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A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

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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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

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Abbreviations

CCID50 :

50% cell-culture infectious dose

CVB:

Coxsackievirus serotype B

EV:

Enterovirus

IAA:

Insulin autoantibodies

IHC:

Immunohistochemistry

ISH:

In situ hybridisation

p.i.:

Post infection

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Acknowledgements

The authors acknowledge J. Laiho and S. Oikarinen (Department of Virology, University of Tampere, Finland), V. Stone (Center for Infectious Medicine, Karolinska Institutet, Sweden) and R. Kuiper (Unit for Morphological Phenotype Analysis, Karolinska Institutet, Sweden) for excellent technical assistance.

Parts of this study were presented at the 2013 Keystone Symposia in Immunopathology of Type 1 Diabetes (poster), the 13th International Congress of the Immunology of Diabetes Society meeting (oral and poster), the 2014 International Picornavirus (Europic) meeting (oral) and in a doctoral thesis by P. G. Larsson in 2014 [50].

Funding

This study was co-funded from academic and industrial sources. The study was supported by the Karolinska Institutet Strategic Research Programme in Diabetes (SPR), the Swedish Child Diabetes Foundation, the Swedish Diabetes Association Research Foundation, the Finnish Funding Agency for Technology and Innovation, the Academy of Finland and the European Commission PEVNET (FP-7 Programme, contract No. 261441). In addition, the study was partly funded by Sanofi Pasteur and Vactech Ltd. MF-T is supported by Karolinska Institutet, Stockholm, Sweden and a VINNMER fellowship from VINNOVA, Sweden.

Duality of interest

HH and MK are minor shareholders (<5%) and members of the board of Vactech Oy, which develops vaccines against picornaviruses. All other authors declare no duality of interest associated with this manuscript.

Contribution statement

PGL performed experiments, researched the data, analysed the data and results and wrote the manuscript. TL performed experiments, researched the data and reviewed the manuscript. OHL designed the study, researched and analysed the data and reviewed the manuscript. RU, SJ, MO, ED, MRLK, PC and ND performed experiments, researched the data and reviewed the manuscript. VL, JA, MK and HH designed the study and reviewed the manuscript. MF-T designed the study and wrote the manuscript. All authors gave their approval for publishing the final version of the manuscript. PGL and MF-T are the guarantors of this work.

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Author notes

  1. Olli H. Laitinen

    Present address: The Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Authors and Affiliations

  1. The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Karolinska University Hospital Huddinge F59, SE-141 86, Stockholm, Sweden

    Pär G. Larsson, Tadepally Lakshmikanth, Renata Utorova, Stella Jacobson, Erna Domsgen & Malin Flodström-Tullberg

  2. Vactech Oy, Tampere, Finland

    Olli H. Laitinen & Minni R. L. Koivunen

  3. Department of Virology, School of Medicine, University of Tampere, Tampere, Finland

    Maarit Oikarinen & Heikki Hyöty

  4. Sanofi Pasteur, Lyon, France

    Pascal Chaux, Nicolas Devard, Valerie Lecouturier & Jeffrey Almond

  5. Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland

    Mikael Knip

  6. Department of Pediatrics, Tampere University Hospital, Tampere, Finland

    Mikael Knip

  7. Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland

    Heikki Hyöty

Authors
  1. Pär G. Larsson
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Corresponding author

Correspondence to Malin Flodström-Tullberg.

Additional information

P. G. Larsson and T. Lakshmikanth contributed equally to this study.

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Larsson, P.G., Lakshmikanth, T., Laitinen, O.H. et al. A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models. Diabetologia 58, 346–354 (2015). https://doi.org/10.1007/s00125-014-3436-0

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