Animal models are essential for understanding mucosal respiratory immunity and development of vaccines and therapeutics for respiratory diseases. Mice, guinea pigs and ferrets are widely used for influenza-virus research, with the ferret considered the "gold standard," but none of these models accurately reflect the immune response in large animals or humans. The pig is an important natural host for the same subtypes as human seasonal influenza strains and a source of new human pandemic viruses. The pig is genetically, immunologically, physiologically, and anatomically more similar to humans than small animals, as well as having a longer lifespan.
We have developed sophisticated tools to study T cell immune responses in pigs and for the first time have identified porcine tissue resident memory cells (TRM), which are crucial for local protective immunity. Because TRM are only effectively induced after local administration of vaccine or natural infection, we evaluated by scintigraphy the deposition of different droplet size aerosols in the respiratory tract in pigs in order to determine how best to deliver vaccines to the respiratory tract. We also examined antigen specific CD8 TRM in the context of influenza infection and immunisation in inbred Babraham pigs, using tetramers carrying three different influenza nucleoprotein epitopes. We demonstrated that responding T cells are present in the airways until at least 63 days post infection, have a stable highly differentiated phenotype, do not proliferate rapidly, and share gene signatures of human TRM.
We have demonstrated that the broadly protective vaccine candidate, S-FLU, has different efficacy in ferrets and pigs, suggesting that testing in small animals only, may not accurately identify vaccine efficacy in natural hosts. We have also established a pre-exposure influenza pig challenge model, which closely mimics the situation in humans and pigs, who are commonly exposed to different influenza viruses. We showed that adenoviral vectored vaccine expressing conserved influenza virus nucleoprotein, matrix protein 1 and neuraminidase induces immune response and protects against H3N2 challenge in the face of H1N1pdm09 pre-exposure.
demonstrated the utility of the pig influenza model in testing the protective efficacy of human therapeutic antibodies and generated the first porcine influenza specific monoclonal antibodies. The porcine mAbs recognised the same immunodominant haemagglutinin epitopes targeted by humans. Most notably one of these sites was not recognised by ferret sera routinely used to monitor virus evolution and inform decisions about annual influenza vaccines.
We have recently developed a porcine respiratory coronavirus (PRCV) model which exhibits similar pathology to human SARS-CoV-2 and have established different PRCV strains which induce a spectrum of disease outcomes. These two large animal natural host infectious models will provide important insights into immunity against respiratory infections for improvement of animal and human health.