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

  1. Freya J. I. Fowkesa,d,r,1
  1. aDisease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia;
  2. bMahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
  3. cCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom;
  4. dCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia;
  5. eVictorian Cytology Service Ltd., Melbourne, VIC 3002, Australia;
  6. fDivision of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan;
  7. gWorldwide Antimalarial Resistance Network, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford OX3 7FZ, United Kingdom;
  8. hHoward Hughes Medical Institute, Malaria Group, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201-1559;
  9. iLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
  10. jNational Center for Parasitology, Entomology and Malaria Control, Phnom Penh 12101, Cambodia;
  11. kFaculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
  12. lOxford University Clinical Research Unit, Hospital for Tropical Diseases, Quan 5, Ho Chi Minh City, Vietnam;
  13. mDepartment of Medical Research, Lower Myanmar, Yangon 11191, Myanmar;
  14. nLao-Oxford-Mahosot Hospital-Wellcome Trust-Research Unit, Mahosot Hospital, Vientiane, Lao PDR;
  15. oFaculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR;
  16. pMalaria Research Group & Dev Care Foundation, Chittagong, Bangladesh;
  17. qShoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Tak 63110, Thailand;
  18. rDepartment of Epidemiology and Preventive Medicine, Department of Infectious Diseases, Monash University, Melbourne, VIC 3004, Australia

  1. Edited by Barry R. Bloom, Harvard T. H. Chan School of Public Health, Boston, MA, and approved February 6, 2017 (received for review September 28, 2016)

Significance

Slow-clearing artemisinin-resistant malaria parasites are now well established in the Greater Mekong Subregion. This large multinational therapy efficacy study incorporating clinical data, molecular drug-resistance markers, and immune profiling aimed to understand how variations in population levels of naturally acquired malarial immunity affect the slow-clearing phenotype, emergence of artemisinin resistance-associated mutations, and assessment of the geographical spread of artemisinin resistance. We found that slow-clearing mutant parasites occur at higher frequencies in areas where immunity is lowest, patients with higher immunity have faster clearance times, and immunity has the greatest effect on clearance in patients with slow-clearing mutant parasites. Immunity plays an important role in the emergence of resistant parasites and can confound the World Health Organization’s phenotype and genotype definitions of artemisinin resistance.

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 (PCt1/2) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2. P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt1/2 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 PCt1/2 (mean difference in PCt1/2 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 PCt1/2 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 artemisinin-resistant 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.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: fowkes{at}burnet.edu.au.

  • Author contributions: E.A.A., J.A.S., N.J.W., and F.J.I.F. designed research; R.A., R.P., J.-A.C., K.O., A.M.D., N.P.D., M.D., R.M.F., P.L., C.A., S.P., T.T.H., Y.H., M.M., M.A.F., F.N., J.A.S., N.J.W., and F.J.I.F. performed research; E.T., C.L., T.T., J.G.B., and F.J.I.F. contributed new reagents/analytic tools; R.A., M.J.M., J.A.S., and F.J.I.F. analyzed data; and R.A. and F.J.I.F. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1615875114/-/DCSupplemental.

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