Subcutaneous Allergen Immunotherapy With Hypoallergenic Bet v 1 Compared to Conventional Extract: Poorer Blocking Antibody Capacity Dominated by IgG 1 Instead of IgG 4

Background 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. Methods 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, IgG 1 , and IgG 4 responses measured by ImmunoCAP, and sIgE‐blocking activity using mediator release and facilitated antigen binding assays. Results Despite SPT‐confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG 1 levels were induced, sIgG 4 levels increased 3‐fold more in AC compared to the BM41 group. In AC, the sIgG 4 /sIgG 1 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 sIgG 4 and sIgG 1 contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity. Conclusion Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG 4 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 IgG 1 ‐dominated response, “modified Th2”‐skewed IgG 4 ‐dominated humoral responses are beneficial in AIT vaccine design.