Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

Abstract

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between-and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt 1/2 ) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt 1/2. P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt 1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt 1/2 (mean difference in PCt 1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt 1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisininresistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.malaria | artemisinin | drug resistance | immunity | serology

Adaptive immunity is essential in preventing recrudescence ofPlasmodium yoeliimalaria parasites after artesunate treatment

“…Since these children are constantly exposed to P. falciparum parasites, they have built overtime, both antibody and T cell responses against the parasite. More recently, it was reported that, in area of low-immunity anti-P. falciparum antibody titers were positively associated with faster parasite clearance rate, having a better effect on slow clearing kelch13 mutant parasites (Ataide et al, 2017). Thus, it is more likely that in individuals with pre-existing immunity, immune memory plays a role in the early clearance and elimination of the parasite, as we have previously reported (Goh et al, 2016).…”

“…Of these, the host immune response is thought to be critical in parasite clearance rates, during and after artemisinin therapy (Ataide et al, 2017;Lopera-Mesa et al, 2013;Monatrakul et al, 2010). Of these, the host immune response is thought to be critical in parasite clearance rates, during and after artemisinin therapy (Ataide et al, 2017;Lopera-Mesa et al, 2013;Monatrakul et al, 2010).…”

“…Although most studies on artemisinin resistance focus on the intrinsic susceptibility of the parasite, a significant proportion of drug failures (~40%) is thought to be attributed other factors. Of these, the host immune response is thought to be critical in parasite clearance rates, during and after artemisinin therapy (Ataide et al, 2017;Lopera-Mesa et al, 2013;Monatrakul et al, 2010). As the precise contribution of host immunity to drug efficacy is difficult to assess in humans, it has remained poorly characterised.…”

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…The kelch 13 genotype is a generally accepted molecular marker for artemisinin resistance, but it is difficult to implement a PCR-based test in field settings which often lack the necessary equipment. The developed nomogram suggested here is a sensitive and field adapted alternative to the day 3 positivity test, although it requires further validation in different epidemiological settings with different levels of immunity (60) and different kelch mutations, and thus different degrees of slow parasite clearance conferred. A simple decision tree for the implementation of the resistance nomogram based on this study's results is proposed in Fig.…”

The Role of Complement Immune Response on Artemisinin Combination Therapy in a Population from Malaria Endemic Region of Western Kenya

“…Acquired immunity has been shown to influence malaria drug treatment outcomes by enhancing the 3 efficacy of sub-optimal drug regimen and delaying the emergence of drug resistance, including artemisinin combination therapies (ACTs), the first-line treatment of Plasmodium falciparum in most malaria endemic countries [4]. ACTs are still highly efficacious in sub-Saharan Africa (sSA) [5], but as malaria transmission reduces, and malaria immunity at population level wanes [6], the efficacy of ACTs is likely to be impacted.…”