The one you have.
A woman in Gwinnett County, Georgia, used a .22 caliber pistol early this morning to kill a home invader who was armed with a knife. You can read the story here.
The keys to this woman's survival: a combination of commitment to the fight, and multiple shots. Whatever caliber you use, or even if you don't use a gun, you have to go into the fight with abandon. Give it your all. And don't stop until the threat is stopped.
No, a .22 would not be my first choice for self defense. But the next time someone insists it can't be used, show them this story.
Michael Bane had an excellent podcast a few weeks ago on the topic of the .22 as a self defense gun, and making the best of whatever gun you have. He explains it much better than I can. Give a listen.