Bioterrorism – Could Smallpox Return?

The variola major virus, which causes smallpox, had a long and terrifying pathogenic history in the human population – the only natural host. Examinations of 3,000-year-old Egyptian mummies identified markings similar to smallpox scars. The smallpox-like disease has been documented worldwide in writings for over 1,000 years. With a mortality rate of approximately 30%, along with possible blindness and severe scaring experienced by the survivors, it was a greatly feared pathogen over recorded human time.

The last natural smallpox outbreak in the United States was in 1949. The last documented naturally occurring case was in 1977 due to an aggressive and successful worldwide vaccination campaign. Due to a very effective global vaccination program, the World Health Assembly declared smallpox eradicated in 1980.

Although smallpox was eradicated from its human population and reservoir, it is still in designated stockpiles controlled by two nations. With the negative lessons learned and not learned from SARS-CoV-2 and possible laboratory leaks, suppose smallpox or a close variant returned to the human population. Immunity to the virus has faded with the end of the routine vaccination process and time, raising concern about how prepared the nation and world would be if smallpox re-emerged accidentally through a laboratory leak or intentionally through an act of bioterror or biowarfare.

Biowarfare or a Naïve Population

It allegedly happened before. Reports state that, in 1763, British officers traded two smallpox-infected blankets to Native Americans during the French and Indian War. They were reportedly from the smallpox hospital inside Fort Pitt.  There was a siege by Native Americans at the fort with over 500 settlers gathered inside. The plan was reportedly to reduce the number of Native Americans outside the walls by disease before the dreadful disease spread further within the fort.  

The three items were reportedly from the smallpox hospital inside Fort Pitt – the British fort built on the confluence of the three rivers in current-day Pittsburgh, Pennsylvania. There was a siege by Native Americans at the fort with over 500 settlers gathered inside, some ill with smallpox. The plan was reportedly to reduce the number of Native Americans outside the walls by disease before the dreadful disease spread further within the fort. The siege broke when the Indians moved their resources from the fort to intercept 500 British troops responding to rescue Fort Pitt.

According to historical research, it was unknown if the exposed blankets could have transmitted the disease due to the age of the blankets. The very contagious disease was reportedly already circulating in the Indian population since 1759 before the transfer of the blankets at the fort. There were additional allegations that smallpox was present in other items traded by early settlers. Either from intentional infection or interactions with infected settlers, smallpox most definitely entered the naïve population with horrifying consequences. It was estimated that between 500,000 and 1.5 million Native Americans died from smallpox. It was yet another example of how smallpox could ravage a population anywhere in the world.

Eradication and Stockpiles

The Thirty-Third World Health Assembly formally declared the global eradication of smallpox. The resolution declared smallpox as a devastating disease sweeping in epidemic form through many countries since the earliest times causing disfigurement, blindness, and death. The World Health Organization (WHO) initiated the global program to eradicate smallpox in 1959 and intensified it in 1967. Success was achieved in just a couple of decades.

Four countries – South Africa, England, the United States, and Russia (Soviet Union) – retained the variola virus after its eradication for research purposes. By 1984, South Africa and England either transferred or destroyed their viral stocks. Currently, the variola virus is reportedly only stored at the State Research Center of Virology and Biotechnology in Russia and the Centers for Disease Control and Prevention (CDC) in the United States (Atlanta, Georgia). According to the CDC:

The goal of smallpox research is to address three areas that are essential for public health:

• Finding better antiviral drugs to treat smallpox disease.
• Making safer vaccines.
• Improving tests to detect variola virus.

In 1996, the Forty-Ninth World Health Assembly recommended destroying the remaining stockpiles of variola virus in 1999. The declaration recognized that the genome sequence information for the variola virus strains allowed scientific questions to be solved and permitted the diagnosis of suspected smallpox. The variola virus escaping laboratories would be a serious risk as an increasing proportion of the population lacks immunity. The World Health Assembly would again discuss or recommend destroying the variola virus stocks in 1999, 2007, 2011, 2016, and 2019.

A 2007 World Health Assembly resolution mandated WHO to inspect the variola virus storage locations every two years to ensure the highest biosafety and biosecurity requirements. In accordance, WHO biosafety inspection teams visit the repositories and inspect the Russian and American containment facilities. The same team reportedly conducts both inspections and provides reports made available on the WHO website. No significant findings were observed in either nation’s 2019 inspections, but there were recommendations for improvements in both countries.

Vaccines and Antivirals

Immunity to the variola virus is likely very low. Routine smallpox vaccinations ended in 1972 after the disease was eradicated in the United States. The antibody levels were estimated to decline five to 10 years after vaccination. Before eradication, WHO recommended revaccination every five to 10 years for international travelers and three years if traveling to endemic areas. Research indicated that decades-old vaccinations would not protect from the disease but could prevent a fatal outcome.

The United States reportedly possesses sufficient smallpox vaccine in its Strategic National Stockpile (SNS) to vaccinate everyone who would need it for an outbreak if utilized as an agent of bioterrorism. Approximately three-quarters of the federal funds obligated for SNS medical countermeasures (MCM) between 2015 and 2021 were to purchase smallpox and anthrax MCM. The current smallpox vaccine does not contain the variola virus but a similar poxvirus. According to the CDC, the current smallpox vaccination protects for approximately three to five years.

CDC reportedly works with federal, state, and local officials to prepare for a smallpox outbreak. These public health officials would decide who would receive the vaccine, focusing on those directly exposed to the virus with prolonged face-to-face contact. After the challenges of the recent response to SARS-CoV-2, a smallpox outbreak response may not be as easy to execute as described by the CDC. There would likely be trust and confidence issues in the process, affecting outcomes.

The CDC is working with vaccine manufacturers to develop new smallpox vaccines. However, since the virus has been eradicated in humans, the ability to prevent the virus is not directly studied. The researchers use indirect methods by using vaccinated subjects’ blood samples and testing the serum against the virus in a laboratory setting.

The Food and Drug Administration (FDA) has approved two antiviral drugs to treat smallpox – teccovirimat and brincidofovir. However, the drugs have not been tested on humans with smallpox disease, so the actual benefit is unconfirmed.

Retention Failure

The smallpox storage and tracking process may not always meet expectations and requirements. The United States experienced the improper storage and handling of smallpox on at least one occasion. During the clean-up of FDA laboratories in 2014 to prepare for a move from the National Institutes of Health (NIH) campus, six vials of variola virus were discovered in a cold storage room. The vials were found among 327 unclaimed vials in the back of the storage area. The variola virus vials, along with a vial of Russian spring-summer encephalitis and nine unidentified vials, were turned over to the CDC. The 16 vials were destroyed in 2015. The remaining 311 vials were either destroyed or retained for research.

According to the FDA, the 327 vials were reportedly made between 1946 and 1964. It was unknown what entity created the vials and how they came to be placed in the storage room. The FDA laboratory shared the cold storage room from 1992 to 2014. An FDA researcher reported that the room was not empty when they started using the space in 1992. The CDC and the Federal Bureau of Investigation investigated the incident. The FDA conducted a review. The FDA identified six findings with corrective actions in 2016 to prevent a similar occurrence with hazardous biological agents and toxins (HBAT) in the future. Below are the FDA review’s corrective measures:

• Enact policies and procedures to ensure that biological material is not orphaned when its owner departs the laboratory;
• Enact policies and procedures to ensure that a single individual is responsible for all contents, including HBATs, in shared storage areas;
• Conduct a full inventory of all units that store HBATs, and require periodic updates to ensure the inventory list remains current at all times;
• Enact appropriate policies and procedures to ensure that individuals are aware of the proper actions to take when they encounter a select agent or toxin in an unregistered facility or laboratory for which they are not trained to handle;
• Enact procedures to ensure that individuals are aware of the proper officials to contact immediately when there is a safety or security incident; and
• Communicate the best practices to ensure that individuals are aware of the proper way to store materials in a cold room.

These corrective actions should have already been in place for the sensitive FDA laboratories on NIH property. From the report, it was unclear how the variola virus was outside the designated CDC storage location – especially after its eradication in 1977 and declaration in 1980. The concerns remain that another vial could be sitting in an unauthorized area anywhere in the world pending accidental exposure.

The Threat

The variola virus can be hardy if protected from heat and ultraviolet light but is relatively easy to kill with strong disinfectants. However, it can be a serious bioweapon since it is easy to grow and aerosolize for delivery. The Soviets reportedly produced massive bioweapon quantities for research and offensive biological warfare decades ago.

According to the CDC website, there is no immediate, direct threat of bioterrorist attack utilizing smallpox. However, even though it has not been used in modern times, the CDC identified that:

There is credible concern that in the past some countries made the virus into weapons, which may have fallen into the hands of terrorists or other people with criminal intentions.

There have been concerns that quantities of variola virus may have been taken or transferred from the Russian stockpile at the end of the Soviet Union. Some fear that then-unemployed scientists or former Soviet bloc nations may have retained, received, or transferred quantities of the pathogen. Also, Russia could possess uninspected covert stocks due to their enormous previous production. There also were allegations in 2002 that France, North Korea, Iraq, and Iran may have had undeclared stockpiles. The offshoring of sensitive or restricted biological research to other countries could be another danger. The actual amount of existing smallpox virus is quite likely unknown.

With the previous smallpox handling and storage violation and the possibility of human error in biosafety laboratories, the smallpox threat could be a public health concern for the United States. The concern could be more significant from unauthorized and undeclared virus possession and research. The possible access by unfriendly actors and gain-of-function or directed evolution research and technology would support current and enhanced planning and considerations. The recent identification of a suspicious biological research site in California with at least 20 potentially infectious agents only highlights these concerns.

Although naturally occurring smallpox was eradicated from the human population, that does not mean it can never return from a bio-leak or bioweapon. The efficacy of current vaccines and MCM may not be sufficient for smallpox or a newly enhanced variation. SARS-CoV-2, with a mortality rate of approximately one percent, would appear quite manageable compared to a virus with a 30 percent death rate – 30 times greater. Although there are numerous other significant biological concerns to consider and plan for, smallpox should continue to be high on that list.

U.S. pandemic preparedness strategies and plans appeared sufficient until SARS-CoV-2 emerged in early 2020. Existing smallpox planning and preparedness levels could be in the same position with much more serious consequences. The strategy looks good on paper, but the vaccines and MCM may not be readily available and sufficiently effective for an entire nation.  Smallpox could return.