7 TLR7 triggering broadens antibody repertoire and affinity
Despite the above-described ability of low affinity allergen-specific
IgG antibodies to block type I hypersensitivity responses, it remains
common thinking that high affinity antibodies would be more effective to
also neutralize the allergen. In addition, induction of high affinity
antibodies continues to be a general and common goal in vaccinology. For
that, induction of germinal centres (GC), also known as secondary
follicles, is a key goal, as GCs are the anatomical location of
hypermutation and antibody affinity maturation. Induction of GCs is
driven by antigen deposition on follicular dendritic cells (FDCs) and
effective stimulation of B cells. Repetitive display of antigens in
general and allergens specifically has been found to induce strong and
rapid B cell responses due to effective B cell receptor cross-linking as
well as engagement of the innate immune system 30.
Indeed, natural IgM recognizes repetitive epitopes on viruses and
virus-like particles (VLPs), causing activation of the classical pathway
of complement (C1q), leading to the deposition of these particles on
FDCs and to GC-reactions 16. In addition, VLPs may
package RNA from E. coli during VLP production, when assembling
inside bacteria. This RNA has not only been observed to effectively
drive class switching to IgG and IgA, but also to increase the affinity
of the induced antibodies as well as to facilitate maintenance of a
broad immunoglobulin repertoire against both VLPs as well as displayed
allergens 31. Furthermore, in a preclinical model of
peanut-allergy, presence of RNA in VLPs displaying Ara h 2 proved
essential for induction of protective IgG responses against peanut
allergy. Hence, repetitive display of allergens on VLPs packaged with
RNA appears an attractive way to increase induction and maintenance of
high affinity antibodies (Figure 3). In studies on VLPs with Fel d 1 and
peanut allergens, a substantially reduced interaction with IgE bound to
mast cells has been shown and a failure to significantly activate the
FcεRI mediated signalling cascade. Hence, under conditions where similar
or higher amounts of allergen were bound to IgE on mast cells, free
allergen induced strong cellular activation while allergens on VLPs
failed to do so 13,14. Together, it was therefore an
attractive choice to bring Ara h 2 displayed on VLPs (VLP-peanut) into
clinical development 24.