I'm making a couple guesses about what you're ultimately trying to do. It sounds like you want to catch messages that aren't addressed to legitimate users and respond to those with some canned response.
When qmail can not find an account to deliver to, it will deliver to the alias user whose home directory is typically /var/qmail/alias (if you followed Life With qmail). Within the alias directory, you can create .qmail-default to perform the auto response.
If instead, you're trying to provide an auto response when you're updating the server and want to catch both existing and non-existing users, then you could accomplish it with a two phase approach. Use the virtualdomains file to map your incoming domain to a particular user. This particular user would have a .qmail-default providing the auto response. When your ready to restore e-mail delivery, reset virtualdomains not to map to the user, send the signal to qmail and delivery will continue as normal.
Please let me know if you had another intent for the auto-response.