Showing papers on "Anthrax vaccines published in 2001"

Identification of the cellular receptor for anthrax toxin.

Abstract: The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

Recognition and management of anthrax--an update.

Abstract: Infection with Bacillus anthracis, commonly known as anthrax, has reemerged as a weapon of bioterrorism. This review article revisits and updates our 1999 review of anthrax and contains practical information for the physician faced with a possible case of this dangerous infection.

The role of antibodies to Bacillus anthracis and anthrax toxin components in inhibiting the early stages of infection by anthrax spores

Abstract: Vaccines which are efficacious against anthrax, such as the human vaccine, Anthrax Vaccine Absorbed (AVA), contain the protective antigen (PA) component of the anthrax toxins as the major protective immunogen. Although AVA protects against inhalational anthrax, the immune responses to and role in protection of PA and possibly other antigens have yet to be fully elucidated. Sera from animals immunized with a toxin-producing, unencapsulated live vaccine strain of Bacillus anthracis have been reported to have anti-spore activities associated with the antitoxin humoral response. The authors performed studies to determine whether anti-PA antibody (Ab)-containing preparations stimulated spore uptake by phagocytes and suppressed the germination of spores in vitro. AVA- and PA-immune sera from several species enhanced the phagocytosis by murine peritoneal macrophages of spores of the virulent Ames and the Sterne vaccine strains. Antitoxin Abs appeared to contribute significantly, although not solely, to the enhanced uptake. Rabbit antisera to PA purified from either Sterne or a PA-producing pX01-cured recombinant, affinity-purified anti-PA IgG, and monkey antisera to AVA were used to assess the role of anti-PA Abs. Rabbit anti-PA Abs promoted the uptake of spores of the PA-producing strains Sterne, Ames and RP42, a mutant of Sterne producing only PA, but not of the pX01-ΔSterne-1 strain, ΔAmes strain, or RP4, a mutant of Sterne with deletions in the loci encoding PA and the oedema factor (EF) toxin component and producing only the lethal factor toxin component. Rabbit anti-PA and monkey anti-AVA Abs also significantly inhibited spore germination in vitro compared to preimmune serum or medium. Spore-associated proteins recognized by anti-PA Abs were detected by electron microscopy and confirmed by immunoblotting of spore coat extracts. Thus, the anti-PA Ab-specific immunity induced by AVA has anti-spore activity and might have a role in impeding the early stages of infection with B. anthracis spores.

Search for correlates of protective immunity conferred by anthrax vaccine.

Abstract: Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r2 = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD50) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.

Protection against anthrax lethal toxin challenge by genetic immunization with a plasmid encoding the lethal factor protein.

Abstract: The ability of genetic vaccination to protect against a lethal challenge of anthrax toxin was evaluated. BALB/c mice were immunized via gene gun inoculation with eucaryotic expression vector plasmids encoding either a fragment of the protective antigen (PA) or a fragment of lethal factor (LF). Plasmid pCLF4 contains the N-terminal region (amino acids [aa] 10 to 254) of Bacillus anthracis LF cloned into the pCI expression plasmid. Plasmid pCPA contains a biologically active portion (aa 175 to 764) of B. anthracis PA cloned into the pCI expression vector. One-micrometer-diameter gold particles were coated with plasmid pCLF4 or pCPA or a 1:1 mixture of both and injected into mice via gene gun (1 μg of plasmid DNA/injection) three times at 2-week intervals. Sera were collected and analyzed for antibody titer as well as antibody isotype. Significantly, titers of antibody to both PA and LF from mice immunized with the combination of pCPA and pCLF4 were four to five times greater than titers from mice immunized with either gene alone. Two weeks following the third and final plasmid DNA boost, all mice were challenged with 5 50% lethal doses of lethal toxin (PA plus LF) injected intravenously into the tail vein. All mice immunized with pCLF4, pCPA, or the combination of both survived the challenge, whereas all unimmunized mice did not survive. These results demonstrate that DNA-based immunization alone can provide protection against a lethal toxin challenge and that DNA immunization against the LF antigen alone provides complete protection.

Delayed Life-Threatening Reaction to Anthrax Vaccine

Abstract: Background: Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Due to the current world threat of unpredictable biological terrorism, the Department of Defense has mandated the systematic vaccination of all US military personnel against this warfare agent. Many may experience a mild flu-like illness and soreness at the injection site, but systemic reactions are rare. Case Report: We report a delayed and potentially serious life-threatening adverse reaction to anthrax vaccine. A previously healthy 34-year-old male was transported to the emergency department with dyspnea, diaphoresis, pallor, and urticarial wheals on his face, arms, and torso after the administration of the third dose of anthrax vaccine. All symptoms resolved after pharmacological intervention and the patient was discharged. Pharmaco-epidemiological data indicate that 30% of anthrax vaccine recipients experience mild local reactions. With large numbers of military personnel being vaccinated, emergency physicians may encounter more vaccine-related adverse reactions.

War against anthrax.

Abstract: Anthrax is a disease caused by the gram-positive bacterium Bacillus anthracis. The disease is usually confined to animals and is rare. Humans may be infected while handling disease-inflicted animals. B. anthracis has become a bane of defense establishments in various countries as, capitalizing on the formation of highly stable spores, it can be used as a potent biological warfare agent sprayed into the air in the form of a finely ground powder. Once inhaled, spores reach the lungs and become lethal. The outbreak of anthrax in Sverdlovsk, Russia, due to an accidental release of spores into the air, led to many deaths and shows the threat associated with the bacterium (1). Human exposure to spores can go undetected for some time, during which the spores germinate inside macrophage cells (2). The population grows to critical-load level inside the body and, subsequently, secretes anthrax toxin into the system. Antibiotic treatment is effective if administered in time, in the initial stages of infection. Once a high enough concentration of the toxin has been released to cause irreversible damage to the body, the antibiotic ceases to be effective. In that regard, ciprofloxacin has been found to be very effective against anthrax. However, excessive intake of the antibiotic can cause undesirable side effects, including a general depletion of the immune system. Anthrax vaccine has been the sole source of preventing the disease. However, vaccination requires injection of a crude mixture of the toxin’s constituent proteins in six doses. The situation poses the threat of a greater demand for the vaccine than its supply. Currently, the vaccination is restricted to military personnel.

Health Risk Communication in the Anthrax Vaccine Immunization Program: Lessons for the Future

Abstract: : When Secretary of Defense William Cohen announced that all military service members would be vaccinated with the anthrax vaccine, few anticipated the widespread reluctance to accept his directive. Service members were already required to take several vaccinations and this new force protection measure involved a vaccine that had been approved by the Food and Drug Administration in 1970. In response to the unanticipated opposition on the Internet and in the press, an extensive information campaign was developed. This paper suggests that a more proactive educational program with a greater utilization of health risk communication techniques could have reduced much of the negative reaction to the anthrax vaccine. Such techniques as early use of focus groups and surveys could have measured the effectiveness and comprehension of the message. Early evaluations could have identified challenges involving trust, credibility, and organizational biases, which appeared as the program matured. More focused application of effective health risk communication techniques in the creation of the Anthrax Vaccine Immunization Program would have reduced the amount of controversy generated by the program. Lessons learned by studying the development and implementation of health risk communication in the anthrax program can be applied to other military programs, including not only those involving vaccines, but also those having to do with controversial issues such as depleted uranium rounds or toxic exposure standards.

The Anthrax Vaccine Debate: A Medical Review for Commanders

Abstract: : There are two distinct yet related aspects to the debate over the safety and efficacy of the anthrax vaccine. An assessment of the clinical safety and efficacy of the anthrax vaccine. The policy level decision to vaccinate military personnel based on intelligence reports and assessments. The policy decision to vaccinate is based on an assessment of relative risk. The risk to an individual of developing side effects and complications after vaccination versus, the risk that Defense Department (DoD) personnel may be exposed to anthrax during an attack. Anthrax causes disease in humans through three mechanisms: cutaneous, gastrointestinal, inhalation. Cutaneous anthrax occurs primarily in unvaccinated workers in goat hair and wool factories. Veterinary practices and vaccination have eliminated anthrax infection as an occupational risk. Inhalation anthrax is the most lethal. Death occurs in nearly 100 percent of victims with symptoms. Inhalation anthrax is the 100% most likely to be used in biological weapons. Requires aerosolization of anthrax spores down to the proper particulate size for inhalation. Aerosolization of anthrax spores is technically difficult to achieve.

The Importance of Health Risk Communication in the Creation of the Anthrax Vaccine Immunization Program

Abstract: : When Secretary of Defense William Cohen announced that military service members would take the anthrax vaccine, few anticipated the widespread reluctance to accept his directive. Service members have been required to take several vaccinations and this new force protection measure involved a vaccine approved by the FDA in 1970. An extensive information campaign was developed in response to the unanticipated opposition on the Internet and in the press. This paper suggests that a more proactive educational program with a greater utilization of health risk communication techniques would have reduced much of the negative reaction to the anthrax vaccine. Such techniques as early use of focus groups and surveys could have measured the effectiveness and comprehension of the message. Early evaluations could have identified the challenges of trust, credibility and organizational biases, which appeared as the program matured. A greater application of health risk communication in the creation of the Anthrax Vaccine Immunization Program Agency would have generated less controversy. Studying the development and implementation of health risk communication in the anthrax program can be applied to other military vaccines or the discussions on depleted uranium rounds or toxic exposure standards.

Anthrax and other vaccines: use in the u.s. military

Abstract: The Department of Defense (DoD) has a robust program to develop and utilize the best countermeasures available to protect our military forces from biological warfare agents. DoD has been instrumental in performing fundamental research leading to identification of candidate vaccines. Since most biological warfare threats do not occur in nature, the large scale clinical trials that the Food and Drug Administration (FDA) normally requires to license a new vaccine cannot be performed. Instead, the DoD relies on data obtained from animal models. For anthrax vaccine, the potency of the vaccine is measured in a guinea pig model in which the animals are vaccinated, then subsequently exposed (challenged) with virulent anthrax spores. A statistical calculation is used to determine the potency of each lot of vaccine versus a reference lot. DoD is currently working with the vaccine manufacturer and the FDA to evaluate a new relative potency test for the vaccine. For other vaccines currently under development (e.g., new vaccines for smallpox and plague) the DoD will continue to rely on validated animal studies, as well as safety and immunogenicity studies in man. When possible, DoD will correlate a surrogate marker from animal protection studies with serological data from vaccinated individuals. Vaccines have been proven over the years to provide sound protection from disease. Vaccination in advance of exposure may preclude the need for detection and warning, and causes minimal impact on the logistical system of the military services. Additional studies are warranted to further evaluate the interactions of multiple vaccinations, as well as long term effects of vaccines. Research is underway to study multi-agent vaccines, delivering protection against more than one pathogen. When vaccination is not possible, DoD will rely on post-exposure treatment; some of these treatment regimes may also involve the use of vaccine. In a civilian bioterrorist scenario, the post-exposure treatment is the most likely course of action, since the majority of the population will not be immunized for the specific threats they may encounter. Abstract #300332. Paper presented Sunday, August 5, 2001 in Atlanta, Georgia at the conference "Anthrax and Other Vaccines: Just the Stats" sponsored by the Committee on Statisticians in Defense and National Security. (http://www.amstat.org/meetings/jsm/2001/onlineprogram/index.cfm?fuseaction=activity_details&sessionid=200140)