Hales has been struck by the virus which laid Chris Jordan and Nick Compton low in Cape Town, and although he was well enough to practice on Wednesday, he did so away from the rest of the group in a bid to prevent the bug spreading.
Should the Nottinghamshire man not be fit tomorrow morning, it is likely Compton would move up to open with Gary Ballance coming into the middle-order.
Victory at the Wanderers would hand Cook’s side an unassailable 2-0 lead with one match to play.
And the opportunity to beat the world’s number one Test side on their own patch is not something Cook is taking lightly.
"It would be a great achievement for this side to come here and beat South Africa away from home. And we're in a position to do that," said Cook.
"The opportunity is there and it's just whether we're good enough to take it.
"It's an exciting time to play on what are probably two result wickets in these next two games. We need to win one to win the series. That is a great situation to be in."
While England’s medical staff will have the opportunity to make a full assessment of Hales before the toss, Cook insists he is not overly concerned by the prospect of further players falling ill during the match.
"We're trying to win this and every Test match." Bullish Cook says team will not be conservative despite 1-0 lead. https://t.co/n2wGiDO2HU
— England Cricket (@englandcricket) January 13, 2016
"Alex Hales has got a bit of a bug, yesterday and today,” he added.
“He's come for a hit and he'll go back after that so he doesn't infect the rest of us.
"We'll have to wait and see on him, but he's having a hit so he can't be too bad.
"It seems to strike a bit randomly. Nick had it the other day and he's fine.
"You can't do anything about it as a captain, the medical team are on it.
"It's just a virus bug, so it's hard to stop. If it happens in the game then it's bad luck isn't it?"
South Africa will be led for the first time at the Wanderers by AB de Villiers, who inherited the reins when Hashim Amla resigned last week.