Reemergence of smallpox: A greater threat now than ever before

By Chris Healey

In the event of a resurgence of smallpox, treatment and containment would be exacerbated by illnesses and medical practices not present when the virus was eliminated.

Smallpox was one of the most significant diseases in human history. Although it was first distinguished from measles in China around 340 AD, evidence of the disease has been found on the remains of Egyptian mummies entombed over a thousand years earlier.

Smallpox is caused by Variola major, a virus in the Orthopoxvirus genus. The illness is known for causing characteristic pustules, severe symptoms and debilitating morbidity. Mortality rates exceeding 30% have been reported. The disease is almost always fatal in immunocompromised individuals.

Efforts to confer immunity against smallpox have been practiced for centuries. A technique called variolation, which involved inoculation with material from smallpox pustules, was used as far back as 1000 AD.

Due to the conserved nature of Orthopoxvirus, immunity to a wide range of viruses within the genus can be conferred after infection with a virus within the same genus. In 1796, Edward Jenner discovered inoculation with cowpox conferred immunity to smallpox. He called the technique vaccination, from the Latin vacca for cow. Vaccination results in less adverse effects and fatalities than variolation, making it the preferred method of conferring smallpox immunity.

Today, vaccinia virus is used in lieu of cowpox virus to confer immunity. Vaccinia virus creates a localized lesion that disappears over time in most individuals.

Persistent vaccination practices lead to the elimination of smallpox from most industrialized countries by the 1950s. In 1966, the World Health Assembly voted to fund an aggressive worldwide vaccination campaign to whittle away remaining pockets of the illness. After a successful campaign, the World Health Organization declared smallpox eradicated on December 9, 1979. The organization issued a recommendation for the cessation of smallpox vaccination in 1980.

Although smallpox is not a public health threat, it still exists. Stockpiles of the virus are maintained at the headquarters of the Centers for Disease Control in Atlanta and at a biotechnology institute in Novosibirsk, Russia.


Reintroduction of smallpox to the population would be devastating. Several immunologically-naïve generations are present. Other than those who received smallpox vaccines through military or specialized research positions, the entire population is almost completely unprotected.

Immunocompromised individuals who receive a vaccine utilizing a virus capable of self-replication, also known as a replication-competent vaccine, have a risk of developing a condition called progressive vaccinia. It is an extremely debilitating condition with no cure and a 90% fatality rate.

Dryvax, the vaccine used to eliminate smallpox, was replication-competent. Progressive vaccinia was reported as a rare adverse reaction when smallpox vaccines were administered during eradication efforts. Although Dryvax is no longer used, another replication-competent vaccine, ACAM2000, has taken its place. If ACAM2000 is administered to the general population today, far more cases of progressive vaccinia are expected to occur.

HIV and immunosuppression drugs are two modern factors contributing to decreased immune function. The World Health Organization estimates 35.3 million people in the world are living with HIV—1.1 million of those in the United States. Immune suppression associated with the illness would make smallpox vaccination undesirable, and smallpox infection fatal. HIV was not a factor during eradication efforts. Individuals with HIV would be at great risk in the event of smallpox reemergence.

Many modern drugs dampen the immune system to alleviate a range of conditions and symptoms, from hay fever and asthma to anti-rejection drugs for transplant recipients. Immunosuppression drugs have become commonplace. Those drugs did not play a significant role during eradication efforts because they were very expensive and uncommon. In the event of a re-emergence, smallpox would likely exploit those taking immunosuppression drugs. Furthermore, immunosuppression drugs dramatically increase the chance of developing progressive vaccinia following smallpox vaccine administration.

There is, however, a vaccine alternative for immunocompromised individuals. Imvamune is a replication-incompetent vaccine produced by Bavarian Nordic. Replication-incompetent vaccines deliver a virus incapable of replication, meaning it cannot cause progressive vaccinia. Unfortunately, there is no way to test the vaccine’s ability to confer smallpox immunity. Replication-incompetent vaccines are generally considered by health experts to be less effective at conferring immunity than replication-competent alternatives.

It is for these reasons that the re-emergence of smallpox would deal a catastrophic blow to the wellbeing of individuals around the world and therefore every effort must be made to prevent the return of smallpox.

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