Randomized controlled trial demonstrating the benefits of delta inulin adjuvanted immunotherapy in patients with bee venom allergy

Abstract

Background: Allergic reactions to Hymenoptera insect stings remain a major global clinical problem. Although effective, parenteral desensitization regimens require use of costly venom extracts and require frequent visits over extended periods of time.

Objective: Adjuvants are commonly used to enhance the efficacy of infectious disease vaccines, and this study asked whether Advax (Vaxine Pty Ltd, Adelaide, Australia), a novel noninflammatory polysaccharide adjuvant, might provide similar benefits for allergy desensitization.

Methods: A randomized, controlled phase 1/2 trial was undertaken in 27 adults with a history of rapid-onset systemic allergic reactions to honeybee stings and positive specific IgE levels to evaluate the safety and efficacy of honeybee venom immunotherapy (HBVIT) combined with Advax adjuvant. Venom immunotherapy (VIT) was administered monthly for 30 months after achievement of maintenance doses.

Results: Advax-adjuvanted HBVIT was well tolerated. Around week 14 of VIT, specific IgG₄ responses peaked in both groups but increased earlier, peaked higher, and were better maintained through the end of the study in the Advax-adjuvanted arm. Several different patterns of serologic response to VIT were seen; some subjects had a dominant IgG₄ response, some had a combined IgG₄ and IgG₁ response, and some had an exclusively IgG₁ response. In some subjects specific IgE levels increased during the induction phase and then decreased, whereas in others specific IgE levels progressively decreased from the start of VIT.

Conclusion: Advax adjuvant favorably enhanced the immunogenicity of HBVIT, with an early and prolonged switch to specific IgG₄ production. The ability of Advax adjuvant to enhance VIT efficacy warrants further study.

Keywords: Hymenoptera; IgG(4); adjuvant; allergy; anaphylaxis; immunotherapy; inulin.

Graphical abstract

Fig 1

CONSORT diagram of study participants and procedures.

Fig 2

Specific IgE and IgG₄ responses to VIT. Shown are the means of specific IgE levels (A), specific IgG₄ levels (B), and specific IgE/IgG₄ ratios (C) at baseline and throughout the induction and maintenance phases of VIT, as measured by using the ImmunoCAP assay (mean ± SEM). Shown at the far right of each figure are the mean specific IgE and IgG₄ levels in participants able to be recalled in mid-2018, 3 to 7 years after their completion of active study treatment.

Fig 3

Bee venom–specific IgG subclass responses determined by means of ELISA. Shown are means of specific IgG₄(A), specific IgG₁(B), and specific total IgG (C) levels, as measured by means of ELISA. Means ± SEs are shown. *Time points in which differences between groups were statistically significant (P < .05).

Fig E1

CRP levels. Data are shown as means and SEs for each group and all study subjects combined for each study time point. Minimums and maximums of normal ranges are shown as horizontal black lines.

Fig E2

Total WCCs. Data are shown as means and SEs.

Fig E3

Complement C3 levels. Data are shown as means and SEs.

Fig E4

Complement C4 levels. Data are shown as means and SEs.

Fig E5

Serum MCT levels. Data are shown as means and SEs.

Fig E6

Responders with positive VIT skin test responses. The number of responders in each group for each assessed time point (week 14, month 12, and month 30) who tolerated a greater dose of venom than was needed to elicit a positive venom skin test response in that subject at baseline is shown.

Fig E7

Adjusted marginal means across time for specific IgE by age. Shown are means and 95% CIs.

Fig E8

Adjusted marginal means across time for specific IgE by sex. Shown are means and 95% CIs.

Fig E9

Standard HBVIT individual subject serologic response data. Shown are specific total IgG, IgG₁, and IgG₄ levels, as measured by means of ELISA, and specific IgE levels, as measured by using an ImmunoCAP assay.

Fig E10

Advax-adjuvanted HBVIT individual subject serologic response data. Shown are specific total IgG, IgG₁, and IgG₄ levels, as measured by means of ELISA, and specific IgE levels, as measured by using an ImmunoCAP assay.

Fig E11

Adjusted marginal means across time for specific IgG₄ levels by sex. Shown are means and 95% CIs.

Fig E12

Adjusted marginal means across time for specific IgG₄ levels by age. Shown are means and 95% CIs.