Vine cut the line 43 seconds ahead of the Spaniard Marc Soler (Movistar), winner Wednesday in Bilbao, and the Estonian Rein Taaramäe (Intermarché Wanty Gobert).
The French Thibaut Pinot, also in the breakaway of the day, finished 4th at 47 seconds, with the group of the last breakaways who clung to the pace imposed by Vine.
The Australian, who had already surprised the peloton on Thursday ten kilometers from the finish to claim his first professional victory, this time accelerated to six kilometers from the line without any of his breakaway companions being able to follow him.
The breakaway, however, included heavyweights in the peloton, like Mikel Landa (Bahrain-Victorious) or Alexey Lutsenko (Astana).
Winner of the stage, Vine, 26, also dominates the mountain classification, and will wear the best climber's jersey on Sunday.
The group of favorites, who were four minutes behind the breakaways at the bottom of the final ascent and regularly withered, arrived more than a minute after Vine.
The young Belgian Remco Evenepoel (22), led by Julian Alaphilippe and his teammates at the start of the final climb, resisted the numerous attacks and ended up crossing the line at the head of this group, 5th in the stage.
The Frenchman Rudy Molard, 2nd overall until then, conceded almost ten minutes on Evenepoel on the line.
Pavel Sivakov, another tricolor representative claiming the top 10 overall and 6th before the stage, lost six places and demoted to 12th overall, 3 min 31 sec from the Belgian.
© 2022 AFP