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Diabetologia

, Volume 58, Issue 2, pp 346–354 | Cite as

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

  • Pär G. Larsson
  • Tadepally Lakshmikanth
  • Olli H. Laitinen
  • Renata Utorova
  • Stella Jacobson
  • Maarit Oikarinen
  • Erna Domsgen
  • Minni R. L. Koivunen
  • Pascal Chaux
  • Nicolas Devard
  • Valerie Lecouturier
  • Jeffrey Almond
  • Mikael Knip
  • Heikki Hyöty
  • Malin Flodström-Tullberg
Article

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.

Keywords

Autoimmune Coxsackievirus Enterovirus Neutralising antibodies Non-obese diabetic mouse Type 1 diabetes Vaccine 

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

Notes

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.

Supplementary material

125_2014_3436_MOESM1_ESM.pdf (726 kb)
ESM Fig. 1 (PDF 726 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Pär G. Larsson
    • 1
  • Tadepally Lakshmikanth
    • 1
  • Olli H. Laitinen
    • 2
    • 3
  • Renata Utorova
    • 1
  • Stella Jacobson
    • 1
  • Maarit Oikarinen
    • 4
  • Erna Domsgen
    • 1
  • Minni R. L. Koivunen
    • 2
  • Pascal Chaux
    • 5
  • Nicolas Devard
    • 5
  • Valerie Lecouturier
    • 5
  • Jeffrey Almond
    • 5
  • Mikael Knip
    • 6
    • 7
  • Heikki Hyöty
    • 4
    • 8
  • Malin Flodström-Tullberg
    • 1
  1. 1.The Center for Infectious Medicine, Department of Medicine HS, Karolinska InstitutetKarolinska University Hospital Huddinge F59StockholmSweden
  2. 2.Vactech OyTampereFinland
  3. 3.The Center for Infectious Medicine, Department of MedicineKarolinska InstitutetStockholmSweden
  4. 4.Department of Virology, School of MedicineUniversity of TampereTampereFinland
  5. 5.Sanofi PasteurLyonFrance
  6. 6.Diabetes and Obesity Research ProgramUniversity of HelsinkiHelsinkiFinland
  7. 7.Department of PediatricsTampere University HospitalTampereFinland
  8. 8.Fimlab LaboratoriesPirkanmaa Hospital DistrictTampereFinland

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