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Shepherd, who has played 37 ODIs and 53 T20s, will be replaced in the squad by left-arm seamer Jediah Blades.
He has played four matches for Royal Challengers Bengaluru in the IPL, including a 14-ball 53 not out in his most recent innings.
Rutherford has played in nine matches for current IPL leaders Gujarat Titans this season.
He will be replaced by top-order batter John Campbell for the Ireland leg of the tour while Shimron Hetmyer will take his place for the matches against England.
Hetmyer is another West Indies player at the IPL but his Rajasthan Royals side are already eliminated. He was originally left out of the Windies ODI squad after a poor run of form.
Seamer Shamar Joseph is at the IPL but has not featured for his side Lucknow Super Giants and remains in the West Indies squad.
The Windies play three ODIs in Ireland from 21 May before a three-match series in England from 29 May.
Three T20s against England follow from 6 June but the tourists are yet to name a squad for that contest.
BBC News
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