Introduction

Vaccines have saved more lives than any other medical intervention in history. They are an essential part of most public health programs around the world, and are required for the control of many emerging or reemerging diseases. Vaccines have been largely developed empirically using small animals such as rodents for vaccine testing. However, with a better understanding of the interaction between the immune system and the pathogen, our knowledge of vaccines and vaccine development has greatly advanced. Vaccinology has now become a discipline of its own, and tremendous progress has been made over the last three decades, with many new vaccines already on the market or in the final stages of development.

The ultimate goal of any vaccine is to elicit a protective immune response and memory to the pathogen of interest. Research over the last three decades has revealed many of the mechanisms involved and the components of the immune response that need to be stimulated in order to induce protective immunity and memory. This knowledge has resulted in a shift from a largely empirical to more rational, evidence-based vaccine design and development, which has led to refinement, reduction, and in some cases even replacement of animals for research. For example, the advance of bioinformatics and computational biology, combined with computer-based modeling and high-throughput screening has allowed us to design vaccines in silico, which has reduced the trial-and-error approach of the past. However, stimulation of the immune system to elicit protective immunity is a very complex process that depends on multiple, highly complex interactions between cells and mediators of the immune systems. Thus, as of today, the use of animals remains the only option to investigate these interactions. Choosing the right animal model is critical for the success of the vaccine and helps reduce the number of animals used in vaccine research. Approximately 60% of the infectious diseases that affect humans are zoonotic and are caused by pathogens that cause disease in multiple host species (Graham et al. 2008). Translational research, therefore, depends on appropriate animal models to understand the threat of zoonotic infectious diseases. Humans and most animals are outbred populations whose immune systems have been shaped by exposure to microbes over millennia. Thus, in contrast to inbred rodent animal models in which breeding has been manipulated by researchers, it is reasonable to predict that adaptation in immune system performance over time in one outbred species may be informative to the other (Hein and Griebel 2003). Studying pathogens that infect large animals can be critical to understanding human diseases; this applies to genetically closely related pathogens as well as zoonotic diseases that infect both the large animal model and humans (Bean et al. 2013). Here we will review the advantages of using large animal models for the development of human vaccines.

Large Animal Models—General Considerations

Nonhuman primates are often the model of choice to test human vaccines against many pathogens. However, due to their limited accessibility and high housing cost, nonhuman primates are only used at late stages of development for selected pathogens. Instead, rodent or large-animal models are routinely used for preclinical vaccine development.

Animal models are typically used to assess (1) vaccine safety; (2) protection against challenge infection from the pathogen of interest; (3) dose and formulation of the vaccine (i.e., enhancement of the immune responses through adjuvants); (4) optimal route of delivery; (5) onset, magnitude, and duration of the immune response; (6) type of immunity; and (7) correlates of protection (see Table 1). In addition, animal models are used to address more specific questions, such as the induction of specific immune compartments, fate of the vaccine components following immunization, and potency of the vaccine after long duration of storage. Ideally, an animal model used to develop human vaccines shares modes of infection and disease similar to those in humans, including how the immune response is induced following vaccination, the route of infection of the pathogen, the infective dose, correlates of protection, and disease progression and pathogenesis.

Table 1

Applications of large-animal modelsin vaccine research