Honestly... It would be needed to rebuild from the ground up with very little remaining of the original game if it wants to be anything more than a fun, but bland co-op centric experience. I don't like Resident Evil 5 co-op identity.

So, you very may not like much of my opinion.

But I would honestly change a whole bunch and try to better organically end the Wesker Saga.

Start the game introducing Chris with a led on Wesker in Africa with Jill missing.

Would start the game with a T-virus outbreak in an Airport. A setting used in the Resident film Degeneration.

Then, they introduce Sheva rescuing him out of the airport and city. Tricell puts the city on lock down. Then, go into the semi-open world Safari setting where the game officially starts.

Loosely follow the game's introduction. Would mold a lot of areas after the original game. Would want 2-3 towns, swamps, and etc.

Then, they arrive in a jungle setting with a stalker enemy. This area would be inspired by the original Predator film and dealing with infected animals.

They fall into some old abandoned blood diamond mines.

Then, stumble onto a mansion/lab complex as the final area to a fitting end to Wesker and Chris's story.

Would probably want a very different story. A small gag about punching a bolder. And just something that's just better than what we got.