Understanding how antiviral antibodies can activate natural killer cells to improve viral control
Aligned with our mission to advance the understanding and impact of microbiology, the Society reached out to our community of microbiologists to share their experiences in responding to SARS-CoV-2. We aim to showcase the perspective of scientists during the COVID-19 pandemic and the variety of roles adopted to mitigate the global crisis.
This is the first case study in our series that comes from a group of Project Investigators (PIs). Professor Ian Humphreys, Professor Eddie Wang, Professor Richard Stanton and Professor Alan Parker are from the Viral Immunology Research Group at Cardiff University, UK. Collectively, they describe how they responded to the COVID-19 pandemic, the challenges they faced and how basic microbiology and immunology are critical components of any pandemic response.
How did you respond to the SARS-CoV-2 during the COVID-19 pandemic?
When we realised that SARS-CoV-2 was spreading worldwide, we took over the Biosafety Level 3 (BSL3) lab and, via links with the UK Health and Safety Executive and Public Health Wales, rapidly repurposed it from a HIV lab to one capable of working with respiratory pathogens. We gained all the necessary approvals, trained our lab staff to work under BSL3 conditions, then made links with the Centre for Virology (University of Glasgow, UK) to take advantage of the early start they had made on learning how to work with the virus. We were successful in receiving funding from the Welsh Government to understand how antiviral antibodies can activate natural killer (NK) cells to improve viral control following the development of humoral immunity, and we were recruited into the Medical Research Council/National Institute for Health Research Covid Immunology Consortium to understand how SARS-CoV-2 interacts with NK functions during the innate phase of immunity.
We were approached regularly by companies asking us to help them develop products against COVID-19. We therefore obtained funding from the Accelerate programme, which enabled us to work with a wide range of industry partners to develop and test products such as non-toxic surface cleansers, long lasting hand sanitisers, reusable personal protective equipmnt, antiviral screening and fogging technologies for large area disinfection.
We were approached by dental researchers who had questions about whether it was possible to sterilise the oral cavity, to reduce the risk of transmission from asymptomatic people during oropharyngeal examinations. This developed into a larger collaboration where we characterised the viral envelope by lipidomics mass spectrometry for the first time, showing that it was highly bioactive and could contribute to disease. We then ran a clinical trial which identified ways of killing live virus for up to an hour in the mouth through targeting the lipid envelope, to improve safety for healthcare workers in disciplines such as ear, nose and throat and dentistry.
We built links with clinical and diagnostic colleagues and performed virological assays to help them understand their patients – for example, examining whether immunosuppressed patients continued to secrete live virus, and assessing the efficacy of different COVID-19 vaccines in eliciting protective immunity in immunosuppressed transplant patients. We repurposed many of our existing adenoviral platforms, developed for oncology applications, as potential platforms for SARS-CoV2 vaccines. When clotting disorders were identified as a risk factor following vaccination with adenovirus vectors, we were recruited onto the Vaccine-Induced Immune Thrombotic Thrombocytopenia consortium. Here, we led a work package using our molecular virology expertise to understand the possible mechanistic basis for this rare side effect.
Outside the lab, we took up advisory roles in Welsh Government, sitting on multiple subgroups of the Technical Advisory Group (the Welsh government equivalent to the Scientific Advisory Group for Emergencies, known as SAGE. We have also been regular media commentators on TV and radio news programmes, including both short news pieces and longer panel discussions for organisations such as the BBC and ITV.
Was this response related to your work prior to the outbreak?
Prior to the pandemic, we worked on the molecular biology and immunology of large DNA viruses in vitro and in vivo, under BSL2 conditions. Once we had established the BSL3 lab, we therefore had the right skills, techniques, equipment and reagents in place to rapidly pivot our research to work on SARS-CoV2.
What were some of the challenges that you faced during this time?
The need to move rapidly was a constant challenge; the pace of change has been phenomenal, and it’s a huge amount of work to keep pace with this, requiring a lot of long hours from the entire team. Our ability to respond was highly dependent on having pre-existing flexible funding; we were lucky that we had secured large grants shortly prior to the pandemic, which meant we had trained staff and an established setup ready to go. Without these, we wouldn’t have been able to respond in the way that we did. We were only able to support industry through the rapid funding by the Accelerate programme, which funded a standing complement of staff who could be deployed to work on different projects as companies approached us.
There were a lot of rapid access calls for funding, but many of these failed to actually provide the money quickly once it was awarded, required underwriting from existing grants to bridge gaps. They were also incredibly inflexible in terms of how money could be used, staff contracts and when projects could run from and until. In addition, these schemes all ended very quickly, leaving a large hole in our ability to respond, despite the pandemic continuing.
There were also issues with quick access to clinical samples due to sometimes inflexible administration of legalities associated with working with primary human tissue governed by the Human Tissue Act, and with ethics. This was partially alleviated due to the nationwide collaborations described above (e.g. UK Coronavirus Immunology Consortium), but remains an issue even now when it comes to publishing clinical studies in a rapid timeframe.
How did your experience throughout the response aid in your development?
It’s been an incredibly collaborative time; we’ve made a huge number of new contacts with academia and industry and we have numerous projects planned as a result. These are both within and outside our usual discipline areas, which has been a real benefit. It’s also been very exciting to apply our existing skillset to a new virus – it’s not normally possible to switch viruses so easily and quickly, and we’ve learnt a huge amount about the underlying biology of the areas we study by being able to run multiple viruses in parallel.
What can we learn about the importance of microbiology from the COVID-19 pandemic?
Basic microbiology and immunology are critical to any pandemic response – every virucidal product on the market needs testing against live virus if it is to be marketed as effective, and every vaccine and therapeutic relies on pre-existing basic virology and immunology research to be developed.
How did the Microbiology Society play a role in your response?
The whole pandemic has been very collaborative. We’ve only been able to move at speed because we pooled knowledge; the links we’ve made in the past within the virology community, and through the Microbiology Society, have been critical to that.
About the authors
Professor Ian Humphreys is Director of Systems Immunity Research Institute at Cardiff University, UK. His laboratory studies the regulation of immune responses during viral infections.
Professor Eddie Wang works within the Viral Immunology Research Group (VIRG) at Cardiff University, UK. His research covers the biology and cellular immunology relating to Human Cytomegalovirus (HCMV) and the biological function of Death Receptor 3, a member of the TNFR superfamily involved in control of inflammatory and autoimmune disease.
Professor Richard Stanton works between the Viral Immunology Research Group (VIRG) and the Cytomegalovirus and Adenovirus Virology' Group at Cardiff University, UK. His research covers the biology, immunology and diagnosis of human cytomegalovirus (HCMV) as well as the development of recombinant adenovirus vectors.
Professor Alan Parker is Head of Section of Solid Cancers at Cardiff University. He has a long standing interest in virology and how this can be applied to cancer therapies using oncolytic adenoviral based vectors (virotherapy), focusing on several aspects of adenovirology, with the overarching aim of developing more selective and efficacious virotherapies for translational applications in cancer.
