It begins with symptoms that could be caused by many diseases – pounding headaches, exhaustion, and searing fevers. Only days later, the cold has become something far worse as a telltale rash begins to spread along the patient’s body, soon swelling with pus and scabbing over to leave raised bumps over the infected skin. Even if the patient survives, the disfiguring scars can last a lifetime. This is the mark of smallpox – or it was, almost five decades ago, when the disease was still common in many parts of the world. In terms of mortality, smallpox tops the list: the smallpox virus has killed more members of the human population over the span of recorded history than all other infectious diseases combined36.
In most of the diseases we have studied, mankind is in a pitched evolutionary battle with the viral co-inhabitants of this planet. Advances in biomedical technology may result in victorious skirmishes, but the war is seldom won as quickly-replicating viruses race to overcome vaccines and other drugs. Smallpox is one of the few true success stories, as the 1980 announcement by the World Health Organization of the worldwide elimination of smallpox marked a true victory. While smallpox vaccination used to be commonplace and widespread, its eradication made such treatment unnecessary. Except for a few isolated laboratory strains – preserved for posterity – smallpox is just a memory.
Or is it? Those same laboratory strains have many worried. Because smallpox has not been a public health threat for decades, stockpiles of vaccine are at an all-time low. If the virus were weaponized, there would be very little that could be done in response – and that is reason to be concerned.
Poxes Small and Large:
Much of what we know about the human smallpox virus comes from studying similar viruses that infect animals. This comparison works because the smallpox virus belongs to a family of closely related pathogens known as Orthopoxviruses. The members of this family are distinguished by their host (i.e. what kind of animal they can infect) and geographical distribution. Some, like the smallpox virus, are species-specific. For example (as seen in the picture below), poxviruses like variola major (smallpox) of humans (a), mousepox virus of mice (b) or camelpox virus of camels (c) remain largely restricted to one host species and rarely, if ever, cause infections outside of that species. Other poxviruses can infect multiple host species. It is the shared characteristics of this family that allow information about smallpox to be inferred from studies of its animal infecting relatives in the viral evolutionary tree. A few of the more important members of the Orthopoxvirus family include:
Variola virus: This is the virus responsible for smallpox in humans. The name, first used to described the disease rather than the virus, is derived from the latin words varius (meaning “spotted”) and varus (meaning “pimple”), and was coined in the 6th Century in Switzerland37. Later, English physicians would use the term pockes, based on the word poc (meaning “pouch”) to describe diseases causing the same raised sores as smallpox38. The designation small came in the 15th Century, when it was necessary to distinguish the disease from the “great pox” – syphillis. The virus has two forms, called major and minor, based on the mortality rate for each strain. The classic form of smallpox is caused by V. major, while V. minor was recognized through epidemiological studies in the 20th Century39. Geographical variants of both V. major and V. minor also exist.
Vaccinia virus: Because variola is so dangerous to handle (requiring strict biohazard safety conditions), much of what we know about the smallpox virus actually comes from work on vaccina, a pox virus that infects several different animals including cattle39. This includes the cowpox virus that Jenner used in his landmark vaccination experiments (see historical section).
The Deadly Brick
Researchers first observed pox viruses under the microscope at the end of the 19th century. Much larger than many viruses, poxes possess a bricklike appearance39. The genomes of the orthopox viruses are composed of DNA, not RNA39. Because DNA polymerase is much less error-prone than RNA polymerase, this feature has important clinical outcomes for mutation rate (discussed below). Zoom in and one can see that the brick structure is composed of three distinct components: (1) an inner “core” containing the DNA and associated proteins, (2) a protein shell that forms the outer membrane, and (3) a plasma membrane derived from the cell from which the virus budded. The virus does not always contain the outer membrane component. Sometimes, instead of budding, the host cell is broken apart and the virus exits wearing only its outer protein layer.
While these “un-enveloped” viruses are still problematic, the lack of a cell-derived membrane has important implications in pathogenesis and vaccination39.
The Pox Virus Life Cycle
The cycle by which the smallpox virus replicates is similar to other viruses. First, a free-floating virion penetrates the cell membrane of its target cell. How efficiently the virus gets through the host’s membrane depends on whether or not it is coated by a plasma membrane39. Those pox virions with a membrane outer coating can enter a host cell more easily and, as a result, are more infectious.
Once inside, the pox virus, like HIV, sheds its outer coating and begins replicating. However, because its genome is made of DNA, the pox virus can copy itself in the cytoplasm unlike RNA viruses that must enter the nucleus of their host. The pox virus generate protein and DNA copies, recombines into a functional virion, and then buds off from the host cell, destroying it as a result. The cycle begins anew as the newly released virions go on to infect other cells.
Even after the smallpox virus has infected a host, no symptoms are seen in the first two weeks41. This is a particularly dangerous time as every silently infected person can infect 10 to 15 more, who unless quarantined, go to infect 10 to 15 more themselves41. An infected individual initially looks and feels fine because the virus has not started actively replicating and shedding copied versions of itself throughout the body. Once this proliferation has begun in earnest, the infected individual begins to experience flu-like symptoms. Just as the patient seems to be getting better, a terrible rash develops, particularly on the face41. The rash worsens, becoming pus-filled bumps that eventually scab over, leaving the pitted scars that are a hallmark of smallpox41.
Less obvious – and even more dangerous – are the ulcers that develop inside the throat and nose of the infected individual. When the skin cells containing the virus die, they release the virus into neighboring saliva and digestive passageways. At this point, the individual’s saliva becomes contagious, able to spread the virus by coughing if precautions are not taken39. The virus is also freed from the confines of the ulcer, and moves throughout the body through the conduit of the digestive system to infect any organ it comes in contact with39. The more organs it infiltrates, the worse for the patient. Simply put, the virus overwhelms the body, killing cells of multiple organ systems.
As noted above, transmission of the smallpox variola virus occurs exclusively from human to human with no insect intermediate or animal reservoir also containing the virus. It is mainly spread through aerosol when infected individuals cough up smallpoxlaced mucous particles42. Once infected, patients are only contagious once the rash has developed and remain contagious even as the rash scabs42. Fallen scabs containing active virus particles can collect on bed sheets or clothing and must be subjected to proper disinfection procedures42. In the more severe V. major, the infected are often incapacitated, and so transmission can be minimized as long as exposure by healthy individuals is kept to a minimum42. However, in the case of V. minor, the symptoms are so mild that infected individuals may spread the virus easily during its infectious stage42.
One of the main reasons a smallpox outbreak would be so deadly is because there is no known drug treatment. The symptoms such as fever and headache can be subsided with traditional medications such as aspirin, but the virus itself cannot be killed by any drug in our current medicinal arsenal. More effective treatments may be on the horizon, though. Cidofovir, a viral DNA polymerase inhibitor used to treat cytomegalovirus (CMV) in AIDS patients, has been shown to kill smallpox virus in laboratory studies43,44. However, the compound must be injected intravenously and causes kidney damage in the large concentrations required to penetrate smallpox-infected cells44. Currently, scientists are working to re-formulate the drug in a less toxic version. Until then, vaccination remains the primary protection against smallpox. To fully appreciate the impact of vaccination on the eradication of smallpox, first we must delve into some history….
The Origins of Smallpox
The earliest records of smallpox emerged from museum collections including mummies dating from 1570 to 1085 B.C.44 From these specimens, scientists have concluded that Ramses V (a young Pharaoh monarch who died in his early thirties) likely died of smallpox45. With this disease and a civil war during his reign, it seems no great wonder that he died young! Other ancient civilizations proved more fortunate. Indeed, even though the global eradication of smallpox had to await modern technologies allowing large-scale vaccine production, mankind has known for millennia that it is possible to shield oneself against the virus. Striking evidence of this comes from the subcontinent of India, where medical texts from 400 C.E. contain what may be a description of an early vaccination procedure46:
Take the fluid of the pock on the udder of the cow or on the arm between the shoulder and elbow of a human subject on the point of a lancer, and lance with it the arms between the shoulders and elbows until the blood appears. Then, mixing this fluid with the blood, the fever of the smallpox will be produced.
If this account is true, then it appears that Indian physicians discovered the
protective power of cowpox a millennia or more before it was known in the West47.
Certainly, the clinical symptoms of the disease were recognized by these early doctors, as indicated by passages such as this:
Before [smallpox] appears, fever occurs, with pain over the body, but particularly in the back . . . . When bile is deranged, in this disease, severe pain is felt in the large and small joints, with cough, shaking listlessness and langour; the palate, lips and tongue are dry with thirst and no appetite. The pustules are red, yellow, and white and they are accompanied with burning pain. This form soon ripens . . . . When air, bile and phlegm are deranged, in this disease the body has a blue colour, and the skin seems studded with rice. The pustules become black and flat, are depressed in the centre, with much pain. They ripen slowly . . . this form is cured with much difficulty, and it is called Charmo or fatal form48.
Indeed, it appears that the disease was so well-known in India that a Hindu Goddess of Smallpox named Sitala was venerated in many regions49. The afflicted would pray to Sitala to rid them of the disease, using drops from the water of immortality she was said to carry with her50. One of the ways in which Brahmin priests venerated Sitala was to journey the countryside each spring, inoculating villagers against smallpox as they went51.
Jenner and Pasteur: The Birth of Vaccination
Development of medical practices in the West comparable to India’s actions would not come until the close of the 18th century when English physician Edward Jenner made a remarkable observation in his country home52. The dairy maids in the surrounding farms bore the lesions of cowpox, but never acquired smallpox: they were seemingly protected from the human virus52. Wondering whether this immunity could be replicated, Jenner injected a young helper with pus from a cowpox lesion from one of the milkmaids, and observed that the boy developed resistance to smallpox afterwards52. Jenner named his discovery vaccine (after the latin vacca, meaning “cow”) though he did not
understand fully why it worked52. The full explanation would await modern theories of immunology, though Jenner’s technique, refined by Louis Pasteur to combat rabies, would become immensely influential nonetheless34.
Vaccination Takes Off
Vaccination would become increasingly widespread through the first half of the 20th century though it was never done extensively enough to eradicate smallpox. Even in countries such as England, where the disease had become uncommon, infected individuals from Africa spread a rash of cases in 1962, and only a quick surge of vaccinations prevented a full-blown epidemic. However, the vaccinations could cause harm as well, resulting in severe adverse reactions in some individuals. To avoid having to negotiate this delicate balance between the benefits and shortcomings of vaccination, the disease would have to be completely eliminated53.
Doubtless this need for a lasting solution drove the 1950-1958 vaccination campaigns in South America, Central America, and the Caribbean, complementing earlier efforts that had pushed cases in the United States into the single digits53. Based on this success a global campaign was launched by the World Health Organization in 1959, though it was not until 1967 that the effort truly intensified to meet the challenge of the task53. At this point, consistent supply networks were established, as well as extensive monitoring systems in many countries so that the effectiveness of the vaccination campaign could be confirmed over time54.
Besides such organization, technological developments also aided this campaign. One was the bifurcated needle (shown to the right). Instead of a standard shot that punctured a vein, vaccinators employed a simple device developed in the 1960s by pharmaceutical firm Wyeth Laboratories. This horseshoe-shaped needle was dipped in vaccine then lightly tapped against a patient’s skin to make a series of small punctures. In selfless move, Wyeth allowed the needle to be used without charging patent royalties. Besides their ease of use, the bifurcated needle also had the advantage of reusability: provided they were sterilized, each instruments could vaccinate hundreds of individuals55. In addition to providing needles, Wyeth was also manufacturing the Dryvax smallpox vaccine used during the eradication campaign56.
During the campaign, field workers would scour the globe, distributing vaccine and controlling outbreaks. Their efforts eventually met with success, with the last instance of smallpox infection recorded in Somalia in 1977. Another aberrant case cropped up in 1978 when a strain escaped a laboratory in England, but besides this, no other infections were reported. In 1980 the disease was declared extinct57-59.
Prior to its eradication, vaccination for smallpox was done using inactivated strains of vaccinia virus. However, only small stocks of the vaccine now remain and are not available for widespread distribution. Typically, only researchers in high security facilities are now vaccinated for smallpox60,61. Despite concerns about future biological warfare, the knowledge that the vaccine has side effects is a major argument against re-instituting more widespread smallpox vaccination in preparation for a bioterrorism attack. These complications usually result in skin rashes or, in more severe cases, potentially fatal tissue death. While health officials predict that only 1-2 out of every million vaccinated would actually die of such complications, the risks are still too much to reinstate vaccination on a large scale41,42.
Resurrecting the Pox?
The existence of laboratory strains of the virus means there is still a possibility of it being resurrected as a bio-terror weapon. While the strains locked away at the CDC can probably be assumed safe from such abuse, the collapse of financial backing for Russian scientific research has raised concerns that private (and unfriendly) hands could now be funding work in former Soviet bioweapons facilities62.
Is there a benefit to maintaining smallpox stocks in the laboratory? Some researchers claim that these supplies are necessary for further research. However, this seems suspicious given that most of what we know about the virus actually comes from animal forms such as vaccinia. Nevertheless, policy makers have supported retaining samples of the human virus. Even though the World Health Organization had promised the destruction of all remaining smallpox stocks in the US and Russia by 1999, the Clinton administration decided to reverse this plan in the US, claiming the samples were needed for future anti viral research, or, in the event that the virus remerged, to develop new vaccines53. However, the rescued stocks have actually generated little scientific interest, with no new pharmaceutical or vaccines developed in the years since they were salvaged from their planned destruction53.
So how deadly would an outbreak be? Certainly, the lack of current vaccination makes smallpox a particularly dangerous threat, and since the vaccine is not used regularly in the US anymore, immunity levels among the American population are effectively nonexistent. Besides this, the virus is a tempting weapon because it can be easily grown and aerosolized53. Thus, because of this threat, the pros and cons of widespread vaccination are still being weighed, with the true threat of a smallpox outbreak remaining unknown.