Rather than a general defense of the Reasonableness, both Vindications are targeted more narrowly at the Presbyterian John Edwards, who had accused Locke of being "all over Socinianized." (As the Reasonableness was published anonymously, Edwards could not at first be sure of its author, though he knew the rumors that it was Locke.) Their disagreement largely revolves around a relatively narrow concern: what to make of Locke's claim that the only necessary belief is that Jesus is the Messiah. (As he had written in Reasonableness, chapter five: "So that all that was to be believed for justification, was no more but this single proposition, that 'Jesus of Nazareth was the Christ, or the Messiah.'")
According to Edwards, this excludes all sorts of important doctrines, such as the Trinity and the atonement. Locke rejects this, though with a rather scattered shotgun blast. He identifies places that his text had implied something like the atonement; he points out that even those incapable of understanding complex theology can yet be saved and so the absolute doctrinal minimum must be quite low; and he argues that the doctrinal criteria were meant to function as membership criteria. That is, believing Jesus to be the Messiah is what it takes to become a Christian, but not all that a Christian must believe and do, just as a citizenship oath might make me an Englishman but would not be all that I must do to obey English law.
The problem in wading through all of this is that most of the substance is lost in quibbles about who said what where. Put bluntly, Edwards' and Locke's quarrel is long, boring, and repetitive. (The Second Vindication alone is a grueling 90,000 words; far longer than the Reasonableness itself. Such tedium was an unfortunate feature of Locke's other rebuttals. The three sequels to the Letter concerning Toleration are equally dull.)