Background JJA sting appears to be a dominant cause of insect sting anaphylaxis in the cooler
areas of southern and eastern Australia where the native ant is prevalent. Immunotherapy for
treatment of stinging insect anaphylaxis involves the administration of increasing doses of
purified insect venom with the aim of inducing clinical tolerance, but also carrying the risk
of allergic reactions to treatment. In a randomised double-blinded, placebo-controlled trial
of JJA VIT7 we have shown JJA VIT to be highly effective at preventing JJA sting anaphylaxis,
with an objective systemic sting reaction rate in those who were on maintenance JJA VIT < 5%
vs.#46;70% for those receiving placebo VIT. Real world experience in Tasmania has supported these
findings with objective systemic reaction rates to sting challenges on 50 and 100 mcg
maintenance doses respectively 14/130 and 12/126 subjects as against reaction rates to stings
in similar subjects without JJA VIT of 70-76% in trial and epidemiological studies.
Although JJA VIT is highly effective at preventing severe objective reactions to JJA stings,
its applicability is limited by
- (1) venom availability with venom collected by venom sac
dissection of ants harvested from wild nests with inherent WH&S risks; (2) venom costs, at $2
per microgram of venom (3) as with honey bee VIT difficulties in a significant minority of
subjects in achieving maintenance because of immediate generalised allergic reactions (4)
prolonged therapy, generally 5 years or longer - for those in whom a previous sting reaction
was immediately life-threatening, treatment continues indefinitely for as long as the risk of
an accidental sting remains.
An adjuvant that would facilitate the wanted immune response to
JJA venom has the potential to reduce venom requirements and thereby reduce costs and
increase availability of JJA VIT, reduce the number of hospital visits required and if the
protective response can be achieved with lower doses of venom and/or earlier in therapy,
reduce the number of systemic allergic reactions to JJA VIT.
Inulin is a natural storage polysaccharide in some plants. It is approved around the world
for intravenous human use in renal function studies and generally regarded as safe. Inulin
exists in different polymorphic forms, and water suspensions of inulin particles in delta
polymorphic form are potent adjuvants that preferentially induce IgG4 without the toxicity
exhibited by other adjuvants and without increasing IgE production as occurs with traditional
aluminum-based adjuvants. This effect is particularly important as one of the functions of
VIT is to reduce IgE and increase IgG4, making inulin an ideal candidate vaccine adjuvant to
be tested in combination with VIT. A cGMP product of delta-inulin adjuvant (Advax™) is
supplied in Australia by Vaxine Pty Ltd (Flinders Medical Centre, Bedford Park, SA 5042) and
is suitable for human use. Delta-inulin adjuvant (Advax) have successfully been tested in
adult human subjects in combination with such antigens as Hepatitis B virus surface antigen
and influenza haemagglutinin, with an excellent safety record and evidence of antigen
dose-sparing, greater sero-protection and fewer systemic adverse effects. In the recently
completed RAH-FMC trial of honey bee venom immunotherapy with and without delta inulin the
addition of the adjuvant delta-inulin to honey bee venom vaccine has been shown in another
study to promote a better immune response than the standard venom preparations.
Study design The aim of this proposed study is to compare responses to in-hospital sting
challenges and JJA venom specific lgE and IgG4 responses to semi-rush JJA VIT at doses of 25
and 50 mcg of JJA venom, with and without delta-inulin adjuvant (Advax). Subjects will be
randomised, ten to each arm, to receive semi-rush JJA VIT with or without delta-inulin (a
fixed dose of 5 mg with each dose of venom) aiming to achieve a maintenance dose of JJA venom
of 25 or 50 mcg. The study will be subject and observer blind because it is very difficult to
mask from attending nursing staff the turbid appearance of the delta-inulin containing
vaccines and we judge it unsafe to use opaque syringes. Furthermore, it is not appropriate to
use a placebo that mimics the cloudy appearance of venom vaccine containing delta-inulin
without first performing a trial on the placebo itself to ensure that it does not either
positively or negatively influence the effect of the venom extract. In a previous study with
256 sting challenges performed after 12 months JJA VIT, 50 mcg and 100 mcg of JJA venom
appear to have similar efficacy as maintenance doses. In an attempt to give all participants
a real possibility of some medium term protection, the study schedule has been designed such
that, after effects of twelve months of maintenance injections have been assessed by sting
challenges, all subjects in 25 mcg maintenance dose arms giving suboptimal responses in
comparison to standard 50 mcg dose group will be offered conversion to the 50 mcg
maintenance.
Selection of subjects Subjects for this study will be recruited from the Royal Adelaide and
Royal Hobart Hospitals. We plan to recruit a total of 40 patients to this study, half of whom
(i.e. 20 subjects) will be recruited from the Royal Adelaide Hospital.
As this is a Phase 1/2 study, no formal sample size estimation is normally required. The
sample of 20 patients for the delta-inulin adjuvant preparation and 20 control subjects
receiving standard venom therapy without adjuvant was chosen in order to provide adequate
evaluation of the study endpoints.
Randomisation Participants will be randomised in equal proportions to receive a top study
dose 25 or 50 mcg of JJA venom with or without 5 mg delta-inulin adjuvant, that is four
- (4)
study groups each of ten (10) subjects.
Randomisation will be performed in real time, with
all calls/emails regarding allocation to be logged to ensure adherence to allocation. Given
the small patient numbers, we will use a randomisation table. Patients will also be
stratified by site, with a target of 20 cases at each site.
Treatment will be given by our established semi-rush regimen adapted for different target
maintenance doses. Following this groups with modified doses will continue designated
maintenance dose monthly to 12 months of maintenance VIT.
Study measurements. 1. Adverse events during venom immunotherapy. Severe (hypersensitivity and
non-hypersensitivity) reactions to JJA VIT, deaths and unexpected hospital admissions
will require immediate notification to a Data Safety Monitor independent of the
investigators.
2. Laboratory studies. 1. Safety tests: At entry, on achieving maintenance and then only if clinically
indicated. Full Blood Examination (FBE), C-reactive Protein (CRP), Urea and
Electrolyte (U&E), Liver Function Test (LFT), Mast Cell Tryptase (MCT)
2. Markers of venom delta-inulin immunogenicity and desensitisation: Sera for
determination of specific IgE and IgG4 to JJA venom using ImmunoCAP assay will be
taken at baseline, at attendance after reaching maintenance VIT, at attendance
after 4th injection of maintenance dose; then at 12 months. Venom skin testing
(VST) will be performed at the same timepoints.
3. JJA in-hospital sting challenges
- - will be performed after 12 months tolerating the
1-month maintenance interval, and one month after the last dose.
