When Johnson caught COVID-19 in March, he tried to work through the illness "in denial" - but ended up wearing an oxygen mask in an intensive care unit and was ultimately out of action for nearly a month.
"The Prime Minister has today been notified by National Health Service Test and Trace that he is required to self-isolate as a contact of someone who has tested positive for COVID-19", his office said.
On 27 March, the British PM announced that he had tested positive for COVID-19, after which he was hospitalised, as symptoms persisted.
According to one version of events, Mr Cain and Mr Cummings had lobbied the Prime Minister to give Mr Cain that coveted position.
Meanwhile, shadow health secretary Jonathan Ashworth highlighted the strain being heaped on the NHS and the public by Covid-19 while "Downing Street is paralysed by the soap opera of these self-indulgent spin doctors".
"It was an honour to be asked to serve as the Prime Minister's chief of staff", Mr Cain said, following reports that he had been lined up for the role by Mr Johnson.
His confinement comes as negotiations with the European Union over Brexit enter a decisive final sprint, with critical announcements being trailed - ahead of Johnson's isolation - by Downing Street to tackle the virus.
Chief adviser Mr Cummings exited Number 10 amid claims he had briefed against Mr Johnson and the Prime Minister's fiancee Carrie Symonds.
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"I'm bursting with antibodies", Johnson said.
"The PM is well and does not have any symptoms of COVID-19", the statement added.
"My wife and I both tested positive".
The MP for Ashfield and Eastwood, north of Nottingham, posted a picture of himself on Facebook standing apart from Mr Johnson after the meeting on Thursday.
The developments came after a power struggle which led to the resignation of No 10 communications director Mr Cain.
On Monday, the Prime Minister was expected to meet Tory MPs from the newly formed Northern Research Group (NRG), which was set up to press the case for "levelling up" northern England.
He said: "This is not simply a problem of a dysfunctional Downing Street, this is a dysfunctional United Kingdom, and we really need a wholesale root-and-branch constitutional review to bring people together at a later stage".
The self-isolation period means he will also miss facing Labour leader Sir Keir Starmer at Prime Minister's Questions (PMQs) on Wednesday.