Host Responses to Viral Infection: Enhancing protective response in vertebrate hosts

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This topic aims to understand complex host processes after infection to underpin the design of new control measures as well as improving existing vaccine induced protection. Our infection studies in natural hosts using high consequence viruses will provide fundamental insights into basic biological mechanisms of life that will have a broad impact on reducing the burden of disease for wildlife livestock and humans.

Many currently available vaccines although effective in providing some clinical benefit induce suboptimal immunity in terms of sterility breadth or length of protection. The work in this topic will build on fundamental immunological knowledge obtained in Topics 1 and 2 defining protective responses and their antigenic targets down to the epitope level. This will aid in the development of novel vaccines and vaccination strategies that can overcome these major challenges by inducing stronger durable and broader cross-reactive immunity.

Many of the viruses studied at Pirbright exhibit regions of high antigenic variability and dominant epitopes that do not provide broadly neutralising antibody responses. However we have also discovered that sub-dominant epitopes and more conserved epitopes exist with enormous potential to inform vaccine antigen design to enhance protection. We will identify and characterise T and B cell antigens and epitopes derived from a range of veterinary species and their viral pathogens focussing on identification of conserved antigenic targets that can provide broad cross-protection. Recent data and our own observations support the idea that prolonged antigen exposure and/or sequential exposure to antigen from divergent strains induce more broadly protective responses. We are also developing assays to study Fc mediated antibody effector functions in addition to neutralisation to broaden and enhance the identification of relevant targets that offer comprehensive protection against viral disease.
The efficacy of vaccines relies on the delivery platforms used. We will evaluate various delivery platforms including virus-like particles nanocarriers viral vectors or live attenuated viruses with the aim of improving the immunogenicity and efficacy of vaccines. The combination of vaccine vector technology and targeted delivery will facilitate delivery of protective antigens to the site of infection. For respiratory viruses in particular it is crucial to achieve delivery to the respiratory tract to induce tissue resident memory cells and durable protection. Our research will also investigate the complex interplay between antibody and T cells in inducing durable protection and to develop the most effective immunisation strategy to induce appropriate immune responses.
The public health burden of respiratory infections (such as influenza and COVID-19) is not adequately addressed by existing vaccines and anti-virals. Identifying approaches that interfere with individual – to - individual transmission of respiratory viruses remains a pressing need. We shall evaluate the ability of novel anti-viral and innate immune stimulators which have been identified in small animal models to block transmission in a relevant large natural host animal model the pig. We will address transmission blocking of influenza virus but in principle the methodology could be extended to other respiratory viruses.
In collaboration with the Livestock Antibody Hub we have generated the first porcine and bovine monoclonal antibodies (mAbs) against swine influenza SARS-CoV-2 PRCV and FMDV. We shall assess the efficacy of these antibodies in their large natural hosts evaluate various delivery platforms and identify the mechanism of protection. This will provide crucial insights in identifying antigen targets and the most efficient delivery mAb platforms to combat high consequence pathogens.

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