Introduction
Smallpox, caused by the variola virus, stands among the most devastating infectious diseases in human history, exerting profound and lasting impacts on human societies across centuries (Henderson, Reference Henderson2011). Characterized by high fever, extensive pustular eruptions, and substantial mortality, the disease reshaped demographic structures and sociopolitical trajectories from antiquity onward. Historical accounts attest to the profound societal disruption and population losses associated with smallpox epidemics across different historical periods (Berche, Reference Berche2022; Finzsch, Reference Finzsch2021). Even into the 20th century, smallpox persisted as a major global health burden.
This trajectory was ultimately reversed through the World Health Organization (WHO) Global Smallpox Eradication Programme, launched in 1967, culminating in the last naturally occurring case in Somalia in 1977 and the formal declaration of eradication in 1980. This achievement remains one of the most significant triumphs of modern public health, demonstrating the transformative power of coordinated vaccination strategies, robust public health infrastructure, and effective transnational governance (Berche, Reference Berche2022).
Despite eradication, the threat posed by smallpox has not been fully extinguished. Variola virus stocks are retained in two designated high-containment repositories in the United States and the Russian Federation, constituting a persistent biosecurity concern. Concurrently, advances in synthetic biology and genetic engineering have introduced the potential technical feasibility of orthopoxvirus reconstruction, exemplified by the laboratory synthesis of horsepox virus in 2017, a close relative of variola (Koblentz, Reference Koblentz2017). Such developments have intensified concerns regarding the deliberate misuse of variola virus as a bioterrorism agent, consistent with its designation as a Category A threat by the U.S. Centers for Disease Control and Prevention (CDC) (Beale et al., Reference Beale, Zolnikov and Firebaugh2021; Rathjen & Shahbodaghi, Reference Rathjen and Shahbodaghi2021). The combination of high transmissibility, substantial case-fatality rates, and a largely nonimmune global population reinforces smallpox’s status as one of the most consequential potential biological weapons (Michalski et al., Reference Michalski, Knap, Bielawska-Drózd and Bartoszcze2022). However, it is critical to distinguish between the de novo synthesis of a viral agent and the massive infrastructure, formulation, and delivery mechanisms required for its effective weaponization. These risks extend beyond theoretical scenarios and directly inform contemporary biosecurity priorities, including stringent laboratory containment, strategic vaccine stockpiling, and sustained preparedness planning as core components of a state’s political capacity (MacIntyre et al., Reference MacIntyre, Heslop, Nand, Schindeler and Chughtai2019).
The discontinuation of routine smallpox vaccination following eradication has inadvertently generated a widening immunity gap in modern populations, increasing susceptibility to zoonotic orthopoxviruses such as monkeypox (Meyer et al., Reference Meyer, Ehmann and Smith2020). Akter et al. (Reference Akter, Hasan, Alam, Das, Afrin, Maisha, Masud and Saif-Ur-Rahman2023) highlighted the durable cross-protective effects of historical smallpox vaccination against monkeypox protection that has progressively waned over time. Nguyen et al. (Reference Nguyen, Ajisegiri, Costantino, Chughtai and MacIntyre2021) further linked the resurgence of monkeypox in West and Central Africa to the erosion of population-level smallpox immunity, emphasizing the growing vulnerability of immunologically naïve cohorts. Martínez-Fernández et al. (Reference Martínez-Fernández, Fernández-Quezada, Guadalupe Casillas-Muñoz, Carrillo-Ballesteros, Ortega-Prieto, Jimenez-Guardeño and Regla-Nava2023) expanded this perspective by demonstrating how ecological disruption, urbanization, and intensified human–wildlife interfaces synergistically promote monkeypox emergence. Chadha et al. (Reference Chadha, Khullar, Gulati, Chhibber and Harjai2022) characterized monkeypox as a “pandemic within the pandemic,” illustrating how zoonotic pathogens exploit both ecological and immunological gaps in the aftermath of global crises such as COVID-19. Epidemiological modeling has additionally shown that the basic reproduction number (R₀) of smallpox is sufficiently high to enable explosive transmission in susceptible populations (Gani & Leach, Reference Gani and Leach2001). Meyer et al. (Reference Meyer, Ehmann and Smith2020) demonstrated that, in immunologically naïve settings, even a single introduction could trigger rapid and widespread outbreaks if containment fails. The close phylogenetic and immunological relationship between variola and monkeypox viruses within the orthopoxvirus genus further complicates preparedness strategies, transforming epidemiological vulnerabilities into a complex governance challenge (Poland et al., Reference Poland, Kennedy and Tosh2022; Roper et al., Reference Roper, Garzino-Demo, del Rio, Bréchot, Gallo, Hall, Esparza, Reitz, Schinazi, Parrington, Tartaglia, Koopmans, Osorio, Nitsche, Huan, LeDuc, Gessain, Weaver, Mahalingam and McFadden2023). Sandbrink and Koblentz (Reference Sandbrink and Koblentz2022) warned that dual-use biotechnologies and synthetic biology platforms expand the threat landscape by enabling the manipulation or recreation of orthopoxviruses with potentially severe consequences, presenting a profound regulatory dilemma for global state actors. Moreover, Taube et al. (Reference Taube, Rest, Lloyd-Smith and Bansal2023) emphasized that historical vaccination policies continue to shape present-day susceptibility patterns to emerging orthopoxviruses, including monkeypox.
Against this multidimensional risk landscape, the present review evaluates the potential for smallpox reemergence in the contemporary era by integrating historical eradication lessons, recent monkeypox resurgence, and advances in synthetic biology and biosecurity. Therefore, the central thesis of this perspective is that the re-emergence of smallpox risk is not merely a technological byproduct of synthetic virology, but a fundamental governance crisis driven by the erosion of institutional memory and the widening gap between rapid biotechnological decentralization and static regulatory frameworks. By examining vulnerabilities within global health security frameworks, including laboratory safety, immunity erosion, and zoonotic spillover dynamics, this work highlights the urgent need for proactive surveillance, adaptive vaccination strategies, and strengthened international coordination as political imperatives rather than purely medical challenges. Such an integrated perspective is essential not only for informing public health policy but also for reinforcing global biosecurity in an era characterized by accelerating technological capability and evolving biological threats.
Smallpox in historical, strategic, and synthetic contexts
Smallpox as a biosecurity and bioterrorism threat
Historical accounts of smallpox transmission illustrate its profound impact in immunologically naïve populations. During the 16th century, the introduction of variola virus into the Americas led to so-called virgin soil epidemics, with mortality rates reported to exceed 80% among Indigenous communities lacking prior exposure and organized public health structures. These events substantially reshaped demographic patterns and geopolitical dynamics across the continent, underscoring the capacity of a single pathogen to alter societal trajectories (Thèves et al., Reference Thèves, Crubézy and Biagini2016). However, it is critical to distinguish between these catastrophic natural epidemics and the intentional use of biological agents in warfare. Much of the published literature repeats unsubstantiated claims of pre-20th-century biological warfare, often creating an “academic urban legend” (Carus, Reference Carus2024). Portraying biological warfare as an ancient practice falsely suggests that it is a persistent and inevitable part of human conflict; in reality, using microbes to deliberately affect battlefield outcomes is a fundamentally modern invention (Carus, Reference Carus2024). While this historical experience continues to inform contemporary risk modeling and supports the classification of smallpox as a high-consequence biological threat, it is imperative to acknowledge the limitations of such models. As highlighted by Leitenberg (Reference Leitenberg2005) and others, many past bioterrorism simulations project worst-case scenarios that fail to account for critical real-world modulators, such as sociological factors and the resilience of modern public health infrastructures. Therefore, contemporary threat assessments must integrate these variables alongside conditions of delayed detection, limited immunity, and airborne transmission potential (Mahy, Reference Mahy2003).
Smallpox (variola virus) is designated by the CDC as a Category A agent owing to its transmissibility, estimated case-fatality rate of ~30%, and the substantial decline in population immunity following cessation of routine vaccination in the early 1980s. Notably, historical surveillance data indicate no confirmed instances of smallpox use in bioterrorism; however, its inclusion in preparedness frameworks reflects intrinsic epidemiological characteristics rather than documented weaponization. A global review of biological terrorism incidents between 1970 and 2019 identified only 33 such events, none involving variola virus (Tin et al., Reference Tin, Sabeti and Ciottone2022). Post-2001 risk assessments within national security discourse identified smallpox as a potential high-impact agent, particularly in scenarios involving covert dissemination and delayed recognition. Subsequent analyses, however, have highlighted uncertainties in earlier projections, including assumptions regarding attack feasibility, healthcare surge capacity, and vaccine deployment logistics (Bitlauer, Reference Bitlauer2017). Furthermore, as demonstrated by historical offensive biological weapons programs, the successful synthesis of a viral agent does not equate to a viable mass-casualty weapon. Biological organisms are highly sensitive to environmental stressors such as UV radiation, high temperatures, and humidity. Consequently, effective weaponization requires specialized formulations for environmental protection, sophisticated delivery mechanisms, and a massive infrastructure of experienced personnel, making successful dissemination highly unpredictable. Regional preparedness assessments in East Asia have similarly considered variola virus within asymmetric threat scenarios, noting that gaps in vaccine stockpiles, trained personnel, and coordinated response structures may amplify consequences in deliberate release contexts (Hwang, Reference Hwang2024).
Advances in synthetic biology have further shaped the contemporary risk landscape by enabling assembly of orthopoxvirus genomes using commercially available DNA synthesis technologies. The 2017 synthesis of horsepox virus provided a proof-of-principle demonstration of the potential technical feasibility of orthopoxvirus genome reconstruction from published sequence data and synthetic fragments (Koch et al., Reference Koch, Lopes, Maiguy, Guillier, Guillier, Tournier and Biot2020). Nevertheless, it is crucial to emphasize that the de novo synthesis of large viral genomes involves profound technical challenges. The successful synthesis of horsepox does not equate to widespread accessibility; such efforts require immense specialized expertise, tacit knowledge, and nuanced contingency protocols (DiEuliis & Gronvall, Reference DiEuliis and Gronvall2018; Nature Biotechnology, 2021). From a biodefense perspective, several biological characteristics contribute to concern regarding variola virus, including its incubation period of ~12–14 days, efficient person-to-person transmission, and nonspecific prodromal symptoms that may delay clinical recognition. In addition, limited diagnostic familiarity among modern clinicians could increase the risk of misdiagnosis and nosocomial transmission during early outbreak stages (Falcinelli et al., Reference Falcinelli, Ciric, Kindrachuk, Singh and Kuhn2019).
Mathematical modeling studies of intentional release scenarios indicate that timely implementation of ring vaccination can substantially reduce secondary transmission and decrease the basic reproduction number (R₀) below unity under optimal contact tracing conditions. Ko et al. (Reference Ko, Seo, Park, Kim, Moon, Kim, Eom, Oh, Kim, Kim, Lee and Jung2024) reported that successful identification of more than 85% of contacts within 48 hours is required for effective containment in densely populated settings. Simulation analyses further suggest that response delays exceeding 96 hours may permit rapid expansion of transmission chains and strain healthcare capacity within 2 weeks of index case detection. Independent probabilistic modeling supports these findings and emphasizes that coordinated application of ring vaccination, case isolation, and risk communication is critical for outbreak control. Delays in vaccine distribution of more than 2 days after case detection were associated with marked increases in projected case counts, whereas vaccination refusal rates above 20% substantially reduced containment effectiveness. Modeling studies also highlight heightened vulnerability in resource-limited settings with constrained cold-chain infrastructure and response capacity (Costantino et al., Reference Costantino, Kunasekaran and MacIntyre2021).
The resurgence of monkeypox and the erosion of cross-protective immunity
Monkeypox virus (MPXV), a zoonotic orthopoxvirus first identified in humans in 1970, has historically circulated in Central and West Africa, primarily through animal-to-human transmission with limited secondary spread. In 2022, however, the epidemiological profile of the virus shifted markedly, with sustained human-to-human transmission documented across multiple non-endemic regions, including Europe, North America, and Asia (McQuiston et al., Reference McQuiston, McCollum, Christie, Torres, Mermin, Jernigan and Hutson2025). This expansion represented the largest recorded geographic dissemination of MPXV outside Africa in the post-smallpox era. The contemporary resurgence of monkeypox has been linked, in part, to the cessation of routine smallpox vaccination following the eradication of variola virus in 1980 (Karama et al., Reference Karama, Akinola and Kama2023). The vaccinia-based smallpox vaccine historically conferred an estimated 85% cross-protection against MPXV infection due to shared orthopoxviral antigens (McCollum & Damon, Reference McCollum and Damon2014). As cohorts born after the early 1980s have not received this immunization, the proportion of immunologically naïve individuals has progressively increased over the past four decades (Bunge et al., Reference Bunge, Hoet, Chen, Lienert, Weidenthaler, Baer and Steffen2022). This expanding immunity gap is now considered a key determinant facilitating renewed human transmission of MPXV (Saadh et al., Reference Saadh, Ghadimkhani, Soltani, Abbassioun, Daniel Cosme Pecho, taha, Jwad Kazem, Yasamineh and Gholizadeh2023).
Epidemiological investigations during the 2022 outbreak indicated that most confirmed infections occurred in individuals without prior smallpox vaccination, and population-level herd protection was not evident in affected urban settings. Transmission patterns also differed from historical zoonotic outbreaks, with sustained person-to-person spread occurring predominantly through close physical contact networks rather than animal exposure alone (Beer & Rao, Reference Beer and Rao2019). These observations underscore how erosion of cross-protective orthopoxvirus immunity can alter transmission dynamics in contemporary populations. Genomic surveillance of MPXV isolates from 2022 to 2023 demonstrated that the global outbreak was largely associated with clade IIb lineages exhibiting multiple single-nucleotide polymorphisms relative to historical reference strains (Adler et al., Reference Adler, Gould, Hine, Snell, Wong, Houlihan, Osborne, Rampling, Beadsworth, Duncan, Dunning, Fletcher, Hunter, Jacobs, Khoo, Newsholme, Porter, Porter, Ratcliffe and Hruby2022).
Clinically, recent outbreaks have also shown broader phenotypic variability compared with classical descriptions of monkeypox. Presentations have included localized anogenital lesions, mucosal involvement, and oropharyngeal manifestations, complicating early clinical recognition in populations lacking prior orthopoxvirus exposure (Yang, Reference Yang2022). Ocular complications, such as conjunctivitis, keratitis, and corneal ulceration, have additionally been reported, particularly among children and immunocompromised individuals (Rayati Damavandi et al., Reference Rayati Damavandi, Semnani and Hassanpour2023). In response to the outbreak, third-generation smallpox vaccines based on Modified Vaccinia Ankara (MVA-BN; marketed as Jynneos, Imvanex, or Imvamune) were deployed under emergency use and targeted vaccination strategies. These replication-deficient vaccines have demonstrated favorable safety and immunogenicity profiles in both clinical trials and real-world deployment, and are currently recommended for pre-exposure prophylaxis in high-risk groups and post-exposure use within contact-tracing frameworks (Toshev et al., Reference Toshev, Petkova-Gueorguieva, Mihaylova, Pavlova, Parahuleva, Balkanski, Peikova, Getova, Madzharov and Gueorguiev2024). Collectively, the reemergence of monkeypox reflects the convergence of multiple post-eradication dynamics, including waning orthopoxvirus immunity, increasing global mobility and urbanization, and limited diagnostic familiarity in regions without historical exposure. In the absence of circulating variola virus, the orthopoxvirus ecological niche remains partially unoccupied, and the monkeypox outbreak illustrates the long-term epidemiological consequences of discontinuing population-wide immunization in the context of persistent zoonotic reservoirs.
Synthetic orthopoxvirus platforms and the dual-use dilemma in vaccine and biodefense research
Advances in synthetic biology have substantially transformed vaccine science, enabling de novo viral genome synthesis, rational antigen design, and improved delivery platforms. Within the orthopoxvirus field, these technological capabilities offer significant opportunities for vaccine innovation while simultaneously introducing dual-use considerations relevant to biosecurity and biodefense, effectively transforming the dual-use nature of synthetic biology into a profound regulatory dilemma for global state actors (Nofal et al., Reference Nofal, AlFayyad, AlJerian, Alowais, AlMarshady, Khan, Heena, AlSarheed and Abu-Shaheen2021; Sandbrink & Koblentz, Reference Sandbrink and Koblentz2022). Increased accessibility of synthetic virology tools has therefore prompted international attention to the governance of research involving variola-related or orthopoxvirus-derived constructs, particularly given prior demonstrations that infectious orthopoxvirus genomes can be assembled from publicly available sequence data and synthetic DNA fragments (Delaune & Iseni, Reference Delaune and Iseni2020).
Medical countermeasures originally developed for smallpox eradication, including vaccines and antiviral agents, have been reexamined for their applicability in contemporary orthopoxvirus outbreaks such as monkeypox. These repositioning strategies benefit from extensive historical safety and efficacy data; however, their modern deployment occurs within an altered epidemiological and technological context that necessitates updated regulatory and biosafety oversight (Islam et al., Reference Islam, Hossain, Roy, Hasan, Rahman, Shahriar and Bhuiyan2022). Concurrently, the cessation of routine smallpox immunization has produced a generation-spanning immunity gap, increasing susceptibility to orthopoxvirus infection and potentially amplifying the public health impact of accidental or intentional release events involving engineered viral strains. Modeling studies indicate that declining cross-protective immunity can substantially increase outbreak magnitude in densely populated, immunologically naïve settings (Taube et al., Reference Taube, Rest, Lloyd-Smith and Bansal2023).
Historical recognition of smallpox as a high-consequence pathogen has informed international biosecurity policy and underscores the need for careful oversight of dual-use research involving orthopoxvirus vectors or variola-like genetic elements. The combination of publicly accessible orthopoxvirus genomic sequences and expanding DNA synthesis capacity represents a technological convergence that requires proportionate governance, surveillance, and responsible research frameworks (Breman, Reference Breman2021). Specifically, the growing accessibility of decentralized benchtop DNA synthesis devices introduces novel biosecurity vulnerabilities, as these platforms could potentially bypass traditional commercial sequence screening and complicate regulatory oversight (Nuclear Threat Initiative, 2023). To anchor these governance challenges, we present emerging vaccine delivery platforms, specifically thermostable microneedle-based systems, as a case study. This technology serves as a tangible illustration of the tension between the need for rapid, decentralized public health response capabilities and the absolute necessity for stringent dual-use regulatory oversight. Their thermostability, dose-sparing characteristics, and simplified administration support rapid deployment during public health emergencies; however, scalable manufacturing and distribution pathways also raise considerations regarding oversight and secure use within biodefense contexts (Mansoor et al., Reference Mansoor, Eassa, Mohammed, Abd el-Fattah, Abdo, Rashad, Eassa, Saleh, Amin, Nounou and Ghoneim2022). To address these dual-use dimensions while sustaining biomedical innovation, recent policy frameworks advocate integrating vaccine development into One Health–aligned biosecurity strategies that connect human, animal, and environmental health sectors. Such approaches emphasize risk-proportionate safeguards, transparency, and international coordination in research involving orthopoxvirus platforms and advanced vaccine technologies (Al-Eitan et al., Reference Al-Eitan, Abu Khiarah and Almahdawi2025).
Anticipating the next threat: Global preparedness, ethical imperatives, and vaccine strategy in a post-smallpox world
Declining vaccine confidence, driven in part by misinformation and hesitancy, has emerged as a significant challenge for global immunization systems, particularly in the post-smallpox era in which residual orthopoxvirus immunity has largely diminished (Chadha et al., Reference Chadha, Khullar, Gulati, Chhibber and Harjai2022). Vaccine refusal and delay have been associated with outbreaks of previously controlled vaccine-preventable diseases, including measles and pertussis (Phadke et al., Reference Phadke, Bednarczyk, Salmon and Omer2016). Separately, the cessation of routine smallpox vaccination may have increased population susceptibility to mpox through declining cross-protective immunity (Bunge et al., Reference Bunge, Hoet, Chen, Lienert, Weidenthaler, Baer and Steffen2022). The interplay of sociobehavioral and biomedical determinants therefore shapes contemporary vulnerability to both naturally emerging and intentionally released poxviruses (Hoffman & Maldonado, Reference Hoffman and Maldonado2024). Modeling analyses of global orthopoxvirus immunity distributions indicate a substantial susceptibility gap among cohorts born after smallpox eradication, illustrating the long-term epidemiological effects of waning cross-protective immunity (Crandell et al., Reference Crandell, Monteiro, Pischel, Fang, Conde, Zhong, Lawres, de Asis, Maciel, Zaleski, Lira, Higa, Breban, Vogels, Caria, Pinto, Almeida, Maltez, Cordeiro and Lucas2025). In parallel, novel vaccine delivery technologies, including microneedle-based platforms, have been developed to address logistical barriers in large-scale immunization campaigns. Their thermal stability and dose-sparing characteristics offer advantages for rapid deployment during public health emergencies and biodefense responses (Jin et al., Reference Jin, Zhao, Wan, Li, Bai, Hu, Wang, Li, Xin, Kang, Yang, Wang and Gao2022). At the same time, the scalability and synthetic design of such platforms introduce considerations regarding oversight and responsible use within dual-use technology frameworks (Sandbrink & Koblentz, Reference Sandbrink and Koblentz2022). The effective adoption of next-generation countermeasures depends not only on technical performance but also on equitable access, transparent risk communication, and trust-building in regions with limited healthcare infrastructure or historical vaccine skepticism (Hulme et al., Reference Hulme, Dechoum, Essl, Martinou, Pauchard, Pyšek, Roy, Sheppard, Vilà and Wilson2025). Accordingly, recent global health security analyses emphasize the integration of predictive surveillance systems, ethical governance, and anticipatory risk assessment into preparedness architectures (Hao et al., Reference Hao, Liu, Shen, Zhao, Jiang, Song, Yan and Ma2022). Within international policy instruments, the Biological Weapons Convention has been identified as insufficiently adapted to address emerging synthetic biology–enabled risks, prompting calls for expanded genomic monitoring and verification mechanisms (Arizti Sanz et al., Reference Arizti Sanz, Dunlap, Nolan and O’Leary2022).
Ethical preparedness further requires prioritization strategies for vulnerable populations, particularly children, within vaccination policies, alongside safeguards such as informed consent procedures and long-term immunological monitoring (Hammershaimb & Campbell, Reference Hammershaimb and Campbell2024). The development and regulatory approval of antiviral agents, including tecovirimat, provide complementary medical countermeasures; however, disparities in access and manufacturing capacity remain global challenges (Merchlinsky et al., Reference Merchlinsky, Albright, Olson, Schiltz, Merkeley, Hughes, Petersen and Challberg2019). Addressing these multidimensional vulnerabilities necessitates cross-sector collaboration, strengthened surveillance and biosafety frameworks, and sustained public engagement grounded in transparency and international cooperation (Ukoaka et al., Reference Ukoaka, Okesanya, Daniel, Ahmed, Udam, Wagwula, Adigun, Udoh, Peter and Lawal2024).
Discussion
The global eradication of smallpox by the World Health Organization remains one of the most consequential achievements in public health. However, a post-eradication paradox has emerged: the absence of circulating variola virus has been accompanied by progressive declines in population immunity and institutional familiarity, while advances in synthetic biology and the re-emergence of zoonotic orthopoxviruses, including monkeypox (mpox), have renewed attention to orthopoxvirus preparedness. Artenstein (Reference Artenstein, Cohen, Opal and Powderly2010) noted that in an increasingly urbanized and highly connected world, even limited reintroduction events could have substantial epidemiological consequences in immunologically naïve populations. This evolving risk context underscores the continued importance of biodefense infrastructures encompassing surveillance, diagnostic capacity, antiviral stockpiles, and next-generation vaccines.
Vaccination remains the central immunological pillar of orthopoxvirus preparedness. Comparative analyses of smallpox vaccine generations by Kennedy et al. (Reference Kennedy, Ovsyannikova and Poland2009) support the transition toward nonreplicating vaccinia-based platforms, including Modified Vaccinia Ankara (MVA) and LC16m8, which provide improved safety profiles while maintaining protective immunogenicity. Similarly, the progression from first-generation vaccines such as Dryvax to third-generation formulations like MVA-BN (IMVAMUNE®), as examined by Vollmar et al. (Reference Vollmar, Arndtz, Eckl, Thomsen, Petzold, Mateo, Schlereth, Handley, King, Hülsemann, Tzatzaris, Merkl, Wulff and Chaplin2006), demonstrates the feasibility of safer population-level immunization strategies, particularly for immunocompromised groups. The durability of vaccine-induced immunity remains a critical consideration. Frey et al. (Reference Frey, Couch, Tacket, Treanor, Wolff, Newman, Atmar, Edelman, Nolan and Belshe2002) showed that both humoral and cellular responses can persist for decades following vaccination, although with evidence of gradual decline over time. These findings support the potential value of periodic serological surveillance and targeted booster strategies in defined risk groups. National antibody monitoring programs, such as those implemented in South Korea and reported by Shin et al. (Reference Shin, Lee, Choi, Yi and Chung2024), illustrate how post-vaccination immunity assessment can inform selective revaccination and optimize preparedness planning.
Alongside immunological strategies, advances in vaccine delivery technologies are reshaping emergency response capabilities. Microneedle-based vaccine systems described by Wen et al. (Reference Wen, Deng, Wang, Gao, Nan, Tang, Xue, Ju, Dai, Wei and Xue2024) demonstrate high immunogenicity, improved tolerability, and logistical advantages including reduced cold-chain dependence and simplified administration, features particularly relevant for outbreak response and rapid deployment scenarios. The mpox outbreak further reinforced the importance of cross-protective orthopoxvirus immunity. Christodoulidou and Mabbott (Reference Christodoulidou and Mabbott2023) reported that prior smallpox vaccination conferred up to 87% protection against mpox, indicating sustained cross-immunity decades after immunization. Real-world deployment of MVA-BN during the outbreak provided additional evidence supporting its use in both pre- and postexposure prophylaxis strategies. Despite these biomedical advances, operational challenges remain. Qzih et al. (Reference Qzih, Alhusamiah, Haddad, Bani Mohammad, Horany, al-ja’freh and Bani Hani2025) identified substantial knowledge gaps among healthcare workers regarding mpox and smallpox vaccines, suggesting that limitations in awareness and training may hinder containment and vaccination efforts. These findings highlight the importance of integrating professional education and risk communication into preparedness frameworks. The broader immunological vulnerability associated with the prolonged absence of routine smallpox vaccination has created an expanding immunologically naïve landscape. As emphasized in recent governance studies, this susceptibility is further compounded by tremendous advances in synthetic biology, which facilitate the potential reemergence of pathogens through dual-use research. Such evolving threats necessitate a multidimensional biosecurity and biosafety approach that effectively integrates clinical immunology, virological surveillance, and robust regulatory frameworks (Li et al., Reference Li, Zhao, Zheng and An2021).
Technological developments in synthetic virology further reinforce the need for sustained countermeasure preparedness. Shchelkunov and Shchelkunova (Reference Shchelkunov and Shchelkunova2022) demonstrated that de novo synthesis of horsepox virus establishes the potential technical feasibility of reconstructing orthopoxvirus genomes from published sequence data, supporting calls for continued investment in vaccine and antiviral research, as well as strengthened governance of dual-use biological research. Therapeutic countermeasures provide an additional layer of defense. Reviews by De Clercq et al. (Reference De Clercq, Jiang and Li2023) highlight antiviral agents such as tecovirimat and brincidofovir as important options for postexposure treatment or for individuals in whom vaccination is contraindicated.
Importantly, biomedical innovation alone is insufficient to ensure effective preparedness. The erosion of institutional memory and the loss of practical, hands-on experience in managing high-consequence biological events present a fundamental governance risk. As evidenced by the 2001 Amerithrax attacks and the 2013–2016 West African Ebola outbreak, even sophisticated health systems can be overwhelmed by logistical friction, diagnostic delays, and public panic when prior operational expertise has waned (Gostin et al., Reference Gostin, Lucey and Phelan2014; Higgins, Reference Higgins2004). Historical analyses of vaccination programs by Montero et al. (Reference Montero, Vidal, Velasco, Carreño, Torres, Benachi, Tovar-Rosero, Oñate and O’Ryan2024) demonstrate that public trust, transparent governance, and sociocultural context critically influence immunization uptake and success. Therefore, maintaining biosecurity requires not only technical countermeasures but also the preservation of “tacit knowledge” and institutional readiness to navigate the political and social complexities of a deliberate release. Complementary ethical analyses by Ogugua et al. (Reference Ogugua, Anyanwu, Olorunsogo, Maduka and Ayo-Farai2024) emphasize the need for frameworks that balance individual autonomy with collective protection in the context of vaccination mandates and emergency immunization policies. Equitable distribution protocols for antivirals (e.g., tecovirimat) and third-generation vaccines must be pre-negotiated at the international level to prevent geopolitical hoarding during a crisis.
A multidimensional policy framework for post-eradication preparedness
The discussion above identifies four interrelated vulnerabilities that should directly inform post-eradication smallpox policy: declining orthopoxvirus immunity, operational constraints in vaccine deployment, the expanding dual-use potential of synthetic biology, and the gradual erosion of institutional expertise. Accordingly, preparedness should move beyond reliance on static vaccine stockpiles toward a coordinated framework that links immunological surveillance, deployable countermeasures, adaptive biosecurity governance, and sustained operational readiness.
First, declining and uneven population immunity supports the use of periodic, risk-based serological surveillance to identify susceptibility gaps and inform targeted revaccination or booster strategies, rather than relying solely on historical vaccination status (Shin et al., Reference Shin, Lee, Choi, Yi and Chung2024). Second, because outbreak containment depends heavily on the speed of vaccine delivery and contact-based interventions, preparedness plans should include predefined regulatory, procurement, and distribution pathways for rapidly deployable countermeasures. Thermostable and microneedle-based vaccine platforms may complement conventional stockpiles by reducing cold-chain and administration constraints, provided that their use is supported by appropriate evidence and regulatory review.
Third, the increasing accessibility of synthetic biology requires governance mechanisms that address not only specific pathogens but also enabling technological capabilities. Risk-proportionate sequence screening, strengthened oversight of dual-use orthopoxvirus research, and international information-sharing mechanisms could improve preparedness without unnecessarily restricting legitimate scientific innovation. Finally, the loss of practical experience in managing high-consequence biological events should be treated as a preparedness vulnerability in its own right. Recurring simulation exercises, clinical recognition training, laboratory readiness assessments, and coordinated risk-communication planning are therefore necessary to preserve institutional memory and operational competence.
These measures should be implemented within a broader One Health and transnational framework, particularly because surveillance capacity, vaccine manufacturing, and access to antivirals remain uneven across countries. The objective is therefore not a single intervention, but an integrated preparedness architecture in which biomedical capability, governance, workforce readiness, and equitable access reinforce one another. Figure 1 illustrates these interdependent domains, while Box 1 summarizes the corresponding policy priorities.
A multidimensional framework for contemporary smallpox and orthopoxvirus preparedness, illustrating the convergence of synthetic biology risks, immunological vulnerabilities, and the necessary proactive countermeasures.
Figure 1. Long description
At the center of the diagram is an illustration of an orthopoxvirus virion with the text Smallpox Eradication: The Paradox and The Convergence.
Surrounding this core is a ring divided into six colored segments, each containing an icon and a title. Moving clockwise from the top:
1. Synthetic Biology Risk (yellow) with a D N A double helix icon.
2. Next-Generation Countermeasures (red) with a vaccine vial and syringe icon.
3. Zoonotic Re-emergence (green) with an icon of people and virus particles.
4. Governance and Ethics (pink) with a world map icon.
5. Immunological Vulnerability (dark blue) with a human silhouette icon.
6. Proactive Surveillance and Readiness (light blue) with a microscope icon.
Arrows point outward from each segment to a corresponding blue callout box containing specific bullet points:
* From Synthetic Biology Risk: De Novo Synthesis Feasibility; Dual-Use Dilemma in Genome Reconstruction.
* From Next-Generation Countermeasures: Third-Generation Vaccines (M V A-B N); Thermostable Microneedle Platforms; Antiviral Stockpiles (Tecovirimat).
* From Zoonotic Re-emergence: Monkeypox (Mpox) Resurgence; Orthopoxvirus Ecological Niche (listed twice).
* From Governance and Ethics: One Health Principles Integration; Dual-Use Ethical Oversight; Public Trust and Risk Communication.
* From Immunological Vulnerability: Waning Immunity and Complacency; Immunologically Naive Cohorts; High Case Fatality Rate (~30%).
* From Proactive Surveillance and Readiness: Serological Mapping (Antibody Monitoring); Genomic Surveillance Protocol; Ring Vaccination Modeling and Rapid Deployment.
A multidimensional policy framework for smallpox and emerging orthopoxvirus threats
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1. Strengthen rapid countermeasure deployment: Ring vaccination and other containment strategies depend on timely contact tracing and vaccine delivery. Preparedness plans should therefore incorporate predefined regulatory, procurement, and distribution pathways for rapidly deployable countermeasures. Thermostable and microneedle-based vaccine platforms may complement conventional stockpiles by reducing cold-chain and administration constraints, subject to appropriate evidence and regulatory review.
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2. Advance capability-based biosecurity governance: The increasing accessibility of synthetic biology requires governance approaches that consider enabling technological capabilities in addition to pathogen-specific controls. Risk-proportionate sequence screening, strengthened oversight of dual-use orthopoxvirus research, and international information-sharing mechanisms should be incorporated into adaptive biosecurity frameworks while preserving legitimate scientific innovation.
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3. Implement risk-based serological surveillance: The expanding immunity gap requires moving beyond assumptions based solely on historical vaccination. Periodic, sentinel, or risk-based serological surveillance can help identify population susceptibility, map cross-protective orthopoxvirus immunity, and inform targeted revaccination or booster strategies.
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4. Preserve institutional memory and operational readiness: Technical countermeasures are insufficient without trained personnel and functioning response systems. Preparedness strategies should include recurring simulation exercises, clinical recognition training, laboratory readiness assessments, and coordinated risk-communication planning to preserve practical expertise for high-consequence biological events.
Cross-cutting principle: These measures should be supported by One Health coordination, equitable access to medical countermeasures, and transnational cooperation.
Conclusion
The eradication of smallpox remains a landmark achievement in global health, yet the post-eradication era has created a distinct preparedness challenge. Declining population immunity, reduced institutional familiarity, the reemergence of zoonotic orthopoxviruses, and advances in synthetic biology have collectively transformed smallpox from a historical disease into a continuing biosecurity concern. In this context, preparedness should not be framed solely as a matter of vaccine availability or laboratory containment, but as a broader governance challenge requiring sustained coordination across public health, biosecurity, and emergency response systems.
The analysis presented in this review supports a multidimensional preparedness strategy centered on four complementary priorities: rapid deployment of medical countermeasures, adaptive governance of dual-use biological capabilities, risk-informed serological surveillance, and preservation of institutional memory and operational readiness. Next-generation vaccine platforms, including thermostable and microneedle-based systems, may strengthen response capacity by reducing logistical constraints, while serological monitoring can help identify emerging immunity gaps and guide targeted vaccination strategies. At the same time, advances in synthetic biology require proportionate oversight mechanisms that address enabling capabilities without unnecessarily constraining legitimate scientific innovation.
Ultimately, the central lesson of the post-eradication era is that technical capability alone does not constitute preparedness. Resilience depends on the ability to translate biomedical tools into timely, coordinated, and trusted action. Sustaining clinical expertise, workforce readiness, public confidence, equitable access to countermeasures, and transnational cooperation is therefore essential to preserving the gains of eradication while preparing for future orthopoxvirus threats. Smallpox preparedness should thus be understood not as an attempt to revive a past eradication program, but as a forward-looking component of contemporary global health security.
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