Two years of treatment with the recombinant grass pollen allergy vaccine BM32 induces a continuously increasing allergen-specific IgG4 response

Abstract

Background: BM32, a grass pollen allergy vaccine containing four recombinant fusion proteins consisting of hepatitis B-derived PreS and hypoallergenic peptides from the major timothy grass pollen allergens adsorbed on aluminium hydroxide has been shown to be safe and to improve clinical symptoms of grass pollen allergy upon allergen-specific immunotherapy (AIT). We have investigated the immune responses in patients from a two years double-blind, placebo-controlled AIT field trial with BM32. Methods: Blood samples from patients treated with BM32 (n = 27) or placebo (Aluminium hydroxide) (n = 13) were obtained to study the effects of vaccination and natural allergen exposure on allergen-specific antibody, T cell and cytokine responses. Allergen-specific IgE, IgG, IgG 1 and IgG 4 levels were determined by Immuno-CAP and ELISA, respectively. Allergen-specific lymphocyte proliferation by 3 H thymidine incorporation and multiple cytokine responses with a human 17-plex cytokine assay were studied in cultured peripheral blood mononuclear cells (PBMCs). Findings: Two years AIT comprising two courses of 3 pre-seasonal injections of BM32 and a single booster after the first pollen season induced a continuously increasing (year 2 > year 1) allergen-specific IgG 4 response without boosting allergen-specific IgE responses. Specific IgG 4 responses were accompanied by low stimulation of allergen-specific PBMC responses. Increases of allergen-specific pro-inflammatory cytokine responses were absent. The rise of allergen-specific IgE induced by seasonal grass pollen exposure was partially blunted in BM32-treated patients. Interpretation: AIT with BM32 is characterised by the induction of a non-inflammatory, continuously increasing allergen-specific IgG 4 response (year 2 > year1) which may explain that clinical efficacy was higher in year 2 than in year 1. The good safety profile of BM32 may be explained by lack of IgE reactivity and low stimulation of allergen-specific T cell and cytokine responses. Fundings: Grants F4605, F4613 and DK 1248-B13 of the Austrian Science Fund (FWF).

Quantification, epitope mapping and genotype cross-reactivity of hepatitis B preS-specific antibodies in subjects vaccinated with different dosage regimens of BM32

“…Of note, at visit 8, 4 weeks after the fifth injection, the preS-specific cumulative IgG 1 and IgG 4 responses reached up to 1.8 mg/ml with median preS-specific IgG 1 and IgG 4 level of 106.8 μg/ml and 30 μg/ml, respectively and thus should eventually be able to neutralize HBV even when soluble preS antigen is present in the blood of chronic HBV patients. While preS-specific IgG 1 declined quickly, preS-specific IgG 4 was maintained and from allergen-specific immunotherapy studies conducted with BM32 we know that IgG 1 titers can be restored and IgG 4 continues to grow after only one booster injection [14] . Our current study provides thus support for the latter speculation and encourages performing clinical trials with BM32 to investigate if it can be indeed used for therapeutic vaccination.…”

“…Therapeutic vaccination with BM32 would therefore have the advantage that one can build up a quite long-lasting concentration of antibodies which are approximately equimolar as compared to an infusion of 20 mg myrcludex B. In this context it should be mentioned that only one single booster injection of BM32 was sufficient to boost specific antibody levels [14] . Therapeutic vaccination would thus have considerable advantages over small molecular inhibitors because only few injections with booster injections in long intervals (i.e., several months) would maintain protective antibody levels and the costs for treatment would be also low.…”

“…These vaccines are constructed to induce in allergic patients upon vaccination focused IgG antibody responses towards the IgE binding sites of allergens in order to block allergen recognition by IgE and IgE-mediated allergic inflammation [13] . In this new generation of hypoallergenic allergy vaccines, preS serves as a carrier protein to provide T cell help for the allergen-specific IgG antibody production avoiding stimulation of allergen-specific T cells and thus the induction of T cell-mediated allergic inflammation in the patients [14] . Interestingly, the analysis of HBV-specific immune responses in allergic patients treated with the preS-containing grass pollen allergy vaccine, BM32 [ 15 , 16 ], revealed that BM32 induces also preS-specific antibody responses against the N-terminus of preS.…”

Preventive Allergen-Specific Vaccination Against Allergy: Mission Possible?

“…Three more important observations were made in the clinical trials with BM32: First, BM32 induced allergen-specific IgG and in particular a continuously growing allergen-specific IgG 4 response without boosting allergen-specific IgE as it is observed for all other AIT vaccines ( 80 ). Second, BM32 did not boost T cell and inflammatory cytokine responses specific for grass pollen allergens and thus seems to have no priming effect on allergen-specific T cell responses ( 80 ). Third, it was found that BM32 induced also IgG antibodies against HBV, which blocked the infection of in vitro cultured liver cells and thus it seems that BM32 also protects against HBV infection ( 81 ).…”

Past, present, and future of allergen immunotherapy vaccines

“…Usually, after 3 years of AIT treatment beneficial effects continue for a few years, even when AIT has been discontinued 20 . These long‐term effects may be attributed to the persistence of high‐affinity and functional allergen‐specific IgG 4 antibodies 21‐23 . However, boosting of antibody responses may become necessary after discontinuation.…”