A century on from housing Spanish flu patients, Melbourne's Royal Exhibition Building is playing another key role in Australia's fight against a rampant virus.

The iconic Victorian building was on Monday reopened as a mass COVID-19 vaccination centre as part of the next phase of the national rollout.

Its transformation has drawn comparisons to 1919 when it was used as a hospital during the Spanish Influenza pandemic, which eventually killed more than 12,000 Australians.

Historian Mary Sheehan, a Melbourne University doctoral candidate considering the social impact and cost of the Spanish flu, says the parallels are striking.

"It's history repeating itself to a degree," she told AAP.

"While I've been doing studies of the pandemic, I've found that there are so many parallels between now and 100 years ago.

"The Exhibition is an example of one of those parallels."

About 4000 patients were treated at the World Heritage-listed building in Carlton from February to mid-September that year.

It wasn't originally intended to be that way but was hastily set up after the military-run Base Hospital on St Kilda Road - now the site of Melbourne University's Southbank campus - stopped admitting civilian patients.

To meet skyrocketing demand, authorities considered erecting tents at Flemington and Caulfield racecourses and converting a Carlton drill hall before settling on the Royal Exhibition Building.

"I suspect the Exhibition was used because of its size and its proximity to the city, and ease of access for ambulances and medical professional," Ms Sheehan said.

"The premier of Victoria, premier (Harry) Lawson, said at the time that it was a 'stop-gap measure', that it was a 'port in the storm'."

In all, 412 people perished at the site, including nurses and doctors, although Ms Sheehan put the death rate into perspective.

"It was comparable to the other public hospitals and even better than some of them," she said.

"Whilst there were that many deaths, it wasn't too bad."

Fast forward to 2021 and the building is front and centre in Victoria's efforts to ramp up COVID vaccinations within the "phase 1b" group, which accounts for six million Australians.

Paramedics, police and fire service members were among 100 frontline emergency workers to receive the jab on Monday as the Carlton hub had its "soft launch".

St Vincent's Hospital chief executive Angela Nolan said the site's vaccination numbers would grow to 400 a day by the end of the week and rise to 2500 at its peak.

"It's a really exciting moment because it marks the start of what we think is hope for our community," she told reporters.

Ms Sheehan highlighted that in a historical twist, St Vincent's Hospital was invited to manage the vaccine centre after Archbishop of Melbourne Daniel Mannix offered to send its nurses to take charge of the makeshift hospital in 1919.

"That created a huge furore," she said.

"It's the opposite of what the experience was 100 years ago."