Cows and buffalo are closely related. They can even interbreed and produce fertile off-spring. Cows get cowpox, a relative of smallpox that can infect humans, but which is usually harmless. Humans who have had cowpox are immune to smallpox for several years, which is the basis for the vaccines that wiped out smallpox in the wild.

Let's say that in a slightly different North America buffalo carry a disease related to cowpox. It causes a mild, short-lived rash among humans who come into contact with an infected buffalo or parts of a recently dead one. It is a little more contagious than cowpox, but it isn't all that infectious and infection almost always occurs from a living animal or one which has been dead only for a very short time.

Indians from outside the buffalo's natural range have almost never been exposed to buffalo pox. The buffalo hunters of the Great Plains have almost all been exposed to it, as have most of their wives and children. The tribes on the fringes of the plains have had some exposure, as have some tribes of the interior eastern woodlands, where the buffalo ranged as far east as Pennsylvania at times.

What would this mean? Well smallpox would have a hard time spreading to the plains Indians, because most of them would be immune to it. They could still get other European diseases like measles and mumps. But those diseases are far less lethal than smallpox. Tribes on the fringes of the plains would get smallpox, but they would be somewhat less devastated by it.

It's hard to know when this partial immunity would start having an impact on history. One school of thought says that the first smallpox epidemic to reach Mexico in 1520 spread hemisphere-wide, killing Indians across the plains and spreading at least as far as upstate New York. The northern part of the spread is controversial and frankly based on very flimsy evidence. I personally suspect that the early epidemics burned themselves out in the sparsely-settled deserts of northern Mexico. If that was the case, not too much would change until at least the late 1560's.

In the 1560s, two things happened that might have been influenced by buffalo pox. First, the Chichemic Wars started. Second, the Spanish founded St. Augustine, their first permanent settlement in Florida, bypassing the desert barrier that slowed the spread of European diseases to the rest of North America. The American southeast may or may not have had smallpox epidemics before the 1560's. After the founding of St. Augustine it certainly did.

Throughout the late 1560's buffalo pox has a small, almost imperceptible impact on events. Chichemic country was for the most part marginal range for buffalo, so a slightly smaller number of desert tribesmen die in the epidemics that sometimes penetrate the fringes of the desert. That in turn makes things a little tougher for the Spanish on that frontier. There is a slave trade in captive Chichemics in New Spain. In this time-line, those captives are somewhat more likely to survive and eventually escape back to their own country. That in turn makes the Chichemic tribes a little better at responding to Spanish pressure. They adopt useful Spanish technology more quickly, and start riding captured horses sooner.

By 1580, the Chichemic Wars have diverged considerably from the ones in our time-line, but the Chichemics are still more of a nuisance than a threat to Spanish Mexido—a bigger nuisance than in our time-line, but still just a nuisance.

Things are also diverging a bit in the American southeast. Smallpox epidemics are a little less devastating on the western fringes of the old Mississippian Mound-builder area, and especially among the Pawnee and other Caddoan tribes of the eastern fringe of the plains. That doesn't have much impact on St. Augustine because the tribes where buffalo pox makes a difference are so far away from Spanish settlements as to be essentially unknown.

In 1592, the divergence gets bigger. The Spanish establish New Mexico colony among the Pueblo Indians of the Southwest. The Pueblo Indians are considerably less vulnerable to smallpox than in our time-line. Contrary to their popular image, the Pueblo Indians did sometimes venture out into the plains on buffalo hunts. More often they traded with the plains nomads for buffalo hides and meat. The Pueblo Indians aren't as protected as the plains nomads, but when they have epidemics of smallpox not everyone gets sick, which is crucial in terms of having people capable of helping the sick during an epidemic. The Pueblo Indian towns don't shrink as much in this time-line as they did in ours, but New Mexico is a isolated backward colony, and there is little impact outside the area. 

The plains tribes remain considerably larger through the next couple of centuries, but that is counterbalanced by the fact that fewer tribes enter the area from the outside. In our time-line, the first well-documented smallpox epidemic of the plains came around 1780, toward the end of the Revolutionary war. In our time-line, the 1780 epidemic reached as far as Hudson Bay in Canada and acted like a virgin-field epidemic, devastating most of the tribes of the plains, and determining winners and losers among the tribes. That has little impact outside the area, but makes an enormous difference inside it. Tribal sizes and ranges in this time-line no longer even approximate what they were at a comparable time in our time-line. Partly agricultural village-dwelling tribes like the Mandan, Hidatsa, and Pawnees are much stronger, while other tribes like the Dakota are relatively weaker. 

The plains tribes get less direct access to European trade goods from Hudson Bay because the smallpox doesn't hurt traditional middlemen tribes like the Cree as much as it did in our time-line. Plains Indians get fewer guns and less ammunition in the late 1700s and early 1800s than they did in our time-line.

Fast forward to the early 1820's. The early settlement and independence of the United States has gone pretty much as in our time-line. The War of 1812 has come and gone on schedule. Tecumseh or his equivalent has tried and failed to unite the frontier Indians of the east against encroaching white settlement. The frontier is pushing into the last desirable Indian-held areas east of the Mississippi. The advance is getting slightly but noticeably tougher. The Indians don't melt away anymore as the frontier dissolves the barriers between them and advancing American civilization. Their response is not strong enough to stop the advance, but it is noticeably stronger. 

Eastern tribes are also finding it much harder to go further west to get out of the way of the US advance. The plains are already filled with still-powerful warlike tribes, and even the strongest and most warlike tribes from outside the areas are having trouble breaking in. The eastern tribes do have easier and more reliable access to guns and ammunition, which gives them an edge, but the plains, and especially the areas where farming is possible are already crowded. The idea of removing eastern Indians across the Mississippi is being tossed around, but is obviously less practical given the numbers and power of the plains tribes. 

The plains in 1825: People familiar with the Great Plains of our time-line would find this time-lines' version somewhat familiar in general outline, but very different in detail. In both time-lines there are buffalo-hunting, tipi-using nomads in the dry center of the Plains. The names and territories of these tribes are somewhat different than they were in our time-line, though most of the major nomadic tribes of our time-line have at least a toe-hold on the plains of this time-line. These are the people most non-Indians think of when they think of Indians. There are also more settled tribes in the fertile river valleys that extend into the plains, though most of those tribes go on extended buffalo hunts away from their villages too. Farming tribes like the Pawnees, Mandans, Hidatsa, Arikara, and others are still around, just as they were in our time-line.

The balance between those two groups is different than in our time-line though. In our time-line partly agricultural groups got hit much harder and earlier by smallpox than the nomadic tribes, and some, like the Mandan were essentially wiped out by it. In this time-line, those groups are still powerful and growing increasingly wary of the advancing frontier.

Spain, and now the new nation of Mexico are also wary of the advancing frontier. The Spanish have missions among the still-numerous Caddoan tribes of Texas. They are also trying to shore up their position against the Americans by allowing refugees from east of the Mississippi to settle on any fertile but sparsely occupied land. Several thousand Cherokees settle in Texas, as do some tribes that barely existed by 1825 in our time-line: the Natchez, Tunica, Biloxi, and Quapaw.

The nomads of the Great Plains also have a larger population than they did in our time-line. The population is putting a great deal of pressure on buffalo populations. Plains Indian wars are becoming more deadly as competition for food resources becomes more of a factor. Military tactics evolve rapidly. Eastern tribes being forced into the fringes of the plains have learned a great deal in over a century of conflict with settlers, and plains tribes are being forced to learn the new tactics in order to cope with the tribes being pushed toward their lands.

So what happens when the frontier reaches the plains? Well things get far nastier than they did in our time-line. I doubt that the frontier's advance would stop, but the Indian wars would be much more serious and hard-fought. Other European diseases like mumps and measles would hit tribes hard, though nowhere near as hard as smallpox did in our time-line. Eventually railroads, mass slaughters of buffalo, and machine guns would bring the plains Indians under US control.