Ok the Out of Office reply sends a reply to all incoming messages per sender.

It is very possible since you are configured using POP connections a reply is sent for each connection as the message is pulled to the client then a reply goes out.

You can test this locally by removing User A from User B's client. Send a test message to User A and see if you get 2 responses.

I will continue to search on why this happens in a non exchange environment.

best Regards