The Reformation is the biggest threat to forming the HRE, so crush it fast. When the first Center of Reformation spawns — usually in a small nation, often an OPM — declare immediately even without a casus belli, as long as you won't trigger a coalition. Enforce religion and the center is gone. The next ones tend to spawn in Brandenburg, Denmark, or Sweden. Attack, split off the capital province so it holds the CoR, enforce religion. Repeat for all six centers, both Protestant and Reformed. Your empire is large enough by this point to handle it.

The Reformation is a major threat, so crush it fast. When the first Center of Reformation spawns — usually in an OPM — declare immediately even without a casus belli, as long as you won't trigger a coalition. Enforce religion and the center is gone. The next ones tend to spawn in Brandenburg, Denmark, or Sweden. Attack, split off the capital province so it holds the CoR, enforce religion. Repeat for all six centers. Your empire is large enough by this point to handle it.