Mwesigwa et al, submitted)

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

    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

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

    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?

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

    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

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

    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

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

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

    0

    0.02

    0.04

    0.06

    0.08

    0.1

    0.12

    0.14

    0.16

    0.18

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