In the wake of surging mpox cases in the DRC and the emergence of novel orthopoxviruses, the US needs to rapidly bolster its smallpox readiness, preparedness, and response, according to a new report from the National Academies of Sciences, Engineering, and Medicine. 

The report brought together experts from across the country to critically evaluate the state of smallpox vaccines, diagnostics, and therapeutics, known as medical countermeasures (MCMs), in the event of an outbreak.

Improving MCMs is crucial for enhancing the nation’s ability to combat a smallpox outbreak or deliberate attack, the report emphasizes. It also stresses the importance of fortifying public health and healthcare systems to swiftly and effectively respond, including mechanisms for rapid vaccine distribution.

An ‘evolving bio-threat and technology landscape’

With advancements in genome sequencing and editing technology, it is now possible to recreate live smallpox virus from published genomes, the report warns. 

US population changes and advancements in gene editing and synthesis technologies have drastically altered the potential for a smallpox outbreak or attack in recent years. But these technologies significantly raise the risk of accidental or intentional release, challenging readiness planning and potentially altering the epidemiology and clinical presentations of the disease. 

The report notes that even if all existing collections of the virus were destroyed, reemergence is still a threat.

Despite the risks, the report underscores the necessity of continued research involving live variola virus for developing and enhancing smallpox MCMs. This research is essential for creating more effective therapies, validating vaccine and treatment efficacy, and establishing animal models for research purposes.

Research using these viruses can also fill gaps in our fundamental understanding of orthopoxvirus biology, ecology, evolution, transmission, and disease onset in humans.

A call for MCM research and development

Three main categories of MCMs need improvement: diagnostics, vaccines, and therapeutics. More accurate diagnostic tests to detect smallpox and related viruses at earlier stages is paramount. 

Vaccine safety is also an issue, and the report calls for research into vaccines that can be used across different populations and that are available as a single dose. 

“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.”

Lastly, the report advocates for safer and more diversified therapeutics, such as antivirals with different and diverse targets, mechanisms, and routes of administration, to supplement existing antivirals. 

Vulnerabilities: too few manufacturers

The report concluded that the small number of manufacturers capable of producing smallpox medical countermeasures is a specific vulnerability, and that 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. 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.

The need for global cooperation

Both the COVID-19 pandemic and mpox outbreaks revealed gaps in the US’s ability to respond to new infectious diseases. Specifically, the COVID-19 pandemic exposed weaknesses in the ability of US public health and health care systems to adapt and respond to an unfamiliar pathogen. Mpox, on the other hand, showed the challenges of rapidly making diagnostics, vaccines, and therapeutics available at scale.

Furthermore, the mpox outbreak brought to light the lack of diverse smallpox therapeutics options. Currently, standard research methods rely on challenge studies in animals to understand MCM efficacy in humans, leading to issues with accurately understanding the safety and efficacy in humans. 

“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 Prof Larry Gostin, director of the O’Neill Institute for National and Global Health Law at Georgetown Law and professor of medicine 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,” added Gostin, who is also director of the WHO Collaborating Center on National and Global Health Law.

Research and development for these MCMs needs to not only consider the actual device or product, but also the ability to “deploy at scale” and equitably to meet the challenges of public acceptance.

The report urges effective risk communication for vaccines, as the same challenges with vaccine hesitancy and misinformation could occur in a smallpox outbreak.

While the report primarily focused on US readiness and response capabilities, it does note the impact of growing global interdependence in detecting and containing potential smallpox outbreaks.

“The COVID-19 pandemic and pox multi-country outbreak, both declared Public Health Emergencies of International Concern (PHEIC) by WHO, underscore the need for further domestic global coordination for preparedness and response against novel pathogens including orthopoxvirus events,” note the report authors. 

This means preemptively supporting international MCM capacity as any US response will be “significantly affected” by the ability of other countries to detect and surveil. The report notes that global solidarity is a key component to rapidly identify, contain, respond, and ensure equitable MCM allocation in a smallpox event.

Preparedness for similar viruses

Smallpox-related viruses such as mpox, Alaskapox, and cowpox are increasingly found in humans, magnifying the need for medical countermeasures that can detect, treat, and prevent these diseases.

The report notes that most mpox therapeutics were developed because of investments in smallpox therapeutics. 

“Direct investment in developing therapeutics targeting circulating orthopoxviruses could similarly benefit smallpox therapeutic preparedness and would likely have more immediate utility and potentially achieve commercial viability.”

Image Credits: Isao Arita/ WHO.