As per the true ending of RER2, Barry adopted Natalia but she is possessed by the mind of Alex Wesker. The Wesker-possessed Natalia gets in touch with her organization and they extract her from Barry's home. Barry resolves to find her and exorcise Natalia of Wesker's influence.
The Wesker-possessed Natalia, meanwhile, is fixated on Sherry Birkin, who she learned of due to Sherry's friendship with Claire. Since Sherry has healing powers and doesn't age beyond sexual maturity, she is considered the ideal vessel for Wesker to attain immortality/godhood. Wesker begins hatching a plan to steal Sherry's body.
Later, terrorists attack a fictitious city in Czechoslovakia.
The city is reminiscent of Prague, with layers of architecture dating back millennia. Perfect for nonsensical puzzles, I might add!
A force field seals off the entire city from the outside world, leaving the trapped inhabitants to succumb to a viral outbreak and renegade BOWs. Faced with a humanitarian crisis, the BSAA tunnels under the force field to infiltrate the city and find a way to shut it down from the inside out.
Eight agents are sent in (some of which are not BSAA proper, but just roll with it):
Team #1: Chris and Jill
Team #2: Leon and Claire
Team #3: Jake and Sherry
Team #4: Barry and Moira
I've paired them up for thematic reasons, of course. This would be one continuous story, switching between different characters in different places at different times, like the Revelations series. At certain points, the teams would mix up. For example: Chris and Leon, Jill and Claire, Claire and Sherry, Leon and Sherry, Jill and Barry, Chris and Barry, etc. Lots of interplay between the characters.
And yes, Piers would be back... working for Wesker! Turns out he survived the ending of RE6, thanks to his mutant form, and Wesker's organization found him and made him their equivalent of Krauser. He's an amnesiac who has been brainwashed to hate the BSAA. Part of the story would involve Chris breaking through Piers' mental conditioning and reminding him of the bromance they share, and then trying to find a way to heal him.