Bovine respiratory syncytial virus : immunopathology and vaccine evaluation

Human and bovine RSVs cause severe disease in humans and in cattle respectively. They have been recognised as important respiratory pathogens in the last five decades, and this has resulted in significant research activities on the pathogenesis and intervention strategies around the world. Physicians and veterinarians have been puzzled by conflicting results from field and experimental observations: for example which mechanism are involved in the development of disease signs and symptoms,; how to diagnose and treat the disease; what is the effect of vaccination with different vaccine candidates, and how to develop other intervention strategies for RSV infections?. The most intriguing observations occurred in the 1960s, when the first hRSV vaccines were evaluated in children under field conditions. The vaccine-enhanced RSV disease has triggered many studies about the possible mechanisms involved, however without delivering a final answer to this question so far. Despite many years of considerable research efforts there are still no effective hRSV vaccines available. For bRSV vaccines that are available on the market, there is still a need for more knowledge regarding efficacy and safety. Essentially two types of animal models can be distinguished: heterologous (so called surrogate) models in which non-natural hosts are used, and homologous (so called natural-host models) infection models. Surrogate RSV models, most commonly using mice and cotton rats, have extensively been used for hRSV research. Unfortunately these animals are semi-permissive for viral replication and do not exhibit hRSV disease as observed in naturally infected children. On the other hand, these laboratory animal models offer the advantage of working in a well defined genetic background, are easy to handle, relatively cheap, can be used more easily with statistically relevant numbers, and can allow all appropriate controls [1]. An other advantage of using mouse models is that many immunological reagents are available, in contrast to cotton rats, for which much less immunological reagents are available. Our homologous challenge model for bRSV in cattle, in which severe disease is observed upon aerosol infection, and vaccination-enhanced disease can be reproduced 4-6 months after vaccination with inactivated and adjuvanted vaccine by challenge-infection, appears instrumental in better understanding the mechanisms underlying disease augmentation. In particular, it has become clear that serological data alone are inadequate or at least insufficient to evaluate safety or potency of vaccines and the data presented in this thesis suggest that a combination of serological, cellular and immunological parameters must be measured in a suitable animal model and preferably in field studies. In this way the potential and limitations of bRSV vaccine candidates may be better assessed in the field. Our studies therefore have added major tools to the field of safety and efficacy evaluation of bRSV vaccines. The higher predictive value of a homologous animal model in natural host species may also provide important insights and tools that can be used in hRSV vaccine development