Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

Rama Raghunandan, Bryan T. Mayer, Yevel Flores-Garcia, Monica W. Gerber, Raphael Gottardo, Hugo Jhun, Sonia M. Herrera, Daniel W. Perez-Ramos, Emily Locke, C. Richter King, Fidel Zavala

Research output: Contribution to journalArticle

Abstract

Background: New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods: Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results: Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion: The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

Original languageEnglish (US)
Article number113
JournalMalaria journal
Volume19
Issue number1
DOIs
StatePublished - Mar 17 2020

Keywords

  • Bioluminescence
  • Circumsporozoite protein (CSP)
  • Functional activity
  • Malaria
  • Monoclonal antibodies
  • P. berghei
  • P. falciparum
  • Transgenic parasite

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein'. Together they form a unique fingerprint.

  • Cite this

    Raghunandan, R., Mayer, B. T., Flores-Garcia, Y., Gerber, M. W., Gottardo, R., Jhun, H., Herrera, S. M., Perez-Ramos, D. W., Locke, E., King, C. R., & Zavala, F. (2020). Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein. Malaria journal, 19(1), [113]. https://doi.org/10.1186/s12936-020-03181-0