Vaughan will not just be under scrutiny as captain of a fresh-faced side, but also as a one-day batsman.
The highest run-scorer in Tests last year and a man with a textbook technique, he has yet to duplicate that form in the one-day game.
When he last played against Pakistan in England two years ago in a triangular series he scored five, nought and two.
A winning start -- and a first one-day century in his 27th appearance -- would strengthen the Yorkshireman's hand as the leading candidate to replace Nasser Hussain in the test arena as well.
Otherwise the three-match series, starting with a day-nighter at Old Trafford on Tuesday, has a strange look to it, with neither side recognisable from the line-ups which met just a few months ago at the World Cup.
England have lost Hussain -- he managed just one century in 88 games -- Nick Knight, Alec Stewart and Andy Caddick following their one-day retirements, while Paul Collingwood and Craig White are injured.
Pakistan, meanwhile, have chosen to ignore six big-name players who lost to England in Cape Town, Wasim Akram, Waqar Younis, Inzamam-ul-Haq and Saqlain Mushtaq among them as well as the electrifying Shahid Afridi.
All rounder Abdul Razzaq, meanwhile, only made the squad belatedly as injury cover.
Both teams, after falling at the first hurdle in South Africa, are looking to youth, although England have balanced their approach by restoring the 32-year-old Darren Gough to their squad to act as mentor to the greenest of bowling attacks.
Pakistan, while keeping faith with strike bowler Shoaib Akhtar despite his one-match ban for ball tampering, are being similarly ambitious but still look vastly more experienced than their hosts.
England's 14-man squad boast 249 one-day caps -- take Gough out of the equation and that plummets to 138 -- while Pakistan captain Rashid Latif and vice-captain Yousuf Youhana have 294 between them.
As worrying perhaps for the hosts, only five of England's players have featured in 10 Tests or more.
The home team's hopes of unearthing a new talent will largely rest on 24-year-old left-handed batsman James Troughton, hard-hitting all rounder Rikki Clarke and quick bowler and part-time model Kabir Ali.
Wicketkeeper Chris Read and batsman Vikram Solanki get a chance of rehabilitation after three years on the sidelines.
Pakistan have similar hopes for batsmen Mohammad Hafeez and Misbah-ul-Haq, while all rounder Azhar Mahmood's return after several season of injury will also command attention.
England: Michael Vaughan (captain), Kabir Ali, James Anderson, Rikki Clarke, Andrew Flintoff, Ashley Giles, Darren Gough, Steve Harmison, Robert Key, Anthony McGrath, Chris Read, Vikram Solanki, Marcus Trescothick, James Troughton.
Pakistan: Mohammad Hafeez, Imran Nazir, Yasir Hameed, Abdul Razzaq, Yousuf Youhana (vice-captain), Younis Khan, Misbah-ul-Haq, Shoaib Malik, Bilal Asad, Azhar Mahmood, Rashid Latif, (captain), Shoaib Akhtar, Mohammad Sami, Shabbir Ahmad, Umar Gul, Danish Kaneria.