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EC-sponsored Research on Safety of Genetically Modified Organisms - A Review of Results
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image Biosafety of vaccines based on self-replicating recombinant alphavirus

Background and objectives

Two serious concerns have been raised about the biosafety of both conventional and novel recombinant vaccines for medical and veterinary use. Firstly, that vaccines may persist in the vaccinated individual, or in food, with possible adverse effects. Secondly, that administration of a vaccine may trigger adverse long-term effects in normal or immune-deficient individuals, which may or may not be linked to persistence. While preclinical research has demonstrated that vaccination with alphavirus-based vaccines can result in protective immunity, concerns about their safety have been expressed by assessment panels, both at national and European levels.

The broad aim of this project is to obtain experimental data which substantiates or alleviates these concerns, and which can be used during the assessment of these vaccines for commercial exploitation. The specific aim is to test and assess the above-mentioned biosafety issues for new generation vaccines based on the recombinant alphavirus, Semliki Forest virus (SFV), using several model systems developed during the course of other projects.


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Electron micrograph showing accumulations of viral protein and viral particles in a Semliki Forest virus infected cell. In the vector, a foreign gene coding for a protective antigen is substituted for the viral structural protein genes, resulting in the synthesis of large amounts of this protein in infected cells in place of the viral structural proteins. This induces efficient protective immunity in an inoculated animal.


Approach and methodology

The model systems used include influenza and louping ill flavivirus (LI) infection in mice, birnavirus in chickens (infectious bursal disease virus, IBDV) and LI in sheep. Avirulent SFV infection of mice is used as a model for possible effects caused by a live attenuated vaccine. In each case, constructs based on the SFV vector are compared to conventional DNA vaccines expressing the same antigens from the cytomegalovirus (CMV) promoter.

The techniques developed for this project include reverse transcriptase polymerase chain reaction (RT-PCR) to detect vaccine persistence, detection of cytokine induction and persistence, immunohistochemistry to detect vaccine and cytokine persistence, and immunopathology. Normal mice, immunodeficient mice and the natural hosts of prototype vaccines will be used.


Main findings and outcome

In the first phase of the project, the techniques described above were established and standardised. Results should allow us to draw firm conclusions regarding the persistence of the vaccine constructs in mouse tissues and the degree of tissue damage inflicted.

One unexpected and intriguing result was the rapid dispersal of vaccine constructs from the inoculation site. This has been confirmed by two groups in this project using immunocompetent mice, by a third group using chickens and by a fourth group using immunodeficient mice. Preliminary results indicate that SFV-based particle vaccines persist for less than seven days in mice, chickens and sheep, but that the persistence of other DNA vaccines is much longer.


Conclusions

Information about the persistence of introduced recombinant vaccine constructs in animal tissues is extremely relevant when making assessments of the biosafety risks involved in the use of new vaccines. SFV-based vaccines appear to offer advantages over standard DNA vaccines, both in terms of efficiency and biosafety.

 

Major publications

Atkins G.J., Sheahan B.J. and Liljeström P., “Semliki Forest virus – a model virus made useful?”.
Journal of General Virology,
80, 1999, pp. 2287-2297.

Atkins G.J., Mc Quaid S., Morris-Downes M.M., Galbraith S.E., Amor S., Cosby S.L. and Sheahan B.J., “Transient virus infection and multiple sclerosis”.
Reviews in Medical Virology,
10, 2000, pp. 291-303.

Fleeton M.N., Liljeström P., Sheahan B.J. and Atkins G.J., “Recombinant Semliki Forest virus particles expressing louping ill virus antigens induce a better protective response than plasmid-based DNA vaccines or an inactivated whole particle vaccine”.
Journal of General Virology,
81, 2000, pp. 749-758.

Morris-Downes M.M., Phenix K.V., Sheahan B.J., Mooney D.A., Lindquist S., Liljeström P., Todd D. and Atkins G.J., "Semliki Forest virus-based vaccines: persistence, distribution and pathological analysis in two animal systems".
Vaccine, 19, 2001, pp. 1978-1988.

Smith J-P., Morris-Downes M.M., Brennan F., Wallace G.J. and Amor S., “A role for alpha-4-integrin in Semliki Forest virus infection of Biozzi ABH mice”.
Journal of Neuroimmunology, 106, 2000, pp. 60-78.
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imageResearch project
 

Contract number
BIO4-CT98-0031

Period
September 1998 - August 2000

Coordinator
G.J. Atkins
Trinity College
Dublin (IE)

 
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Partners


B.J. Sheahan
University College Dublin (IE)

D. Todd
DANI
Belfast (UK)

S. Amor
Imperial College School of Medicine
London (UK)

P. Liljeström
Karolinska Institutet
Stockholm (SE)

K.H.G. Mills
National University of Ireland
Maynooth (IE)

 
 
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