Top: Cow-milker infected from the teats of a cow with natural cow-pox. Large depressed vesicle with a small central crust, tumid (swollen) margin, surrounded by well-marked areola and considerable surrounding induration (hardness associated with swelling)

Bottom: Same case, one week later. Reddish brown crust typical of recovering cow-pox cases, on a reddened elevated and indurated base.

Many mammalian species have members of the Orthopoxviridae that are specialized to exist within their systems - humans have smallpox, cows have cowpox, monkeys have monkeypox, and so on (note: chicken pox is NOT a member of this group - its name comes from an old English word meaning “Itchy”, and is completely unrelated).

However, sometimes, the similar viruses can cross species barriers, as in the case of cowpox. Though the viruses are specialized to their host species enough that they don’t easily spread between atypical hosts, they’re related enough that once an individual is infected with one pox virus, their immune system is able to to recognize and fend off the whole lot of them. This is why, with the assistance of cowpox (Vaccinia) cultures in administered vaccines (rather than all of humanity having to be in direct contact with cows…), smallpox was able to be eradicated in the wild.

A Text-Book of Bacteriology, including the Etiology and Prevention of Infectious Diseases. Edgar M. Crookshank, 1897.

Here’s something you don’t see around anymore–smallpox is the only human infectious disease that has ever been eradicated, with the last known natural case occurring in Somalia in 1977. The virus itself still exists in two labs, one in Russia and one in the US, so there’s still stockpiles of vaccine kept around, including enough for everyone in the US due to fears of it being a potential bioterrorism agent.

The vaccine is a really interesting one in that it actually does not contain smallpox virus itself. Instead, it’s made with a much weaker but closely related virus called vaccinia. The virus is administered with a small, two-pronged (bifurcated) needle, with the vaccinator making fifteen small pokes that cause a blister to develop. After two weeks, the blister becomes a scab, and in the third week the scab falls off, leaving behind a scar.

As you can imagine, this method of vaccinating wasn’t the easiest, so vaccinators in underdeveloped countries made extensive use of jet injectors, which were needleless and fired the vaccine into the skin through pressure. These unfortunately fell out of favor due to concern that they might become contaminated with patients’ blood–just think of what use an improved version might have among the needle-phobic population!

It should now be obvious that during the two centuries of smallpox vaccination and up until the 1990s there was no certain way of testing for distinct orthopox viruses. During the two centuries of vaccination, the viruses were likely to mutate, and certain strains could have been selected out as a result of vaccination.

Therefore, does anyone know how much ‘smallpox’ disease was actually monkeypox or vaccinia? Given that monkeypox is thought to be an ancient virus, where was it during the smallpox epidemics? Was it called hemorrhagic smallpox?

In 1972, scientists were asking similar questions when they said:

“Is it possible that there is an animal reservoir for smallpox infection? Could monkeypox be a source of new outbreaks of true variola? Or, can the monkeypox virus undergo certain mutations and become identical in its pathogenicity and infectiveness to the variola virus?” [18]

ACCORDING TO SCIENTIFIC AMERICAN, monkeypox is not that rare. Seven hundred and sixty cases of monkeypox were counted in the Congo between 2006 and 2007.

Before and during the time of eradication declaration, PCR was unavailable, and the different poxviruses couldn’t be distinguished by their DNA, but by a skin test on rabbits, chick embryo membranes, and blood tests that were fraught with uncertainty. It seems to me that what was once called smallpox was likely a very non-uniform disease that could have been anything from cowpox to two forms of smallpox to chickenpox to monkeypox.

“Monkeypox virus is closely related to some other orthopoxviruses such as variola (smallpox) virus, and it cannot be distinguished from these viruses in some laboratory tests….In 1996-1997, an outbreak [of monkeypox] in the DRC continued for more than a year, with a person–to–person transmission rate estimated at 78%. However, epidemiological evidence suggests that many of the cases in this outbreak may have been chickenpox (varicella); the number of monkeypox cases and the transmission rate might have been overestimated due to self-reporting and the unavailability of laboratory testing.” [19]

When vaccination stopped, monkeypox was suddenly diagnosed in humans. Diagnostic methods were absent during the great vaccine campaigns and everything pox-like was considered smallpox and counted as smallpox. Differentiating was not a priority.

Variola, the smallpox virus, is not in the smallpox vaccine. Instead, a cultured form of cowpox, called vaccinia, is the virus used to prevent smallpox. That same vaccine also covers monkeypox, according to the CDC:

Smallpox vaccine is effective at protecting people against monkeypox when it is given before they are exposed to monkeypox. (Exposure includes very close contact with a person or animal that has monkeypox.) Experts believe that vaccination after exposure to monkeypox may help prevent the disease or make it less severe.“ [20]

"Because the monkeypox virus is related to the virus that causes smallpox, the smallpox vaccine can protect people from getting monkeypox as well as smallpox.

Even though PCR can distinguish between the three viruses, clinically and immunologically the viruses are so similar, that one virus in the vaccine is thought to immunize against the two other viruses. During outbreaks they all look the same.

Vaccinia virus infections guide new vaccine designs

If we mapped out the family tree of poxviruses, then vaccinia virus (the causative agent of cowpox) and variola virus (the causative agent of smallpox) would probably be sisters. Or at the very least, cousins. This close heritage allows the relatively benign vaccinia virus to confer variola virus-protective immune responses in vaccinated individuals.

Read more at:

Image credit: Weltzin et al 2003, Nat Med 9 (9):1125-30

As we have learned more about the world of microbes, we have realised that it’s possible to use bacteria and viruses as treatments against disease. But although microbes often work incredibly well at protecting against infections or attacking tumours, we still don’t really know exactly how they work.

We know that our immune systems have developed ways to keep up with the devious tricks and schemes of microbes. When our cells become infected, the immune system activates a huge cascade of pathways, one of which leads to the activation of T cells against infected targets.

For T cells, forming a tight bond with these infected target cells is thought to be incredibly important in achieving a high-grade T cell killing performance.

Now, a team of scientists from the Chinese CDC has found that the tightness of the bond between a T cell and a target cell infected with vaccinia virus (administered as a therapeutic vaccine) relies heavily on the expression of the signalling molecule, MyD88. Surprisingly, it doesn’t rely much on the affinity of the T cell receptor, or the inflammatory conditions generated by the infection.

This exciting research suggests that vaccines capable of engaging the MyD88 pathway might perform better by tuning T cells to bind more tightly and kill more effectively their intended target cells.

You can find out more about this research here:

Image credit: Abcam. MyD88 staining appears in green, nuclear staining in blue and plasma membrane staining in red.