According to Bloom County, Calvin went off into space and almost forgot Hobbes. They had to return him to Calvin. My god I wish this was in book form because it was one of the best comic strip series ever.
No, they are too familiar with each other, and Calvin's animosity (even if playful) is too deep to overcome.
Compare with Kevin+Wendy (The Wonder Years) who had a very sweet and positive relationship growing up. If Wendy hadn't moved away then I could see them have a little encounter during preadolescence, but, as perfect as it might be, I can't see them becoming a permanent couple. Very, very few people in real life go that path.