Author did not make the major changes asked during the review process
There are three possibilities: 


The authors think they have addressed your major comment: in this case, since you think they haven't, either they haven't understood your initial comment, or they believe that another change they have done is enough. It might be your fault (because you didn't explain your comment well enough) or theirs (because they didn't understand it). It's ok to point out that you believe your comment has not been addressed, and explain it in a different way, to avoid any possible confusion. 
The authors disagree with your major comment, and did not change the paper accordingly: in this case, they should have explained it in the response to reviewers. It's ok to mention that your comment is not addressed, and it's up to the editor to decide whether the authors should comply and change the paper accordingly. 
The authors did not see your major comment in the original review, or simply forgot to address it. It's ok to mention that your comment is not addressed, and if you believe that it could be addressed quickly (e.g., some references missing), then perhaps it can go as a minor change for the next version, to speed up the process. 


In any case, it's ok to mention that your comment has not been addressed. You might not know the exact reason why, so it's always better to assume that it's just a mistake. The responsibility to accept the paper as such is not yours, it's the editor's. You simply mention that you believe something is wrong with the current paper, you explain why you believe it's wrong, and whether you think it should published without changing it. 

A typical response in this case could be: "The new version of the paper addresses most of my previous comments, with the exception of XXX. Indeed, it is not clear how the authors address the fact that YYY (another version of XXX) in the new version."