The ideal veterinary vaccine is safe, efficacious, and provides robust and durable protection against a broad spectrum of pathogens. At the same time, it must be easily administered, often on a large scale, and be cost-effective. However, many currently available veterinary vaccines have limitations that reduce their usefulness for preventing diseases and decreasing the need for antibiotics. For example, contagious bovine pleuropneumonia, caused by the bacterium Mycoplasma mycoides, remains an economically important disease of cattle in sub-Saharan Africa that often necessitates considerable antibiotic use . The currently available live vaccine has limited efficacy and duration of immunity, and potentially severe side effects . The development of a safer and more efficacious vaccine is complicated by a variety of factors such as a limited understanding of host–pathogen interactions including basic pathophysiological and immunological processes during infection, a suboptimal challenge model that complicates data interpretation, and the possibility of considerable additional regulatory requirements for the licensing of genetically modified live vaccines .
Although not likely to directly reduce antibiotic consumption, the European Commission’s project to generate an improved classical swine fever vaccine (CSFV-GODIVA project) also provides useful insights into the types of challenges associated with many current veterinary vaccines. Specifically, the project developed a new modified live classical swine fever marker vaccine that overcame many limitations of the previously existing vaccines with regard to the ability to distinguish vaccinated from naturally infected animals, the immunogenicity of the vaccine, and the suitability for oral applications, in particular for mass-scale wildlife vaccination . The development of a safe and effective vaccine against African swine fever has been similarly complicated by various factors such as a limited understanding of the immune response to infection, strain-dependent effects of gene deletions on virulence attenuation and protection, a dearth of small-animal and in vitro models, and a complex disease epidemiology. Modified live vaccines against this viral disease have various drawbacks, including severe side-effects and the potential for undetected, subclinical infections in vaccinated animals that may result in viral shedding and can also lead to recombination between field and vaccine strains . The development of African swine fever subunit vaccines, on the other hand, has been hampered by suboptimal delivery or vector systems that often fail to induce a protective immunity .
As can be inferred from these examples, a variety of challenges are shared broadly across different veterinary vaccines. Additional file 1 synthesizes some of these general limitations associated with many current veterinary vaccines, based on an assessment of an OIE ad-hoc Group on Prioritisation of Diseases for which Vaccines could Reduce Antimicrobial Use in Animals (see next section) and a review of research gap data for more than 50 infectious diseases of animals produced by expert groups and captured in DISCONTOOLS, a database created as part of the Action Plan of the European Technology Platform for Global Animal Health and funded under the EU 7th framework program .
As shown in Additional file 1, current veterinary vaccines often fall short with regard to efficacy, safety and/or user-friendliness. The reasons why veterinary vaccines may have limited efficacy are quite varied. In some cases [e.g., Streptococcus suis, swine influenza virus, Haemophilus parasuis, Eimeria species (Additional file 2)], the vaccine strain may not be a good match for the field strain. For instance, the pathogen may be evolving quickly and the vaccine may not be updated to confer protection against current strains [e.g., infectious bronchitis virus, porcine reproductive and respiratory syndrome virus (PRRSV) (Additional file 2)], or it may only protect against a limited subset of strains [e.g., PRRSV, Actinobacillus pleuropneumoniae (Additional file 2)]. In other cases, protection after vaccination may be short-lived and require frequent booster vaccinations [e.g., Clostridium perfringens, bovine respiratory syncytial virus (Additional file 2 and DISCONTOOLS)]. In some cases vaccines do not generate a protective immune response at all (e.g., African swine fever virus, see DISCONTOOLS). This is most commonly the case for inactivated or subunit vaccines. Because these vaccines are not actively replicating in the host cells they tend to only induce humoral immune responses, even though cellular immune responses are vitally important for effective protection against many pathogens. Vaccine efficacy depends on the existence of an intact and properly functioning immune system, and administration has to be timed correctly to account for the lag period required to develop a protective immune response. Eliciting protective immune responses in young animals tends to be particularly challenging because the immune system is still developing, and because maternal antibodies can interfere with the development of protective immunity. Vaccination against diseases that require protective immunity in young animals can therefore be particularly challenging [e.g., infectious bursal disease virus (Additional file 2)]. In addition, many veterinary vaccines effectively reduce the severity and economic impact of the disease, but do not fully prevent infection and shedding and therefore do little to reduce disease incidence [e.g., M. hyopneumoniae (Additional file 2)]. In some cases, vaccination can actually increase the survival time for infected animals and therefore enhance opportunities for disease transmission. Vaccines are also not available for all economically important veterinary diseases, including many parasitic infections as well as secondary bacterial infections, diseases of “minor species” such as bees, and diseases that have been largely eliminated by management practices but that are recently increasing in incidence [e.g., liver flukes, nematodes, varroa mites, omphalitis, airsacculitis, cellulitis (Additional file 2 and DISCONTOOLS)].
A variety of safety issues are shared by various current veterinary vaccines. Potentially severe side-effects are a concern for many veterinary vaccines, in particular for attenuated-live vaccines and certain adjuvants, and can result in abortions, malformations and deaths (e.g., contagious bovine pleuropneumoniae, African horse sickness, lumpy skin disease, rift valley fever virus, see DISCONTOOLS). Even for vaccines with less dramatic side-effects, such as coccidia vaccines, productivity losses can be impactful and discourage routine use. Attenuated live vaccines can also carry a risk of reversion to virulent wild type strains, particularly when the molecular changes responsible for the attenuation of the vaccine strain have not been well-characterized (e.g., bovine respiratory syncytial virus, African horse sickness virus, bluetongue virus, PRRS, see DISCONTOOLS). Similarly, some live vaccines carry a risk of horizontal and/or vertical transmission and outbreaks caused by vaccine strains have been described (e.g., orf, PRRS, rift valley fever, see DISCONTOOLS). Finally, for some diseases prior vaccination can actually lead to an exacerbation of clinical symptoms after infection (e.g., bovine respiratory syncytial virus, Mycoplasma bovis, see DISCONTOOLS). The immunological reasons for this exacerbation are generally not well understood, but are thought to be due to a shift in immune response after vaccination (e.g., towards Th2-type responses).
User-friendliness issues can further limit the usefulness of current vaccines. For instance, mass vaccination through spray, drinking water or bait can significantly reduce labor costs, directly deliver vaccines to mucosal surfaces, and may be the only feasible strategy in certain situations such as widespread vaccination of wildlife reservoirs. Unfortunately, immunological processes such as the development of tolerance after mucosal antigen exposure (discussed in detail in section below) complicate the development of vaccines for mass application and most current inactivated, subunit and DNA vaccines require administration by injection. The potential for user errors can also limit vaccine usefulness, for instance errors in vaccination route, dose and frequency of vaccination, and in proper vaccine handling. Some vaccines, in particular certain attenuated live vaccines, are of limited stability, leading to cumbersome cold storage requirements and short shelf life, which can complicate vaccine use under field conditions (e.g., foot and mouth disease virus, Theileria, see DISCONTOOLS). Vaccine manufacturing quality can also be a challenge, in particular with certain autogenous or regional vaccines. In some cases, limited diagnostic capabilities can make it difficult to verify vaccinated animals have mounted a protective immune response, which can hinder both the effective use of existing vaccines and the development of new ones (e.g., mastitis vaccines, bovine respiratory syncytial virus, paratuberculosis). Marker vaccines allow vaccinated animals to be distinguished from naturally infected animals, a vital distinction for many disease control and eradication programs. Unfortunately, marker vaccines are currently only available for a subset of animal diseases and the development of additional vaccines will likely be complicated by the need for sensitive and specific diagnostic tests that can be used in combination with the marker vaccine. Commercial interest in developing vaccines for animal diseases is a critically important driver of innovation, but in reality often remains limited. Reasons include the relatively high cost of production for many vaccines, the costs and time associated with laborious administration protocols, in particular if multiple booster vaccinations are required, and the limited cost-effectiveness compared to other available control options including antibiotics. Regulatory restrictions, for instance related to novel vaccine technologies such as genetically modified live vaccines, can further limit commercial interest in vaccine development.