Opportunities and Challenges in Developing a Cryptosporidium Controlled Human Infection Model for Testing Antiparasitic Agents

Abstract

Cryptosporidiosis is a leading cause of moderate-to-severe diarrhea in low- and middle-income countries, responsible for high mortality in children younger than two years of age, and it is also strongly associated with childhood malnutrition and growth stunting. There is no vaccine for cryptosporidiosis and existing therapeutic options are suboptimal to prevent morbidity and mortality in young children. Recently, novel therapeutic agents have been discovered through high-throughput phenotypic and target-based screening strategies, repurposing malaria hits, etc., and these agents have a promising preclinical in vitro and in vivo anti- Cryptosporidium efficacy. One key step in bringing safe and effective new therapies to young vulnerable children is the establishment of some prospect of direct benefit before initiating pediatric clinical studies. A Cryptosporidium controlled human infection model (CHIM) in healthy adult volunteers can be a robust clinical proof of concept model for evaluating novel therapeutics. CHIM could potentially accelerate the development path to pediatric studies by establishing the safety of a proposed pediatric dosing regimen and documenting preliminary efficacy in adults. We present, here, perspectives regarding the opportunities and perceived challenges with the Cryptosporidium human challenge model.

An update on Cryptosporidium biology and therapeutic avenues

“…Challenges involving in vitro and in vivo models during the development of therapeutics for Cryptosporidium are extensively reviewed elsewhere (Jumani et al 2021 ; Manjunatha et al 2016 ). Briefly, using the mouse stem cell-derived intestinal epithelial monolayers, long-term C. parvum growth can be supported.…”

“…Various novel in vivo animal models for parasite infection has been depicted elsewhere (Costa et al 2012 ; Lee et al 2019 ; Sateriale et al 2019 ). A recent review describes a controlled human model named CHIM (controlled human infection model) in volunteers for accelerated and robust drug discovery (Jumani et al 2021 ). Despite initial success in animal model-related studies, host specificity of the parasite, different symptoms, and diverse infection patterns should be kept in mind while addressing the issue in humans.…”

Controlled Human Infection Models To Accelerate Vaccine Development

“…In considering the re-establishment of the Cryptosporidium CHIM (525), one element that merits careful consideration is long-term safety risks of volunteers. In the studies conducted in the 1990s and early 2000s, there were no reported safety assessments of adverse events related to challenge beyond 60 days.…”

“…Several methods have been reported for perpetual propagation of C. hominis or C. parvum in cell culture(522)(523)(524), but these are not widely available nor used routinely. More recent epidemiology studies highlighting the burden of Cryptosporidium in low-and middle-income countries (LMICs) have rekindled the interest in this model for the purposes of testing drug and vaccine candidates for treatment or prevention of infection with the parasite(525). Studies of the natural history of cryptosporidiosis in LMIC populations demonstrate there are fewer infections among older children(502), suggesting that adaptive immunity induced by a vaccine is achievable.…”

Emerging treatment options for cryptosporidiosis

“…It is feasible that the clinical pathway for anticryptosporidial NCEs may diverge between the different target populations and use cases, and therefore, these studies could serve as a small-scale first pass to determine proof-of-concept efficacy of NCEs before a large financial investment in specific studies involving immunocompromised patients or young children. Although there is interest and precedence of CHIM for cryptosporidiosis [ 42 ], the most recent studies were conducted nearly two decades ago, and new regulatory requirements present unique challenges that complicate the re-establishment of this model [ 43 ▪ ].…”