Malaria caused by Plasmodium falciparum is a major cause of morbidity and mortality, particularly in young children, resulting in approximately 225 million clinical cases and 1 million deaths each year.

The first line of defence against falciparum malaria, as recommended by the World Health Organisation (WHO), is Artemisinin Combination Therapy (ACT).

ACT has played a fundamental role in controlling malaria, especially since many of the established drugs were phased out due to parasite resistance. Currently, more than 70 percent of clinical cases globally rely on ACT to treat this devastating disease.

Given how much we depend on ACT, it is extremely alarming that resistance against it has just been reported in Asia. These resistant strains have the potential to spread, creating a catastrophic, global threat for malaria treatment as there is nothing to replace ACT. This puts millions of lives at risk and ACT will become redundant in malaria control and elimination efforts.

Antimalarial drug resistance is evaluated by examining drug efficacy (ie: how well the drug works). Drug efficacy is determined by observing how long a patient takes to clear parasites from their blood. If a patient fails to clear parasites (ie: treatment failure), or take longer than normal to clear parasites, this indicates that circulating parasites are resistant to drug treatment.

However, the evaluation of how well an antimalarial drug works is severely impeded by the presence of immunity to malaria. Immunity develops in individuals living in malaria endemic areas that protect them against the clinical symptoms of malaria. Antibodies are an important part of this immunity and act by reducing the number of parasites in the blood. Because antibodies will clear parasites independently of antimalarial drugs, antibodies will improve rates of parasite clearance during drug treatment.

The implications are that in areas with high immunity, clinicians and scientists will believe that the drugs are working better than they actually are and early signs of emerging drug resistance will go unnoticed.

Surprisingly, no study has investigated how protective antibodies facilitate parasite clearance during ACT treatment and how antibodies may mask the emergence of ACT resistance.

Aim

The aim of the proposed study is to understand how host human immunity can interfere with evaluating how well ACT drugs work. This knowledge will be used to effectively monitor emerging ACT resistance.

Research Plan

At the Shoklo Malaria Research Unit (SMRU), located in north-west Thailand, data on ACT efficacy has previously been collected from more than 10,000 patients. We will determine antibody levels to a broad range of malaria proteins in 450 of these patients using established immunoassays.The hypothesis that patients with higher levels of antibodies to malaria proteins will have reduced ACT treatment failure and faster parasite clearance (ie: better drug efficacy) compared to patients with low antibodies, will be tested using statistical approaches recommended by the WorldWide Antimalarial Resistance Network (WWARN). In these analyses we will identify which antibodies best predict how well the drugs work.

Outcomes

• Provide solid evidence base for defining and quantitating the targets of host immunity that influence ACT efficacy Identifying immune biomarkers that predict ACT efficacy are needed to ensure accurate measurements of drug efficacy and to effectively monitor emerging drug resistance. This is particularly imperative in the context of assessing the global spread of antimalarial resistance, which is currently a World Health Organization (WHO) priority.

• Develop a strategy to incorporate measures of immunity in studies monitoring drug resistance

Ultimately, this work will enable us to provide the most accurate estimates of ACT efficacy and will allow scientists to evaluate the spread of ACT resistance to the highest degree.