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

Abstract

Background Chronic hepatitis B virus (HBV) infections are a global health problem. There is a need for therapeutic strategies blocking continuous infection of liver cells. The grass pollen allergy vaccine BM32 containing the preS domain of the large HBV surface protein (LHBs) as immunogenic carrier induced IgG antibodies in human subjects inhibiting HBV infection in vitro . Aim of this study was the quantification, epitope mapping and investigation of HBV genotype cross-reactivity of preS-specific antibodies in subjects treated with different dosage regimens of BM32 Methods Hundred twenty eight grass pollen allergic patients received in a double-blind, placebo-controlled trial five monthly injections of placebo (aluminum hydroxide, n = 34) or different courses of BM32 (2 placebo + 3 BM32, n = 33; 1 placebo + 4 BM32, n = 30; 5 BM32, n = 31). Recombinant Escherichia coli -expressed preS was purified. Overlapping peptides spanning preS and the receptor-binding sites from consensus sequences of genotypes A–H were synthesized and purified. Isotype (IgM, IgG, IgA, IgE) and IgG subclass (IgG 1 -IgG 4 ) responses to preS and peptides were determined by ELISA at baseline, one and four months after the last injection. IgG 1 and IgG 4 subclass concentrations specific for preS and the receptor-binding site were measured by quantitative ELISA. Findings Five monthly injections induced the highest levels of preS-specific IgG consisting mainly of IgG 1 and IgG 4 , with a sum of median preS-specific IgG 1 and IgG 4 concentrations of >135 μg/ml reaching up to 1.8 mg/ml. More than 20% of preS-specific IgG was directed against the receptor-binding site. BM32-induced IgG cross-reacted with the receptor-binding domains from all eight HBV genotypes A-H. Interpretation BM32 induces high levels of IgG 1 and IgG 4 antibodies against the receptor binding sites of all eight HBV genotypes and hence might be suitable for therapeutic HBV vaccination. Funding This study was supported by the PhD program IAI (KPW01212FW), by Viravaxx AG and by the Danube-ARC funded by the Government of Lower Austria. Rudolf Valenta is a recipient of a Megagrant of the Government of the Russian Federation, grant No 14.W03.31.0024.

Novel vaccines for allergen-specific immunotherapy

“…In the meantime, the BM32 vaccine has been shown to be clinically effective in a multicenter DBPC phase IIb study [ 64 ] (Table 1 ) and is scheduled for phase III studies. The analysis of sera from a recent phase IIb study confirmed the robust induction of IgG antibodies against the domain of PreS, which is critical for the binding of the HBV virus to liver cells and demonstrated cross-reactivity with the most common HBV strains [ 65 ▪▪ ] (Table 1 ). Thus PreS-based allergy vaccines may be useful for vaccination against HBV.…”

Neutralization of SARS‐CoV‐2 requires antibodies against conformational receptor‐binding domain epitopes

“…For other viruses (eg, hepatitis B, HBV), unfolded surface antigens have been found to induce protective antibodies and virus attachment can be blocked with unfolded peptides derived from the viral receptor‐binding site. 14 , 15 , 16 For SARS‐CoV‐2, it is not yet known if antibodies toward sequential or conformational epitopes or both determine the neutralizing activity of the natural polyclonal antibody response.…”

Hepatitis-B-Impfstoffe – Geschichte, Erfolge, Herausforderungen und Perspektiven

“…a 3 HBsAg-Proteine (S, M, L) adw [ 35 , 36 ] 2001 Hepagene®, Medeva (n.v.) 3 HBsAg-Proteine (S, M, L) adw und ayw [ 2 , 37 ] Neue Konzepte 2016 BM32®, Viravaxx (exp.) PräS-Graspollenallergen Fusionsprotein [ 38 , 39 ] Al. Aluminium, exp.…”

“…Als erfreulichen Nebeneffekt der Immunisierung von allergischen Probanden mit ihrem experimentellen Impfstoff BM32 ® fand die Gruppe im Jahr 2016 HBV-neutralisierende Anti-PräS1-Antikörper [ 38 ]. Bei weiteren Probanden wurde gezeigt, dass diese Antikörper tatsächlich gegen die Rezeptorbindungsstelle im PräS1 gerichtet sind und mit allen HBV-Genotypen von A bis H reagieren [ 39 ]. Da es schon erste Erprobungen im Menschen mit Graspollenallergie gibt, sollten nunmehr spezielle Studien zur Schutzwirkung gegen HBV-Exposition möglich sein.…”