Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes.

Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease, defined by insulin resistance and insufficient insulin secretion to maintain normoglycemia. Amyloidogenic aggregates are a hallmark of T2DM patients; they are cytotoxic for the insulin producing ß-cells, and cause inflammasome-dependent secretion of IL-1ß. To avoid the associated ß-cell loss and inflammation in advanced stage T2DM, we developed a novel monoclonal therapy targeting the major component of aggregates, islet amyloid polypeptide (IAPP). The here described monoclonal antibody (mAb) m81, specific for oligomeric and fibrils, but not for soluble free IAPP, is able to prevent oligomer growth and aggregate formation in vitro, and blocks islet inflammation and disease progression in vivo. Collectively, our data show that blocking fibril formation and prevention of new amyloidogenic aggregates by monoclonal antibody therapy may be a potential therapy for T2DM.

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

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 ß-cell secretory products-extracellular aggregates are cytotoxic for insulin-producing ß-cells and are associated with ß-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 1ß (IL-1ß). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

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

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.

Correction: Zika Virus-Derived E-DIII Protein Displayed on Immunologically Optimized VLPs Induces Neutralizing Antibodies without Causing Enhancement of Dengue Virus Infection. Vaccines 2019, 7, 72.

The authors wish to make the following correction to their paper [...].

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

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.

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

Zika virus (ZIKV) is a flavivirus similar to Dengue virus (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 Cucumber mosaic virus (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.

Correction to: Vaccination with nanoparticles combined with micro-adjuvants protects against cancer.

Following publication of the original article [1], the author reported an author's family name has been misspelled. Paul Engroff should be replace Paul Engeroff.Furthermore, there are two mistake in two affiliations: 9) Department of dermatology, University of Zurich, Bern, Switzerland and 10) Department of Oncology, University of Lausanne, Bern,Switzerland should be replace with 9) Department of dermatology, University of Zurich, Zurich, Switzerland.10) Department of Oncology, University of Lausanne, Lausanne, Switzerland.

Vaccination with nanoparticles combined with micro-adjuvants protects against cancer.

BACKGROUND: Induction of strong T cell responses, in particular cytotoxic T cells, is a key for the generation of efficacious therapeutic cancer vaccines which yet, remains a major challenge for the vaccine developing world. Here we demonstrate that it is possible to harness the physiological properties of the lymphatic system to optimize the induction of a protective T cell response. Indeed, the lymphatic system sharply distinguishes between nanoscale and microscale particles. The former reaches the fenestrated lymphatic system via diffusion, while the latter either need to be transported by dendritic cells or form a local depot. METHODS: Our previously developed cucumber-mosaic virus-derived nanoparticles termed (CuMVTT-VLPs) incorporating a universal Tetanus toxoid epitope TT830-843 were assessed for their draining kinetics using stereomicroscopic imaging. A nano-vaccine has been generated by coupling p33 epitope as a model antigen to CuMVTT-VLPs using bio-orthogonal Cu-free click chemistry. The CuMVTT-p33 nano-sized vaccine has been next formulated with the micron-sized microcrystalline tyrosine (MCT) adjuvant and the formed depot effect was studied using confocal microscopy and trafficking experiments. The immunogenicity of the nanoparticles combined with the micron-sized adjuvant was next assessed in an aggressive transplanted murine melanoma model. The obtained results were compared to other commonly used adjuvants such as B type CpGs and Alum. RESULTS: Our results showed that CuMVTT-VLPs can efficiently and rapidly drain into the lymphatic system due to their nano-size of ~ 30 nm. However, formulating the nanoparticles with the micron-sized MCT adjuvant of ~ 5 µM resulted in a local depot for the nanoparticles and a longer exposure time for the immune system. The preclinical nano-vaccine CuMVTT-p33 formulated with the micron-sized MCT adjuvant has enhanced the specific T cell response in the stringent B16F10p33 murine melanoma model. Furthermore, the micron-sized MCT adjuvant was as potent as B type CpGs and clearly superior to the commonly used Alum adjuvant when total CD8+, specific p33 T cell response or tumour protection were assessed. CONCLUSION: The combination of nano- and micro-particles may optimally harness the physiological properties of the lymphatic system. Since the nanoparticles are well defined virus-like particles and the micron-sized adjuvant MCT has been used for decades in allergen-specific desensitization, this approach may readily be translated to the clinic.

DOPS Adjuvant Confers Enhanced Protection against Malaria for VLP-TRAP Based Vaccines.

Vaccination remains the most effective and essential prophylactic tool against infectious diseases. Enormous efforts have been made to develop effective vaccines against malaria but successes remain so far limited. Novel adjuvants may offer a significant advantage in the development of malaria vaccines, in particular if combined with inherently immunogenic platforms, such as virus-like particles (VLP). Dioleoyl phosphatidylserine (DOPS), which is expressed on the outer surface of apoptotic cells, represents a novel adjuvant candidate that may confer significant advantage over existing adjuvants, such as alum. In the current study we assessed the potential of DOPS to serve as an adjuvant in the development of a vaccine against malaria either alone or combined with VLP using Plasmodium falciparum thrombospondin-related adhesive protein (TRAP) as a target antigen. TRAP was chemically coupled to VLPs derived from the cucumber mosaic virus fused to a universal T cell epitope of tetanus toxin (CuMVtt). Mice were immunized with TRAP alone or formulated in alum or DOPS and compared to TRAP coupled to CuMVtt formulated in PBS or DOPS. Induced immune responses, in particular T cell responses, were assessed as the major protective effector cell population induced by TRAP. The protective capacity of the various formulations was assessed using a transgenic Plasmodium berghei expressing PfTRAP. All vaccine formulations using adjuvants and/or VLP increased humoral and T cell immunogenicity for PfTRAP compared to the antigen alone. Display on VLPs, in particular if formulated with DOPS, induced the strongest and most protective immune response. Thus, the combination of VLP with DOPS may harness properties of both immunogenic components and optimally enhance induction of protective immune responses.