Stocks Of Variola Virus Research Articles

Teaching a new mouse old tricks: Humanized mice as an infection model for Variola virus.

Smallpox, caused by the solely human pathogen Variola virus (VARV), was declared eradicated in 1980. While known VARV stocks are secure, smallpox remains a bioterrorist threat agent. Recent U.S. Food and Drug Administration approval of the first smallpox anti-viral (tecovirimat) therapeutic was a successful step forward in smallpox preparedness; however, orthopoxviruses can become resistant to treatment, suggesting a multi-therapeutic approach is necessary. Animal models are required for testing medical countermeasures (MCMs) and ideally MCMs are tested directly against the pathogen of interest. Since VARV only infects humans, a representative animal model for testing therapeutics directly against VARV remains a challenge. Here we show that three different humanized mice strains are highly susceptible to VARV infection, establishing the first small animal model using VARV. In comparison, the non-humanized, immunosuppressed background mouse was not susceptible to systemic VARV infection. Following an intranasal VARV challenge that mimics the natural route for human smallpox transmission, the virus spread systemically within the humanized mouse before mortality (~ 13 days post infection), similar to the time from exposure to symptom onset for ordinary human smallpox. Our identification of a permissive/representative VARV animal model can facilitate testing of MCMs in a manner consistent with their intended use.

Co-administration of tecovirimat and ACAM2000™ in non-human primates: Effect of tecovirimat treatment on ACAM2000 immunogenicity and efficacy versus lethal monkeypox virus challenge

Naturally occurring smallpox has been eradicated but research stocks of variola virus (VARV), the causative agent of smallpox, still exist in secure laboratories. Clandestine stores of the virus or resurrection of VARV via synthetic biology are possible and have led to concerns that VARV could be used as a biological weapon. The US government has prepared for such an event by stockpiling smallpox vaccines and TPOXX®, SIGA Technologies’ smallpox antiviral drug. While vaccination is effective as a pre-exposure prophylaxis, protection is limited when administered following exposure. Safety concerns preclude general use of the vaccine unless there is a smallpox outbreak. TPOXX is approved by the FDA for use after confirmed diagnosis of smallpox disease. Tecovirimat, the active pharmaceutical ingredient in TPOXX, targets a highly conserved orthopoxviral protein, inhibiting long-range dissemination of virus. Although indications for use of the vaccine and TPOXX do not overlap, concomitant use is possible, especially if the TPOXX indication is expanded to include post-exposure prophylaxis. It is therefore important to understand how vaccine and TPOXX may interact. In studies presented here, monkeys were vaccinated with the ACAM2000TM live attenuated smallpox vaccine and concomitantly treated with tecovirimat or placebo. Immune responses to the vaccine and protective efficacy versus a lethal monkeypox virus (MPXV) challenge were evaluated. In two studies, primary and anamnestic humoral immune responses were similar regardless of tecovirimat treatment while the third study showed reduction in vaccine elicited humoral immunity. Following lethal MPXV challenge, all (12 of 12) vaccinated/placebo treated animals survived, and 12 of 13 vaccinated/tecovirimat treated animals survived. Clinical signs of disease were elevated in tecovirimat treated animals compared to placebo treated animals. This suggests that TPOXX may affect the immunogenicity of ACAM2000 if administered concomitantly. These studies may inform on how vaccine and TPOXX are used during a smallpox outbreak.

The Threat of Synthetic Smallpox: European Perspectives.

This article explores how advances in synthetic biology, and the potential threat of deliberately recreating and spreading smallpox, are affecting the multilateral debate on the remaining variola virus stocks. It draws on in-depth, semi-structured interviews with 10 high-profile, European-based experts in biosecurity and synthetic biology. Four overarching themes affecting the retention or destruction debate are discussed, relating to biosecurity, dangerous knowledge, accidental releases, and eradication. We conclude that while synthetic biology seems to affect all the main discourses in the variola stocks debate, a range of views is present and it is not apparent that advances in synthetic biology are causing a shift toward either retention or destruction of the stocks.

Smallpox still haunts scientists: results of a questionnaire-based inquiry on the views of health care and life science experts and students on preserving the remaining variola virus stocks.

The World Health Organization (WHO) declared eradication of the dreadful disease “smallpox” in 1980. Though the disease has died down, the causative virus “variola” has not, as it has been well preserved in two high security laboratories—one in USA and another in Russia. The debate on whether the remaining stocks of the smallpox virus should be destroyed or not is ongoing, and the World Health Assembly (WHA) in 2011 has decided to postpone the review on this debate to the 67th WHA in 2014. A short questionnaire-based inquiry was organized during a one-day stem cell meeting to explore the views of various health care and life science specialists especially students on this aspect. Among the 200 participants of the meeting, only 66 had answered the questionnaire. 60.6% of participants who responded to the questionnaire were for preserving the virus for future reference, while 36.4% of the participants were for destroying the virus considering the magnitude with which it killed millions. However, 3% of the respondents were not able to decide on any verdict. Therefore, this inquiry expresses the view that “what we cannot create, we do not have the right to destroy.”

Consensus is needed at a global level concerning dual‐use research

Consensus is needed at a global level concerning dual‐use research

Synthetic Biopower, Comprador Governmentality and Necrodevelopment

Classical political theory, based on sovereignty, contract, right and duty, was contested by Foucault with ‘biopower’ meant to discipline and control the individuals and their bodies. With the Genomics revolution by the turn of the millennium, the treasure of genetic history and make up of population has became an attractive research target for biomedical researchers and pharmaceutical corporations. During the same time, United States has visualized a new role for itself by transcending national-interest paradigm to deploy its “soft power” position in global health. Biopower and necropolitics have been two sides of the same coin, as Mbembe has observed. Breakthroughs in post genome biology has changed the focus of proliferation problem from biological or chemical warfare agents as the object of malign manipulation to the physiological target in the human body as the object of attack. Synthetic biology enables rational adjustment of genes beyond naturally occurring sequences. The emerging Synthetic Biopower has opened up vast possibilities for vaccines, drugs, hydrogen fuel, etc. and parallel tensions for abuse or inadvertent disasters. Thus weaponization and aerosolization of virus of diseases are possible with recent discoveries in dual-use genomics and synthetic biotechnology. USA has not ratified Biological Weapons Convention and Chemical Weapons Convention, although ratified by USA, exercises very lax monitoring in this context. Thus the unique danger lies in its possible deployment in unilateral climate geoengineering by global powers. It is alleged that Synthetic Biology has paved a robust and strategic platform of synthesizing variola virus, responsible for completely eradicated ‘small pox’, in a much simpler way. In 1994, WHO (World Health Organization) Ad Hoc Committee on orthopoxvirus infections had banned genetic engineering of variola. But this protection may be miserably ineffective if synthesis of variola genes is carried out. Thus WHO draft small pox resolution, January 2007 has been challenged by Sandia National Laboratory of US Department of energy arguing that WHA (World Health Assembly) has no jurisdiction over synthetic, as opposed to genetically engineered, variola viruses. WHO’s Variola Advisory Committee (VAC) in its 2006 meeting has started a process that may modify the rules set in 1994 concerning possession of and use of variola virus and its genes. VAC has always been manned by northern scientists with interest in variola virus research and thus has been over-tolerant of failed and dangerous animal model experiments in the USA. Soviet Russia and USA vehemently oppose any move for total destruction of the stocks of variola virus retained by them with dubious speech act on world peace in WHO forum. Their stocks are actually WHO repositories of strains collected decades ago in many corners of the world and only temporarily retained at the discretion of the WHA. The malign deployment of Synthetic Biopower, with immense potential to achieve Millennium Development Goals, may be used to pathologize unruly ‘others’. Global powers’ rivalry leads to burgeoning biopolitics to subject humanity’s body and thus endangers the human security of millions and the sustainability of the planet.

Killing a Killer: What Next for Smallpox?

Now that the 20th century has passed into the domain of history books, we can retrospectively begin to assess the relative contributions that the many advances in the realm of infectious disease have actually made to public health in general. At the top of this virtuous list will surely be the discovery of antibiotics in the 1930s and the use of vaccination to eradicate smallpox as an extant human disease in the 1960s and 1970s. As clearly pointed out in a recent book by D. A. Henderson, one of the leaders of the global smallpox eradication program, this task of ridding Homo sapiens from the curse of this ancestral disease was neither easy nor without controversy [1]. In fact, the history of the many consequences of smallpox on humankind reads like a long litany of human misery and calamitous events, but is juxtaposed with the more noble accomplishments that began with the discovery of vaccination by Jenner in 1798 and culminated with the World Health Organization (WHO) certifying the world free of smallpox in 1980 [2]. With this singular accomplishment, as many as 60–100 million individuals who would have been predicted to die of smallpox have been spared from a truly gruesome death. Nevertheless, as is intimated by the timeline in Table 1, which summarizes the history of smallpox and the orthopoxvirus that caused the disease (variola virus), the narrative of smallpox did not stop with its eradication as a pandemic human disease. Instead, we find ourselves still wrestling with an issue that intermingles public health policy, philosophy, national security, and bioterrorism, and affects our perceptions of research ethics with extreme pathogens in general. It boils down to a not-so-simple question: What exactly should the Victor do with the Vanquished? Table 1 History of Smallpox: Timeline of a Serial Killer. In 1980, this question seemed simpler than now. Following the smallpox eradication, all declared stocks of the live variola virus were rounded up and distilled into two WHO-approved repositories, now residing at the Centers for Disease Control (CDC), Atlanta, United States of America, and at Vector, Novosobirsk, Russia. WHO convened a standing committee to oversee these repositories and issue regulatory approval for any research studies that utilized the live virus stocks at the two sites, with the tacit assumption that the only justifiable long-term fate for these stocks was an autoclave. Then, the revelation that variola virus had been covertly weaponized and stockpiled by the Soviet military [3],[4] led to escalating waves of mistrust and suspicion amongst politicians, government officials, scientists, and health policy experts alike [5]. Factions then formed, with the two sides collectively promulgating an agenda that was either pro-destruction or anti-destruction, and cogent arguments were made by members of both camps as to why the declared stocks of variola virus should be maintained or not [6]–[8]. In the meantime, the member states holding the declared stocks of live virus (i.e., the US and Russia) held their own internal deliberations of what to do next, in a kind of pas de trois with the WHO that continues to this day. In the case of the US, input was sought from the Institute of Medicine (IOM), which has struck two expert committees (the first issued its report in 1999, and the second committee report was released in July 2009 at http://www.iom.edu/Reports/2009/LiveVariolaVirusContinuingResearch.aspx; [9]) on the scientific rationale for any further research that would require live variola virus. It is expected that these two IOM reports will be factored into the US decision as to how to respond to any future request from WHO (expected in 2011), following a vote of member states of the World Health Assembly on the specific issue of whether the declared live variola virus stocks held at both sites should now finally be destroyed.

Therapeutic and Prophylactic Drugs to Treat Orthopoxvirus Infections

With the global eradication of smallpox in 1979, the causative agent, variola, no longer circulates in human populations. Other human poxvirus infections, such as those caused by vaccinia, cowpox virus and molluscum, are usually relatively benign in immunocompetent individuals. Conversely, monkeypox virus infections cause high levels of mortality and morbidity in Africa and the virus appears to be increasing its host range, virulence and demographic environs. Furthermore, there are concerns that clandestine stocks of variola virus exist. The re-introduction of aerosolized variola (or perhaps monkeypox virus) into human populations would result in high levels of morbidity and mortality. The attractiveness of variola as a bioweapon and, to a certain extent, monkeypox virus is its inherent ability to spread from person-to-person. The threat posed by the intentional release of variola or monkeypox virus, or a monkeypox virus epizoonosis, will require the capacity to rapidly diagnose the disease and to intervene with antivirals, as intervention is likely to take place during the initial diagnosis, approximately 10-15 days postinfection. Preimmunization of 'at-risk populations' with vaccines will likely not be practical, and the therapeutic use of vaccines has been shown to be ineffective after 4 days of infection with variola. However, a combination of vaccine and antivirals for those infected may be an option. Here we describe historical, current and future therapies to treat orthopoxvirus diseases.

Smallpox vaccines: Past, present, and future

The global eradication of smallpox was a tremendous achievement made possible by the development of an effective vaccine. Routine vaccination of the general population is no longer recommended. However, stocks of variola virus, the causative agent of smallpox, still exist in 2 secure laboratories, and permanent disposal has been controversial. In addition, there is speculation that variola virus may exist outside of these 2 facilities, and there is a concern that the threat of smallpox will be used as a bioterrorist weapon. In 2002, this concern led to a vaccination campaign in US military and civilian healthcare workers and first responders. Although the historical live virus vaccine has proven efficacy, it also is associated with serious adverse events and rare fatal reactions, particularly in the setting of immunodeficiency and atopic eczema. In addition, this vaccine was historically produced using animal intermediaries in a process that was prone to contamination and not acceptable for current manufacturing standards. Development of alternative poxvirus vaccines is focused on replication-defective viruses, gene-based vectors, and subunit approaches to improve safety and immunogenicity. The conundrum is that in the absence of an intentional release of variola, efficacy evaluation of new candidate vaccines will be limited to animal model testing, which creates new challenges for the vaccine licensure process. Although motivated by the threat of bioterrorism, the hope is for new poxvirus vaccines to have their greatest utility against other pathogenic orthopoxviruses such as monkeypox and for the development of recombinant poxvirus-based vectors to treat and prevent other diseases.

Smallpox containment updated: considerations for the 21st century

Smallpox containment updated: considerations for the 21st century

Discovery of antivirals against smallpox.

Smallpox, a devastating infectious disease dreaded throughout much of recorded history, is caused by the variola virus, a member of the poxviridae family. In the 20th century alone, smallpox deaths worldwide numbered in the millions. In 1980, after an intensive program of immunization with vaccinia virus, a related but relatively nonpathogenic virus, the World Health Organization (WHO) declared the disease eradicated. By 1983, all known stocks of variola virus were in two WHO collaborating centers: the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta and (after a transfer in 1994) the Russian State Research Center of Virology and Biotechnology (the Vektor Institute) in Novosibirsk. The WHO Committee on Orthopoxvirus Infections voted on several occasions to recommend destruction of the stocks, but each time the decision was deferred to permit more research on live variola virus. A 1999 National Academies report summarized and assessed scientific needs for live variola virus (1). The concern that undeclared stocks of variola virus might exist and that they might be used as a bioterrorist weapon (2) was heightened in late 2001 by the deliberate release of Bacillus anthracis , the agent of anthrax, in the weeks after the September 11, 2001, attacks. That concern prompted a voluntary national-preparedness effort to vaccinate healthcare workers, first responders, and members of the military against smallpox. However, given the substantial side effects, the risks associated with the smallpox vaccine, and the absence of information about an imminent bioterrorist attack, vaccination was not accepted by all members of those groups, nor was it recommended for the general public by the government (3). Whatever the likelihood of covertly held variola virus stocks, an intentional release of the virus would pose a serious health threat and would probably provoke a …

Recent events and observations pertaining to smallpox virus destruction in 2002.

To destroy all remaining stocks of variola virus on or before 31 December 2002 seems an even more compelling goal today than it did in 1999, when the 52d World Health Assembly authorized temporary retention of remaining stocks to facilitate the possible development of (1) a more attenuated, less reactogenic smallpox vaccine and (2) an antiviral drug that could be used in treatment of patients with smallpox. We believe the deadline established in 1999 should be adhered to, given the potential outcomes of present research. Although verification that every country will have destroyed its stock of virus is impossible, it is reasonable to assume that the risk of a smallpox virus release would be diminished were the World Health Assembly to call on each country to destroy its stocks of smallpox virus and to state that any person, laboratory, or country found to have virus after date x would be guilty of a crime against humanity.

Monkeypoxvirus infections.

During and after the smallpox eradication campaign, human cases of monkeypox appeared in West and Central Africa, as isolated cases or as small epidemics. Since inter-human transmission has never or only very exceptionally been documented, monkeypox does not represent a serious threat to humans. The virus reservoir is among tree squirrels living in the tropical rain forests of Africa and humans are infected by hunting, killing and skinning these animals. However, the modernization of society lessens human contact with the virus reservoir. Since the eradication of smallpox, stocks of variola virus have been maintained; whether these stocks should now be destroyed is a political question, which is seriously compromised by mistrust between countries.

Smallpox: gone but not forgotten.

Smallpox represents both the acme of man's efforts to combat infectious diseases and one of his greatest fears. The disease emerged in prehistoric times to spread throughout the world causing blindness and death in millions of people. An acute infection caused by variola virus, one of the Orthopoxviruses, with skin eruption and marked toxemia had an average case fatality rate of 30%. Variola minor, a milder form of the disease, had a case fatality of one percent. Humans are the sole host, and survival confers lifelong immunity. Immunization was practiced since ancient times by inoculation with the variola virus until Jenner's demonstration of the efficacy and safety of vaccination with vaccinia virus. Following an intensive eradication effort by the World Health Organization, the world was declared to be free of smallpox in 1979. The decision to destroy all remaining stocks of variola virus in 1999 has met with some controversy.