Safety and tolerability of experimental hookworm infection in humans with metabolic disease

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Safety and tolerability of experimental hookworm infection in humans with metabolic disease: Proof of Concept (Phase 1b) clinical trial Aims: 1. To establish the acceptability, safety and tolerability of experimental infection with the hookworm Necator americanus (Na) in young obese adults with features of the metabolic syndrome (MetS). 2. Conduct exploratory studies into the impact of hookworms on stabilizing or improving immune/inflammatory, metabolic and microbiological parameters associated with metabolic disease Background: Central obesity and subsequent type 2 diabetes (T2DM) are causing a global epidemic of disability and premature death which threatens to bankrupt health systems even in wealthy countries. The vast majority (80%) of all diabetes cases and 88% of deaths occur in low to middle income countries, many of which still have a significant infectious disease burden. T2DM and several associated chronic conditions are increasingly recognized as having common pro-inflammatory pathways and it is these effects which account for much end-organ damage, especially in the liver, muscle, kidneys, vascular endothelium and brain (Calle et al, 2012). Animal studies and more recently, human observational reports from those transitional populations with high prevalence of helminth exposure and metabolic illness, suggest that helminth infection protects against T2DM and MetS (Hayes, 2015; Tracey, 2016). A plausible biological pathway for this effect has been demonstrated in animal models, where helminth infection stimulates a T helper Type 2 (Th2)-type immune response that, in concert with worm-induced regulatory T cell responses may improve insulin sensitivity, either directly or via suppression of pro-inflammatory Th1/Th17 immune responses. There is evidence that this effect is mediated, at least in part, by changes induced by the worm to the host gut microbiota. Members of the team (AL, PG) have established that experimental inoculation with the human hookworm Necator americanus is safe and efficacious in the treatment of humans with celiac disease (CeD), and which is currently in use in a NHMRC-funded multi-centre clinical trial (ref protocol, Croese 2016). Previous studies have demonstrated that these controlled hookworm infections are associated with a biased Type 2 cytokine response (Gaze at al 2012), with concomitant regulatory T cell responses (Croese et al 2015) that fit the profile of an agent that may be effective at treating the dysregulated inflammation associated with MetS or T2DM. Thus, we propose to use this experimental human infection model in a proof-of-concept phase 1 trial of safety in healthy young adults with central obesity and features of the Metabolic Syndrome (MetS). Hypotheses: That experimental hookworm infection 1. will be tolerated and safe in otherwise healthy obese young adults; 2. will induce a biased Type 2 and regulatory immune response and suppression of systemic pro-inflammatory Type 1 immune responses