AniMAb: Establishing a monoclonal antibody platform to interrogate animal antibody responses to inform rational design of veterinary vaccines

Many animal [and human] infections are difficult to control through vaccination because they are caused by viruses, bacteria and parasites that are able to out-run the immune system by constantly mutating. All-too-often, the antibody and killer cells that the body makes to fight off infection target these mutating regions of the microbe. However, we suspect that microbes also possess much more conserved regions that could be targeted by vaccines, and therefore if we could identify these conserved regions we would be able to make a vaccine that would work against lots of different strains. In this project, we will develop a system that will allow us to isolate monoclonal antibodies from animals, in the first instance cows. Having this technology will allow us to dissect out the antibody response that cows make to vaccines or to natural infection. We can then screen these antibodies to find those that are able to recognise and kill different strains of a microbe, e.g. a virus. We can then work out what part of the microbe these antibodies target and use this information to make better vaccines. Importantly, we can expand this technology to inform vaccine design for all species of animals.

Vaccines improve animal health and welfare by controlling animal infections. Many existing veterinary (and human) vaccines were developed empirically, but the field is moving rapidly towards rational vaccine design. One of the major drivers in this evolution is the need to develop vaccines with increased breadth. Key livestock viruses, for example, influenza and vector-borne viruses (such as bluetongue virus), exist as diverse serotypes.

Antibodies offer potent protection against viral and parasitic infection, but not all antibodies are protective. Effective vaccine design will require a better understanding of the most protective determinants. Whilst analysis of the polyclonal response to natural infection or vaccination provides some insight into protective determinants, analysis of single specificities, using monoclonal antibodies, provides a more eloquent definition of protective responses to human and animal pathogens. Crucially, the most informative information arises from study of antibody responses in the target animal, rather than surrogate models (such as the mouse), as the latter repertoire differs markedly due to variation in germline complexity and CDR length.

Therefore, we will create a monoclonal antibody isolation platform, concentrating on bovines in the first instance, which is amenable to high throughput functional screening. We will establish methodologies to isolate memory B cells then culture them in low-density (single-cell) using conditions that allow proliferation then differentiation into antibody secreting cells. We will also develop cloning methods for subsequent antibody recovery from those cultures containing B cells producing antibodies with a cross-reactive phenotype.

This platform would be expandable to other animal species and will be a significant tool for future vaccine design.

The beneficiaries will be academics, industry and the veterinary healthcare sector. They will benefit through the provision of a monoclonal antibody platform that can be used to interrogate immunity to a diverse array of pathogens (and other diseases and illnesses such as cancer). Resulting monoclonal antibodies could be used for improved diagnosis of disease, novel therapeutic interventions and be used to increase our understanding of pathogen life cycle and in the design of vaccines to prevent infections and disease.

Improved treatments and vaccines will benefit practicing veterinarians and the animal health benefits that the research will lead to will positively impact on agriculture and the wider public and their companion animals.

This research will foster increased collaboration - local, national and international and between different sectors. It will increase the economic competitiveness of the United Kingdom - The research will have significant commercial potential and therefore will directly benefit SMEs and larger industry.
Improved knowledge will be achieved immediately and tangible outputs from this (e.g. new diagnostics, treatments and vaccines) could be realised within the next 5-10 years.

The project will also lead to an upskilling of the staff recruited to the project, in particular making available new techniques and giving the PDRA skills to be able to work in the veterinary and animal science arena, both in academia and industry.