Aus dem Institut für Virologie der Tierärztlichen Hochschule Hannover Untersuchungen zur Wirksamkeitsprüfung und praktischen Anwendung von viralen Rinderimpstoffen [Investigations on the efficacy testing and practical application of viral cattle vaccines] Habilitationsschrift zur Erlangung der Venia legendi an der Tierärztlichen Hochschule Hannover Vorgelegt von Dr. med. vet. Birgit Makoschey Hannover 2009 Tag der nichtöffentlichen wissenschaftlichen Aussprache 15. Juni 2010 Table of contents Table of contents Table of contents.....................................................................................................................................3 Abbreviations..........................................................................................................................................4 List of used publications ........................................................................................................................6 A. Introduction...................................................................................................................................8 Vaccines in veterinary medicine.........................................................................................................8 Live attenuated vaccines .................................................................................................................8 Inactivated vaccines ........................................................................................................................9 Alternative approaches to vaccine development...........................................................................10 Production of Vaccines .................................................................................................................11 Viruses used in the studies described ...............................................................................................12 Bovine viral diarrhoea virus..........................................................................................................12 Infectious bovine rhinotracheitis virus..........................................................................................16 Bovine respiratory syncytial virus ................................................................................................20 Use of vaccines in control programs for viral cattle diseases in Europe ........................................23 B. Definition of the problem ...........................................................................................................26 C. Results..........................................................................................................................................27 Challenge models for the experimental evaluation of vaccine efficacy..........................................27 Combined application of a live infectious bovine rhinotracheitis vaccine with other cattle vaccines ...........................................................................................................................................................31 Marker aspect of inactivated BVD vaccine......................................................................................33 Risk assessment for unintended immunisation of cattle by use of vaccines...................................36 D. Discussion ....................................................................................................................................38 Critical factors in the development of animal models for the evaluation of vaccine efficacy........38 Effect of a live infectious bovine rhinotracheitis marker vaccine on the immune response to other cattle vaccines applied at the same time...........................................................................................42 Evaluation of the marker vaccine concept for an inactivated bovine viral diarrhoea virus vaccine ...........................................................................................................................................................43 Risk assessment for unintended immunisation of cattle by use of vaccines...................................45 E. Summary......................................................................................................................................48 F. Zusammenfassung.......................................................................................................................50 G. References....................................................................................................................................52 Statement own contribution to scientific publications ......................................................................80 Dankwort...............................................................................................................................................84 Anhang ..................................................................................................................................................86 - 3 - Abbreviations Abbreviations BDV Border disease virus BRSV Bovine respiratory syncytial virus BTV Bluetongue virus BVDV Bovine viral diarrhoea cp Cytopathic CSF Classical swine fever virus ELSIA Enzyme linked immunosorbent assay F BRSV fusion protein FCS Fetal calf serum FMD Foot and mouth disease g BoHV-1 glycoprotein G BRSV glycoprotein GMP Good manufacturing practice IPB Infectious balanoposthitis IBR Infectious bovine rhinotracheitis IPV Infectious pustular vulvovaginitis M BRSV matrix protein MD Mucosal disease Mh Mannheimia haemolytica L BRSV polymerase ncp Non-cytopathic N BRSV nucleoprotein NS Non-structural NTR Non-translated regions P BRSV phosphoprotein PI Persistently infected PI3 Bovine parainfluenza type 3 virus Pm Pasteurella multocida - 4 - List of used publications List of used publications Makoschey, B.; Janssen, M.G.J.; Vrijenhoek, M.P.; Korsten, J.H.M. and van der Marel, P. (2001) An inactivated bovine virus diarrhoea virus (BVDV) type 1 vaccine affords clinical protection against BVDV type 2. Vaccine 19, 3261-3268 Makoschey, B., van Gelder, P.T., Keijsers, V. and Goovaerts, D. (2003) Bovine viral diarrhoea virus antigen in foetal calf serum batches and consequences of such contamination for vaccine production, Biologicals, 31, 203-208. Makoschey, B.; Becher, P.; Janssen, M.G.J.; Orlich, M.; Thiel; H.-J. and Lütticken, D. (2004) Bovine viral diarrhea virus with deletions in the 5’-nontranslated region: reduction of replication in calves and induction of protective immunity. Vaccine 22, 3285-3294 Makoschey, B. and Beer, M. (2004) Assessment of the risk of transmission of vaccine viruses by using insufficiently cleaned injection devices. The Veterinary Record, 155, 563-564 Makoschey, B.; Chanter, N. and Reddick, D.A. (2006) Comprehensive protection against all important primary pathogens within the bovine respiratory disease complex by combination of two vaccines; Der praktische Tierarzt 87, 819-826 Álvarez, M.; Muñoz Bielsa, J.; Santos, L. and Makoschey, B. (2007) Compatibility of a live Infectious Bovine Rhinotracheitis (IBR) marker vaccine and an inactivated Bovine Viral Diarrhoea Virus (BVDV) vaccine. Vaccine 25, 6613 - 6617 Makoschey, B. and Beer, M. (2007) A live bovine herpesvirus-1 marker vaccine is not shed after intramuscular vaccination. Berliner und Münchner Tierärztliche Wochenschrift, 120, 480-482 Makoschey, B.; Sonnemans, D.; Muñoz Bielsa, J.; Franken, P.; Mars, M.; Santos, L. and Álvarez, M. (2007) Evaluation of the induction of NS3 specific BVDV antibodies using a commercial inactivated BVDV vaccine in immunization and challenge trials. Vaccine 25, 6140 - 6145 Kuijk. H.; Franken, P.; Mars, M.; bij de Weg, W. and Makoschey, B. (2008) Monitoring of a BVDV infection in a vaccinated herd by testing of milk for antibodies against NS3. The Veterinary Record 163; 482 - 484 - 6 - List of used publications Álvarez, M.; Donate, J. and Makoschey, B. Development of antibodies against non- structural proteins of the bovine viral diarrhoea virus in serum and milk samples from vaccinated animals. Submitted Makoschey, B. and Janssen, M.G.J. Investigations on fetal infection models with bovine viral diarrhoea virus (BVDV). Submitted van der Sluijs, M.T.W.; Kuhn, E.M. and Makoschey, B. A single vaccination with an inactivated bovine respiratory syncytial virus vaccine primes the cellular immune response in calves with maternal antibodies. BMC Veterinary Research Accepted - 7 - Introduction A. Introduction Vaccines in veterinary medicine The first successful use of a vaccine was in 1796 by Edward Jenner, who inoculated an 8-year-old boy with cowpox which subsequently protected the boy against challenge with Smallpox. Since then, vaccines have been widely used to control viral infectious diseases of humans and animals. In the case of humans and companion animals, vaccinology primarily focuses on the individual, while concern for the health of the herd is the main reason for vaccination of lifestock. The first vaccines for veterinary use were live attenuated and one of the most successfully applied attenuated vaccines was the Plowright vaccine against rinderpest (Plowright & Ferris 1962). This vaccine has been instrumental in the near eradication of rinderpest. Another important achievement in the field of vaccinology was the development of the vaccine against foot and mouth disease (FMD), the first inactivated vaccine produced at industrial scale (Waldmann et al. 1937). More recently, the first vaccines allowing differentiation