Professor Sir Jonathan Van-Tam is leaving his post as England's deputy chief medical officer, Sajid Javid has confirmed.
Sir Jonathan, who was recently knighted, is departing his role to take up a new post at the University of Nottingham.
The health secretary said it has been "an honour" to work with Sir Jonathan and wished him "all the best for the future".
"It has been an honour to work with JVT and I am hugely grateful for his advice & the vital role he has played in our vaccination programme," he posted on Twitter.
Prime Minister Boris Johnson added: "I would like to thank Jonathan Van-Tam for his extraordinary contribution to our country and his invaluable advice throughout the pandemic. Wishing him the very best for the future."
Sir Jonathan - or JVT, as the prime minister likes to call him - became a household name during the COVID pandemic, known for explaining scientific concepts in layman's terms and his love of football analogies.
In a statement announcing his departure, he described his time as deputy chief medical officer as "the greatest privilege" but "the most challenging of my professional career".
Sir Jonathan has been on secondment to the Department of Health from the University of Nottingham since 2017 and will return to be the Pro-Vice-Chancellor for Faculty of Medicine and Health Sciences at the end of March.
Sir Jonathan said: "My time as DCMO have been the most challenging of my professional career, especially the COVID response.
"We all wish COVID had never happened. Notwithstanding, it has been the greatest privilege of my professional career to have served the people of the UK during this time."
He continued: "I want to pay tribute to Professor Chris Whitty, the CMO team, my fellow scientists, public health professionals and clinicians whose support, wisdom and energy has been inspiring.
"There are countless numbers who work behind the scenes - all of whom have an unrelenting commitment to help and support the British public. It has been an honour to work with them all."
Sir Jonathan is widely known for his use of colourful quotes to break down the otherwise complex scientific data at the government's coronavirus briefings, with his memorable creative takes on the latest medical advice labelled affectionately by some as "Van-Tamisms".
University of Nottingham Vice-Chancellor Professor Shearer West said the university is "incredibly proud" of Sir Jonathan's work, adding that the institution is "delighted" that he will be returning.
"His academic and leadership expertise is second to none, and the integrity that he has demonstrated in his government role is fully aligned to our values. I know that he will take our university's reputation for excellence in medicine and health sciences to new heights," Prof West said.
Housing Secretary Michael Gove tweeted: "JVT = Hero."
Sir Jonathan is best-known for his work in the COVID-19 pandemic where he worked on the Vaccine Taskforce and supported the development of treatments for the virus.
However, as deputy chief medical officer, he has also played important roles in numerous different health incidents, including domestic outbreaks of Monkeypox, the 2017/19 flu season and the Novichok attacks.