Publications by authors named "Martin F Bachmann"

194 Publications

On Iron Metabolism and Its Regulation.

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Department of Rheumatology, Immunology and Allergology, Inselspital, University Hospital Bern, 3010 Bern, Switzerland.

Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.
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http://dx.doi.org/10.3390/ijms22094591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123811PMC
April 2021

Development of a Vaccine against SARS-CoV-2 Based on the Receptor-Binding Domain Displayed on Virus-Like Particles.

Vaccines (Basel) 2021 Apr 16;9(4). Epub 2021 Apr 16.

International Immunology Centre, Anhui Agricultural University, Hefei 230036, China.

The ongoing coronavirus disease (COVID-19) pandemic is caused by a new coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) first reported in Wuhan City, China. From there, it has been rapidly spreading to many cities inside and outside China. Nowadays, more than 110 million cases with deaths surpassing 2 million have been recorded worldwide, thus representing a major health and economic issues. Rapid development of a protective vaccine against COVID-19 is therefore of paramount importance. Here, we demonstrated that the recombinantly expressed receptor-binding domain (RBD) of the spike protein can be coupled to immunologically optimized virus-like particles derived from cucumber mosaic virus (CuMV). The RBD displayed CuMV bound to ACE2, the viral receptor, demonstrating proper folding of RBD. Furthermore, a highly repetitive display of the RBD on CuMV resulted in a vaccine candidate that induced high levels of specific antibodies in mice, which were able to block binding of the spike protein to ACE2 and potently neutralize SARS-CoV-2 virus in vitro.
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http://dx.doi.org/10.3390/vaccines9040395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073353PMC
April 2021

AP205 VLPs Based on Dimerized Capsid Proteins Accommodate RBM Domain of SARS-CoV-2 and Serve as an Attractive Vaccine Candidate.

Vaccines (Basel) 2021 Apr 19;9(4). Epub 2021 Apr 19.

Department of Immunology, RIA, Bern University Hospital, 3010 Bern, Switzerland.

COVID-19 is a novel disease caused by SARS-CoV-2 which has conquered the world rapidly resulting in a pandemic that massively impacts our health, social activities, and economy. It is likely that vaccination is the only way to form "herd immunity" and restore the world to normal. Here we developed a vaccine candidate for COVID-19 based on the virus-like particle AP205 displaying the spike receptor binding motif (RBM), which is the major target of neutralizing antibodies in convalescent patients. To this end, we genetically fused the RBM domain of SARS-CoV-2 to the C terminus of AP205 of dimerized capsid proteins. The fused VLPs were expressed in , which resulted in insoluble aggregates. These aggregates were denatured in 8 M urea followed by refolding, which reconstituted VLP formation as confirmed by electron microscopy analysis. Importantly, immunized mice were able to generate high levels of IgG antibodies recognizing eukaryotically expressed receptor binding domain (RBD) as well as spike protein of SARS-CoV-2. Furthermore, induced antibodies were able to neutralize SARS-CoV-2/ABS/NL20. Additionally, this vaccine candidate has the potential to be produced at large scale for immunization programs.
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http://dx.doi.org/10.3390/vaccines9040403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073683PMC
April 2021

Low-affinity but high-avidity interactions may offer an explanation for IgE-mediated allergen cross-reactivity.

Allergy 2021 Apr 18. Epub 2021 Apr 18.

International Immunology Center, Anhui Agricultural University, Anhui, China.

Background: Allergy is a global disease with overall frequencies of >20%. Symptoms vary from irritating local itching to life-threatening systemic anaphylaxis. Even though allergies are allergen-specific, there is a wide range of cross-reactivities (eg apple and latex) that remain largely unexplained. Given the abilities of low-affinity IgG antibodies to inhibit mast cells activation, here we elucidate the minimal affinity of IgE antibodies to induce type I hypersensitivity.

Methods: Three mature (high-affinity) IgE antibodies recognizing three distinct epitopes on Fel d 1, the major cat allergen, were back-mutated to germline conformation, resulting in binding to Fel d 1 with low affinity. The ability of these IgE antibodies to activate mast cells in vitro and in vivo was tested.

Results: We demonstrate that affinities as low as 10  M are sufficient to activate mast cells in vitro and drive allergic reactions in vivo. Low-affinity IgE antibodies are able to do so, since they bind allergens bivalently on the surface of mast cells, leading to high-avidity interactions.

Conclusions: These results suggest that the underlying mechanism of allergen cross-reactivity may be low-affinity but high-avidity binding between IgE antibodies and cross-reactive allergen.
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http://dx.doi.org/10.1111/all.14864DOI Listing
April 2021

The impact of size on particle drainage dynamics and antibody response.

J Control Release 2021 Mar 12;331:296-308. Epub 2021 Jan 12.

Department of BioMedical Research, University of Bern, Bern, Switzerland; Department of Immunology RIA, University Hospital Bern, Bern, Switzerland; Interim Translational Research Institute "iTRI", National Center for Cancer Care & Research Doha, Qatar. Electronic address:

Vaccine-induced immune response can be greatly enhanced by mimicking pathogen properties. The size and the repetitive geometric shape of virus-like particles (VLPs) influence their immunogenicity by facilitating drainage to secondary lymphoid organs and enhancing interaction with and activation of B cells and innate humoral immune components. VLPs derived from the plant Bromovirus genus, specifically cowpea chlorotic mottle virus (CCMV), are T = 3 icosahedral particles. (T) is the triangulation number that refers to the number and arrangements of the subunits (pentamers and hexamers) of the VLPs. CCMV-VLPs can be easily expressed in an E. coli host system and package ssRNA during the expression process. Recently, we have engineered CCMV-VLPs by incorporating the universal tetanus toxin (TT) epitope at the N-terminus. The modified CCMV-VLPs successfully form icosahedral particles T = 3, with a diameter of ~30 nm analogous to the parental VLPs. Interestingly, incorporating TT epitope at the C-terminus of CCMV-VLPs results in the formation of Rod-shaped VLPs, ~1 μm in length and ~ 30 nm in width. In this study, we have investigated the draining kinetics and immunogenicity of both engineered forms (termed as Round-shaped CCMV-VLPs and Rod-shaped CCMV-VLPs) as potential B cell immunogens using different in vitro and in vivo assays. Our results reveal that Round-shaped CCMV-VLPs are more efficient in draining to secondary lymphoid organs to charge professional antigen-presenting cells as well as B cells. Furthermore, compared to Rod-shaped CCMV-VLPs, Round-shaped CCMV-VLPs led to more than 100-fold increased systemic IgG and IgA responses accompanied by prominent formation of splenic germinal centers. Round-shaped CCMV-VLPs could also polarize the induced T cell response toward Th1. To our knowledge, this is the first study investigating and comparing the draining kinetics and immunogenicity of one and the same VLP monomer forming nano-sized icosahedra or rods in the micrometer size.
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http://dx.doi.org/10.1016/j.jconrel.2021.01.012DOI Listing
March 2021

SARS-CoV-2 structural features may explain limited neutralizing-antibody responses.

NPJ Vaccines 2021 Jan 4;6(1). Epub 2021 Jan 4.

University Hospital and University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1038/s41541-020-00264-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782831PMC
January 2021

Shaping Modern Vaccines: Adjuvant Systems Using MicroCrystalline Tyrosine (MCT).

Front Immunol 2020 24;11:594911. Epub 2020 Nov 24.

Allergy Therapeutics (UK) Ltd, Worthing, United Kingdom.

The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT, was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant-Monophosphoryl Lipid A (MPL)-producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success.
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http://dx.doi.org/10.3389/fimmu.2020.594911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721672PMC
June 2021

Glycan-specific IgG anti-IgE autoantibodies are protective against allergic anaphylaxis in a murine model.

J Allergy Clin Immunol 2021 Apr 9;147(4):1430-1441. Epub 2020 Dec 9.

University Hospital for Rheumatology, Immunology, and Allergology, University of Bern, Bern, Switzerland; Department of BioMedical Research, University of Bern, Bern, Switzerland. Electronic address:

Background: IgE causes anaphylaxis in type I hypersensitivity diseases by activating degranulation of effector cells such as mast cells and basophils. The mechanisms that control IgE activity and prevent anaphylaxis under normal conditions are still enigmatic.

Objective: We aimed to unravel how anti-IgE autoantibodies are induced and we aimed to understand their role in regulating serum IgE level and allergic anaphylaxis.

Methods: We immunized mice with different forms of IgE and tested anti-IgE autoantibody responses and their specificities. We then analyzed the effect of those antibodies on serum kinetics and their in vitro and in vivo impact on anaphylaxis. Finally, we investigated anti-IgE autoantibodies in human sera.

Results: Immunization of mice with IgE-immune complexes induced glycan-specific anti-IgE autoantibodies. The anti-IgE autoantibodies prevented effector cell sensitization, reduced total IgE serum levels, protected mice from passive and active IgE sensitization, and resulted in cross-protection against different allergens. Furthermore, glycan-specific anti-IgE autoantibodies were present in sera from subjects with allergy and subjects without allergy.

Conclusion: In conclusion, this study provided the first evidence that in the murine model, the serum level and anaphylactic activity of IgE may be downregulated by glycan-specific IgG anti-IgE autoantibodies.
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http://dx.doi.org/10.1016/j.jaci.2020.11.031DOI Listing
April 2021

Accuracy of serological testing for SARS-CoV-2 antibodies: First results of a large mixed-method evaluation study.

Allergy 2021 03 13;76(3):853-865. Epub 2020 Nov 13.

University Institute of Clinical Chemistry, Inselspital University Hospital, Bern, Switzerland.

Background: Serological immunoassays that can identify protective immunity against SARS-CoV-2 are needed to adapt quarantine measures, assess vaccination responses, and evaluate donor plasma. To date, however, the utility of such immunoassays remains unclear. In a mixed-design evaluation study, we compared the diagnostic accuracy of serological immunoassays that are based on various SARS-CoV-2 proteins and assessed the neutralizing activity of antibodies in patient sera.

Methods: Consecutive patients admitted with confirmed SARS-CoV-2 infection were prospectively followed alongside medical staff and biobank samples from winter 2018/2019. An in-house enzyme-linked immunosorbent assay utilizing recombinant receptor-binding domain (RBD) of the SARS-CoV-2 spike protein was developed and compared to three commercially available enzyme-linked immunosorbent assays (ELISAs) targeting the nucleoprotein (N), the S1 domain of the spike protein (S1), and a lateral flow immunoassay (LFI) based on full-length spike protein. Neutralization assays with live SARS-CoV-2 were performed.

Results: One thousand four hundred and seventy-seven individuals were included comprising 112 SARS-CoV-2 positives (defined as a positive real-time PCR result; prevalence 7.6%). IgG seroconversion occurred between day 0 and day 21. While the ELISAs showed sensitivities of 88.4% for RBD, 89.3% for S1, and 72.9% for N protein, the specificity was above 94% for all tests. Out of 54 SARS-CoV-2 positive individuals, 96.3% showed full neutralization of live SARS-CoV-2 at serum dilutions ≥ 1:16, while none of the 6 SARS-CoV-2-negative sera revealed neutralizing activity.

Conclusions: ELISAs targeting RBD and S1 protein of SARS-CoV-2 are promising immunoassays which shall be further evaluated in studies verifying diagnostic accuracy and protective immunity against SARS-CoV-2.
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http://dx.doi.org/10.1111/all.14608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537154PMC
March 2021

Special Issue "Virus-Like Particle Vaccines".

Viruses 2020 08 10;12(8). Epub 2020 Aug 10.

University Hospital for Rheumatology, Immunology, and Allergology, University of Bern, 3010 Bern, Switzerland.

Virus-like particles (VLPs) have become a key tool for vaccine developers and manufacturers [...].
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http://dx.doi.org/10.3390/v12080872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472007PMC
August 2020

COVID-19: Mechanisms of Vaccination and Immunity.

Vaccines (Basel) 2020 Jul 22;8(3). Epub 2020 Jul 22.

International Immunology Centre, Anhui Agricultural University, Hefei 230036, China.

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world's population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.
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http://dx.doi.org/10.3390/vaccines8030404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564472PMC
July 2020

Strategies to Prevent SARS-CoV-2-Mediated Eosinophilic Disease in Association with COVID-19 Vaccination and Infection.

Int Arch Allergy Immunol 2020 16;181(8):624-628. Epub 2020 Jun 16.

Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

A vaccine to protect against COVID-19 is urgently needed. Such a vaccine should efficiently induce high-affinity neutralizing antibodies which neutralize SARS-CoV-2, the cause of COVID-19. However, there is a concern regarding both vaccine-induced eosinophilic lung disease and eosinophil-associated Th2 immunopotentiation following infection after vaccination. Here, we review the anticipated characteristics of a COVID-19 vaccine to avoid vaccine-associated eosinophil immunopathology.
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http://dx.doi.org/10.1159/000509368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360494PMC
August 2020

The 3Ds in virus-like particle based-vaccines: "Design, Delivery and Dynamics".

Immunol Rev 2020 07 30;296(1):155-168. Epub 2020 May 30.

Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland.

Vaccines need to be rationally designed in order be delivered to the immune system for maximizing induction of dynamic immune responses. Virus-like particles (VLPs) are ideal platforms for such 3D vaccines, as they allow the display of complex and native antigens in a highly repetitive form on their surface and can easily reach lymphoid organs in intact form for optimal activation of B and T cells. Adjusting size and zeta potential may allow investigators to further fine-tune delivery to lymphoid organs. An additional way to alter vaccine transfer to lymph nodes and spleen may be the formulation with micron-sized adjuvants that creates a local depot and results in a slow release of antigen and adjuvant. Ideally, the adjuvant in addition stimulates the innate immune system. The dynamics of the immune response may be further enhanced by inclusion of Toll-like receptor ligands, which many VLPs naturally package. Hence, considering the 3Ds in vaccine development may allow for enhancement of their attributes to tackle complex diseases, not usually amenable to conventional vaccine strategies.
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http://dx.doi.org/10.1111/imr.12863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496916PMC
July 2020

Safety Profile of a Virus-Like Particle-Based Vaccine Targeting Self-Protein Interleukin-5 in Horses.

Vaccines (Basel) 2020 May 9;8(2). Epub 2020 May 9.

Department of Dermatology, University Hospital Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.

: Insect bite hypersensitivity (IBH) is an eosinophilic allergic dermatitis of horses caused by type I/IVb reactions against mainly bites. The vaccination of IBH-affected horses with equine IL-5 coupled to the Cucumber mosaic virus-like particle (eIL-5-CuMV) induces IL-5-specific auto-antibodies, resulting in a significant reduction in eosinophil levels in blood and clinical signs. the preclinical and clinical safety of the eIL-5-CuMV vaccine. The B cell responses were assessed by longitudinal measurement of IL-5- and CuMV-specific IgG in the serum and plasma of vaccinated and unvaccinated horses. Further, peripheral blood mononuclear cells (PBMCs) from the same horses were re-stimulated in vitro for the proliferation and IFN-γ production of specific T cells. In addition, we evaluated longitudinal kidney and liver parameters and the general blood status. An endogenous protein challenge was performed in murine IL-5-vaccinated mice. Results: The vaccine was well tolerated as assessed by serum and cellular biomarkers and also induced reversible and neutralizing antibody titers in horses and mice. Endogenous IL-5 stimulation was unable to re-induce anti-IL-5 production. The CD4 T cells of vaccinated horses produced significantly more IFN-γ and showed a stronger proliferation following stimulation with CuMV as compared to the unvaccinated controls. Re-stimulation using -derived proteins induced low levels of IFNγCD4 cells in vaccinated horses; however, no IFN-γ and proliferation were induced following the HEK-eIL-5 re-stimulation. Vaccination using eIL-5-CuMV induces a strong B-cell as well as CuMV-specific T cell response without the induction of IL-5-specific T cell responses. Hence, B-cell unresponsiveness against self-IL-5 can be bypassed by inducing CuMV carrier-specific T cells, making the vaccine a safe therapeutic option for IBH-affected horses.
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http://dx.doi.org/10.3390/vaccines8020213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349629PMC
May 2020

Vaccination against Allergy: A Paradigm Shift?

Trends Mol Med 2020 04 13;26(4):357-368. Epub 2020 Feb 13.

Allergy Therapeutics (UK) Ltd, Dominion Way, Worthing, UK; Bencard Adjuvant Systems (a division of Allergy Therapeutics), Dominion Way, Worthing, UK. Electronic address:

Since the discovery that IgE antibodies mediate allergy, decades of research have unraveled complex mechanisms associated with conventional immunotherapy and the vital protagonists that shape 'immune tolerance' to allergens. Debate exists on what should constitute the dominant effector mechanism in driving rational drug designs for next-generation immunotherapies. As vaccine technology continues to advance, the development of novel vaccines in this area of continued medical need might stand on a threshold of breakthrough inspired by experiments by Dunbar on the passive vaccination of allergic animals more than 100 years ago. In this opinion article, we discuss both novel insights into IgG antibodies as the principle effector modality induced by specific immunotherapy and advances in antigen-carrier design that may catapult allergy treatment into our modern world.
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http://dx.doi.org/10.1016/j.molmed.2020.01.007DOI Listing
April 2020

Immunization of Cats against Fel d 1 Results in Reduced Allergic Symptoms of Owners.

Viruses 2020 03 6;12(3). Epub 2020 Mar 6.

Department of Immunology, Inselspital, University of Bern, Salihaus 2, 3007 Bern, Switzerland.

An innovative approach was tested to treat cat allergy in humans by vaccinating cats with Fel-CuMV (HypoCat), a vaccine against the major cat allergen Fel d 1 based on virus-like particles derived from cucumber mosaic virus (CuMV-VLPs). Upon vaccination, cats develop neutralizing antibodies against the allergen Fel d 1, which reduces the level of reactive allergen, thus lowering the symptoms or even preventing allergic reactions in humans. The combined methodological field study included ten cat-allergic participants who lived together with their cats ( = 13), that were immunized with Fel-CuMV. The aim was to determine methods for measuring a change in allergic symptoms. A home-based provocation test (petting time and organ specific symptom score (OSSS)) and a general weekly (or monthly) symptom score (G(W)SS) were used to assess changes in allergic symptoms. The petting time until a pre-defined level of allergic symptoms was reached increased already early after vaccination of the cats and was apparent over the course of the study. In addition, the OSSS after provocation and G(W)SS recorded a persistent reduction in symptoms over the study period and could serve for long-term assessment. Hence, the immunization of cats with HypoCat (Fel-CuMV) may have a positive impact on the cat allergy of the owner, and changes could be assessed by the provocation test as well as G(W)SS.
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http://dx.doi.org/10.3390/v12030288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150904PMC
March 2020

A Single Monoclonal Antibody against the Peanut Allergen Ara h 2 Protects against Systemic and Local Peanut Allergy.

Int Arch Allergy Immunol 2020 10;181(5):334-341. Epub 2020 Mar 10.

Immunology, RIA, Inselspital, University of Bern, Bern, Switzerland.

Background: Peanut allergy is the most prevalent and dangerous food allergy. Peanuts consist of a large number of different allergens and peanut-allergic patients are frequently sensitized to multiple allergens. Hence, conventional desensitization approaches aim at targeting as many allergens as possible.

Methods: The monoclonal anti-Ara h 2 antibody (mAb) was produced by hybridoma cells derived from WT BALB/c mice after immunization with a vaccine based on virus-like particles coupled to Ara h 2. BALB/c mice were sensitized intraperitoneally with peanut extract absorbed to alum and mAbs were applied i.v. Challenge was performed the next day with the whole peanut extract intravenously and via skin prick test.

Results: Here we show in peanut-allergic mice that a single high-affinity mAb specific for Ara h 2 is able to block systemic and local allergic reactions induced by the complex peanut extract. We confirm in vitro binding of the mAb to the inhibitory low-affinity FcγRIIb receptor using a sensitive biosensor and demonstrate in vivo that protection was dependent on FcγRIIb.

Conclusion: A single mAb specific for Ara h 2 is able to improve local and systemic allergic symptoms induced by the whole allergen mixture.
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http://dx.doi.org/10.1159/000505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265771PMC
November 2020

Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus.

Vaccines (Basel) 2020 Mar 2;8(1). Epub 2020 Mar 2.

Department of Rheumatology, Immunology and Allergology (RIA), University Hospital, University of Bern, 3010 Bern, Switzerland.

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These-originally β-cell secretory products-extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.
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http://dx.doi.org/10.3390/vaccines8010116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157615PMC
March 2020

Correction: -Derived E-DIII Protein Displayed on Immunologically Optimized VLPs Induces Neutralizing Antibodies without Causing Enhancement of Infection. 2019, , 72.

Vaccines (Basel) 2020 Feb 20;8(1). Epub 2020 Feb 20.

The Jenner Institute, Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), University of Oxford, Oxford OX1 2JD, UK.

The authors wish to make the following correction to their paper [...].
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http://dx.doi.org/10.3390/vaccines8010094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157487PMC
February 2020

Vaccine against peanut allergy based on engineered virus-like particles displaying single major peanut allergens.

J Allergy Clin Immunol 2020 04 19;145(4):1240-1253.e3. Epub 2019 Dec 19.

Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland; Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology, The Jenner Institute, University of Oxford, Oxford, United Kingdom. Electronic address:

Background: Peanut allergy is a severe and increasingly frequent disease with high medical, psychosocial, and economic burden for affected patients and wider society. A causal, safe, and effective therapy is not yet available.

Objective: We sought to develop an immunogenic, protective, and nonreactogenic vaccine candidate against peanut allergy based on virus-like particles (VLPs) coupled to single peanut allergens.

Methods: To generate vaccine candidates, extracts of roasted peanut (Ara R) or the single allergens Ara h 1 or Ara h 2 were coupled to immunologically optimized Cucumber Mosaic Virus-derived VLPs (CuMVtt). BALB/c mice were sensitized intraperitoneally with peanut extract absorbed to alum. Immunotherapy consisted of a single subcutaneous injection of CuMVtt coupled to Ara R, Ara h 1, or Ara h 2.

Results: The vaccines CuMVtt-Ara R, CuMVtt-Ara h 1, and CuMVtt-Ara h 2 protected peanut-sensitized mice against anaphylaxis after intravenous challenge with the whole peanut extract. Vaccines did not cause allergic reactions in sensitized mice. CuMVtt-Ara h 1 was able to induce specific IgG antibodies, diminished local reactions after skin prick tests, and reduced the infiltration of the gastrointestinal tract by eosinophils and mast cells after oral challenge with peanut. The ability of CuMVtt-Ara h 1 to protect against challenge with the whole extract was mediated by IgG, as shown via passive IgG transfer. FcγRIIb was required for protection, indicating that immune complexes with single allergens were able to block the allergic response against the whole extract, consisting of a complex allergen mixture.

Conclusions: Our data suggest that vaccination using single peanut allergens displayed on CuMVtt may represent a novel therapy against peanut allergy with a favorable safety profile.
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http://dx.doi.org/10.1016/j.jaci.2019.12.007DOI Listing
April 2020

Interleukin 31 in insect bite hypersensitivity-Alleviating clinical symptoms by active vaccination against itch.

Allergy 2020 04 6;75(4):862-871. Epub 2020 Feb 6.

Department of Dermatology, University Hospital Zurich, Schlieren, Switzerland.

Background: Insect bite hypersensitivity (IBH) is the most common seasonal pruritic allergic dermatitis of horses occurring upon insect bites. In recent years, a major role for IL-31 in allergic pruritus of humans, monkeys, dogs, and mice was acknowledged. Here, we investigate the role of IL-31 in IBH of horses and developed a therapeutic vaccine against equine IL-31 (eIL-31).

Methods: IL-31 levels were quantified in allergen-stimulated peripheral blood mononuclear cells (PBMCs) and skin punch biopsies of IBH lesions and healthy skin from IBH-affected and healthy horses. The vaccine consisted of eIL-31 covalently coupled to a virus-like particle (VLP) derived from cucumber mosaic virus containing a tetanus toxoid universal T-cell epitope (CuMVTT). Eighteen IBH-affected horses were recruited and immunized with 300 μg of eIL-31-CuMVTT vaccine or placebo and IBH severity score was recorded.

Results: IL-31 was increased in PBMCs and exclusively detectable in skin lesions of IBH-affected horses. Vaccination against eIL-31 reduced delta clinical scores when compared to previous untreated IBH season of the same horses and to placebo-treated horses in the same year. The vaccine was well tolerated without safety concerns throughout the study.

Conclusion: TH2-derived IL-31 is involved in IBH pathology and accordingly the immunotherapeutic vaccination approach targeting IL-31 alleviated clinical scores in affected horses.
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http://dx.doi.org/10.1111/all.14145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217000PMC
April 2020

Murine CD8 T-cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density.

Eur J Immunol 2020 04 10;50(4):505-514. Epub 2019 Dec 10.

Department of Oncology, University of Lausanne, Switzerland.

It is known that for achieving high affinity antibody responses, vaccines must be optimized for antigen dose/density, and the prime/boost interval should be at least 4 weeks. Similar knowledge is lacking for generating high avidity T-cell responses. The functional avidity (FA) of T cells, describing responsiveness to peptide, is associated with the quality of effector function and the protective capacity in vivo. Despite its importance, the FA is rarely determined in T-cell vaccination studies. We addressed the question whether different time intervals for short-term homologous vaccinations impact the FA of CD8 T-cell responses. Four-week instead of 2-week intervals between priming and boosting with potent subunit vaccines in C57BL/6 mice did not improve FA. Equally, similar FA was observed after vaccination with virus-like particles displaying low versus high antigen densities. Interestingly, FA was stable in vivo but not in vitro, depending on the antigen dose and the time interval since T-cell activation, as observed in murine monoclonal T cells. Our findings suggest dynamic in vivo modulation for equal FA. We conclude that low antigen density vaccines or a minimal 4-week prime/boost interval are not crucial for the T-cell's FA, in contrast to antibody responses.
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http://dx.doi.org/10.1002/eji.201948355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187562PMC
April 2020

Cytoplasmic glycoengineering enables biosynthesis of nanoscale glycoprotein assemblies.

Nat Commun 2019 11 27;10(1):5403. Epub 2019 Nov 27.

Institute of Microbiology, ETH Zurich, 8093, Zurich, Switzerland.

Glycosylation of proteins profoundly impacts their physical and biological properties. Yet our ability to engineer novel glycoprotein structures remains limited. Established bacterial glycoengineering platforms require secretion of the acceptor protein to the periplasmic space and preassembly of the oligosaccharide substrate as a lipid-linked precursor, limiting access to protein and glycan substrates respectively. Here, we circumvent these bottlenecks by developing a facile glycoengineering platform that operates in the bacterial cytoplasm. The Glycoli platform leverages a recently discovered site-specific polypeptide glycosyltransferase together with variable glycosyltransferase modules to synthesize defined glycans, of bacterial or mammalian origin, directly onto recombinant proteins in the E. coli cytoplasm. We exploit the cytoplasmic localization of this glycoengineering platform to generate a variety of multivalent glycostructures, including self-assembling nanomaterials bearing hundreds of copies of the glycan epitope. This work establishes cytoplasmic glycoengineering as a powerful platform for producing glycoprotein structures with diverse future biomedical applications.
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http://dx.doi.org/10.1038/s41467-019-13283-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881330PMC
November 2019

State-of-the-art in marketed adjuvants and formulations in Allergen Immunotherapy: A position paper of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 04;75(4):746-760

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper, we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH) ) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre-existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is presensitized to the antigen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response towards Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three-to-five-year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.
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http://dx.doi.org/10.1111/all.14134DOI Listing
April 2020

Virus-like particles for vaccination against cancer.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2020 01 27;12(1):e1579. Epub 2019 Aug 27.

Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland.

Active immunotherapy of cancer aims to treat the disease by inducing effective cellular and humoral immune responses. Virus-like particle-based vaccines have evolved dramatically over the last few decades, greatly reducing morbidity and mortality of several infectious diseases and expectedly preventing cervical cancer caused by human papilloma virus. In contrast to these broad successes of disease prevention, therapeutic cancer vaccines remain to demonstrate clinical benefit. Yet, several preclinical and clinical trials have revealed promising results and are paving the way for medical breakthroughs. This study reviews and discusses the recent preclinical development and clinical trials in this field. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
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http://dx.doi.org/10.1002/wnan.1579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916610PMC
January 2020

Virus-Specific Secondary Plasma Cells Produce Elevated Levels of High-Avidity Antibodies but Are Functionally Short Lived.

Front Immunol 2019 6;10:1831. Epub 2019 Aug 6.

Department of Rheumatology, Immunology and Allergology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Most vaccines aim at inducing durable antibody responses and are designed to elicit strong B cell activation and plasma cell (PC) formation. Here we report characteristics of a recently described secondary PC population that rapidly originates from memory B cells (MBCs) upon challenge with virus-like particles (VLPs). Upon secondary antigen challenge, all VLP-specific MBCs proliferated and terminally differentiated to secondary PCs or died, as they could not undergo multiple rounds of re-stimulation. Secondary PCs lived in bone marrow and secondary lymphoid organs and exhibited increased production of antibodies with much higher avidity compared to primary PCs, supplying a swift wave of high avidity antibodies early after antigen recall. Unexpectedly, however, secondary PCs were functionally short-lived and most of them could not be retrieved in lymphoid organs and ceased to produce antibodies. Nevertheless, secondary PCs are an early source of high avidity antibodies and induction of long-lived MBCs with the capacity to rapidly differentiate to secondary PCs may therefore be an underestimated possibility to induce durable protection by vaccination.
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http://dx.doi.org/10.3389/fimmu.2019.01831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691049PMC
October 2020

CD23 provides a noninflammatory pathway for IgE-allergen complexes.

J Allergy Clin Immunol 2020 01 19;145(1):301-311.e4. Epub 2019 Aug 19.

Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland; Department of BioMedical Research, University of Bern, Bern, Switzerland. Electronic address:

Background: Type I hypersensitivity is mediated by allergen-specific IgE, which sensitizes the high-affinity IgE receptor FcεRI on mast cells and basophils and drives allergic inflammation upon secondary allergen contact. CD23/FcεRII, the low-affinity receptor for IgE, is constitutively expressed on B cells and has been shown to regulate immune responses. Simultaneous binding of IgE to FcεRI and CD23 is blocked by reciprocal allosteric inhibition, suggesting that the 2 receptors exert distinct roles in IgE handling.

Objective: We aimed to study how free IgE versus precomplexed IgE-allergen immune complexes (IgE-ICs) target the 2 IgE receptors FcεRI and CD23, and we investigated the functional implications of the 2 pathways.

Methods: We performed binding and activation assays with human cells in vitro and IgE pharmacokinetics and anaphylaxis experiments in vivo.

Results: We demonstrate that FcεRI preferentially binds free IgE and CD23 preferentially binds IgE-ICs. We further show that those different binding properties directly translate to distinct biological functions: free IgE initiated allergic inflammation through FcεRI on allergic effector cells, while IgE-ICs were noninflammatory because of reduced FcεRI binding and enhanced CD23-dependent serum clearance.

Conclusion: We propose that IgE-ICs are noninflammatory through reduced engagement by FcεRI but increased targeting of the CD23 pathway.
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http://dx.doi.org/10.1016/j.jaci.2019.07.045DOI Listing
January 2020

Early Transcriptional Signature in Dendritic Cells and the Induction of Protective T Cell Responses Upon Immunization With VLPs Containing TLR Ligands-A Role for CCL2.

Front Immunol 2019 2;10:1679. Epub 2019 Aug 2.

The Jenner Institute, Oxford University, Oxford, United Kingdom.

Inducing T cell responses by therapeutic vaccination requires appropriate activation of antigen presenting cells (APCs). The use of virus-like particles (VLPs) containing Toll-like receptor (TLR) ligands has demonstrated remarkable potential in activating APCs and modulating the immune response both for prophylactic vaccines as well as immunotherapy. Here, we employed VLPs associated to TLR ligands as tools to modulate cytotoxic response mediated by CD8 T cells and provide further insight in the development of T cell-based immunotherapy. We have investigated the transcriptional signature in dendritic cells (DCs) from mice immunized with VLPs containing distinct classes of nucleic acid and correlated the expression patterns with the efficiency of induced T cell responses. We identified key pathways activated in DCs that are involved in the appropriated induction of T cell responses and show evidence for the modulatory effect of CCL2 in CD8 T cells responses. These insights shed light on immune networks that are pivotal for the induction of potent cytotoxic T cell responses and identify key genes for appropriate DC activation and subsequent modulation of the adaptive immune response.
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http://dx.doi.org/10.3389/fimmu.2019.01679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687836PMC
October 2020

-Derived E-DIII Protein Displayed on Immunologically Optimized VLPs Induces Neutralizing Antibodies without Causing Enhancement of Infection.

Vaccines (Basel) 2019 Jul 23;7(3). Epub 2019 Jul 23.

The Jenner Institute, Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), University of Oxford, Oxford OX1 2JD, UK.

(ZIKV) is a similar to (DENV) in terms of transmission and clinical manifestations, and usually both viruses are found to co-circulate. ZIKV is usually transmitted by mosquitoes bites, but may also be transmitted by blood transfusion, via the maternal-foetal route, and sexually. After 2015, when the most extensive outbreak of ZIKV had occurred in Brazil and subsequently spread throughout the rest of South America, it became evident that ZIKV infection during the first trimester of pregnancy was associated with microcephaly and other neurological complications in newborns. As a result, the development of a vaccine against ZIKV became an urgent goal. A major issue with DENV vaccines, and therefore likely also with ZIKV vaccines, is the induction of antibodies that fail to neutralize the virus properly and cause antibody-dependent enhancement (ADE) of the infection instead. It has previously been shown that antibodies against the third domain of the envelope protein (EDIII) induces optimally neutralizing antibodies with no evidence for ADE for other viral strains. Therefore, we generated a ZIKV vaccine based on the EDIII domain displayed on the immunologically optimized (CuMVtt) derived virus-like particles (VLPs) formulated in dioleoyl phosphatidylserine (DOPS) as adjuvant. The vaccine induced high levels of specific IgG after a single injection. The antibodies were able to neutralise ZIKV without enhancing infection by DENV in vitro. Thus, the here described vaccine based on EDIII displayed on VLPs was able to stimulate production of antibodies specifically neutralizing ZIKV without potentially enhancing disease caused by DENV.
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http://dx.doi.org/10.3390/vaccines7030072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789886PMC
July 2019