Invited Abstract 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Vaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial (#13)

Paul Chapman 1
  1. Royal Brisbane and Women’s Hospital, -, QLD, Australia

Control of human hookworm infection would be greatly aided by the development of an effective human vaccine. A radiation attenuated hookworm larval vaccine has previously been successfully developed and commercialised for use in dogs.  We replicated this animal model, developing an ultra-violet light attenuated Necator americanus vaccine for use in humans.  In this work we reviewed the historical origins of experimental human hookworm infection, developed N. americanus larval culture methods, characterised the larvae and developed methods for UV attenuation, for use in a phase 1b clinical trial.  We demonstrated that larval viability (assessed by thermally induced motility assay at day 14 post-harvest) was inversely associated with UV light exposure.  We then performed a two-stage clinical trial.  In stage 1, participants received dermally applied larvae attenuated with either 700µJ or 1000µJ of UV light.  We demonstrated that fewer larvae penetrated the skin when attenuated with 1000µJ than with 700µJ of UV light.  In stage 2 we performed a phase 1b randomised, controlled, challenge study, comparing safety and tolerability, immune responses, and efficacy of vaccination with 2 doses of dermally applied larvae attenuated with 700µJ UV light to placebo (tabasco sauce).  We demonstrated that attenuated larvae are safe and well tolerated.  Vaccination was associated with the development of an antigen specific IgG response.  Polymorphonuclear blood cells of vaccinated participants produced significantly greater levels of IFNγ, TNFα, IL-2, IL-4, and IL-5 than the PBMC of unvaccinated participants following stimulation with larval antigens.  Following challenge with normal larvae, all participants developed patent infection. Significantly fewer larvae per g of faeces were recovered in the vaccine group than in the placebo group.  This is the first published soil transmitted helminth human challenge model and the first trial exploring an attenuated hookworm vaccine in humans.