Allergoids low allergenicity linked to low immunogenicity


Allergy Immunotherapy is performed by highly trained specialists for many reason but a significant one is the increased risk of serious adverse reaction and anaphylaxis.  Given the inherent risks involved in administering immunotherapy there is a rising  number of Allergists who are prescribing Allergoids due to their stated ‘low allergenicity’ and relatively short up dosage time (ranging from 1 Day to 2 weeks depending on the protocol).

Allergoids are created when intact allergens are modified with either glutaraldehyde or formaldehyde, which their makers claim reduces the allergenicity whilst preserving the T-cell activation, thus achieving the aim of immunotherapy whilst reducing the inherent risk.

Unfortunately the clinical evidence does not support their marketed claims and, in the case of allergoids created through glutaraldehyde modification, the end results may be no better than a placebo.

The three papers linked here all contain data from studies comparing allergoids created by modifying intact allergens (with glutaraldehyde, formaldehyde or both types) to the use of intact allergens.  We have provided a brief summary of the studies below but they all have one finding in common, that the low allergenicity observed when administering treatment was linked to low immunogenicity.

The risk is clear, widespread reduction in efficacy for patients will lead to an erosion of trust in the effectiveness of allergy vaccines and the public health segment we all work in.

Summary of Studies

Reduced in vitro T-cell responses induced by glutaraldehyde-modified allergen extracts are caused mainly by retarded internalization of dendritic cells. Immunology.

Heydenreich B, Bellinghausen I, Lorenz S, et al. 2012;136(2):208-217. doi:10.1111/j.1365-2567.2012.03571.x

Link to Study

This study sets out to analyse the differences between intact allergens and differently modified/aggregated allergoids (glutaraldehyde or formaldehyde) concerning their internalization as well as T-cell and basophil activation.

The glutaraldehyde-modified allergoid showed statistically significant lower T-cell activation (fig 2), uptake (fig 4c) and decreased leukotriene release by basophils compared (fig 1b) to the intact allergens or the formaldehyde allergoid.

The study concludes that: “in summary, the glutaraldehyde-modified allergoids used in this study had disrupted IgE-binding sites and induced a lower T-cell stimulatory capacity in antigen presenting DC, which is mainly the result of diminished uptake but probably also of a lower frequency of responding T cells.”

Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.

Henmar H, Lund G, Lund L, Petersen A, Würtzen PA. Clin Exp Immunol. 2008;153(3):316-323. doi:10.1111/j.1365-2249.2008.03710.x

Link to Study

Of the 4 allergoid products included in this study, there was only one formaldehyde modified allergoid with the remainder being glutaraldehyde modified allergoids. The study results show that all of the glutaraldehyde modified allergoids show a decreased level of T-cell (fig 3a) and sIgG (fig 4a) responses when compared to the intact allergens.

“Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies.

Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids”

The paper concludes “Moreover, our results indicate that despite equal or higher protein content in all the allergoids before modification, their functional immunogenicity was either equal to or lower than the lowest-performing intact allergen (Intact-Allergen-3) in all assays. This result indicates that after modification, the allergoids are not inducing immunological responses in accordance with the content of active ingredient measured before the modification, thereby questioning further the rationale behind the allergoid concept.”

Chemical modification of birch allergen extract leads to a reduction in allergenicity as well as immunogenicity.

Würtzen PA, Lund L, Lund G, Holm J, Millner A, Henmar H. Int Arch Allergy Immunol. 2007;144(4):287-95. doi: 10.1159/000106317. Epub 2007 Jul 20. PMID: 17641548.

Link to Study

This study examines a glutaraldehyde allergoids which are adsorbed onto aluminum hydroxide.

Here the study shows significant differences between T cell responses (fig 3) and creation of dendritic cells (fig 4) between intact allergens and the allergoids. Additionally the study showed that specific IgG was significantly higher after day 63 for the intact allergen as opposed to the allergoid (fig 5).

The study finishes with “In conclusion, birch allergoids show clearly reduced histamine release even though some variation from patient to patient was observed. However, this indication of increased safety is likely to be at the expense of immunological efficacy because the chemical modifications lead to a clear reduction in T cell activation in vitro and in the ability to induce murine allergen-specific IgG antibody responses in vivo.”