The start of a new year is always a good time to reflect on past achievements and progress. Here at COI, we are taking the time to look back on how we responded to the COVID-19 pandemic and celebrating the hard-work and achievements of our COI-funded researchers and projects.
When the first reports of a new virus were coming out of China, COI Director Prof. Tao Dong was quick to act, and her group immediately started work on the viral entry receptor ACE2. At the same time, preparations were being made to begin work to understand T cell responses to the virus. In March 2020, cases in the UK were rapidly rising and our first lockdown loomed large. Despite the lockdown, our researchers were keen to help in the understanding of the virus and its pathogenesis and several projects were funded by COI to help support this activity.
To date, COI has funded 11 COVID-19 projects, contributing 21 published research articles to the field. Many of these projects required collaboration across different departments and the high output during this time reflects the success that close collaboration can bring.
The research highlights are summarised below.
Understanding T cell responses to SARS-CoV-2
Prof. Tao Dong’s group started receiving acute SARS-CoV-2 patient samples (mild and severe cases) in April 2020 and began mapping CD4+ and CD8+ T cell responses. This required close collaboration with several other Oxford University researchers, all working towards a common goal. During this study, they found broad and strong T cell responses against SARS-CoV-2 in all donors, identifying six immunodominant regions within the viral genome. From here they were able to define six optimised CD8+ T cell epitopes. Since then, the number of defined epitopes confirmed by the group has increased to 16 CD8+ and 19 CD4+ epitopes. Identification of the epitopes that illicit strong T cell responses across a range of HLA types, benefits our understanding of immune responses to the virus as well as helps to inform vaccine design. Read the full article here: Peng et al, Nat Immunol. Nov 2020
In the above study, the group also found that while the breadth and magnitude of T cell responses were significantly higher in severe cases compared with mild cases, mild cases showed higher proportions of SARS-CoV-2-specific CD8+ T cells. They went on to find that T cell responses to a specific epitope within the nucleoprotein (NP105–113) were associated with milder COVID-19 infection. These NP105–113-B*07:02-specific CD8+ T cells had high anti-viral efficacy and were maintained up to 6 months after infection. Read the full article here: Peng et al, Nat Immunol. Dec 2021
Following identification of specific T cell epitopes, further studies looked at whether naturally occurring mutations within these epitopes could affect T cell responses. Global sequence data for SARS-CoV-2 was interrogated to look for mutations within the identified T cell epitopes and mutated peptides were used to elicit T cell responses, with wild-type epitope peptides as a control. Complete loss of T cell responsiveness was seen due to six mutations across three CD8+ epitope sequences, suggesting that mutations in the viral sequence can drive T cell escape. Read the full article here: de Silva et al, iScience. Nov 2021
Understanding antibody responses to SARS-CoV-2
In addition to understanding T cell responses to SARS-CoV-2, COI funding also supported research into the understanding of antibody responses. Huang K-YA et al mapped complete antibody responses from three COVID-19 patients with different severities. They found a subset of antibodies that were able to cross-react with other betacoronaviruses, as well as mapping antibody epitopes across the spike protein. Read the full article here: Kuan-Ying et al, PLOS Path, Feb 2021
Dejnirattisai et al investigated the antigenic anatomy of the SARS-CoV-2 receptor binding domain and characterised antibodies generated against this region to improve understanding of humoral immune responses. Read the full article here: Dejnirattisai et al, Cell, Apr 2021
In April 2021, two papers published in Cell investigated whether mutations in the SARS-CoV-2 spike protein found in specific variants of concern affected antibody responses. They found that both the Alpha (B1.1.7) and Beta (B.1.351) variants had reduced antibody responses due to mutations within the spike receptor binding domain that contacts the host receptor ACE2. Further antibody evasion was also demonstrated with the Gamma (P.1) variant in May 2021, Delta (B.1.617.2) variant in August 2021 and Omicron (B.1.1.529) variant in January 2022. Understanding of antibody responses to each variant is critical to understanding how populations will respond and whether vaccination will be protective. Results of these studies helped to campaign for the inclusion of the omicron spike in a bi-valent vaccine. Read the full articles here: Supasa et al, Cell, Apr 2021; Zhou et al, Cell, Apr 2021; Dejnirattisai et al, Cell, May 2021; Liu et al, Cell, Aug 2021 & Dejnirattisai et al, The Lancet, Jan 2022.
In addition to studies into the response of antibodies, COI-funded researchers from Alain Townsend’s group created a haemagglutination test for the rapid detection of antibodies to SARS-CoV-2. These tests do not require laboratory facilities, can be administered at the point of care, have short development times and are low-cost, while still retaining high sensitivity (90%) and specificity (99%). The authors offer to supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world. Read the full article here: Townsend et al, Nat Comms. Mar 2021
Understanding the effect of host genetics on disease severity
The COMBAT (COVID-19 Multi-Omic Blood ATlas) Consortium, led by the University of Oxford, brings together over 200 researchers to determine the nature, drivers and predictors of severe COVID-19 disease through deep immune phenotyping of peripheral blood. Using multiple experimental modalities, clinical information and integrative analyses (including machine learning, mathematical techniques and data visualisation), the consortium aims to identify immune signatures and correlates of host response, and to advance the development of new drugs and personalised medicine approaches in the treatment of COVID-19. Their first paper was published in Cell in March 2022. Here, they presented data showing that disease severity could be identified through immune profiling. While some signatures were shared with influenza and sepsis patients, persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19.
Understanding immune responses following vaccination
Oxford University researchers played an integral role in the development of vaccines against SARS-CoV-2, most famously through the creation of the ChAdOx1 nCoV19 vaccine, with funding support from COI. The clinical trial results for this vaccine can be found here. Strong antibody responses and Th1 CD4+ T cell responses were reported for the vaccine in September 2021. Read more about the research here: Feng et al, Nat Med. Sep 2021 & Swanson II et al, Science Translational Medicine, Sep 2021
In addition to the ChAdOx1 vaccine, COI funding helped to develop a vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain. This protein nanoparticle vaccine induced a strong neutralising antibody response in mice and pigs. The vaccine is affordable, thermostable and can be lyophilised without losing immunogenicity making it suitable for global distribution and reducing cold-chain dependence. The Coalition for Epidemic Preparedness Innovations (CEPI) has partnered with a consortium of research and technological institutions to develop a novel vaccine based on this technology to provide protection against COVID-19 caused by current and future SARS-CoV-2 variants, as well as to protect against other SARS-like Betacoronaviruses. Read about the vaccine here: Tan et al, Nat Comms. Jan 2021 & CEPI News
Understanding SARS-CoV-2 pathogenesis
In addition to furthering knowledge on immune responses, COI-funded researchers also focussed on the pathogenesis and virology of SARS-CoV-2. A large body of work supports the role of the circadian clock in regulating various aspects of viral replication, host responses, and associated pathogenesis. In the context of SARS-CoV-2 infection, this review brings together the current information: Sengupta et al, J. Bio Rhythms, January 2021.
Zhuang et al showed that silencing the circadian regulator Bmal1 reduced ACE2 expression and therefore SARS-CoV-2 entry and replication. Circadian rhythms are evolutionarily conserved anticipatory systems that allow the host to prepare and respond to threats in its environment. Read the original research article here: Zhuang et al, iScience, October 2021
SARS-CoV-2 primarily infects cells of the respiratory tract, an area where oxygen tension will play a key role in infection. Wing et al, demonstrated that hypoxic conditions can reduced ACE2 expression and thereby reduce SARS-CoV-2 entry and replication. This research raises the possibility of the use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19. Read the full article here: Wing et al, Cell Rep. Apr 2021
COI-Awarded COVID-19 Projects
|Project Title||Awarded To|
|Understanding T cell immunity in COVID-19 infected individuals||Prof. Tao Dong|
|Understanding SARS-CoV-2 T cell memory in COVID-19 infected individuals||Prof. Tao Dong & Dr Yanchun Peng|
|Leveraging host genetics and genomics to understand nature and drivers of disease severity in COVID-19 infection||Prof. Julian Knight|
|Identification of vaccine candidates and therapeutic monoclonal antibodies directed at the receptor binding domain of SARS-CoV-2||Prof. Alain Townsend|
|Antibody responses to SARS-CoV-2||Prof. David Stuart|
|Characterisation of SARS-CoV-2 encoded spike and Mpro protease and their molecular targets||Prof. Benedikt Kessler|
|Evaluation of SARS-CoV-2-specific immune responses and longevity of immune memory in COVID-19 patients||Prof. Chris Conlon|
|Understanding antibody immunity in COVID-19 infected individuals||Prof. Gavin Screaton|
Mapping human immune responses post-vaccination with ChAdOx1 nCoV-19
|Mapping human immune responses against variants of concern post-vaccination with ChAdOx1 nCoV-19||Prof. Teresa Lambe|
|Defining the role of hypoxia SARS-CoV-2 replication||Prof. Jane McKeating|