If limited disease contact managed to get to Central America, where the huge population centers are, then couldn't that have a substantial effect? Would immunity set in quickly enough for the e.g. Aztecs to stage a comeback as an indigenous superpower?
If smallpox reaches Mesoamerica, we're going to see high mortality rates as the population there was relatively dense (so less chance of quarantine). In places like the valley of Mexico where there is a lot of people living close to each other, the disease will become endemic-i.e. a disease which strikes most people when they're children, allowing them to be cared for by their parents and so decreasing the mortality rate of the disease.
Mesoamerica is unlikely to recover demographically by the time greater European contact begins-after all, smallpox isn't likely to reach Vinland before the 1200's (when it first reached Iceland) and it will take a long time to reach Mesoamerica from the northeast. However, if the disease breaks out before European contact, the region could stabilize politically between that contact and the start of the epidemic. With this political strength and without the destabilizing influence of a virgin soil smallpox epidemic, it could fight off initial attempts at conquest (if the alternate Europeans even want to attempt that).
While outbreaks of new diseases like malaria will hurt the region, these epidemics will be a lot less lethal if the Mesoamericans suffer them while independent and not suffering enslavement by conquistadors.