The Covid-19 pandemic – and the more recent mpox outbreaks – have drawn fresh attention to the world's readiness and response posture for emerging infectious diseases, say experts, who warn that more could, and should, be done in preparation to overcome these threats in the future.
Although the World Health Assembly declared smallpox eradicated in 1980, research on variola virus has continued at officially sanctioned laboratories in the US and the Russian Federation.
With the possibility that unofficial specimens exist, and with advances in gene editing and synthesis technologies that could re-create, even enhance, variola virus, there is a potential threat of an unintentional or deliberate release, write Lawrence Gostin, Shalini Singaravelu and Noreen Hynes in JAMA Network.
The cessation of smallpox vaccination also has rendered populations susceptible to other orthopoxviruses, such as mpox, vaccinia-like viruses, and borealpox (formerly Alaskapox) virus. A smallpox outbreak anywhere would immediately trigger a global health emergency.
A recent report by the National Academies of Sciences, Engineering and Medicine, entitled Future State of Smallpox Medical Countermeasures, underscores the importance of enhancing US readiness and response against smallpox and emerging orthopoxviruses.
Develop safer and more effective medical countermeasures
The US maintains a Strategic National Stockpile (SNS) containing three types of smallpox vaccines, two antivirals, and vaccinia immune globulin to treat adverse reactions of live, attenuated, replicating smallpox vaccines.
The SNS stores first-generation vaccinia-based replication-competent vaccines (ACAM2000 and Aventis Pasteur Smallpox Vaccine) at greater volumes compared with newer, live, non-replicating vaccine (Modified Vaccinia Ankara-Bavarian Nordic [MVA-BN]) – intended for a population subset for whom ACAM2000 may be contraindicated; ACAM2000 has potential for severe adverse events in certain populations.
MVA-BN has an improved safety profile, but the effectiveness of the recommended two-dose regimen remains uncertain.
The SNS also stores antivirals (tecovirimat and brincidofovir) with contraindications for patients with severe kidney impairment and potential for viral resistance with extended use. Repurposing vaccinia immune globulin is possible, although treatment of smallpox or mpox is not proven. Use of other non-vaccine biologics, such as monoclonal antibodies and antibody cocktails, in concert with antivirals, show promise in animal models.
Before the 2022 mpox outbreak, basic poxvirus research had been declining. Yet this research is essential to improve the safety and effectiveness of medical countermeasures. Ongoing mpox and other orthopoxvirus outbreaks merit research and development of safer and more effective countermeasures under a broadened orthopoxvirus-focused portfolio.
Continued importance of live variola virus research
Since eradication, the WHO has undertaken a prolonged and complex debate whether to destroy the last remaining stocks of live variola virus. Currently, temporary retention of existing variola virus stocks is used to facilitate essential research overseen by the Advisory Committee for Variola Virus Research at the WHO.
Despite scientific advances, live variola virus will be needed for the foreseeable future to validate diagnostics and develop more effective vaccines and therapeutics against smallpox and other orthopoxviruses.
Multiple knowledge gaps exist in variola virus biology, pathogenesis, evolution, transmission, and ecology that require continued live virus research. Although nonvariola orthopoxviruses share common genetic features with variola, disease presentation of specific viruses can vary, warranting continued research using variola and other orthopoxviruses.
Affordable, accessible, and equitable access
Equity is a universal value unto itself and is vital to US readiness and response. As Covid-19 and mpox demonstrated, rapid disease identification and effective deployment of vaccines and therapeutics is essential for containing outbreaks wherever they arise, while limiting opportunities for the virus to mutate into a dangerous variant.
A lack of product diversification, the limited number of smallpox manufacturers, and limitations of smallpox diagnostic testing may significantly impede affordable and equitable access to, and allocation of, medical countermeasures in a smallpox emergency.
Inequitable access also limits response flexibility and timeliness needed adapt to varying scales of a smallpox or other orthopox emergency. Planning for equity up front requires advance consideration of implementation challenges, multijurisdictional coordination, community engagement, risk communication, information sharing, and training of frontline responders.
Trust in science and medicine
Vaccine hesitancy and distrust of health systems challenged smallpox eradication, but greater community involvement expanded vaccine coverage. During Covid-19, false or misleading information about vaccine safety and effectiveness reduced public acceptability.
The potential for adverse effects and uncertainties with a rapidly developed vaccine impeded the response, despite decades of research and investment in messenger RNA technology.
In a smallpox emergency, decisions must be made quickly to deploy and administer medical countermeasures. Achieving population-level protection, and reducing morbidity and mortality, will hinge on individuals’ willingness to accept prophylactic and treatment measures.
The mpox experience also highlights the importance of clinician and patient engagement and clinical education for case detection. Given lack of familiarity with smallpox and other poxviruses among most clinicians, case identification could be a weak link in readiness and response. Building trust also begins at the first point of patient contact with a health care professional.
Clinicians will need training to engage in a dialogue with patients that facilitates acceptance.
The smallpox readiness and response posture
The federal government, in co-ordination with international partners, should continue to establish research and development priorities for smallpox medical countermeasures. This should be coupled with judicious stockpiling and with strategic plans for rapid and equitable distribution in the event of a smallpox or other poxvirus outbreak in the US or globally.
The national and global threat may be significantly increased due to rapidly advancing technologies in genome editing, gene amplification, synthetic biology, and artificial intelligence. Malicious exploitation of such technologies could create novel bioterror agents that render established medical countermeasures ineffective, yet these same technologies could be leveraged to develop faster, more accessible, and more distributed countermeasures.
The US and its partners will need to demonstrate greater flexibility to adapt to multiple future emergency scenarios, including varying geographic scope, unanticipated modes of release (eg, unintentional, deliberate, environmental resurrection), and naturally occurring or engineered virus.
This requires robust capabilities to develop, manufacture, distribute, administer, and stockpile medical countermeasures that are flexible to respond to the scale and speed of any type of smallpox or novel orthopox emergency.
Preparedness plans should focus on pathogen-agnostic response systems and whole-of-society readiness for all emergency scenarios, including frontline readiness for case identification, access to care, and acceptance of medical countermeasures; regulatory readiness for oversight of new medical countermeasures based on scientific evaluations of safety, efficacy, and real-world evidence; research readiness to conduct clinical trials and understand the utility of cross-protective orthopoxvirus medical countermeasures; operational readiness to adapt response and stockpiling measures through partnerships with public and private-sector entities; and political readiness, to act swiftly on policy opportunities that will safeguard against the nefarious uses of emerging technologies and misinformation/disinformation.
Scenario-based planning will also need to be updated based on iterative risk and threat assessments and on tiered exercises to assess readiness at national, state, local, tribal, and territorial levels. Implementation research is needed to assess operational parameters such as test uptake, testing turnaround times, and equity-related testing factors that could affect preparedness, stockpiling, and response strategies.
The US and international community can learn vital lessons from prior health emergencies.
This certainly requires investment in scientific research and public/private incentives for manufacturing at scale. Smallpox medical countermeasures that are cross-reactive for other orthopoxviruses and harness multidisease platforms provide advantages to rapidly scale production and adapt medical countermeasures to novel strains in a future emergency.
The use of common ingredients and processes not only has manufacturing benefits but also may alleviate public hesitancy or mistrust of medical countermeasures. The SNS will need to make wise and judicious decisions about which countermeasures to store, while also planning for manufacturing scale-up in the event of a novel outbreak.
Yet even the best medical countermeasures may prove ineffective without whole-of-society and systems readiness, including implementation, acceptance, and equitable distribution.
Reliable and equitable access to smallpox medical countermeasures will depend on the ability of the countermeasures enterprise to surge, meet demand, and protect high-risk populations.
The threat level is high and increasing. The nation’s preparedness must be equal to that threat.
Lawrence Gostin, JD – Georgetown University Law Centre, Washington; Shalini Singaravelu – National Academies of Sciences, Engineering, and Medicine, Washington;
Noreen Hynes – Schools of Medicine and Public Health, Johns Hopkins University, Baltimore.
Future state of smallpox medical countermeasures (Open access)
See more from MedicalBrief archives:
Prepare for more pandemics in the future, experts warn
Covid lessons could prepare world for ‘Disease X’
WHO: Eradication of smallpox could give pointers in the fight against COVID-19
Monkeypox possibly linked to decrease in smallpox vaccine – global experts
One dose of smallpox jab cuts mpox risk – Canadian study