PITCH2 - Protective Immunity through T Cells in Healthcare workers 2

COVID-19 has had a devastating impact on lives for many reasons, including illness, loss of life, restrictions to way of life and economic losses. We now see lower rates of severe disease and death despite continued infections from the virus (severe acute respiratory syndrome coronavirus 2: SARS-CoV-2), but we need to protect people with immune problems and be ready for future variants and related viruses. It is crucial that we understand how people's immune systems protect against both infection and severe disease, and how long immunity lasts. This information tells us whether we need to give booster vaccines again, who is at increased risk of infection and severe disease, how to fine tune the next generation of vaccines and can guide development of new drug treatments.

Much research on the immune response to COVID-19 focusses on measuring antibodies in the blood, but there is a second vital arm to the body's learned response to infection: T cells. T cells are a group of white blood cells patrolling the bloodstream to defend against infection, and can be trained by vaccination and/or previous infection to recognise and destroy the virus causing COVID-19. T cells are likely to be particularly important at preventing severe disease, but are difficult to measure because fresh blood samples and specialised skills and equipment required. We have established a national group to track the T cell response to the SARS-CoV-2 virus in over time in over 2000 healthcare workers working in one of five cities (Birmingham, Liverpool, Newcastle, Oxford and Sheffield). This group, called the PITCH (Protective Immunity through T Cells in Healthcare workers) consortium, includes researchers from UK Health Security Agency who run the wider SIREN study which undertakes regular PCR screening and antibody testing from 44,546 healthcare workers in 135 NHS sites across the UK. PITCH allows study of the immune response in greater detail in our subgroup.

So far our research findings have helped the UK government make decisions about when to give vaccines and who remains especially vulnerable. We demonstrated that people with previous infection make a much better antibody and T cell response after receiving vaccines, even after the third (booster) dose. We also showed that a longer dosing interval for the Pfizer vaccine gave higher antibody responses and lower but better memory quality T cell responses than a short dosing interval. Our latest work shows that after two doses of vaccine, the antibody response declines over six months, but the T cell response is well maintained, re-enforcing the idea that T cells are important for long term protection. T cells in vaccinated people still work well against the Omicron variant, which evades much of the body's neutralising antibody response. We have shared our T cell laboratory techniques with other researchers, and we work with national study teams such as OCTAVE to look at T cell responses in patients with immune issues compared to our healthier population of healthcare workers.

We are now applying for funding to maintain the systems we have set up for the PITCH consortium. We need to follow-up our group of healthcare workers to see if the antibody and T cell response is wearing off in time, and to measure how people's immune response deal with any future variants of the virus. We also have an opportunity to learn more about the immune response to influenza (flu) because there has not been any flu in circulation since winter 2019/2020 due to the restrictions put in place for COVID-19. We will work together with the British Society for Immunology to explain our research to healthcare workers and the wider public, and listen to opinions on what the important questions are.

We have assembled a highly productive group of researchers and will use PITCH2 as a springboard for long term deeper research studies to answer questions on the character and duration of immunity to SARS-CoV-2 virus and flu.

This application seeks to support continuation of a highly successful partnership for COVID-19 research - the PITCH (Protective Immunity through T Cells in Healthcare workers) consortium, which was established in 2020 to address the T cell response to SARS-CoV-2 in a national healthcare worker cohort. PITCH is a longitudinal observational study of 2149 healthcare workers (HCW) in 5 sites - Oxford, Liverpool, Birmingham, Sheffield, and Newcastle in collaboration with UKHSA's SIREN study. We seek to maintain the infrastructure to follow up the cohort with collection of cellular, humoral and mucosal specimens. We will also sample participants after infections with future variants of concern, preserve governance of the extensive sample archive and undertake ongoing engagement with the HCW participants and the general public. In addition, PITCH2 will continue to provide the healthy control group for a number of national studies evaluating SARS-CoV-2 immunity in immunocompromised patient groups, including OCTAVE/DUO, COVAD, SCORPIO, PETReA, and local cohort studies. PITCH is part of the wider SIREN Collaboration including UKHSA, The Francis Crick Institute, and the HICC Study.

PITCH has a strong track record of delivery, with 22 high impact publications to date and presentations to national and global bodies such as the UK's JCVI and WHO, for example on the impact of extending the dose interval for mRNA vaccines. The long-term sustainability of the partnership will provide an environment to secure future grant income from research project/programme applications to address the crucial scientific questions on T cell immunity to SARS-CoV-2 that continue to emerge, as well as providing unique opportunities to investigate immunity to other endemic respiratory viruses including influenza. We are also building global partnerships to support capacity strengthening in low- and middle-income countries to understand the impact of variants worldwide.