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Swine influenza as a model to support the development of monoclonal antibody therapies

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Title: Swine influenza as a model to support the development of monoclonal antibody therapies
Authors: McNee, Adam David
Committee Members: Tchilian, Elma; Graham, Simon; La Ragione, Roberto Marcello; Van Vliet, Arnoud
Summary: 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.
URL: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.838384
Database: OpenDissertations
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AccessLevel: 6
PubType: Dissertation/ Thesis
PubTypeId: dissertation
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  Data: Swine influenza as a model to support the development of monoclonal antibody therapies
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  Data: <searchLink fieldCode="CO" term="%22Tchilian%2C+Elma%22">Tchilian, Elma</searchLink>; <searchLink fieldCode="CO" term="%22Graham%2C+Simon%22">Graham, Simon</searchLink>; <searchLink fieldCode="CO" term="%22La+Ragione%2C+Roberto+Marcello%22">La Ragione, Roberto Marcello</searchLink>; <searchLink fieldCode="CO" term="%22Van+Vliet%2C+Arnoud%22">Van Vliet, Arnoud</searchLink>
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  Label: Summary
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  Data: 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.
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      – Code: eng
        Text: English
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      – TitleFull: Swine influenza as a model to support the development of monoclonal antibody therapies
        Type: main
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            NameFull: McNee, Adam David
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          Dates:
            – D: 01
              M: 01
              Type: published
              Y: 2021
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