What measures of malaria do we need to monitor elimination? Chris Drakeley

The Spectrum of Malaria Infection Infectious bite Biological parameters for assessing transmission intensity Infection Clinical malaria Less Common events: identified via health facilities or DSS Severe malaria Death (Greenwood et al. Parasitology Today 1992;7,277.)

Figure 1.P. falciparum Malaria Risk Defined by Annual Parasite Incidence (top), Temperature, and Aridity (bottom) Areas were defined as stable (dark-red areas, where PfAPI ≥ 0.1 per thousand pa), unstable (pink areas, where PfAPI < 0.1 per thousand pa), or no risk (light grey). The few areas for which no PfAPI data could be obtained, mainly found in India, are coloured in dark grey. The borders of the 87 countries defined as P. falciparum endemic are shown. Highland areas where risk was excluded due to temperature appear in light grey. The aridity mask excluded risk in a step-wise fashion, reflected mainly in the larger extents of unstable (pink) areas compared to the top panel, particularly in the Sahel and southwest Asia (southern Iran and Pakistan). (Guerra et al Plos Med 2008)

Entomological monitoring Requires long term, regular monitoring Sampling needs to be increasingly intense as the number of mosquitoes (and infected mosquitoes) decreases.

Mosquito human dynamics Routine entomology remains key for monitoring changes in vector behaviour What species are they? Do mosquitoes bite earlier? Do they bite outside? Are they resistant to insecticide? (Killeen et al BMC ID 2006)

Measuring parasites The gold standard measure Allows detection and enumeration of parasites Allows speciation and identification of potentially infectious individuals

Limitations of microscopy This method is limited by how much of a blood film can be read……. Ideally we need to identify all those infected (& infectious) RDT have similar sensitivity to microscopy

Progress with molecular methods Two new methods the LAMP (above) & NALFIA have 5 fold better sensitivity that microscopy or RDT. Species, density and gametocytes remain issues Figure 3 | Detection of the loop-mediated isothermal amplification (LAMP) reaction using fluorescent metal indicator. (a) Irradiating the tube using a handheld-UV lamp (wavelength: 365 nm) from the bottom. (b) Under daylight. Plus sign denotes positive reaction (with target DNA), minus sign denotes negative reaction (without target DNA). Fig. 2. Example of positive and negative NALFIA. The left stick shows the negative control sample that does not contain targetDNA.Only the control line becomes positive. The stick on the right shows a NALFIA with the amplified Plasmodium product (lower band) and the control line (upper band).

Serological alternatives Detecting anti malarial antibodies in the blood of people who have been exposed to malaria is another approach Antibodies last for a long time and represent cumulative exposure to malaria Cheap, easy and high through-put Modern techniques are sensitive and specific

Identification of transmission sites: regional level Blue bars –parasite prevalence , purple bars -sero prevalence Data from the Thai-Cambodia boarder Increased sensitivity of serology to allows Identification of potential foci of infection for the control of drug resistance Cook et al unpublished

Identification of transmission sites: village level Data from Kenya showing that individuals closer to mosquito breeding sites have more antibodies or malaria exposure. Malaria transmission remains heterogenous and Identification and targeting high transmission foci within a village will be key. Wilson et al BMC ID 2006

Monitoring progress of the elimination effort Historical precedents for serological evaluation of malaria eradication attempts -Mauritius -Greece Antibodies to detect changes in exposure to both P.falciparum and P.vivax.

Monitoring will require a combination of approaches When & how to measure? Monitoring will require a combination of approaches Rapid situational assessments to identify key areas leading to Detailed surveys (MIS) for risk factor analysis Sentinel site monitoring for vector studies and parasite and vector resistance

Biological tools for the eradication toolbox Use of existing tools to monitor entomological, parasitological and serological changes. Technological developments to increase the sensitivity Develop appropriate sampling frames for representative sample collection