Development of an ovine polyclonal immunoglobulin therapy against COVID-19.

Interventions against the newly emerged coronavirus disease (COVID-19) are urgently required. Antibody approaches are widely recognised as an appropriate method due to their ability to bind proteins which can disrupt entry into cells. Antibodies which are polyclonal, so bind to multiple areas of the protein, are preferential in that small changes in the virus associated with mutations will have little effect compared to monoclonal antibodies which only recognise a single site. Ovine antibodies are suitable for development as large volumes can rapidly be made and they are widely used for treatment for other applications, including antivenoms. For this proposal, we will raise antibodies against the spike protein of the causative agent of COVID-19, termed SARS-CoV-2. The protein will be recombinantly manufactured before being used to immunise sheep. The sheep side will be conducted in Australia due to regulatory issues around BSE, so countries free of BSE need to be used. Once a sufficient level of antibodies are detected in the sheep, they will used as donors to provide plasma samples from which the antibodies can be purified. These will then be used as a therapeutic and tested for their effects against COVID-19 disease progression in a susceptible animal model.

This COVID-19 Rapid Response award is jointly funded (50:50) between the Medical Research Council and the National Institute for Health Research. The figure displayed is the total award amount of the two funders combined, with each partner contributing equally towards the project.

The new coronavirus disease that emerged in 2019 (COVID-19) is caused by a pathogen termed SARS-CoV-2. To develop a rapid and effective therapy against infection, we are proposing to develop an ovine immunoglobulin treatment against the spike protein of this virus. Binding of antibodies to this protein will neutralise cell entry and prevent it's infectivity. Use of ovine immunoglobulin therapy is widespread for other applications, and a therapy rapidly developed for Ebola virus disease (termed EBOTAb) which demonstrated protection in guinea pigs and non-human primates. The use of polyclonal sera recognising muitiple epitopes eliminates risks of escape mutations occuring and eliminating the effectiveness of antibody therapy. This approach is also rapid, cost-effective and has a proven path to regulatory approval. To develop this therapy, recombinant spike protein will be produced in a mammalian expression system to ensure relevant protein folding and confirmation. A large batch will be produced for immunisation of sheep. Immunisations will be conducted using a facility in Australia, to mitigate risks associated with BSE. Sera will be sent to PHE for assessment of antibody levels and once sufficient antibody levels are achieved, plasmapheresis sampling will be undertaken. Immunoglobulin from these samples will be purified to develop the therapeutic material. This will be characterised at PHE for binding and functional properties before being testing using a susceptible animal model for protection against infection and disease progression.