Modified-live vaccines, also called attenuated vaccines, are those which employ live replicating whole pathogen that has been weakened in the laboratory. Attenuation of pathogenic strains can be obtained by modifying the molecular construction of the genome, using chemical mutagenesis, gene deletion or by extensive serial passaging in non-host cell culture or embryonated chick eggs. Chemical mutagenesis has also been coupled with low temperatures to develop a cold-adapted temperature-sensitive strain (ctss) of HRSV that can only replicate in the upper respiratory tract [67]. Only two diseases have been successfully eradicated across the globe—smallpox in humans [68] and rinderpest in cattle [69,70]—and both have been achieved using modified-live vaccines, thus illustrating their significant contribution to human and veterinary health.

Inactivated vaccines, also known as killed vaccines, are those which do not contain any live replicating pathogenic material and cannot cause disease. For this reason they have a superior safety profile to their live counterparts [71] and are considered suitable for use in pregnant or lactating animals. The pathogenic agents are destroyed by heat, chemicals or radiation. Furthermore, inactivated vaccines do not require refrigeration and can be lyophilised for transport purposes [72].

As attenuated vaccines broadly mimic the immune response garnered from a natural infection, they are universally recognised for producing stronger, longer lasting and more robust immune responses for many pathogens [72,73,74,75]. Furthermore, it is surmised that modified-live vaccines can initiate cellular responses in a way that inactivated vaccines are not reported as doing [76,77]. Several studies report the benefits of using modified-live vaccines in calves [78,79,80,81]. However, several studies now indicate that evidence on this is conflicting [81,82] and even if this were conclusive, often the immunogenicity advantages gained from MLV are offset by the increased safety risks posed, particularly in neonates.

Conversely, the immune response garnered from using inactivated vaccines is considered by some as inadequate with suggestions that inactivated vaccines can effectively prime CD4+ T cells but encourage eosinophila [83] and others providing evidence that IFNγ expression is reduced [84]. A further study demonstrated a link between maternal vaccination for BVDV using inactivated vaccines and neonatal pancytopenia—a fatal autoimmune disease contracted from ingesting colostrum [85]. Further, although antibody titres can be high these are often found to be non-neutralising [86]. However, again, in contrast, several studies observed that using inactivated vaccines generated protection and they are at least as efficacious as using modified-live virus [83,87].

Of particular note for BRSV is the observation that vaccination could actually augment disease. This was first noted in 1967 after a failed vaccine trail using a formalin-inactivated RSV (FI-RSV) vaccine against HRSV [88] which led to investigations in cattle where a similar pathology was reported [89,90]. In this study, one group was vaccinated with a FI-BRSV vaccine while the other was sham-vaccinated. Both groups were challenged with live BRSV post-vaccination. No significant difference in gross lung lesions and in lung function was noted between the two groups, indicating the failure of the vaccine to provide any protective immunity. Further, although two groups were challenged with the same amount of BRSV, the sham vaccinated cohort demonstrated lower mean clinical scores [90] indicating disease exacerbation arising from vaccination. High titres of non-neutralising antibodies have also been observed, which can be associated with a high IgE titres and an allergic, inflammatory Th2-type response [91] and it is hypothesised that disease escalation is attributed to FI-RSV generation of low affinity antibodies [92] targeted at non-protective epitopes. Consequently, apprehension surrounds trials employing inactivated vaccines and scientists are cautious about developing candidate vaccines using inactivated antigen. Although antibody titres generated from vaccination are not always correlated with reduced disease, vaccination against any other pathogen implicated in BRD does not appear to have had such a detrimental effect [30].