Subcutaneous Allergen Immunotherapy With Hypoallergenic Bet v 1 Compared to Conventional Extract: Poorer Blocking Antibody Capacity Dominated by IgG₁ Instead of IgG₄.

Abstract

Hypoallergenic recombinant fold-variants of major allergens have been suggested as safer and more effective AIT candidates. The Bet v 1-fold variant BM41, with confirmed preclinical hypoallergenicity and increased immunogenicity, was proposed for the treatment of birch pollen allergy. We performed a 6-month randomized, double-blind, placebo-controlled first-in-human clinical trial with BM41, a licensed birch pollen extract-based treatment, as the active comparator (AC), and placebo (n = 16, n = 16, and n = 15, respectively). The primary endpoint was safety. Secondary outcomes were Bet v 1-specific (s)IgE, IgG, IgG₁, and IgG₄ responses measured by ImmunoCAP, and sIgE-blocking activity using mediator release and facilitated antigen binding assays. Despite SPT-confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG₁ levels were induced, sIgG₄ levels increased 3-fold more in AC compared to the BM41 group. In AC, the sIgG₄/sIgG₁ ratio tripled over time, whereas for BM41 it stagnated. BM41 induced efficient serum inhibitory activity for sIgE compared to placebo but was 12%-32% less efficient than AC. Both sIgG₄ and sIgG₁ contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity. Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG₄ by the fold variant in the course of the treatment was less efficient in blocking sIgE-mediated responses. This is the first study providing evidence that, instead of a Th1-favored IgG₁-dominated response, "modified Th2"-skewed IgG₄-dominated humoral responses are beneficial in AIT vaccine design.