[Show abstract][Hide abstract] ABSTRACT: AIMS/HYPOTHESIS:
Enterovirus infections have been implicated in the aetiology of autoimmune type 1 diabetes. A vaccine could be used to test the causal relationship between enterovirus infections and diabetes development. However, the development of a vaccine against a virus suspected to induce an autoimmune disease is challenging, since the vaccine itself might trigger autoimmunity. Another challenge is to select the enterovirus serotypes to target with a vaccine. Here we aimed to evaluate the function and autoimmune safety of a novel non-adjuvanted prototype vaccine to Coxsackievirus serotype B1 (CVB1), a member of the enterovirus genus.
A formalin-inactivated CVB1 vaccine was developed and tested for its immunogenicity and safety in BALB/c and NOD mice. Prediabetic NOD mice were vaccinated, infected with CVB1 or mock-treated to compare the effect on diabetes development.
Vaccinated mice produced high titres of CVB1-neutralising antibodies without signs of vaccine-related side effects. Vaccinated mice challenged with CVB1 had significantly reduced levels of replicating virus in their blood and the pancreas. Prediabetic NOD mice demonstrated an accelerated onset of diabetes upon CVB1 infection whereas no accelerated disease manifestation or increased production of insulin autoantibodies was observed in vaccinated mice.
We conclude that the prototype vaccine is safe and confers protection from infection without accelerating diabetes development in mice. These results encourage the development of a multivalent enterovirus vaccine for human use, which could be used to determine whether enterovirus infections trigger beta cell autoimmunity and type 1 diabetes in humans.
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
We wished to define highly conserved areas of the rhinovirus polyprotein and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model.
Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across rhinoviruses. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype humoral immune responses.Copyrights: Figure S1, Figure 1, Figure S3, Figure 5 and Figure 6 were reproduced with kind permissions from Glanville N et al. (2013) PLoS Pathog 9(9): e1003669.
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Human rhinovirus infections cause the majority of common colds as well as asthma and chronic obstructive pulmonary disease (COPD) exacerbations. The disease burden attributable to rhinoviruses is therefore huge. Despite this and the fact that human rhinoviruses were discovered over 50 years ago, there are currently no specific antiviral therapies or vaccine available. The lack of a rhinovirus vaccine can at least in part be attributed to the fact that rhinoviruses like other pathogens have high variability in surface antibody binding regions, resulting in >100 serotypically distinct strains. We have defined areas of the rhinovirus polyprotein which are highly conserved across strains and which may therefore induce cross-reactive immune responses capable of providing broader protection. Using a mouse model, we show that immunization with a recombinant rhinovirus capsid protein induces cross-reactive cellular and humoral immune responses. After subsequent infection, immunization enhances both neutralising antibody and lung effector and memory T cell responses, expediting virus clearance. Importantly these effects were evident upon challenge with multiple heterologous rhinovirus serotypes, indicating that immunization with conserved rhinovirus capsid proteins may represent a viable strategy for producing a broadly cross-reactive vaccine.
[Show abstract][Hide abstract] ABSTRACT: The rapidly increasing incidence of type 1 diabetes implies that environmental factors are involved in the pathogenesis. Enteroviruses are among the suspected environmental triggers of the disease, and the interest in exploring the possibilities to develop vaccines against these viruses has increased. Our objective was to identify enterovirus serotypes which could be involved in the initiation of the disease process by screening neutralizing antibodies against 41 different enterovirus types in a unique longitudinal sample series from a large prospective birth-cohort study. The study participants comprised 183 case children testing persistently positive for at least two diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. Coxsackievirus B1 was associated with an increased risk of β-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and it was attenuated by the presence of maternal antibodies against the virus. Two other Coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern suggesting immunological cross-protection against Coxsackievirus B1. These results support previous observations suggesting that the group B Coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon.
[Show abstract][Hide abstract] ABSTRACT: For human vaccines to be available on a global scale, complex production methods, meticulous quality control, and reliable distribution channels are needed to ensure that the products are potent and effective at the point of use. The technologies used to manufacture different types of vaccines can strongly affect vaccine cost, ease of industrial scale-up, stability, and, ultimately, worldwide availability. The complexity of manufacturing is compounded by the need for different formulations in different countries and age-groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, to ensure optimum access and uptake, strong partnerships are needed between private manufacturers, regulatory authorities, and national and international public health services. For vaccines whose supply is insufficient to meet demand, prioritisation of target groups can increase the effect of these vaccines. In this report, we draw from our experience of vaccine development and focus on influenza vaccines as an example to consider production, distribution, access, and other factors that affect vaccine uptake and population-level effectiveness.
[Show abstract][Hide abstract] ABSTRACT: The increased incidence and extended geographical reach of Dengue virus over the past two decades have made the development of an effective vaccine an international urgency. Various strategies are being pursued, including live, vectored and killed/recombinant preparations. For all approaches, the challenge is to induce a broad durable immune response against all four serotypes of Dengue virus simultaneously whilst avoiding the possible exacerbation of risk of developing the severe forms of disease through incomplete or modified responses. This review presents the current state of knowledge and discusses the challenges of further clinical development.
No preview · Article · Apr 2008 · Comparative Immunology Microbiology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.
[Show abstract][Hide abstract] ABSTRACT: Vaccines are one of the most useful and cost-effective tools for reducing the morbidity and mortality that are associated with infectious diseases. Here, Jeffrey Almond discusses the selection of articles in this Focus issue, in the context of the challenges and opportunities facing vaccine developers today.
No preview · Article · Aug 2007 · Nature Reviews Microbiology
[Show abstract][Hide abstract] ABSTRACT: A review article recently appeared in the Lancet by Seligman and Gould, in which the authors raise a safety concern for flavivirus vaccines based on possible recombination between wild-type viruses and live, attenuated vaccine viruses. Flaviviruses are small enveloped viruses with a single positive sense RNA genome containing a single long open reading frame encoding three structural and seven nonstructural genes. There is considerable controversy about whether recombination events occur between flaviviruses. Unfortunately, by emphasizing this remote and theoretical risk, rather than the potential public health benefits of new vaccines, the authors have provided an unbalanced view that may impede the progress of a number of promising live, attenuated vaccines under development. Over 2.5 billion people are at risk of dengue, and this disease has a total impact of the same order of magnitude as malaria, tuberculosis, bacterial meningitis and others. The World Health Organization (WHO) and the Gates Foundation have placed a high priority on the development and introduction of live, attenuated vaccines against Japanese encephalitis and dengue.