Chris,
I understand the dilemma, but that's reality - some people just aren't interested. The nice thing is you can score those folks and even remove them from the flow eventually.
I wouldn't rely on Opens as the only measure, not all Opens are reported back. So clicks is better. Marketo does a score based on clicks and opens, but you can't really use it for much.
What I have done sometimes (although I don't inherently agree with it) is to have paired streams -
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First Emails
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Non Open/Clicks - these include variations of Email 1 with new subject lines.
If someone engages in Stream 2, they get pushed back to Stream 1. Of course, that can get a bit complicated if you want them to receive the content in order. A better way is to also have Fast Stream and Slow Stream with similar content.