WASHINGTON — A new report from the National Academies of Sciences, Engineering, and Medicine says that action is needed to enhance U.S. readiness for smallpox and related diseases, as well as to improve diagnostics, vaccines, and therapeutics that could be used in case of an outbreak. The COVID-19 pandemic revealed weaknesses in the ability of U.S. public health and health care systems to adapt and respond to an unfamiliar pathogen, as did challenges during the recent mpox outbreak to rapidly making diagnostics, vaccines, and therapeutics available at scale.

The development of better diagnostics, vaccines, and therapeutics — also called medical countermeasures — would improve the nation’s ability to respond to a smallpox outbreak or attack using the virus, the report says. It also calls for strengthening the systems and policies that would allow public health and health care systems to act quickly and effectively, such as those that could support rapid distribution of a vaccine.

The report says U.S. population changes and advancements in gene editing and synthesis technologies have drastically altered the potential for a smallpox outbreak or attack in recent years. It is now possible to engineer variola virus, the virus that causes smallpox, raising the possibility of accidental or intentional release. Furthermore, illnesses related to smallpox such as mpox, Alaskapox, and cowpox are increasingly found in humans, presenting the need for medical countermeasures that can detect, treat, and prevent these diseases.

In 1980, the World Health Assembly declared smallpox eradicated, and no naturally occurring smallpox cases have been reported since that time. Two WHO sanctioned collections of the live variola virus — at the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia, and the Laboratory for Applied Microbiology at Koltsovo in Russia — store samples and use variola virus in research. Viruses related to variola, called orthopoxviruses, are also used in research.  

Research using live variola and related viruses is essential for creating and improving medical countermeasures for smallpox and other related diseases, and to ensuring the U.S. is ready to respond to an outbreak, says the report. Live variola in particular is essential for developing new targets for more effective therapeutics; verifying the efficacy of vaccines, treatments, and diagnostics for smallpox; and creating animal models that can be used in research in place of humans. Research using these viruses can also fill gaps in our fundamental understanding of orthopoxvirus biology, ecology, evolution, transmission, and disease onset in humans.

As biotechnologies including gene editing and DNA synthesis continue to advance, the report says decision-makers need to consider the benefits and risks for smallpox medical countermeasures, noting such impacts will be amplified and accelerated by advances in artificial intelligence. For example, AI models could be used to understand how variola virus might naturally evolve within a population, helping to mitigate the spread of a new outbreak. However, such models could also aid those seeking to render existing treatments ineffective. The report concludes a risk-benefit analysis is needed for smallpox research using emerging technologies.

Smallpox Diagnostics, Vaccines, and Therapeutics  

The committee that wrote the report examined the state of medical countermeasures that have been developed and stockpiled in the U.S. Strategic National Stockpile to identify, prevent, and treat smallpox. Despite research done in recent decades and the fact that more smallpox medical countermeasures are available now than before the disease was eradicated, the nation’s ability to respond to a smallpox event could be strengthened. The report says:

• Diagnostic tests are needed that can more accurately detect smallpox and related viruses, identify potential cases at earlier stages of disease, assess prior exposure or immunity to smallpox, be used across biosafety levels and in field settings, support disease surveillance, and enhance equitable access to testing than those available today.

• Vaccines that are safer, can be used across different populations, and are available as a single dose would support a faster and more effective response to a smallpox outbreak. Developing new smallpox vaccines that use a multi-vaccine platform — which use common vaccine vectors, manufacturing ingredients, and processes — would improve the capacity for rapid production and reduce the need for stockpiling.

• Therapeutic options that are safer and more diversified — such as antivirals with different and diverse targets, mechanisms of action, and routes of administration, or treatments based on novel technologies and platforms — would be advantageous supplements to existing therapeutics.

• Diagnostic tests are needed that can more accurately detect smallpox and related viruses, identify potential cases at earlier stages of disease, assess prior exposure or immunity to smallpox, be used across biosafety levels and in field settings, support disease surveillance, and enhance equitable access to testing than those available today.

• Vaccines that are safer, can be used across different populations, and are available as a single dose would support a faster and more effective response to a smallpox outbreak. Developing new smallpox vaccines that use a multi-vaccine platform — which use common vaccine vectors, manufacturing ingredients, and processes — would improve the capacity for rapid production and reduce the need for stockpiling.

• Therapeutic options that are safer and more diversified — such as antivirals with different and diverse targets, mechanisms of action, and routes of administration, or treatments based on novel technologies and platforms — would be advantageous supplements to existing therapeutics.

“The gaps in our ability to respond to a new infectious disease were revealed by the COVID-19 pandemic and recent mpox outbreak,” said committee chair Larry Gostin, distinguished university professor and director of the WHO Organizing Collaborating Center on National and Global Health Law at Georgetown University. “It is vital to prioritize research into the development of safer and more effective smallpox diagnostics, vaccines, and therapeutics, make judicious choices in stockpiling, and have modern, well-practiced, and adaptable plans for responding in the event of a smallpox outbreak.”

“The eradication of smallpox is one of the most significant accomplishments of medicine and public health, ending an ancient scourge of humanity,” said Victor J. Dzau, president of the National Academy of Medicine. “We have to protect against the reemergence of this disease by maintaining and strengthening effective and safe medical countermeasures.”

Readiness and Response

The report says that plans for responding to a smallpox outbreak or attack need to be flexible and continually updated to meet the challenges of multiple potential scenarios. The small number of manufacturers capable of producing smallpox medical countermeasures is a specific vulnerability, and there is currently insufficient capacity to scale production in the event of a large outbreak or attack. Logistics and supply chain management planning is critical, as is planning for regulatory responsiveness. COVID-19 and mpox demonstrated the challenge in public acceptance and effective risk communication for vaccines, and the same challenges with vaccine hesitancy and misinformation could occur in a smallpox outbreak. Clinical and public health guidance also needs to be updated to reflect new data and medical countermeasures so that health care providers and others on the front line of public health have the capability and capacity to respond to smallpox.

In the case of an international smallpox emergency, U.S. readiness and response capabilities will be significantly affected by the ability of other countries to detect and contain smallpox transmission. Supporting international capacity and ability to access smallpox medical countermeasures will improve U.S. biosecurity in turn.

The study, undertaken by the Committee on the Current State of Research, Development, and Stockpiling of Smallpox Medical Countermeasures, was sponsored by the Administration for Strategic Preparedness and Response. 

The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, engineering, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln.

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