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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 (IgG1-IgG4) responses to preS and peptides were determined by ELISA at baseline, one and four months after the last injection. IgG1 and IgG4 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 IgG1 and IgG4, with a sum of median preS-specific IgG1 and IgG4 concentrations of >135 ?g/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 IgG1 and IgG4 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.

SUBMITTER: Tulaeva I

PROVIDER: S-EPMC7502672 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Tulaeva Inna I Cornelius Carolin C Zieglmayer Petra P Zieglmayer René R Schmutz René R Lemell Patrick P Weber Milena M Focke-Tejkl Margarete M Karaulov Alexander A Henning Rainer R Valenta Rudolf R

EBioMedicine 20200824

<h4>Background</h4>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 ...[more]

PMID: 32855110

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Project description:BackgroundBM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein.ObjectiveWe sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen-induced rhinitis and controlled asthma.MethodsA double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 μg, n = 60) or high dose (160 μg, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC.ResultsAlthough statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year.ConclusionsInjections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

Project description:BackgroundPenicillin is important for treatment of pigs, but data on its absorption and disposition in pigs are sparse. This is reflected by the variation in recommended dosages in the literature. Inadequate dosage may lead to treatment failure and selection of resistant bacteria. To optimize treatment regimens, plasma exposure to benzylpenicillin for two sustained release formulations of procaine benzylpenicillin for intramuscular administration was studied in growing pigs by means of tandem mass spectrometry (UPLC-MS/MS). One formulation was an aqueous suspension, Ethacilin® vet (ETH), and the other an oily suspension, Ultrapen vet (UPA). Benzylpenicillin exposure after intravenous administration of potassium benzylpenicillin was also explored. Exposure profiles were first studied after single administrations of the approved dosages in healthy pigs and then after repeated administration of different dosages in pigs inoculated intranasally with an Actinobacillus pleuropneumoniae serotype 2 strain.ResultsAfter intravenous administration of benzylpenicillin (n = 6), maximum plasma concentration (Cmax), 1860-9318 µg/L, was observed after 15 min. At four h, plasma concentrations decreased to 15-76 µg/L. After intramuscular administration of ETH (n = 6) Cmax, 1000-4270 µg/L, was observed within one h (tmax) in 5 pigs but at four h in one pig. Cmax for UPA (n = 6), 910-3220 µg/L, was observed within one h in three pigs, but at four or 24 h in three pigs. For both ETH and UPA, the terminal phase was characterized by slow decline compared with intravenous administration. Repeated administration of different dosages of ETH and UPA in pigs inoculated with A. pleuropneumoniae (n = 54) showed that the approved dose for UPA (30 mg/kg, qd) but not for ETH (20 mg/kg, qd) gave adequate plasma exposure for bacteria with a penicillin MIC of 500 µg/L. However, more frequent dosing of ETH (bid) or increased dosage gave an adequate exposure.ConclusionsThe approved dosage of ETH provided insufficient plasma exposure for adequate therapy of infections caused by A. pleuropneumoniae or other bacteria with a penicillin MIC of 500 µg/L. More frequent ETH dosing (bid) or an increased dosage would improve exposure. The approved dosage of UPA however provided adequate exposure.

Project description:BackgroundComprehensive characterization of exposures and immune responses to viral infections is critical to a basic understanding of human health and disease. We previously developed the VirScan system, a programmable phage-display technology for profiling antibody binding to a library of peptides designed to span the human virome. Previous VirScan analytical approaches did not carefully account for antibody cross-reactivity among sequences shared by related viruses or for the disproportionate representation of individual viruses in the library.MethodsHere we present the AntiViral Antibody Response Deconvolution Algorithm (AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection with species-level resolution by considering sequence alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. We further assessed AVARDA's utility in associating viral infection with type 1 diabetes and lupus.FindingsBy comparing acute and convalescent sera, AVARDA successfully confirmed or detected encephalitis-associated responses to human herpesviruses 1, 3, 4, 5, and 6, improving the rate of diagnosing viral encephalitis in this cohort by 44%. AVARDA analyses of VirScan data from the type 1 diabetes and lupus cohorts implicated enterovirus and herpesvirus infections, respectively.InterpretationAVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases.FundingThis work was made possible by support from the National Institutes of Health (NIH), the US Army Research Office, the Singapore Infectious Diseases Initiative (SIDI), the Singapore Ministry of Health's National Medical Research Council (NMRC) and the Singapore National Research Foundation (NRF).

Dataset Information

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

Publications

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

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