Tametomo's force driving away the gods of smallpox. Yoshitoshi Taiso, 1890
Tametomo’s force driving away the gods of smallpox. Yoshitoshi Taiso, 1890

Following up to my last post , about the Gates Foundation’s call to eradicate malaria, I thought I would talk about historical experience with eradication of infectious diseases. Here is the list of diseases that have been eradicated throughout all of recorded history:

  1. Smallpox

I’ll pause so you can write that down.

OK, there are a couple of other diseases that are, hopefully, on their way to eradication (notably poliovirus), and there are a bunch of others whose incidence has been spectacularly reduced through vaccination (such as measles, diphtheria, and rubella),1 sanitation (such as guinea worm), and even antibiotics (leprosy). But only smallpox has been eradicated. 2

Why was smallpox eradicated, where four other global eradication campaigns3 failed? What was special about smallpox and its vaccine? What are the factors that allowed this disease to be reduced from millions of cases per year, to none? And, most to the point, what aspects of smallpox eradication are applicable to malaria?

In fact, most of the special aspects of smallpox that allowed it to be eradicated are not particularly true for malaria. Smallpox …

  • Has no animal host. If you can eradicate the disease in humans, it won’t re-emerge from a mouse, or monkey, or bat reservoir — compare to yellow fever, for example.
  • Has no persistent phase. Smallpox either kills people, or they recover completely and eliminate the virus. In either case, if there are no clinical cases over a reasonable period, then you can be confident that there is no more virus.
  • Induces long-term immunity in survivors.
  • Was a fearful enough disease that the political will to eradicate it lasted through the campaign. Smallpox vaccination continued throughout civil wars and other upheavals.
 Vaccinating the poor / Drawn by Sol Ettinge, Jun. 1872
Vaccinating the poor. Sol Ettinge, Jr., 1872

And the smallpox vaccine (vaccinia virus) is also exceptional in that it …

  • Induces very long-term immunity with a single dose. Vaccinia virus induces a memory, and probably protective, immune response for an extraordinarily long time — response have been shown for up to 60 years.
  • Is relatively stable and easy to transport and deliver. With large-scale vaccination campaigns, logistics become the limiting factor, especially as the campaign progresses and the final reservoirs of disease may be in remote, third-world areas.
  • Leaves a marker of treatment. Vaccinated people usually had a small scar at the site of scarification, so that it was possible to identify susceptible people and protect them.

The smallpox vaccine is also exceptional in its frequency and severity of adverse effects. I think that for no disease today would the risks of smallpox vaccine be tolerated — back to the fourth point above, that smallpox was such a terrible disease that people were willing to take the risks of vaccination. 4

There were also a vast number of technical and logistic components that, I think, are mostly applicable to any eradication program (for example, the cost per dose of a vaccine is much less if the vaccine can be prepared in large, multi-dose vials; but that means you need to use the vial up all at once, which means in turn organizing large numbers of vaccination on a single day; and that in turn implies an efficient communication network and so on), and which I won’t talk about here. There’s a fascinating review in Henderson, D. A. (1987). Principles and lessons from the smallpox eradication programme. Bull World Health Organ, 65(4), 535-546. if you want to learn more.

“A much greater change — not apparent but real — was produced by the introduction of vaccination in 1798. It was computed, that, in 1795, when the population of the British Isles was 15,000,000, the deaths produced by the small-pox amounted to 36,000, or nearly 11 per cent. of the whole annual mortality. Now, since not more than one case in 330 terminates fatally under the cow-pox system, either directly by the primary infection, or from the other diseases supervening; the whole of the young persons destroyed by the small-pox might be considered as saved, were vaccination universal, and always properly performed. This is not precisely the case, but one or one and a half per cent. will cover the deficiencies; and we therefore conclude, that vaccination has diminished the annual mortality fully nine per cent. After we had arrived at this conclusion by the process described, we found it confirmed by the authority of Mr Milne, who estimates, in a note to one of his tables, that the mortality of 1 in 40 would be diminished to 1 in 43-45, by exterminating the small-pox. Now this is almost precisely 9 per cent.”
Combe, George. 1847. The Constitution of Man and Its Relation to External Objects. Edinburgh: Maclachlan, Stewart, & Co., Longman & Co.; Simpkin, Marshall, & Co., W. S. Orr & Co., London, James M’Glashan, Dublin.
It’s important to point out that eradication of a disease is possible when not all of these factors are matched — poliovirus, which is almost eradicated (and could have been eradicated altogether with a bit more political help) is different in several ways. But it does offer a checklist for known success. How does malaria match up?

Not so well, actually. Malaria …

  • May have an animal reservoir. Apes can be infected experimentally, and are sometimes naturally infected. This is not a practical issue today, where the animal reservoir is negligible, but if human infection is reduced an animal reservoir might serve as a source for reinfection.
  • Does have a persistent phase. This is especially a concern since partially-immune people (common in endemic areas) can be infected and trasmit the disease without showing clinical symptoms — again, a potential reservoir of re-infection.
  • Does not consistently induce protective immunity.
  • Is a terrible scourge, but one to which the world has become accustomed. Is there the will to take on the cost of eradication? The last attempt at malaria eradication — which failed — cost a billion dollars. As Melinda Gates pointed out, the cost of the disease in perpetuity is greater than the cost of eradication, but the costs come from different places.

Since there are no effective malaria vaccines as yet, we can’t very well compare them to the smallpox vaccine. I don’t know enough about the irradiated vaccine that will enter trials next year, but the “RTS,S/AS02D” vaccine in phase I/II trials5 requires multiple doses and apparently offers relatively low protection — certainly better than nothing, if this holds true through phase III trials, but it’s hard to imagine that it’s sufficient for eradication.

So vaccines are probably going to be an important component of malaria eradication (if it happens) but the nature of the disease means that they’re not likely to be sufficient. Melinda Gates said in her eradication speech that “This is a long-term goal; it will not come soon,” and she focused on four “intervention points”:

To eradicate malaria, you have to end transmission — and there are multiple points where you can intervene. Reduce the number of infected mosquitoes. Keep mosquitoes from biting people. Keep people who are bitten from getting infected. Keep people who are infected from transmitting malaria back to mosquitoes.

Vaccines are good candidates to help with the last two points, and may help with the first. But overall, this is a more complex problem than smallpox. Nevertheless, smallpox eradication has plenty of lessons for malaria, as well.

  1. A great review, with dramatic incidence tables is: Roush, S. W. & Murphy, T. V. (2007). Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA, 298(18), 2155-2163. I have adapted their numbers to make a table here []
  2. It is probably true that there are stocks of the virus around as well as the official stocks. However, there have been no cases of “wild” human smallpox since 1977.[]
  3. Henderson, D. A. (1999). Lessons from the eradication campaigns. Vaccine, 17 Suppl 3, S53-5. []
  4. Belongia, E. A. & Naleway, A. L. (2003). Smallpox vaccine: the good, the bad, and the ugly. Clin Med Res, 1(2), 87-92.[]
  5. Aponte, J. J., Aide, P., Renom, M., Mandomando, I., Bassat, Q., Sacarlal, J. et al. (2007). Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet, 370(9598), 1543-1551.[]