Scott Parker has yet to feature this term due to an Achilles injury, while Younes Kaboul and Benoit Assou-Ekotto have been out since sustaining injuries early in the campaign.
That trio are still a way off returning, although manager Andre Villas-Boas is likely to be able to welcome back Mousa Dembele and Emmanuel Adebayor.
Gareth Bale is also in line to feature against his former club after the birth of his first child — a welcome boost for a Spurs side that suffered a 4-2 home defeat to Chelsea in their last Premier League outing.
“I think the Chelsea game was just one incident,” Vertonghen said. “We missed many players and I hope a few can come back against Southampton. It has been an unlucky season for us with all those injuries and I am looking forward to playing with our best team very soon because we can be so strong.
“We’re very confident for the rest of the Premier League. Southampton are next and they really want to play good football. They believe in their own philosophy and I think we have done better in the away games until now so hopefully we can carry that on.”
If Spurs do get three points it will only increase the pressure on Saints boss Nigel Adkins, whose side sit in the bottom three of the Barclays Premier League.
However, Adkins insisted yesterday he does not fear for his job.
“When we have got through this period we will be able to experience the good times together,” he said.