Krishna milking a cow
Krishna, milking a cow

Vaccinia virus is a widespread virus whose natural host remains unknown.  It turns out to be pretty good at jumping across species.

Vaccinia, of course, is the vaccine against smallpox.  Even though smallpox is eliminated in the wild,1 vaccinia is still very widely used in research and even, to some extent, in the clinic, because the broad and deep experience with the virus gained from its importance in vaccination has carried over into other fields.

When Jenner developed his vaccine against smallpox, he used the cowpox virus.  But — in spite of a widespread misconception — vaccinia is not cowpox.  They’re quite distinct viruses, though they are related.  At some point along the centuries of vaccine use cowpox was replaced by vaccinia. (It’s also worth pointing out that the disease Jenner called cowpox, may not have been cowpox as we know it today. 2  It may have been a distinct strain of virus, or it may have been a different virus altogether.)

Remember that for a couple of hundred years, there was no tissue culture to grow the virus in, and it was basically propagated by continually re-infecting animals and collecting virus from their scabs.  At some point, presumably a cow that was being used as a vaccine incubator was infected with vaccinia instead of cowpox, and the vaccinia proved more effective, or perhaps safer or more convenient, as a vaccine, crowding out the vaccine cowpox.

Cowpox innoculation - Zhu Chunxia
“Cowpox inoculation sites”
Douzhen dinglun (Definitive Treatise on Pox Diseases)
by Zhu Chunxia, 1888

(By the way, it’s interesting to note that cowpox has an MHC class I immune evasion function,3 whereas vaccinia virus does not.  Obviously this immune evasion doesn’t prevent cowpox from acting as a strong immunogen, because it was an effective  vaccine for decades if not centuries, but perhaps it’s one reason vaccinia was a more popular vaccine.)

Where vaccinia virus came from — what animal it was infecting before it jumped into cattle  — no one knows.  Although vaccinia must have (or have had) a natural host at one point, the true host for the virus is now cultured cells in the lab incubator.

Does that mean vaccinia isn’t found in the wild? Not at all.  Vaccinia virus does infect a bunch of animals, in many parts of the world.  But what’s happened is that the virus has gone feral: It’s jumped from vaccinated humans into other species — usually cattle — and then spread among that population.  In Brazil, this feral vaccinia virus has become a significant emerging disease in cattle, from which it jumps back again into humans:

Starting in 1999 several VACV strains were shown to be responsible for zoonotic disease affecting more than 1100 dairy cattle and up to 80% of their handlers in rural tropical rainforest and woodland savanna areas in southeast Brazil 4

The origin of this Brazilian bovine vaccinia is unknown.  Almost certainly it’s derived from the vaccine — the alternative explanation, that it’s derived from the original, natural host of vaccinia, seems really unlikely, especially since the disease has only been detected in the past ten to twenty years. But genetically, it doesn’t look much like any of the known vaccine strains.5  (However, I remember reading a paper that I can’t turn up right now, that talked about vaccinia-based vaccines in the early 20th century. It made the point that there wasn’t particularly careful oversight or recording of precise strains or provenance of smallpox vaccines, and emphasized that there were several different strains of vaccinia used in South America, not all of which were well characterized.)   Grant McFaddden’s interpretation of the feral virus’s relationships is that there were probably recombinations between different strains of the virus, which makes it hard to reconstruct the genetic history of the virus; complicated by a long period of adaptation to its new host(s):

On the other hand, the Brazilian isolates appear to have escaped in a single event or in multiple events and probably adapted to a new host, until they re-emerged in man or cattle at least 25 years later. 2

Cowpox (Wellcome Images)
Cowpox on a cow’s udder
Trattato di vaccinazione con osservazioni sul giavardo e vajuolo pecorino
by Luigi Sacco, 1809

There’s another puzzling aspect to the Brazilian vaccinia epidemics: How are they spreading? Although most of the epidemics can be traced back to infected humans, there are some exceptions:

… some VACV outbreaks are temporally and spatially distant from previously notified BV areas. … Rats, mice, opossums, foxes, wild dogs and small felids are frequently observed around farming properties. In theory, some of these species, especially rodents, could be VACV reservoirs. 6

Indeed, the virus was recently isolated from a wild mouse,6 suggesting that rodents might be spreading the virus between farms.

The implication is that over the past hundred years or so, vaccinia virus has sequentially jumped from its original, unknown host, into cattle, into humans, then back into cattle, into rodents, back into cattle, and then back into humans, not counting its long side-trip into the laboratory incubator.  It’s the Michael Jordan of jumping viruses.

  1. Hopefully! But see this post for more[]
  2. Moussatché N, Damaso CR, & McFadden G (2008). When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond. Journal of infection in developing countries, 2 (3), 156-73 PMID: 19738346[][]
  3. Alzhanova, D., Edwards, D., Hammarlund, E., Scholz, I., Horst, D., Wagner, M., Upton, C., Wiertz, E., Slifka, M., & Früh, K. (2009). Cowpox Virus Inhibits the Transporter Associated with Antigen Processing to Evade T Cell Recognition Cell Host & Microbe, 6 (5), 433-445 DOI: 10.1016/j.chom.2009.09.013[]
  4. Essbauer, S., Pfeffer, M., & Meyer, H. (2010). Zoonotic poxviruses? Veterinary Microbiology, 140 (3-4), 229-236 DOI: 10.1016/j.vetmic.2009.08.026[]
  5. DRUMOND, B., LEITE, J., DAFONSECA, F., BONJARDIM, C., FERREIRA, P., & KROON, E. (2008). Brazilian Vaccinia virus strains are genetically divergent and differ from the Lister vaccine strain Microbes and Infection, 10 (2), 185-197 DOI: 10.1016/j.micinf.2007.11.005[]
  6. Abrahão, J., Guedes, M., Trindade, G., Fonseca, F., Campos, R., Mota, B., Lobato, Z., Silva-Fernandes, A., Rodrigues, G., Lima, L., Ferreira, P., Bonjardim, C., & Kroon, E. (2009). One More Piece in the VACV Ecological Puzzle: Could Peridomestic Rodents Be the Link between Wildlife and Bovine Vaccinia Outbreaks in Brazil? PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007428[][]