Tecovirimat for smallpox infections.

SIGA Technologies, Inc. is a small biotech company committed to developing novel products for the prevention and treatment of serious viral diseases, with an emphasis on products to combat outbreaks that could result from bioterrorism. With government support, SIGA has developed the necessary infrastructure to successfully advance new antiviral drugs from the discovery stage through to licensing. Currently, there is a need to develop safe and effective inhibitors for poxvirus-induced diseases such as smallpox caused by variola, which is a potential biological warfare agent. Likewise emerging zoonotic infections due to cowpox virus and monkeypox virus require the development of effective countermeasures. Tecovirimat, also known as ST-246, has shown efficacy in all small animal and nonhuman primate prophylaxis and therapeutic efficacy models of poxvirus-induced disease tested to date. Phase I clinical trials and new drug application-enabling toxicology studies have been completed with tecovirimat. A phase II clinical study is being run and SIGA has initiated commercial scale-up manufacturing and preparation for the pivotal safety and efficacy studies. SIGA is committed to getting approval for tecovirimat and supplying it to the Strategic National Stockpile, the Department of Defense and global health authorities.

Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection.

Since the eradication of naturally occurring smallpox in 1980, the fear that variola virus could be used as a biological weapon has become real. Over the last 10 years, emergency preparedness programs have been launched to protect populations against a smallpox outbreak or the possible emergence in humans of other orthopoxvirus infections, such as monkeypox. Vaccination against smallpox was responsible for its eradication, but was linked with high rates of adverse events and contraindications. In this context, intensive research in the poxvirus field has led to the development of safer vaccines and to an increase in the number of anti-poxvirus agents in the pipeline. SIGA Technologies Inc, under license from ViroPharma Inc, is developing tecovirimat (ST-246). Tecovirimat is a novel antiviral that inhibits the egress of orthopoxviruses by targeting viral p37 protein orthologs. The development of tecovirimat during the last 5 years for the treatment of smallpox and for its potential use as adjunct to smallpox vaccine is reviewed here.

[The American bacteriologist: Dr. Meyer].

Karl F. Meyer who was born in Switzerland was American famous bacteriologist of 20th century. During the World War II, Dr. Meyer urged the U. S. military to take positive reply measures against the bacteria war started by Japanese army and achieved significant accomplishments in the preventive and therapeutic theory of plague as well as the manufacture of plague vaccine. After the World War II, Meyer devoted to the scientific field of plague prevention and made great achievements in the area of animal diseases and public health. In 1951, he received the Lasker Award of America.

Development pathway for biodefense vaccines.

At the present time it is estimated that the process of development of a vaccine from discovery to licensure takes approximately 18-20 years and costs in excess of US$500 million. For "routine" vaccines, the case for developing a vaccine is straightforward in terms of economics and large scale public health utilization each year. For vaccines used for biodefense and emerging diseases, the considerations are somewhat different as the vaccine may not be needed every year to control outbreaks and may be stockpiled only as a countermeasure that hopefully may never be needed. Furthermore, efficacy trials are often difficult as the natural disease may be rare or not present. Consequently, animal models will play a critical role in demonstrating efficacy. Nonetheless, the vaccine pathway still requires the same fundamental components of basic science/discovery, preclinical development, clinical trials, registration/licensure, and a plan for implementation.

Pharmaceuticals and the strategic national stockpile program.

This article discusses current stockpile practices after exploring a history of the use of biologic agents as weapons, the preventive measures that the federal government has used in the past, and the establishment of a Strategic National Stockpile Program in 2003. The article also describes the additional medical supplies from the managed inventory and the federal medical stations. The issues (financial burden, personnel, and materiel selection) for local asset development are also discussed. Critical is the cost to local communities of the development and maintenance of a therapeutic agent stockpile and the need for personnel to staff clinics and medical stations. Finally, the important role of the dental profession for dispensing medication and providing mass immunization in the event of a disaster is described.

The occupational role of women in military service: validation of occupation and prevalence of exposures in the Millennium Cohort Study.

To better understand the US military's global peacekeeping and combat operations, which may expose a growing population of American service women to challenging occupations and environments. Concordance between self-reported and electronic occupation codes for female participants in the Millennium Cohort was measured using kappa statistics. Multivariable logistic regression modeling was used to assess the odds of five self-reported potentially toxic environmental exposures or disturbing experiences among different occupational categories, while adjusting for demographic and military characteristics, including deployment. Self-reported occupations were moderately to highly reliable when compared with electronic occupation data. Active-duty and Reserve/Guard females differentially reported witnessing death or trauma and exposure to chemical or biological warfare, depleted uranium, or pesticides. Findings suggest that self-reported occupation can be used with a high degree of confidence. Occupational groups with higher odds of reporting military exposures of concern will be followed longitudinally through 2022 and prospectively compared using baseline and follow-up evaluations.

Psychosomatic medicine and biodefense preparedness--a new role for the American Psychosomatic Society.

Biodefense preparations in the United States have focused mostly on improving biosurveillance and hospital surge capacity in the event of an outbreak or a weapons of mass destruction (WMD) event. However, what if an invisible bioweapon or dirty bomb was released in a major population center, or if avian flu took hold with sustained human to human transmission? Suddenly, we need to combine efforts from psychosomatic medicine and general medicine with public health practice to triage nonexposed patients with somatic symptoms from those with medical sequelae resulting from hazardous exposures. This would better enable the limited acute care resources to be directed to those most in need of urgent medical care. Furthermore, psychosomatic medicine experts are potentially important players in biodefense planning related to risk communication and health education strategies in a WMD scenario or outbreak in which individuals must make informed choices about their need for immediate medical attention.

Rapid induction of protective tolerance to potential terrorist agents: a systematic review of low- and ultra-low dose research.

OBJECTIVE: To systematically review the literature on the ability of low-dose (LD) and ultra-low-dose (ULD) toxin exposure to prevent and treat biological and chemical threats. METHODS: Laboratory research articles on protection or treatment from LD or ULD exposure for the 13 high-risk chemical and biological warfare threats were collected and systematically evaluated for quantity and scientific quality using pre-defined methodological criteria. RESULTS: Over 2600 articles were screened. Only five studies met the inclusion criteria examining stimulation and protective effects of LD- or ULD-exposures to the 13 pre-identified biological and chemical agents. The quality evaluation (QE) of these studies was above average with a mean QE score of 70.6% of maximum. Two articles of fair to good quality reported both protective and treatment efficacy from exposure of animals or humans to LD- and ULD-exposures to toxins of risk in biochemical warfare. CONCLUSION: There is little research on agents of biological and chemical warfare investigating the possible use of LD- and ULD-toxins for protection and treatment. The existing literature is generally of good quality and indicates that rapid induction of protective tolerance is a feasible but under-investigated approach to bioterrorist or biowarfare defense. In our opinion, further research into the role of induced protection with LD- and ULD-toxic agents is needed.

The history of anthrax.

Anthrax, a potentially fatal infection, is a virulent and highly contagious disease. Descriptions of this disease begin in antiquity, with the best ancient account being by the Roman poet Virgil. During the 19th century, anthrax was the infection involved in several important medical developments. It served as the prototype for Koch's postulates regarding the causation of infectious disease. The first vaccine containing attenuated live organisms was Louis Pasteur's veterinary anthrax vaccine. In the 1900s, human inhalation anthrax occurred sporadically in the United States among textile and tanning workers, but the incidence of the illness had declined dramatically. An outbreak of inhalation anthrax occurred in Sverdlovsk near a Soviet military microbiology facility in 1979. This epidemic represented the largest documented outbreak of human inhalation anthrax in history. In October and November 2001, 22 cases of confirmed or suspected inhalation and cutaneous anthrax were reported associated with the intentional release of the organism in the United States. An additional case of cutaneous disease occurred in March of 2002.

The Army chemical/biological SMART (SMART-CB) team: the nurse's role.

A chemical or biologic attack probably will be covert, rather than overt. Because presenting signs and symptoms may mimic minor nonspecific illnesses or naturally produced disease syndromes and may not appear for several days, it is likely that nurses in emergency rooms and primary care settings will be among the first to come into contact with victims of a chemical or biologic agent exposure. Early recognition, reporting, decontamination, self-protection, prophylaxis, and treatment are imperative. After the terrorist attack on September 11, 2001, the anthrax incidents, and the heightened publicity of chemical and biologic agent attacks brought on by media coverage, the need for highly trained and well-prepared medical personnel has increased dramatically. Army nurses have led the way in training and expanding the capabilities of specialized medical response teams. Team members require ongoing training, state-of-the-art protective equipment and medical supplies, and constant practice to maintain the high state of readiness required to respond rapidly and effectively to chemical or biologic threats. Army SMART-CB nurses and their team members are well prepared to provide lifesaving care in highly contaminated areas. It is no longer a question of if but rather when and where the next attack will occur.

[Anthrax and carbuncle: two sides of the same coin]. / Antrace e Carbonchio: due facce della stessa medaglia.

The disease caused by Bacillus anthracis is one of the most critical concerns to the general public and public health authorities due both to the anthrax cases caused by the intentional release of the germ in the USA at the close of 2001 when letters and packages were contaminated with anthrax spores, and the current threat of biological warfare. After a brief excursus on the history of the terms Anthrax and Carbuncle, we survey the main evidence of anthrax found in the ancient literature, and deal with the identification of the pathogenic agent responsible for the disease and the subsequent discovery of the first anthrax vaccine and its use in order to control the spread of the disease in the cattle. Finally, we examine some of the most important episodes of occupational exposure to the Bacillus anthracis that occurred in the past two centuries and the preventive measures applied both to employees and the workplace.

Biological warfare in a historical perspective.

There are some early examples of biological warfare (BW), but in modern times it was used first for sabotage by Germany during WWI. Development of biological weapons on a military significant scale was initiated in several countries in the period between the world wars. During WWII, several countries had active programs such as the USA, UK, Canada, Germany, Japan and the Soviet Union. It was only Japan that on a fairly large scale used BW. The US program continued until 1969, when President Nixon took a decision to end it in connection with signing the BTWC. The Soviet Union had also continued its program after the war, and this was enhanced after signing the BTWC: in the 1980s the program consisted of around fifty facilities and involved around 60,000 people. The Soviet Union produced and maintained a large stockpile of BW-agents. After the collapse of the Soviet Union, and due to pressure from USA and UK, President Yeltsin issued a decree in 1992 banning continued offensive BW activity. However, there are still concerns of residual activity in Russia. Another program of concern is the Iraqi BW-program. After 10 years of UN inspections that were stopped in 1998, there are still many unanswered questions concerning the BW program. There was also a covert BW-program in South Africa that was terminated around 1993. There have also been a number of allegations of alleged use or possession. In addition, there are indications that 10-12 states are now trying to acquire BW, and this assessment is based on intelligence information, mainly from the USA. For example Iraq, North Korea, Iran, Syria, Sudan and Libya. Another aspect is the strong driving force of technology developments to promote this type of program, opening new risks for future potential military misuse.

Bacillus anthracis and antibacterial agents.

Anthrax is one of the oldest threats to humankind, and remains endemic in animals in many parts of the world. Human cases are infrequent, and some result from biological warfare. This review summarizes the current knowledge on the antibacterial activity of available antibiotics. For potential use in the most severe cases of anthrax, antibacterials need to exhibit potent in vitro activity, intracellular bioactivity, and suitable locations in lymph nodes. In animal models, it has been shown that doxycycline and fluoroquinolones are the most active compounds. There is a lack of data for animal models for macrolides and ketolides, some of them exhibiting good in vitro activity. However, systemic anthrax (inhalation or gastrointestinal) is mainly due to anthrax toxin, and therapy directed against intoxication is needed as basic treatment.

Smallpox--eradicated, but a growing terror threat.

Smallpox is a disease that followed humanity for thousands of years up until 30 years ago. It was possible to eradicate, because an effective live vaccine from crossreacting vaccinia could be developed. Twenty years have passed since vaccinations stopped and very few people are protected against the disease today. Variola today has become an object of discussion due to the possibility that it can be used as a bioweapon. Due to the number of complications that can be expected a general vaccination is probably not possible. Research is ongoing to develop new vaccines. Many countries are improving their capabilities to respond to a renewed threat of a smallpox epidemic.

A short history of biological warfare.

Biological weapons have been used in war from the start of recorded history. This article reviews the history of the subject, including the outbreak of the Black Death and the use of smallpox against American Indians. The new science of microbiology was misused from soon after its start and, despite the 1925 Geneva Protocol, the Japanese experimented extensively on prisoners in China. The Allies carried out extensive research during the Second World War, notably the United Kingdom into anthrax on Gruinard Island and the United States into a variety of agents. Despite the 1972 Biological Weapons Convention (BWC), a major programme continued in the former Soviet Union (leading to an accidental outbreak of anthrax). Most recently Iraq was revealed as having an extensive programme, with weaponization of large amounts of various agents, and several terrorists groups have attempted to use biological agents as weapons. Modern developments in biotechnology could lead to even more serious developments, and effective preventive measures, including strengthening of the BWC, are imperative.