I have a system that builds SQLite databases and uploads them to S3. Once they're in S3, they are never changed. The program that builds the databases only does writes, and the program that queries the databases only does reads. It uses a VFS to query the database in-place with HTTP range requests.

This is indeed not an optimal setup. A more careful design from first principles would not require seeking around the file as much as SQLite does, we'd do a better job on reading exactly the correct range of bytes for a given query since we know ahead of time what the access patterns are, and we could do reads in parallel. With SQLite we have to be very careful about the schema design to ensure it won't have to seek too many times to answer a query. But SQLite was expedient, and I'm confident I'll always be able to read the files. That's less certain for a custom file format.