Taking their places in midfield are Ben Johnston, fresh from England 'A' duty, and Nicky Little while Kyran Bracken is restored to scrum-half as well as the captaincy.
In the pack, Stuart Hooper comes in for Abdel Benazzi while Tony Roques replaces Ryan Peacey. On the bench Ben Skirving and Ben Russell reappear while Dan Kirton gets the back-up scrum-half slot.
Andy Goode, after making way for Castaignède is joined on bench for the first time at Vicarage Road by Rugby League convert Nathan McAvoy who, if he gets on the pitch, will be making his home debut.
"From our last outing the only changes in the forwards are Abdel (Benazzi) and Ryan (Peacey) who have both got niggling injuries," Saracens coach Wayne Shelford told the club's official website Saracens.com.
"These two are replaced by Stuart (Hooper) and Tony (Roques). Kyran (Bracken) gets the No.9 jersey following his escapades on the wing for England and it'll be good to see him playing in his usual position.
"Thomas (Castaignède) and Nicky (Little) will combine at fly-half and inside centre with Ben (Johnston) in at outside centre. I think the backline will give us a strong defence, and we'll need this to cope with the attacking Wasps loose forwards as they really enjoy penetrating in midfield.
"Tim Horan will play fullback on Sunday and I'm sure that his experience and angles of running will benefit the rest of the line in this slot.
"We've prepared well and as I've said before, we're encouraging the players to think about their performance and not the result. If we work to make every pass accurate, don't miss tackles, scrummage well and so on, the results will come.
"It's our first game for six weeks and we want to perform and give the fans something to get excited about."
Saracens: 15 Tim Horan, 14 Richard Haughton, 13 Ben Johnston, 12 Nicky Little, 11 Darragh O'Mahony, 10 Thomas Castaignède, 9 Kyran Bracken (captain), 8 Kris Chesney, 7 Richard Hill, 6 Tony Roques, 5 Stuart Hooper, 4 Craig Yandell, 3 Mike Storey, 2 Robbie Russell, 1 Christian Califano.Replacements: 16 Johnny Marsters, 17 Matt Cairns, 18 Ben Skirving, 19 Ben Russell, 20 Dan Kirton, 21 Andy Goode, 22 Nathan McAvoy.
Kick-off: 15.00 GMT