Evidence for histidine-rich protein 2 immune complex formation in symptomatic patients in Southern Zambia

Christine F. Markwalter, Lwiindi Mudenda, Mindy Leelawong, Danielle W. Kimmel, Armin Nourani, Saidon Mbambara, Philip E. Thuma, David W. Wright

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: Rapid diagnostic tests based on histidine-rich protein 2 (HRP2) detection are the primary tools used to detect Plasmodium falciparum malaria infections. Recent conflicting reports call into question whether α-HRP2 antibodies are present in human host circulation and if resulting immune complexes could interfere with HRP2 detection on malaria RDTs. This study sought to determine the prevalence of immune-complexed HRP2 in a low-transmission region of Southern Zambia. Methods: An ELISA was used to quantify HRP2 in patient sample DBS extracts before and after heat-based immune complex dissociation. A pull-down assay reliant on proteins A, G, and L was developed and applied for IgG and IgM capture and subsequent immunoprecipitation of any HRP2 present in immune complexed form. A total of 104 patient samples were evaluated using both methods. Results: Immune-complexed HRP2 was detectable in 17% (18/104) of all samples evaluated and 70% (16/23) of HRP2-positive samples. A majority of the patients with samples containing immune-complexed HRP2 had P. falciparum infections (11/18) and were also positive for free HRP2 (16/18). For 72% (13/18) of patients with immune-complexed HRP2, less than 10% of the total HRP2 present was in immune-complexed form. For the remaining samples, a large proportion (≥ 20%) of total HRP2 was complexed with α-HRP2 antibodies. Conclusions: Endogenous α-HRP2 antibodies form immune complexes with HRP2 in the symptomatic patient population of a low-transmission area in rural Southern Zambia. For the majority of patients, the percentage of HRP2 in immune complexes is low and does not affect HRP2-based malaria diagnosis. However, for some patients, a significant portion of the total HRP2 was in immune-complexed form. Future studies investigating the prevalence and proportion of immune-complexed HRP2 in asymptomatic individuals with low HRP2 levels will be required to assess whether α-HRP2 antibodies affect HRP2 detection for this portion of the transmission reservoir.

Original languageEnglish (US)
Article number256
JournalMalaria journal
Issue number1
StatePublished - Jul 9 2018


  • Antibodies
  • HRP2
  • Histidine-rich protein 2
  • Immune complexes
  • Malaria diagnosis
  • Plasmodium falciparum

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases


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