KLH Challenge to Explore the Human Immune Response

Overview

One approach to improve the efficiency of the drug development process is the use of human 'immune challenge' studies. In these studies, healthy volunteers are given small amounts of substances which are foreign to their immune system to provoke a temporary response: the 'challenge'. Depending on the nature and dose of the challenge, the body's immune system will react in a different but predictable way, elements of which mimic those seen in disease, thereby 'modelling' them. These models can help safely bridge the gap between animal experiments and patient groups and, if sufficiently understood, test the effect of new drugs without exposing patients to risk. Sadly, whilst immune challenge models have been used in drug development for many years, this has been done in a largely non-standardised, ad hoc manner, which greatly limits the usefulness of the approach. The purpose of this research is to better understand, improve, and standardise a common method of immune challenge which uses a protein called 'Keyhole Limpet Haemocyanin' (KLH). KLH is available as a highly-purified formulation, and because it is not usually encountered by the human immune system (it is derived from an inedible shellfish), it allows us to study the development of immune responses right from the time it is administered. We plan to give different groups of healthy volunteers different doses of KLH with or without an 'immune-boosting' agent (Alhydrogel™ or Montanide ISA™51, commonly referred to as adjuvants), before measuring and comparing their response. We will then re-challenge all the volunteers a month later by injecting different doses of KLH into the skin on their forearms, similar to an allergy test, taking images, blood samples and skin biopsies to understand the nature, time course, and variability of the immune response in each individual. No previous studies have directly explored the effects of KLH dose or adjuvants in a rigorous manner. The results will help us to determine both whether administering KLH with different adjuvants elicits qualitatively different immune response profiles (thus modelling different diseases) and the optimal doses of KLH to evaluate new drugs with. In turn, we hope this will help improve the percentage of drugs progressing from concept to clinical therapy, addressing unmet health needs.

This is a single blind, parallel group, two-phase challenge study to determine the relative immunogenicity of subunit KLH, with and without aluminium hydroxide adjuvant, in healthy UK volunteers aged 18-45. The prime dose of subunit KLH (+/- aluminium hydroxide or Montanide ISA-51) will be administered IM, and the re-challenge dose of subunit KLH for assessment of DTH will be administered ID. This trial will be conducted at a Clinical Research Facility based at the University of Oxford supporting researchers from Oxford University Joint Research Office (JRO) approved research. There will be 7 randomised study groups (plus one non-randomised 'blood sample only' group, group 8 - see section 8.6) and it is anticipated that a maximum of 39 volunteers will be enrolled (excluding dropouts). Eligible participants will be randomised into any of 7 study groups (section 7.1) according to study phase. Randomisation and enrolment will occur in two phases. Phase 1 will consist of group 1 (placebo prime dose) and the standard (1000mcg) KLH dose +/- adjuvant groups (2, 3, and 4). Following interim analysis of data from these 21 participants, recruitment into Phase 2 (the lower \[10mcg\] KLH dose groups: groups 5,6,7) will occur provided there is sufficient evidence of immunogenicity in the standard dose group. Should participants withdraw or dropout of the study, replacement volunteers will be enrolled to ensure the target number of participants per group is achieved with all participants competing the full follow-up period. A maximum of 6 additional volunteers may be sought for this purpose.