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An important trial will test how to boost Covid jab protection in vulnerable patients whose immune systems are weakened by drugs they need for other health conditions.
About 1.3 million people in the UK are on methotrexate for conditions such as rheumatoid arthritis and psoriasis.
It stops flare-ups, but can make the body less able to fight infections or respond to vaccines.
The team will check if a two-week drug holiday timed to vaccination will help.
A previous study from Korea showed that a fortnight's break from methotrexate immediately after the flu vaccine increased the patients' immune response to that jab.
The University of Nottingham researchers, working with other universities and hospitals, will recruit 560 methotrexate patients, and half of them will try the two-week break when they are due to have their third, or booster, Covid jab.
Although the Vroom study will take one to two years to complete, scientists hope it will provide confidence for some of the most vulnerable patients at risk from Covid.
One of the participants is 48-year-old Nottingham mum Annabelle Imray.
She takes methotrexate for her psoriatic arthritis to help treat her swollen joints and dry skin. At times, she feels so tired because of her condition that she has to plan her days carefully.
She was shielding earlier in the year, and says she is still very cautious now because she is worried about catching Covid.
"I explain to the kids that if I catch it, I'm much more likely to be seriously ill than them.
"When I do go out, I'm worried walking close to strangers, or if someone is coughing without a mask I would be worried about the potential of catching something.
"Hopefully the trial will make a big difference for people on immune-suppressing medicines giving reassurance and confidence to do things they enjoy in their lives and know that we are more protected. It's the uncertainty that is the worst."
Prof Abhishek Abhishek, the chief investigator, said people on immunosuppressants faced being more at risk of getting ill if they catch Covid, as well as potentially being less able to mount the strongest possible immune response to vaccines against the virus.
He said: "We hope to find out whether they can safely take a break from medications for their inflammatory conditions and an improved protection from the booster jab, without the risk of flare-up of their long-term illness which affects their daily lives so heavily.
"Many people take methotrexate for more than 10 to 20 years, so we hope to provide high quality evidence which can help them with their day-to-day lives going forward."
Prof Andy Ustianowski from the National Institute for Health Research, which is funding the work, said: "This pivotal study will help develop our understanding of immune responses in people taking this widely-prescribed medicine."
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