Investigating Systemic Immune Biomarkers in a Controlled Human Hookworm Infection Model

The alarming rise in the prevalence of chronic inflammatory conditions in developed countries has recently been proposed to be associated with the disappearance of helminth infections. It’s hypothesised that helminths such as hookworms can regulate the immune system via their release of excretory-secretory products to suppress inflammatory immune responses. This has led to the concept of hookworm therapy for the treatment of chronic inflammatory disorders such as multiple sclerosis and inflammatory bowel disease. However, to date, there has not been sufficient longitudinal immunological data in healthy humans infected with hookworm. This thesis aimed to characterise key serum immune biomarkers elicited in a controlled human hookworm infection model phase I longitudinal clinical study. Thirteen healthy participants were administered 30 infective L3 N. americanus larvae and followed across 48 weeks. Serum immunoassays were performed to assess a broad range of biomarkers including immunoglobulins, cytokines, and chemokines in participants at baseline and following N. americanus infection. These results were analysed alongside other cellular, symptomatic, and physiological parameters performed to assess safety/tolerability and patency following N. americanus infection.

The clinical study demonstrated that patency was established from week 8 onwards following N. americanus infection and there were no severe symptoms reported however one participant was dewormed at week 6 post- infection (p.i.) due to gastrointestinal discomfort. The findings outlined in this thesis revealed that total IgE levels were elevated from week 8 onwards however total IgA, IgM, IgG1, IgG2, IgG3, and IgG4 were relatively stable following N. americanus infection. Antigen-specific IgG responses were markedly elevated from week 8 to week 48 p.i. Elevations in total IgE and antigen-specific IgG responses coincided with the establishment of patency. There was a dramatic spike in serum IL-5 levels at week 4 following N. americanus infection. However, the remaining serum cytokines and chemokines did not significantly increase in most participants over the course of the infection. Furthermore, a positive correlation was determined between serum IL-5 levels and whole blood eosinophil counts which peaked at week 8 following infection. Taken together, this data suggests that infection with 30 infective L3 N. americanus larvae was safe and tolerated in healthy participants. Additionally, IgE, antigen-specific IgG, IL-5 and eosinophil responses were elicited systemically during N. americanus infection, suggesting a dominant Th2 response. This offers insights into the potential immune mechanistic pathways implicated in human hookworm infection.