Abstract
BackgroundNew 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.MethodsTwo 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.ResultsOverall, 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.ConclusionThe 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.
Highlights
New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies that target the circumsporozoite protein (CSP)
The current study focuses on the use of two in vivo models of Plasmodium sporozoite infection to measure the functional activity of anti-PfCSP Monoclonal antibody (mAb)
Inter‐assay consistency in reduction in parasite liver burden studies Two human active mAbs were tested, AB311 and AB317, that bind to the NANP repeats of P. falciparum CSP
Summary
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). Malaria remains a global health emergency, with an estimated 228 million cases and over 400,000 deaths occurring worldwide in 2018 [1]. While control measures, such as insecticide-treated nets, sensitive diagnostics tools and effective case management, have helped reduce the number of cases and deaths, progress has stalled in recent years [1]. PfSPZ, administered by intravenous (i.v.) injection have shown efficacy in some populations [8] and induce both antibody responses to CSP and cellular responses to multiple antigens expressed during the liver stage [8]
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