Improved research tools for porcine vaccination success by CD-PIGVAC

Improved research tools for porcine vaccination success by CD-PIGVAC

The Christian Doppler Laboratory for Optimized Prediction of Vaccination Success in Pigs (CD-PIGVAC) is a public private partnership initiative to advance knowledge in animal health.

Why is CD-PIGVAC advancing knowledge in animal vaccination?

CD-PIGVAC recognises that vaccination is one of the most powerful means of preventing infectious diseases and preventing suffering in humans and animals. Through exposing the organism to immunogenic proteins (antigens) in a safe way, the immune system gets trained to recognise and respond swiftly and effectively to potential infections.

While immunity against some pathogens is easily induced, a number of diseases are still difficult to prevent through vaccination. Part of this is related to the fact that these pathogens effectively change their properties involved in recognition by the immune system and by the evolution of complex immune escape mechanisms. Moreover, the lack of understanding of the immune response against a certain pathogen, as well as the interplay between the pathogen and the host immune system, is still a major hurdle for designing efficacious vaccines for the prevention of many diseases.

The immune system is a complex system of the body and the interplay between many of its components is still incompletely understood. In addition, while over the past 30 years substantial investigations have been made in research into the human immune system, partially as a result of the HIV/AIDS epidemic, our understanding of the immune system of domestic animal species has significantly lagged behind. Important differences exist in the immune system of different mammalian species, including the cells involved, their role in the overall system and their way to communicate by means of small signaling molecules (cytokines, chemokines). One can speculate that these differences are (at least in part) the consequence of adaptation to different living environments.

The need for modern vaccines

Keeping domestic animals healthy and preventing infectious diseases is an important aspect of modern veterinary medicine, and the impact of diseases in animals – companion and livestock – on the health of people has been widely acknowledged, leading to the development of the ‘one health’ concept. While in all animals prevention of infectious diseases has an obvious direct animal welfare benefit through avoidance of suffering, in livestock the impact of infectious diseases on food quality, responsible use of resources, and financial livelihood of farmers are additional areas of benefit.

The constant increase in the number of pigs raised worldwide requires intense measures to sustain and improve their health. Prophylactic vaccination is one of the major tools in the health management of pig breeding facilities and is a key approach for reduction of use of antibiotics. However, for a number of widespread diseases, current vaccines still provide suboptimal protection and emerging diseases require the rapid development of novel vaccines. The success of vaccination is based on the establishment of long-term immunity via the generation of pathogen-specific memory cells (Fig. 1). However, the detailed study and understanding of the formation and maintenance of so-called ‘memory B and T cells’ in pigs is still hampered by a lack of reagents to identify and study such cells. Most of these reagents are monoclonal antibodies (mAbs) that bind specifically to proteins presented inside or on the cell membrane of immune memory cells, which allow their identification, but also analyses on their differentiation and activation stage.

Generating tools (among them mAbs), and their subsequent application to study immune responses after vaccination or infection, is the core activity of CD-PIGVAC. It aims at advancing knowledge on the immune system of pigs since this species is one of the most widely kept farm animal species and, as such, plays an important role in the nutrition of many people.

CD-PIGVAC and the pig: focus on an important farm animal species

The available data on the immune response towards vaccination largely stem from experiments with human lymphocytes, usually isolated from blood, or with genetically modified inbred mouse strains that allow detailed in vivo studies. For obvious reasons, studies in humans are limited by the availability of samples and experimental conditions. Inbred mouse strains are used in most functional studies on the cellular immune system and many tools for genetic modification, in vivo monitoring, and molecular study of the cell populations involved are available.

However, although these studies have brought valuable insights, there is a growing awareness that, focusing on a model organism, has some disadvantages. The mouse strains used in immunological experiments have a limited genetic diversity and live under fully controlled environmental conditions that may not reflect the variability and flexibility of the immune systems of species living in more conventional environments. In addition, there is a growing awareness that the study of how a pathogen interacts with the natural host in the course of an infection is superior to understand the complex pathogenicity and adaptation strategies of the microorganisms involved.

The study of the immune systems of large animals and their host-pathogen interactions is, thus, an important field of present and future research, with sheep, cattle and pigs all being investigated. Therefore, beyond their role as a major source of animal-derived protein for human consumption, pigs are also an important species for the study of zoonotic infections with pathogens such as Staphylococcus aureus, influenza A virus and Salmonella.

Over the last ten years, global pork production has increased by approximately 15% and about 21% of the meat has been produced within the European Union (United States Department of Agriculture, 2016). These figures illustrate the scope of pig production and highlight the importance of keeping these animals healthy in the breeding facilities to sustain animal welfare and to ensure the highest possible safety of food for human consumption.

Aims and benefits of CD-PIGVAC

The formation of memory B and T cells is a hallmark of protective vaccines. According to the current immunological paradigm for various mammalian species, cells of the so-called ‘innate immune system’ (macrophages, granulocytes, dendritic cells) sense invading microorganisms, or vaccine antigens, and activate cells of the adaptive immune system, namely B and T cells. For their full mode of action, these cell types require a replication (clonal expansion by proliferation), which lasts for up to two weeks. After this expansion, a small subset of T and B cells specific to the particular microorganism or vaccine antigen differentiates into long-lived memory T and B cells. These cells are capable of responding much quicker (starting within hours) to a second encounter with the same microorganism or the microorganism for which the vaccine antigen is specific for, sometimes even if this second encounter occurs years later.

In its initial phase of operation, CD-PIGVAC develops novel mAbs, mainly against molecules involved in the function of B and T cells. Three groups of molecules have been selected to address major aspects related to function in the immune response:

  1. Molecules involved in the functional specialisation of T and B cells;
  2. Molecules involved in the differentiation from the naïve to terminal stage of cell differentiation; and
  3. Molecules involved in migration into tissues where T and B cells actively fight infections.

The development of mAbs against the outlined molecules serves two purposes: first, the newly developed mAbs will be used for basic immunological research in the fundamental understanding of porcine immunology and will be valuable to the entire research community working in this field. Secondly, the combination of mAbs in so-called ‘marker panels’, and their subsequent combined application, will allow the study of the porcine cellular immune response in unprecedented detail. This will be achieved by studying porcine immune responses under various conditions. First, the porcine immune system will be investigated during ageing, an important aspect considering that – as in humans – young pigs in particular have to be protected against infectious diseases. Moreover, small-scale vaccination and infection experiments will be performed to investigate the development of T and B cells which are specific to a particular pathogen or vaccine antigen. In this way, the work of the CD-PIGVAC will enable a detailed characterisation of the porcine cellular immune response. The identification of functionally characterised memory T and B cell subsets will broaden our knowledge of basic aspects of the porcine immune system, and will be of substantial importance for improved monitoring of the immune response following infection or vaccination.

Related to the latter, a major aim of the work in CD-PIGVAC is the identification of candidates for so called ‘correlates of protection’. Correlates of protection are a measurable predictor of an individual’s immunity to a pathogen following vaccination or infection (Fig. 2). Such correlates can provide insight into promising vaccine candidates in a timely manner and with a substantially reduced number of animals. The potential correlates will further be investigated in the context of multiple infectious diseases to identify some that could be broadly used. We expect our novel marker panels to enable a more detailed understanding of the subsets of T and B cells involved in the adaptive immune response in pigs, enabling tight monitoring after vaccination.

An improved understanding of these mechanisms will yield multiple benefits, including:

  1. Enabling the discovery and development of vaccines for diseases where there is currently no vaccine available. Many of these diseases are caused by bacteria or are associated with secondary bacterial infections. In many cases, the only effective treatment is the use of antibiotics. The development of vaccines for these diseases would reduce the disease burden in these animals, while at the same time allowing for a reduction in antibiotics use;
  2. Accelerating the development of new vaccines. To achieve better and more effective vaccines, multiple candidates often have to be tested. In addition, the combinations of these candidates with different delivery platforms (e.g. enhancers of the immune response or adjuvants) have to be tested and defined. Currently, the ability to answer these questions in cell culture systems (in vitro) is limited by the poor ability to predict the response in a complex system, like the entire host organism. But in the host, answering these questions is not often feasible because of a lack of precise tools to identify potential correlates of protection, hence why such studies are currently extremely complex, requiring specialised facilities, long studies and large numbers of animals; and
  3. Candidate parameters for potential correlates of protection will also enable the replacement, reduction and refinement of studies in animals (3R principle). Use of surrogate parameters will allow replacing a number of experiments by in vitro tests, reducing the number of animals used in studies and minimising the need to expose animals to infectious agents.

Taken together, these improved research tools will enable the faster and even more animal welfare-conscious development of new vaccines for pigs.

CD-PIGVAC is a public private partnership

Public private partnerships (PPPs) have proven to be a key driver for innovation in many areas, allowing for both partners to contribute their core strengths while simultaneously benefitting the basic understanding of scientific issues on the one hand, whilst enhancing commercial product development, ultimately benefitting society through creation of employment and tax revenues on the other.

CD-PIGVAC is a PPP initiative between the University of Veterinary Medicine Vienna, Austria, and Boehringer Ingelheim Vetmedica GmbH, and is supported by the Christian Doppler Research Association.

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The partners

The University of Veterinary Medicine Vienna (Vetmeduni Vienna) is one of the leading veterinary teaching and research institutions globally. In addition to applied and clinical research, the Vetmeduni Vienna conducts excellent basic research in veterinary medicine. Teaching and research activities are closely linked to ensure the principle of research-based teaching. In addition, Vetmeduni has a large array of research co-operations with the animal health industry and is a preferred partner for many companies.

Boehringer Ingelheim (BI) is a globally leading supplier of innovative animal health products with a focus on providing advanced, preventive animal healthcare. BI develops vaccines, parasiticides and pharmaceuticals that protect animals against disease and pain. Through innovative and ground-breaking solutions, BI supports farmers, veterinarians and pet owners who raise and deeply care for their animals. BI is partner in multiple public private partnership (PPP) initiatives and prides itself on being globally leading in innovative pig vaccines. BI strives to be the partner of choice for identifying and developing innovative solutions that help veterinarians and owners to better care for their animals.

The Christian Doppler Research Association (CDG) is considered one of the leading sponsors for co-operations between science and the private sector in Austria for over 25 years. The CDG forms an important interface between business and science. It enables co-operations between companies and scientists in CD Laboratories and Josef Resells Centres. CD Laboratories have opened the door for co-operation partners to perform application-orientated basic research of mutual benefit for the scientific community and industrial partners.

Authors

Wilhelm Gerner, University of Veterinary Medicine Vienna

Armin Saalmüller, University of Veterinary Medicine Vienna

Randolph Seidler, Boehringer Ingelheim Vetmedica GmbH

Konrad Stadler, Boehringer Ingelheim Veterinary Research Center GmbH & Co. KG

Dr Randolph Seidler

Global Business Development

& Licensing

Boehringer Ingelheim

Vetmedica GmbH

+49 (6132) 77 3203

randolph.seidler@boehringer-ingelheim.com

https://boehringer-ingelheim.com/animal-health

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