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Antibody Correlates of Protection from Clinical Plasmodium falciparum Malaria in an Area of Low and Unstable Malaria Transmission

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  • 1 Division of Global Pediatrics, University of Minnesota, Minneapolis, Minnesota;
  • | 2 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota;
  • | 3 CDC Foundation, Atlanta, Georgia;
  • | 4 Department of Biochemistry and Molecular Biology, Egerton University, Nakuru, Kenya;
  • | 5 Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya;
  • | 6 Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
  • | 7 Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota;
  • | 8 Walter Reed Army Institute for Research, Silver Spring, Maryland;
  • | 9 Statens Serum Institut, Copenhagen, Denmark;
  • | 10 Jaramogi Oginga Odinga University of Science and Technology, Bondo, Kenya;
  • | 11 Department of Pediatrics, Indiana University, Indianapolis, Indiana

ABSTRACT

Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case–control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36–0.89], 0.56 [0.36–0.87], and 0.77 [0.43–1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41–0.89], 0.60 [0.43–0.84], and 0.49 [0.24–0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

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Author Notes

Address correspondence to Chandy C. John, Department of Pediatrics, Indiana University, Indianapolis, IN 46202. E-mail: chjohn@iu.edu

Financial support: This project was supported by grants from NIH-NIAID (NCT00393757), NIH Fogarty International Center (D43 TW0080085), and the University of Minnesota Amplatz Children’s Hospital, and an NIH research training grant (R25 TW009345) awarded to the Northern Pacific Global Health Fellows Program by Fogarty International Center in partnership with several NIH institutes (NIMH, NIGMS, NHLBI, OAR, and OWH).

Disclosures: Drs. K. E. S. H., B. N. O., S. D., M. T., G. A., and C. C. J. report no competing interests with this research or findings. Dr. J. S. H. reports grants from the National Institutes of Health and University of Minnesota Amplatz Children’s Hospital.

Disclaimer: The funding agencies were not involved in any aspect of the study including design, analysis, or interpretation of results.

Authors’ addresses: Karen E. S. Hamre, CDC Foundation, Atlanta, GA, E-mail: mry0@cdc.gov. Bartholomew N. Ondigo and George Ayodo, Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya, E-mail: ondigo2002@gmail.com and gayodo@gmail.com. James S. Hodges, Division of Biostatistics, University of Minnesota, Minneapolis, MN, E-mail: hodge003@umn.edu. Sheetij Dutta, Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MA, E-mail: sheetij.dutta.civ@mail.mil. Michael Theisen, Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark, E-mail: mth@ssi.dk. Chandy C. John, Department of Pediatrics, Indiana University, Indianapolis, IN, E-mail: chjohn@iu.edu.

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