type 1 diabetes Vaccine
9983230
Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice
Immune tolerance is executed partly by Foxp3+regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin producing b cells. The development of autoantigen specific vaccination strategies for Foxp3+Treg induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell engrafted NSG HLA DQ8 transgenic mice, we provide direct evidence for human autoantigen specific Foxp3+Treg induction in vivo. We identify HLA DQ8 restricted insulin specific CD4+T cells and demonstrate efficient human insulin specific Foxp3+Treg induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL 2Ra and TIGIT and can efficiently suppress effector T cells. Such Foxp3+Treg induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3+Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D.
Nature communications
Isabelle Serr Rainer W Furst Peter Achenbach Martin G Scherm Fusun Gokmen Florian Haupt Eva-Maria Sedlmeier Annette Knopff Leonard Shultz Richard A Willis Anette-G Ziegler Carolin Daniel
14043029
Design of a Type 1 Diabetes Vaccine Candidate Using Edible Plants Expressing a Major Autoantigen
Type 1 diabetes (T1D) is a metabolic disease involving the autoimmune destruction of insulin producing pancreatic beta cells. It is often diagnosed by the detection of autoantibodies, typically those recognizing insulin itself or the 65 kDa isoform of glutamic acid decarboxylase (GAD65) Oral insulin can be used to induce systemic immunological tolerance and thus prevent or delay the onset of T1D, suggesting that combination treatments with other autoantigens such as GAD65 could be even more successful. GAD65 has induced oral tolerance and prevented T1D in preclinical studies but it is difficult to produce in sufficient quantities for clinical testing. Here we combined edible plant systems, namely spinach (Spinacia oleracea cv Industra) and red beet (Beta vulgaris cv Moulin Rouge) with the magnICON(r) expression system to develop a safe, cost effective and environmentally sustainable platform for the large scale production of GAD65. The superior red beet platform was extensively characterized in terms of recombinant protein yields and bioequivalence to wild type plants, and the product was tested for its ability to resist simulated gastric digestion. Our results indicate that red beet plants are suitable for the production of a candidate oral vaccine based on GAD65 for the future preclinical and clinical testing of T1D immunotherapy approaches.
Front. Plant Sci.
Edoardo Bertini Matilde Merlin Elisa Gecchele Andrea Puggia Annalisa Brozzetti Mauro Commisso Alberto Falorni Vittorio Bini Victor Klymyuk Mario Pezzotti Linda Avesani
4009063
Prospects of a type 1 diabetes vaccine
The hallmark characteristic of a vaccine is either prevention or cure of a disease by sensitizing or desensitizing the immune system to specific antigen(s) (Ags) and avoiding propagation of the pathogenic immune responses. In the case of autoimmune type 1 diabetes (T1D) in which the insulin producing beta cells within the pancreatic islets of Langerhans are selectively destroyed by the immune system (primarily the pathogenic T cells) this entails reinstallment of immune tolerance to beta cell Ags or peptides. Ag specific therapies have the potential to reset the immune system toward long standing tolerance to the involved Ags, if applied correctly. Tolerance induction depends heavily on the route of administration (i.e. oral or parenteral) the time of administration with respect to disease stages and the Ag dose. High doses of Ag preferentially promote anergy or apoptosis of pathogenic T cells, while low doses favor regulatory T cell (Treg) induction or prevent immune cell interactions [1] Although the primary Ag in T1D is not yet identified, several exogenous Ags like dietary wheat and cow's milk derived proteins, displaying molecular mimicry with beta cell surface proteins, in addition to endogenous (pro)insulin, glutamic acid decarboxylase (GAD65) the tyrosine phosphatase related islet antigen (IA 2) heat shock protein (HSP60) islet specific glucose 6 phosphatase catalytic subunitrelated protein (IGRP) and zinc transporter (ZnT8) have been linked to T1D initiation and progression and are, therefore, potential therapeutic targets. Also environmental infectious agents, like viruses, contribute to triggering T1D; true vaccination against these agents could help in preventing disease. The ideal timing for a prophylactic vaccine in T1D is probably before disease onset during the presymptomatic stages, particularly before any immune attack against the beta cell has been initiated [2] Intervention at this stage is often studied in T1D animal models, like the nonobese diabetic (NOD) mouse, and Ag specific interventions with administration of the suspected autoAgs, for example insulin, are effective in arresting disease. Unfortunately, clinical translation of these findings remains tough, as timing of Ag administration, Ag dose, repetition of Ag administration etc. are crucial factors in determining success or failure. Moreover, treating humans at this stage of the disease means treating at risk populations without clinical symptoms, namely neonates or small children (often first degree relatives of T1D patients) identified through genetic screening with high risk HLA genotypes and autoantibody positivity. In this population, an Ag based vaccine should not only prevent activation of naive T cells but also control activated effector T cells that are already damaging the betacell, as shown by autoantibody production from bystander B cells, in order to prevent progression of the autoimmune attack and onset of disease. Importantly, although the majority of high risk individuals are subjected to one or multiple environmental triggers, only a limited group will progress to disease. Once hyperglycemia is present, the challenge for successful vaccination becomes even greater as not only reinstallation and regulation of tolerance is needed, but the therapeutic success will depend on the moment of intervention and the amount of functioning beta cells around to be saved. In the two latter stages of disease, when autoimmunity is happening, pure vaccination as in 'administration of Ag in a tolerogenic way' will probably not suffice to achieve disease prevention. In these cases, it is to be expected that combinations with immunomodulators will be necessary to arrest progression of disease.
Expert opinion on biological therapy
Dana Paulina Cook Conny A Gysemans Chantal Mathieu
31101596
Type 1 diabetes vaccine development: Animal models vs. humans
The loss of tolerance towards self antigens on pancreatic b cells is the hallmark of type 1 diabetes that ultimately causes destruction of the islets of Langerhans, loss of blood glucose control and severe long term complications. One major aspect that contributes to the emergence of autoreactivity may be the interplay of several microbial agents with the immune system that, depending on its nature, may promote autoreactivity or confer protection. Since there is no curative treatment available that can be safely administered to the increasing number of patients suffering from this disease, the development of a vaccine that prevents autoreactivity or re introduces immune regulation once autoreactivity occurs is of great interest, particularly because other treatment options almost entirely depend on general immunosuppression. Here, we will discuss recent developments in vaccine discovery and, since a majority of the available information is derived from animal models, will focus on the question, how these observations may be translated to a therapy for human type 1 diabetes.
Human vaccines
Tobias Boettler Matthias G von Herrath
189763839
Lower Incidence Rate of Type 1 Diabetes after Receipt of the Rotavirus Vaccine in the United States, 2001 2017
We evaluated whether rotavirus vaccination is associated with the incidence of type 1 diabetes among children. We designed a cohort study of 1,474,535 infants in the United States from 2001 2017, using data from a nationwide health insurer. There was a 33% reduction in the risk of type 1 diabetes with completion of the rotavirus vaccine series compared to the unvaccinated (95% CI: 17% 46% Completion of the pentavalent vaccine series was associated with 37% lower risk of type 1 diabetes (95% CI: 22% 50% Partial vaccination (incompletion of the series) was not associated with the incidence of type 1 diabetes. There was a 31% reduction in hospitalizations in the 60 day period after vaccination (95% CI: 27% 35% compared to unvaccinated children. Overall, there was a 3.4% decrease in incidence annually in children ages 0 4 in the United States from 2006 2017 which coincides with the vaccine introduction in 2006. We conclude that rotavirus vaccination is associated with a reduced incidence of type 1 diabetes. Rotavirus vaccination may be the first practical measure that could play a role in the prevention of this disease.
Scientific Reports
Mary A M Rogers Tanima Basu Catherine Kim
26333575
In light of recent clinical trial results, what lies next for Type 1 diabetes vaccine research?
A number of avenues are worthy of future research in the development of a Type 1 diabetes (T1D) vaccine. For example, recent research has shown that C peptide levels of above 0.2 nmol/l stimulated by very limited b cell function may reduce the long term complications associated with T1D [1] Furthermore, there is increasing evidence that C peptide is a hormone with its own effects [2] and that as b cells regenerate [3] it may be extremely important to stop the destructive process. Immune suppression to treat T1D had some effect, but was outweighed by adverse events. More recently, selective immune suppression has been tried. Phase II trials showed promising efficacy, but Phase III studies have been disappointing [4 8] Treatment using autoantigens to induce immunological tolerance has been proposed as an alternative. Parenteral insulin, as well as nasal insulin, had no effect when used to prevent T1D [9] In the Diabetes Prevention Trial, oral insulin treatment failed to achieve its primary end point, despite an apparent response from patients with high concentration of insulin autoantibodies; however, this occurred only for the duration for which treatment was given [10] A peptide derived from heat shock protein 60, DiaPep 277, has been reported to have positive effects in adults [11] but not in children with newly diagnosed T1D [12] In a Phase II trial, treatment with glutamic acid decarboxylase (GAD)alum was associated with preserved fasting and stimulated C peptide at 30 months post treatment [13] The eff icacy was mainly seen in patients treated <6 months from diagnosis, and these patients still showed preservation of fasting C peptide after 4 years [14] Recently, a Phase II trial of GAD alum in patients with newly diagnosed T1D failed to show efficacy [15] Also, the European Phase III GAD trial failed to reach its primary end point, although there were some positive results in certain subgroups [16] The positive results of the Phase II GAD trial, and that seen in some subgroups of the Phase III GAD trial, may together be regarded as support of the concept of using autoantigen therapy. This idea has gained further support from recently presented preliminary data, which seem to confirm that DiaPep 277 given repeatedly can preserve residual b cell function. Of the 457 included patients (302 men and 155 women, 16 45 years old, with a mean age of 27 years, and fasting C peptide >0.22 nmol/l) 169 in the active and 169 in the placebo arm had been evaluated after 24 months. Patients who received DiaPep 277 every 3 months up to 21 months had a 23% better preservation of C peptide (AUC) than in the placebo arm (p 0.037) These results are encouraging, although the effect may be restricted to mild cases of T1D in adults.
Expert review of vaccines
Johnny Ludvigsson
53873164
A multi epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes.
Type 1 diabetes (T1D) is caused by diabetogenic T cells that evaded tolerance mechanisms and react against multiple b cell antigens. Antigen specific therapy to reinstate tolerance (typically using a single b cell antigen) has so far proved unsuccessful in T1D patients. Plasmid DNA (pDNA) mediated expression of proinsulin has demonstrated transient protection in clinical trials, but long lasting tolerance is yet to be achieved. We aimed to address whether pDNA delivery of multiple epitopes/mimotopes from several b cell antigens efficiently presented to CD4+ and CD8+ T cells could also induce tolerance. This approach significantly delayed T1D development, while co delivery of pDNA vectors expressing four full antigens protected more mice. Delivery of multiple epitopes resulted in a broad engagement of specific T cells, eliciting a response distinct from endogenous epitopes draining from islets. T cell phenotypes also varied with antigen specificity. Unexpectedly, the repertoire of T cells reactive to the same epitope was highly polyclonal. Despite induction of some CD25+ Foxp3+ regulatory T cells, protection from disease did not persist after treatment discontinuation. These data demonstrate that epitope based tolerogenic DNA vaccines constitute effective precision medicine tools to target a broad range of specific CD4+ and CD8+ diabetogenic T cell populations for prevention or treatment of T1D.
Journal of autoimmunity
Jorge Postigo-Fernandez Remi J Creusot
53949062
Developing a vaccine for type 1 diabetes by targeting coxsackievirus B
ABSTRACT Introduction: Virus infections have long been considered as a possible cause of type 1 diabetes (T1D) One virus group, enteroviruses (EVs) has been studied extensively, and clinical development of a vaccine against T1D associated EV types has started. Areas covered: Epidemiological studies have indicated an association between EVs and T1D. These viruses have a strong tropism for insulin producing b cells; the destruction of these cells leads to T1D. The exact mechanisms by which EVs could cause T1D are not known, but direct infection of b cells and virus induced inflammation may play a role. Recent studies have narrowed down the epidemiological association to a subset of EVs: group B coxsackieviruses (CVBs) These findings have prompted efforts to develop vaccines against CVBs. Prototype CVB vaccines have prevented both infection and CVB induced diabetes in mice. This review summarizes recent progress in the field and the specifics of what could constitute the first human vaccine developed for a chronic autoimmune disease. Expert commentary: Manufacturing of a clinical CVB vaccine as well as preclinical studies are currently in progress in order to enable clinical testing of the first CVB vaccine. Ongoing scientific research projects can significantly facilitate this effort by providing insights into the mechanisms of the CVB T1D association.
Expert review of vaccines
Heikki Hyoty Francisco Leon Mikael Knip
205606068
Construction of a novel vaccine by conjugating a B cell epitope of DPP4 to peptide IA2(5) P2 1 to significantly control type 1 diabetes in NOD mice.
Type 1 diabetes is a chronic organ specific autoimmune disease in which selective destruction of insulin producing b cells leads to impaired glucose metabolism and its attendant complications. IA2(5)P2 1, a potent immunogenic carrier which designed by our laboratory, can induce high titer specific antibodies when carry a B cell epitope, such as B cell epitopes of DPP4, xanthine oxidase, and Urate transporter protein. In this report, we describe a novel multi epitope vaccine composing a peptide of DPP4, an anti diabetic B epitope of Insulinoma antigen 2(IA 2) and a Th2 epitope (P2:IPALDSLTPANED) of P277 peptide in human heat shock protein 60 (HSP60) Immunization with the multi epitope vaccine in non obese diabetic (NOD) mice successfully induced specific anti DPP4 antibody, inhibited plasma DPP4 activity, and increased serum GLP 1 level. Moreover, this antibody titer was correlated with the dose of immunization (20mg, 100mg) Inoculation of this vaccine in NOD mice significantly control blood glucose level, improved glucose excursion and increased insulin level in vivo. Consistent with a lower diabetic and insulitis incidence, a induced splenic T cells proliferation and tolerance were observed. IFN g secretion reduced and IL 10 increased significantly in the D41 IA2(5) P2 1 treated mice compared to P277 and control group due to the potential immunomodulatory effect of the epitope in the vaccine. Immunohistochemical analysis and cytometry showed a rebalance of Th1/Th2 in NOD mice. Our results demonstrate that this multi epitope vaccine may serve as a promising therapeutic approach for type 1 diabetes.
Vaccine
Ya Li Huimin Cao Yiping Li Zhixin Li Xiaomin Wei Ruibao Jiao Peng Cheng Xiaoran Liu YanJie Ma Yun Xing Jiali Tang Min Wang Taiming Li
23561478
A Coxsackievirus B vaccine protects against virus induced diabetes in an experimental mouse model of type 1 diabetes
Aims/hypothesisEpidemiological studies suggest a role for Coxsackievirus B (CVB) serotypes in the pathogenesis of type 1 diabetes, but their actual contribution remains elusive. In the present study, we have produced a CVB1 vaccine to test whether vaccination against CVBs can prevent virus induced diabetes in an experimental model.MethodsNOD and SOCS1 tg mice were vaccinated three times with either a formalin fixed non adjuvanted CVB1 vaccine or a buffer control. Serum was collected for measurement of neutralising antibodies using a virus neutralisation assay. Vaccinated and buffer treated mice were infected with CVB1. Viraemia and viral replication in the pancreas were measured using standard plaque assay and PCR. The development of diabetes was monitored by blood glucose measurements. Histological analysis and immunostaining for viral capsid protein 1 (VP1) insulin and glucagon in formalin fixed paraffin embedded pancreas was performed.ResultsThe CVB1 vaccine induced strong neutralising antibody responses and protected against viraemia and the dissemination of virus to the pancreas in both NOD mice (n 8) and SOCS1 tg mice (n 7) Conversely, 100% of the buffer treated NOD and SOCS1 tg mice were viraemic on day 3 post infection. Furthermore, half (3/6) of the buffer treated SOCS1 tg mice developed diabetes upon infection with CVB1, with a loss of the insulin positive beta cells and damage to the exocrine pancreas. In contrast, all (7/7) vaccinated SOCS1 tg mice were protected from virus induced diabetes and showed no signs of beta cell loss or pancreas destruction (p 0.05).Conclusions/InterpretationCVB1 vaccine can efficiently protect against both CVB1 infection and CVB1 induced diabetes. This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes.
Diabetologia
Virginia M Stone Minna M Hankaniemi Emma Svedin Amir-Babak Sioofy-Khojine Sami Oikarinen Heikki Hyoty Olli H Laitinen Vesa Pekka Hytonen Malin Flodstrom-Tullberg