Animal Infection Models for Vaccine Development

Animal health is considered one of the cornerstones of the “One Health” concept, which includes the interaction and fight against human, animal and wildlife pathogens able to cause disease. Moreover, reduction of antibiotic use is nowadays a compulsory future direction both in animals and humans. In these scenarios, the control of diseases through vaccination is considered of paramount importance. This review aims to discuss the need, design, use and benefit of utilising animal infection models to develop vaccine products able to reduce the impact not only of human diseases and zoonotic pathogens transmitted by animals, but also diseases causing significant economic problems in livestock. Introduction A vaccine is a biological preparation that improves adaptive immunity to a particular disease (WHO). The vaccine product contains a killed or attenuated disease-causing microorganism, its toxins, one or several of its proteins or its DNA or part of it (European Pharmacopoeia, 2013; Kutzler and Weiner, 2008). The previous stimulation of the immune system with these products allow subsequent recognition of the infecting pathogen as foreign, and destroying it. Vaccination is the administration of these products, and it is considered that it has saved more lives worldwide than many other therapeutic interventions combined (Babiuk and Gerdts, 2012). Therefore, vaccination has had, is currently having, and will continue to have, a major impact on the health of both humans and animals, including their interconnection (“One Health” concept). The webpage of the One Health Initiative defines the “One Health” concept as a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of healthcare for humans, animals and the environment (http://www. onehealthinitiative.com/about.php). Such a scenario implies textually the advance of “healthcare for the 21 century and beyond by accelerating biomedical research discoveries, enhancing public health efficacy, expeditiously expanding the scientific knowledge base, and improving medical education and clinical care”. All these concepts are very well represented by vaccinology, which is the science or methodology of vaccine development. Basic and applied research knowledge on diseases and pathogens generated all over the world has expanded incredibly during the last 100 years, and has been the cornerstone for vaccine-producing companies. In the meantime, the vaccine biomedical field has evolved towards a very high-tech and specialised industry, with increasing expenses, risk in the research and development process, and complex regulatory environment (Mahmoud, 2005). Moreover, vaccine development has become very stringent in terms of requirements for the qualitative and quantitative composition, the tests to be carried out, and substances and materials used in their production. Efficacy and safety are two of the requirements to license a vaccine. There are a number of methods able to test those two aspects during the product development, but in most cases animal models are used. This review aims to discuss the need, design, use and benefit of utilising animal infection models to develop vaccine products able to prevent not only human diseases and zoonotic pathogens transmitted by animals, but also diseases causing significant economic problems in livestock. Animal Disease Model Considerations Translational medicine is often described as an effort to carry scientific knowledge “from bench to bedside”, representing the process by which the laboratory research results are directly used to develop new ways to treat/ prevent illness/cure patients (Cohrs et al., 2015). This terminology also applies to the vaccine world (translational vaccinology), and includes an interdisciplinary approach built on basic research advances (including the study of biological in vitro processes as well as animal models) used to develop new vaccine products. Therefore, the use of animal models is an intrinsic component of different stages of vaccine development. However, the use of animals for experimentation is highly regulated and must be driven by the lack of other substitutive methodologies. Importantly, vaccinology is based on the immune response of humans and animals as well as its measurement, which limits the scope of models to work with. An in-depth knowledge on immune responses against a given pathogen within the target species is the basis for vaccine development, including safety and efficacy testing. Obviously, development of vaccines intended for humans has major limitations since some efficacy studies are not ethical or feasible. In fact, the Food and Drug Administration (FDA, USA) has recently published a document entitled “Product Development Under the Animal Rule Guidance for Industry” (FDA, 2015). The Animal Rule from FDA states that the agency “may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans”. At this point, however, it must be emphasised that sometimes there is a lack of a fully predictive animal model, as well as well-defined markers of immune protection for human diseases (Girard and Plotkin, 2012). This scenario is summarised with the statement “mice lie and monkeys exaggerate” (attributed to Dr David B. Weiner, University of Pennsylvania, USA), which reflected the difficulties of finding a sound animal