The Prime Minister acknowledged cases could again spiral as restrictions are relaxed, with the "stay local" order having ended in Wales and larger outdoor meetings being permitted in England from Monday.
But he said on Saturday that the "key difference" this time is that the rise in prevalence should be "sufficiently mitigated" by the successful vaccine rollout.
However, there were warnings that more must be done to prevent the import of new variants from overseas as vaccines minister Nadhim Zahawi raised the prospect of booster shots beginning in September.
During a discussion at the Conservatives' virtual spring forum, the Prime Minister said that a "third wave" is being witnessed in parts of Europe and "bitter experience" has taught him that this could hit the UK "three weeks later".
"The question is - is it going to be, this time, as bad it has been in the past? Or have we sufficiently mitigated, muffled, blunted the impact by the vaccine rollout?" he added.
"There's lots of promising evidence that a lot of people who could be vulnerable are now protected against death and serious disease, that's my hope, my hunch.
"But we haven't yet seen the real conclusive proof in the sense that we haven't seen a take-off in infection rates that hasn't been accompanied by a lot of hospitalisations and deaths. That'll be the key difference this time round, if we're lucky."
Mr Johnson, however, remained optimistic that his roadmap to easing England's restrictions can continue, saying there is a "good chance" of allowing non-essential retail reopening on April 12, when hairdressers are also earmarked to reopen.
"In just a few days' time, I'm finally going to be able to go to the barbers," he said in a subsequent speech.
"But more important than that, I'm going to be able to go down the street and cautiously, but irreversibly, I'm going to drink a pint of beer in the pub.
"And as things stand, I can see absolutely nothing in the data to dissuade me from continuing along our road map to freedom, unlocking our economy and getting back to the life we love."
Meanwhile, vaccines minister Nadhim Zahawi said the first booster doses would go to the top four priority groups, including the over-70s care home staff, NHS workers and the clinically extremely vulnerable.
He told the Telegraph that this would likely begin in September and was said to have added that the Government is expecting up to eight different jabs to be available by the autumn, including one protecting against three different variants in a single dose.
A number will reportedly be manufactured in the UK, which could ease the pressure on supplies amid tensions with the European Union as it faces shortages from AstraZeneca.
Asked when the booster programme would begin, Mr Zahawi told the newspaper: "The most likely date will be September.
"Jonathan Van-Tam (the deputy chief medical officer) thinks that if we are going to see a requirement for a booster jab to protect the most vulnerable, (it) would be around September."
Dr Mike Tildesley, who advises the Government on the Spi-M modelling group, said it was "good news" that September has been suggested for boosters, but warned the arrival of new variants must be stalled.
"In the shorter term, we are worried about new variants, but if we can keep these out for a longer period of time, enough time for these boosters to be developed, then that should hopefully protect us as we go into the winter," he told Times Radio.
Ministers were facing pressure to protect the success of the vaccination programme against the import of new variants from overseas, with the Guardian reporting officials met on Friday to consider expanding the travel "red list" mandating hotel quarantine.
Labour's shadow home secretary Nick Thomas-Symonds said: "Ministers need to do everything possible to stop new variants reaching the UK - and move to a comprehensive hotel quarantine system now."
European Union leaders gave their backing to more stringent vaccine shipment controls as the bloc struggles with its rollout, but stopped short of imposing an export ban.
European Commission president Ursula von der Leyen said AstraZeneca must "catch up" on deliveries to the EU before exporting doses elsewhere.
Prime Minister Boris Johnson and US president Joe Biden discussed their vaccination programmes in a call on Friday afternoon.
"The Prime Minister stressed that global access to vaccines will be key to defeating the pandemic," a Downing Street spokesman said.
Meanwhile, the Government was accused by a senior Tory of failing black, Asian and minority ethnic (BAME) communities and young women on hesitancy towards vaccines.
Caroline Nokes, the chairwoman of the Commons Women and Equalities Committee, said in a letter to Mr Zahawi that not tackling the issue could be "devastating" for vaccine-hesitant groups as well as wider society.
The vaccines minister told the Telegraph that drive-through vaccination centres could be opened in the coming months in a bid to tackle hesitancy.
"It's a great way as you do the under-50s, the under-40s, under-30s. Convenience becomes a much greater tool to deploy because you want to make sure for those people, where we think there may be greater hesitancy, we make it as convenient as we can make it," he said.
The Government announced that retailers in England will be able to stay open until 10pm six days a week when they are permitted to trade again from April 12.
Communities Secretary Robert Jenrick said it will allow them to reopen "safely", as Chancellor Rishi Sunak encouraged people to "go have fun" by spending their savings.
But Dr Tildesley, an infectious disease expert at Warwick University, warned against Mr Sunak's choice of language for "flipping from one extreme to the other", like in his Eat Out To Help Out scheme last summer.
"I totally understand the need to reinvigorate the economy, but I think we need slightly more measured language here, to encourage people to do that, but to do it within the rules, to make sure that we observe social distancing," he told Times Radio.
In Wales, lockdown restrictions were being eased as the "stay local" requirement was dropped on Saturday and people being allowed to stay in self-contained holiday accommodation.
A relaxing of England's lockdown will take place on Monday when the "stay home" order ends, and groups of up to six people, or two households, are able to meet outside.