Abstract
Influenza A virus (IAV) is responsible for one of the most important infectious diseases
worldwide that affects both humans and livestock. The rapid evolution of IAV together with
its high zoonotic potential contribute to the periodic emergence of strains causing influenza
pandemics. In the face of emerging pandemics, therapeutic monoclonal antibody (mAb)
therapy might be used to treat severe cases and control the virus whilst vaccines are developed.
Small animal models are commonly used to assess influenza therapeutics; however, mAb
efficacy within established models has poorly predicted efficacy in humans. Therefore, this
project aimed to investigate whether pigs could provide an alternative model for assessing the
efficacy of mAb therapies.
In the first part of the project, porcine Ab responses to IAV infection were
characterised. Pigs generated a robust Ab response following IAV infection which persisted
after virus elimination. As in humans, Ab titres correlated with protection, with a high titre
preventing viral shedding upon re-challenge. The efficacy of prophylactic mAb in protecting
against IAV infection was then tested. Prophylactic administration of a well characterised
human mAb reduced lung pathology after challenge, providing a positive control for further
experiments. Experiments showed that low doses of mAb and alternative DNA based mAb
platforms (dMAb) could decrease influenza-associated pathology when administered
prophylactically. However, human mAb induced an anti-drug Ab (ADA) response that could
limit the use of mAb over time. To obviate the ADA response, we characterised mAbs isolated
from pigs infected with IAV. The binding and neutralising capacity of porcine mAbs were
determined. High affinity porcine mAb demonstrated similar binding and functional activity
as the human mAb control. Porcine mAb targeted K130 and K163 on the IAV haemagglutinin
head region, mirroring those recognised by human mAbs. Finally, a study was conducted to
assess the efficacy of a highly neutralising porcine mAb in our pig influenza model. A high
dose of porcine mAb completely eliminated gross pathology, and a lower dose reduced
pathology following IAV infection, identifying a porcine equivalent of the human mAb
standard.
It is hoped that this work will form the basis for future assessment of mAbs in the pig
model, which will inform the development of influenza therapies for humans and potentially
pigs.