Full-back Soares is expected to be out for around three weeks with knee ligament damage suffered in the midweek win at Crystal Palace, while centre-back Vestergaard (concussion) and forward Long (knee) also picked up problems at Selhurst Park.
Saints boss Ralph Hasenhuttl plans to make some changes for the all-Premier League tie. Jan Bednarek is expected to be available after missing out against Palace with an Achilles issue, but fellow defender Yan Valery remains sidelined due to a viral infection.
Tottenham will be without Harry Winks for the trip to the south coast.
The midfielder picked up an ankle injury in the midweek win over Norwich and is set for several weeks on the sidelines.