Anthrax Vaccine Adsorbed Research Articles

Anthrax vaccine absorbed: genomic assessment of markers of protective immunity

Bacillus anthacis is a nonmotile sporulating Gram-positive rod that can exist in normal soil flora. Inhalational anthrax has a high fatality rate if not detected and treated very rapidly, but early clinical diagnosis is difficult with nonspecific flu-like symptoms that can rapidly progress over a few days to respiratory distress and circulatory collapse. Antibiotic treatment at this later point is ineffective, so protection from anthrax using vaccines is a mainstay of dealing with potential anthrax infection. Anthrax Vaccine Adsorbed (AVA) was FDA approved 1970, based on limited data on mill workers (1950s). To predict the level of protection, antibody titers to protective antigen are used, but that antibody response takes weeks to occur, and immunity conferred prior to this elevation in anti-PA is unclear. Global gene analysis, in correlation with a classical immune function studies, can predict the protection conferred or impending adverse reaction. In this study, volunteers were vaccinated with 4 iterations of AVA and 2 months after the last dose, cells were obtained by leukopheresis, purified and exposed to B. anthracis in vitro. Global host gene expression responses were determined for comparisons with unvaccinated volunteers whose leukocytes were also exposed to B.anthracis. Bioinformatics mining tools have identified key factors showing unique responses between the vaccinated vs naïve volunteers

Patterns of antibody response in humans to the anthrax vaccine adsorbed (AVA) primary (six-dose) series

The antibody profile during and after the six-dose primary vaccination series with anthrax vaccine adsorbed (AVA, Biothrax™) was characterized in 86 human volunteers. Ninety-three percent of recipients developed IgG antibodies to Bacillus anthracis protective antigen (PA) after two doses, and 100% were seropositive after dose #3. Geometric mean concentrations (GMC) of IgG to PA measured before and after each dose were significantly lower after injection #3 (peak GMC = 146.65 μg/mL, trough GMC = 15.16 μg/mL) than after injections #4 (peak GMC = 430.46 μg/mL, trough GMC = 94.57 μg/mL), #5 (peak GMC = 415.05 μg/mL, trough GMC = 81.94 μg/mL), or #6 (peak GMC = 401.16μg/mL, trough GMC = 96.19 μg/mL) ( p ≤ 0.0001 for each); but not between injections #4 and #5, #5 and #6, or #4 and #6 ( p ≥ 0.7923 for each). Decay rates for IgG to PA were significantly faster after injection #3 (half life [ T 1/2] = 39.21 days) than after injections #4 ( T 1/2 = 72.03 days), #5 ( T 1/2 = 70.14 days), and #6 ( T 1/2 = 74.59 days) ( p ≤ 0.0282 for each). Toxin neutralizing assay (TNA) antibody patterns generally paralleled those for IgG to PA. The 6-month dose in the AVA primary series appears to be critical in sustaining IgG to PA concentrations in a substantial proportion of recipients.

Identification of a Protein Subset of the Anthrax Spore Immunome in Humans Immunized with the Anthrax Vaccine Adsorbed Preparation

We identified spore targets of Anthrax Vaccine Adsorbed (AVA)-induced immunity in humans by screening recombinant clones of a previously generated, limited genomic Bacillus anthracis Sterne (pXO1(+), pXO2(-)) expression library of putative spore surface (spore-associated [SA]) proteins with pooled sera from human adults immunized with AVA (immune sera), the anthrax vaccine currently approved for use by humans in the United States. We identified 69 clones that reacted specifically with pooled immune sera but not with pooled sera obtained from the same individuals prior to immunization. Positive clones expressed proteins previously identified as localized on the anthrax spore surface, proteins highly expressed during spore germination, orthologs of proteins of diverse pathogens under investigation as drug targets, and orthologs of proteins contributing to the virulence of both gram-positive and gram-negative pathogens. Among the reactive clones identified by this immunological screen was one expressing a 15.2-kDa hypothetical protein encoded by a gene with no significant homology to sequences contained in databases. Further studies are required to define the subset of SA proteins identified in this study that contribute to the virulence of this pathogen. We hypothesize that optimal delivery of a subset of SA proteins identified by such studies to the immune system in combination with protective antigen (PA), the principal immunogen in AVA, might facilitate the development of defined, nonreactogenic, more-efficacious PA-based anthrax vaccines. Future studies might also facilitate the identification of SA proteins with potential to serve as targets for drug design, spore inactivation, or spore detection strategies.

Lessons learned from the CDC's post‐exposure prophylaxis program following the anthrax attacks of 2001

The bioterrorism-related outbreak of anthrax in Fall 2001 was the result of unprecedented attacks on residents of the United States. Although addressees of anthrax spore-filled letters were most likely the targets of the attacks, thousands of U.S. postal employees and others were exposed through aerosolization of spores in mail processing facilities. 1 These attacks precipitated decisions to recommend post-exposure prophylaxis (PEP) to an estimated 10 000 individuals potentially exposed to Bacillus anthracis to prevent inhalational anthrax. 2 Initially, the Centers for Disease Control and Prevention (CDC) recommended 60 days of antimicrobial PEP (initial PEP program), mainly either doxycycline or ciprofloxacin. 2 The CDC eventually extended its recommendation to 40 additional days of antimicrobial prophylaxis with or without three doses of anthrax vaccine adsorbed (AVA) under an investigational new drug (IND) protocol (extended PEP program). 3 Overall, approximately 5420 individuals received education about the extended PEP program. Of these, 1727 individuals agreed to take antibiotics for a full 100 days, but only 199 also chose to be vaccinated with AVA. 4,5 Fifty-seven percent of those who took at least one dose of antimicrobial prophylaxis during the first 60 days of PEP sustained an adverse event (AE), of which less than 1% were considered serious. 6 No deaths were attributed to PEP. Of the thousands of exposed individuals who were advised to take PEP, none developed any form of anthrax, whether or not they

Anthrax Vaccines

SUMMARYAnthrax, an uncommon disease in humans, is caused by a large bacterium, Bacillus anthracis. The risk of inhalation infection is the main indication for anthrax vaccination. Pre-exposure vaccination is provided by an acellular vaccine (anthrax vaccine adsorbed or AVA), which contains anthrax toxin elements and results in protective immunity after 3 to 6 doses. Anthrax vaccine precipitated (AVP) is administered at primovaccination in 3 doses with a booster dose after 6 months. To evoke and maintain protective immunity, it is necessary to administer a booster dose once at 12 months. In Russia, live spore vaccine (STI) has been used in a two-dose schedule. Current anthrax vaccines show considerable local and general reactogenicity (erythema, induration, soreness, fever). Serious adverse reactions occur in about 1% of vaccinations. New second-generation vaccines in current research programs include recombinant live vaccines and recombinant sub-unit vaccines.

An overview of adverse events reported by participants in CDC's anthrax vaccine and antimicrobial availability program

The CDC's Anthrax Vaccine and Antibiotic Availability Program was implemented under an Investigational New Drug (IND) application to provide additional post-exposure prophylaxis for individuals potentially exposed to Bacillus anthracis in the fall of 2001. Participants were provided with two options: (1) 40 additional days of antimicrobial prophylaxis (i.e., ciprofloxacin, doxycycline, or amoxicillin); or (2) 40 additional days of antimicrobial prophylaxis plus three doses of anthrax vaccine adsorbed (AVA). Participants were monitored for adverse events (AEs). Participants were asked to complete 2-week AE diaries for 6 weeks post-enrollment, and approximately 2 months after enrollment, active surveillance was conducted through telephone interviews with 1113 (64%) participants. A total of 1727 of approximately 10 000 previously prophylaxed persons enrolled to receive 40 additional days of antibiotics. Of these, 199 opted at enrollment to receive three doses of AVA in addition to the additional 40 days of antibiotic. Overall, 28% of participants reported at least one AE on their diaries. Results varied by surveillance mechanism, the diary data indicated differences in the proportion reporting AEs between participants receiving antibiotic only and participants receiving antibiotic and AVA. However, during the active 2-month telephone follow-up, the rates of AEs reported for both the antibiotic only and antibiotic plus AVA treatment regimens were similar. Additionally, ciprofloxacin and doxycycline had similar AE profiles, with only rigors reported significantly more often among ciprofloxacin recipients. Overall, the rates of AEs experienced by all participants were acceptable given the seriousness of potential B. anthracis exposure.

CpG Oligodeoxynucleotides Adsorbed onto Polylactide-Co-Glycolide Microparticles Improve the Immunogenicity and Protective Activity of the Licensed Anthrax Vaccine

To reduce the biothreat posed by anthrax, efforts are under way to improve the protection afforded by vaccination. This work examines the ability of immunostimulatory CpG oligodeoxynucleotides (ODN) adsorbed onto cationic polylactide-co-glycolide (PLG) microparticles (CpG ODN-PLG) to accelerate and boost the protective immunity elicited by Anthrax Vaccine Adsorbed (AVA, the licensed human anthrax vaccine). The results indicate that coadministering CpG ODN-PLG with AVA induces a stronger and faster immunoglobulin G response against the protective antigen of anthrax than AVA alone. Immunized mice were protected from lethal anthrax challenge within 1 week of vaccination with CpG ODN-PLG plus AVA, with the level of protection correlating with serum immunoglobulin G anti-protective antigen titers.

Disability Among U.S. Army Personnel Vaccinated Against Anthrax

This study was conducted to examine whether U.S. Army personnel receiving > or =1 dose of anthrax vaccine adsorbed (AVA) between March 1998 and February 2002 were at higher risk of disability than unvaccinated personnel. We studied a historical cohort study of 716,833 active-duty soldiers (154,456 vaccinated) followed for 4.25 years to determine rates of evaluation for disability discharge. Cox proportional hazards models compared estimated risk of evaluation for disability, accounting for occupation and sociodemographics. Adjusted hazard ratio (HR) and 95% confidence interval (CI) was 0.96 (CI = 0.92-0.99). Separate adjusted HRs for men, women, permanent and temporary disability, musculoskeletal and neurologic conditions were similar, ranging from 0.90 to 1.04. Latency assumptions did not affect results. Anthrax vaccination does not increase risk of disability. This finding may be partially the result of factors influencing selection for vaccination or vaccine tolerance.

Validation of an anti-PA-ELISA for the potency testing of anthrax vaccine in mice

The potency test for the anthrax vaccine currently licensed for human use in the United States (Anthrax Vaccine Adsorbed) involves the protection of actively immunized guinea pigs from a lethal challenge with a virulent strain of Bacillus anthracis. Lethal challenge tests entail the use of specialized containment facilities for the safe and secure handling of the challenge strain. This potential difficulty, plus humane considerations, have prompted us to investigate non-lethal, alternative immunogenicity assays that could be considered as potency tests not only for the current vaccine, but also for vaccines under development. Immunogenicity tests will require suitable measurement of an antibody response to relevant antigens, by methods such as enzyme linked immunosorbent assay (ELISA) or a toxin neutralization assay. Any assay chosen for this purpose should be adequately validated and reproducible by other laboratories. Validation of an analytical procedure requires the demonstration that the assay is suitable for its intended purpose. The objective of this work was to study the performance of an anti-PA-ELISA designed to assess the antibody response to anthrax vaccines in mice. Validation studies were performed according to the guidelines of the International Conference of Harmonization (ICH), and we have established the working range of the assay (37–1159 EU/mL) on the bases of the following parameters: linearity (20–1159 EU/mL; r 2 = 0.99; p-value = 0.21), accuracy (91–118% recovery), precision (≤20%CV, repeatability; ≤9 and ≤21%CV, intermediate precision per day and per analyst, respectively), detection limit (5 EU/mL), and quantification limit (37 EU/mL). We believe that assay specificity and the above characteristics are adequate to allow this ELISA to be considered for use in a mouse immunogenicity (potency) test of anthrax vaccines, and for the standardization of reagents.

A cationic lipid-formulated plasmid DNA vaccine confers sustained antibody-mediated protection against aerosolized anthrax spores.

DNA vaccines provide an attractive technology platform against bioterrorism agents due to their safety record in humans and ease of construction, testing, and manufacture. We have designed monovalent and bivalent anthrax plasmid DNA (pDNA) vaccines encoding genetically detoxified protective antigen (PA) and lethal factor (LF) proteins and tested their immunogenicity and ability to protect rabbits from an aerosolized inhalation spore challenge. Immune responses after two or three injections of cationic lipid-formulated PA, PA plus LF, or LF pDNAs were at least equivalent to two doses of anthrax vaccine adsorbed (AVA). High titers of anti-PA, anti-LF, and neutralizing antibody to lethal toxin (Letx) were achieved in all rabbits. Eight or nine animals in each group were challenged with 100x LD(50) of aerosolized anthrax spores 5 or 9 weeks after vaccination. An additional 10 animals vaccinated with PA pDNA were challenged >7 months postvaccination. All animals receiving PA or PA plus LF pDNA vaccines were protected. In addition, 5 of 9 animals receiving LF pDNA survived, and the time to death was significantly delayed in the others. Groups receiving three immunizations with PA or PA plus LF pDNA showed no increase in anti-PA, anti-LF, or Letx neutralizing antibody titers postchallenge, suggesting little or no spore germination. In contrast, titer increases were seen in AVA animals, and in surviving animals vaccinated with LF pDNA alone. Preclinical evaluation of this cationic lipid-formulated bivalent PA and LF vaccine is complete, and the vaccine has received U.S. Food and Drug Administration Investigational New Drug allowance.

Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed

BackgroundPotent anthrax toxin neutralizing human monoclonal antibodies were generated from peripheral blood lymphocytes obtained from Anthrax Vaccine Adsorbed (AVA) immune donors. The anti-anthrax toxin human monoclonal antibodies were evaluated for neutralization of anthrax lethal toxin in vivo in the Fisher 344 rat bolus toxin challenge model.MethodsHuman peripheral blood lymphocytes from AVA immunized donors were engrafted into severe combined immunodeficient (SCID) mice. Vaccination with anthrax protective antigen and lethal factor produced a significant increase in antigen specific human IgG in the mouse serum. The antibody producing lymphocytes were immortalized by hybridoma formation. The genes encoding the protective antibodies were rescued and stable cell lines expressing full-length human immunoglobulin were established. The antibodies were characterized by; (1) surface plasmon resonance; (2) inhibition of toxin in an in vitro mouse macrophage cell line protection assay and (3) in vivo in a Fischer 344 bolus lethal toxin challenge model.ResultsThe range of antibodies generated were diverse with evidence of extensive hyper mutation, and all were of very high affinity for PA83~1 × 10-10-11M. Moreover all the antibodies were potent inhibitors of anthrax lethal toxin in vitro. A single IV dose of AVP-21D9 or AVP-22G12 was found to confer full protection with as little as 0.5× (AVP-21D9) and 1× (AVP-22G12) molar equivalence relative to the anthrax toxin in the rat challenge prophylaxis model.ConclusionHere we describe a powerful technology to capture the recall antibody response to AVA vaccination and provide detailed molecular characterization of the protective human monoclonal antibodies. AVP-21D9, AVP-22G12 and AVP-1C6 protect rats from anthrax lethal toxin at low dose. Aglycosylated versions of the most potent antibodies are also protective in vivo, suggesting that lethal toxin neutralization is not Fc effector mediated. The protective effect of AVP-21D9 persists for at least one week in rats. These potent fully human anti-PA toxin-neutralizing antibodies are attractive candidates for prophylaxis and/or treatment against Anthrax Class A bioterrorism toxins.

Evaluation of the compatibility of a second generation recombinant anthrax vaccine with aluminum-containing adjuvants

Recombinant protective antigen (rPA) is the active pharmaceutical ingredient in a second generation anthrax vaccine undergoing pre-clinical evaluation. This rPA vaccine differs from the currently licensed vaccine, anthrax vaccine adsorbed (AVA), in that the sole component is a recombinant form of protective antigen (PA). Unlike AVA the rPA vaccine contains no lethal factor (LF) or edema factor (EF), components of the two bipartite toxins, nor many other Bacillus anthracis-related contaminating proteins that are present in AVA. The proposed clinical protocol involves adsorption of the rPA to an aluminum-based adjuvant. The adsorptive characteristics of rPA and two aluminum-containing adjuvants were examined in a physiological buffer with and without EDTA. Based on the p I of rPA (p I=5.6) and the zero charge point of aluminum hydroxide adjuvant (11.5) and aluminum phosphate adjuvant (4.5), it was predicted and demonstrated that rPA bound in a more efficient manner to aluminum hydroxide adjuvant than to aluminum phosphate adjuvant in the physiological buffer. Binding of the rPA to the aluminum hydroxide adjuvant was decreased by increasing amounts of phosphate in the buffer. The adsorptive capacity for rPA onto aluminum hydroxide adjuvant in the physiological buffer and in water were calculated to be 0.46 mg rPA/mg aluminum in DPBS and 0.73 mg rPA/mg aluminum in water. This study also demonstrated that upon desorption from the aluminum hydroxide adjuvant the rPA was physically intact and free of detectable aggregates. Further, the eluted material was biologically active in an in vitro cytotoxicity assay. Desorption was only possible after an overnight incubation of 2–8 °C and not after a room temperature incubation reflecting increased contact with the aluminum hydroxide adjuvant over time. These data suggest that the interaction between rPA and aluminum hydroxide adjuvant is predominantly electrostatic in character.

Bacillus anthracis virulence in Guinea pigs vaccinated with anthrax vaccine adsorbed is linked to plasmid quantities and clonality.

Bacillus anthracis is a bacterial pathogen of great importance, both historically and in the present. This study presents data collected from several investigations and indicates that B. anthracis virulence is associated with the clonality and virulence of plasmids pXO1 and pXO2. Guinea pigs vaccinated with Anthrax Vaccine Adsorbed were challenged with 20 B. anthracis isolates representative of worldwide genetic diversity. These same isolates were characterized with respect to plasmid copy number by using a novel method of quantitative PCR developed for rapid and efficient detection of B. anthracis from environmental samples. We found that the copy numbers for both pXO1 and pXO2 differed from those in previously published reports. By combining the data on survival, plasmid copy numbers, and clonality, we developed a model predicting virulence. This model was validated by using a randomly chosen set of 12 additional B. anthracis isolates. Results from this study will be helpful in future efforts to elucidate the basis for variation in the virulence of this important pathogen.

Analysis of adverse events after anthrax immunization in US Army medical personnel.

A broad range of health effects in a cohort of 601 health care personnel, immunized with anthrax vaccine adsorbed (AVA) as a military occupational health requirement, were assessed to evaluate adverse events both qualitatively and quantitatively. Active surveillance showed that localized reactions were common and occurred more often in women than men. Five patients were reported to the Vaccine Adverse Event Reporting System, but only one event could be definitively attributed to immunization, a large localized reaction. Two separate cohort studies, one using nested data from a standardized health risk appraisal instrument and the other comparing rates of outpatient visits and hospitalizations, did not reveal significant differences between AVA-immunized and unimmunized individuals. Our findings suggest that AVA is relatively reactogenic but do not indicate serious adverse health effects due to immunization.

Comprehensive systematic surveillance for adverse effects of Anthrax Vaccine Adsorbed, US Armed Forces, 1998–2000

Routine vaccinations of US military personnel with Anthrax Vaccine Adsorbed began in 1998. To systematically identify clinical diagnoses reported more frequently after vaccination than before, all military personnel were retrospectively assigned to pre- or post-vaccination cohorts. Cohort assignments were based on vaccination statuses each day of the 3-year surveillance period. For each cohort, rates of hospitalizations and ambulatory visits for 843 specific diagnoses were calculated using data in a public health surveillance system. Compared to the pre-vaccination cohort, the post-vaccination cohort had statistically higher rates of hospitalizations for 17 diagnoses, of ambulatory visits for 34 diagnoses, and in both clinical settings for one diagnosis (malaria). After accounting for systematic differences in coding/reporting and residual confounding, the number and nature of clinical diagnoses more frequent after anthrax vaccination than before were consistent with expectations due to random variation. This surveillance suggests that Anthrax Vaccine Adsorbed has few, if any, clinically significant adverse effects.

Aluminum-containing vaccine associated adverse events: role of route of administration and gender

Anthrax vaccine, adsorbed (AVA) is a vaccine containing aluminum hydroxide that is administered as six subcutaneous (SQ) doses over 18 months. It is the only aluminum hydroxide licensed for SQ administration. To optimize the vaccination schedule and route of administration, a prospective pilot study comparing the use of fewer doses administered intramuscularly (IM) as well as SQ with the licensed schedule and route was performed. Data from that study on injection site reactions were extracted for this report. Erythema and induration occurred more commonly when the vaccine was administered SQ compared to IM ( P<0.0001, P=0.002, respectively). SQ nodules were found only among the SQ group ( P<0.0001). Erythema, induration and SQ nodules were more common in women compared with men ( P<0.001) after the first SQ dose of AVA dose. Reaction rates decreased when the interval between the first two doses of AVA was increased from 2 to 4 weeks.

Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed

Specific lots of Anthrax Vaccine Adsorbed, administered to members of the US Armed Forces, have been described on various Internet sites and in news articles as a source of squalene, a chemical purported by these media to be associated with the Gulf War Syndrome. We have developed and validated a method using high-performance liquid chromatography with ultraviolet detection for the determination of squalene in anthrax vaccine preparations. The method has a limit of detection of 140 parts per billion and has been successfully applied to a commercial vaccine known to contain squalene. We have applied this method to 17 lots of Anthrax Vaccine Adsorbed administered to members of the US Armed Forces. No squalene has been detected in any lot. The results of these analyses provide direct evidence for the absence of squalene as an ingredient or a manufacturing contaminant in Anthrax Vaccine Adsorbed.

Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid

We evaluated the prevalence and concentration of serum antibodies 18–24 months after primary inoculation with anthrax and botulinum vaccines, and assessed the reactogenicity and immunogenicity of a significantly delayed booster dose of these vaccines. Five hundred and eight male active-duty military personnel received one, two or three inoculations with anthrax vaccine and/or botulinum toxoid in 1990/1991 in preparation for Operations Desert Shield/Desert Storm. Subjects were vaccinated with the licensed anthrax vaccine, adsorbed (AVA) and pentavalent (ABCDE) botulinum toxoid (PBT) BB-IND 3723. Anthrax protective antigen (PA) IgG antibody was measured in serum using an immunocapture enzyme-linked immunosorbent assay (ELISA). A mouse neutralization test was used to determine the titer of Clostridium botulinum type A antitoxin in serum samples. The prevalence of anti-PA IgG was 30% in individuals 18–24 months after priming with one, two or three doses of AVA. After boosting, 99% of volunteers had detectable anti-PA IgG; only two individuals failed to respond. The prevalence of antibodies against botulinum toxin type A was 28% 18–24 months after initial priming. Following boosting, 99% of volunteers had serum titers >0.02 IU/ml, and 97% responded with titers ≥0.25 IU/ml. Systemic reactions to booster vaccinations could not be specifically ascribed to one or the other vaccine, but were generally mild and of brief duration. Forty-five percent of volunteers reported one or more systemic reactions over the course of 7 days. Injection site reactions of any kind occurred in 25% of AVA recipients and in 16% of PBT recipients; persistence of local reactions beyond 7 days was infrequent. While the kinetics and durability of immune responses must be studied, these findings suggest that booster doses of anthrax vaccine and botulinum toxoid sufficient to stimulate a robust anamnestic response may be given at times distant from receipt of the primary inoculations.

Anthrax vaccine: immunogenicity and safety of a dose-reduction, route-change comparison study in humans

Anthrax vaccine adsorbed (AVA), an effective countermeasure against anthrax, is administered as six subcutaneous (SQ) doses over 18 months. To optimize the vaccination schedule and route of administration, we performed a prospective pilot study comparing the use of fewer AVA doses administered intramuscularly (IM) or SQ with the current schedule and route. We enrolled 173 volunteers, randomized to seven groups, who were given AVA once IM or SQ; two doses, 2 or 4 weeks apart, IM or SQ; or six doses at 0, 2, 4 weeks and 6, 12, and 18 months (control group, licensed schedule and route). IM administration of AVA was associated with fewer injection site reactions than SQ administration. Following the first SQ dose of AVA, compared to males, females had a significantly higher rate of injection site reactions such as erythema, induration and subcutaneous nodules ( P<0.001). Reaction rates decreased with a longer dose interval between the first two doses. The peak anti-PA IgG antibody response of subjects given two doses of AVA 4 weeks apart IM or SQ was comparable to that seen among subjects who received three doses of AVA at 2-week intervals. The IM route of administering this aluminum hydroxide adsorbed vaccine is safe and has comparable peak anti-PA IgG antibody levels when two doses are administered 4 weeks apart compared to the licensed initial dose schedule of three doses administered 2 weeks apart. A large pivotal study is being planned by the Centers for Disease Control and Prevention to confirm these results.

Anthrax vaccine: short-term safety experience in humans

Bacillus anthracis is the major terrorist and biological warfare agent of concern to civilian and military medical planners. The licensed anthrax vaccine, adsorbed (AVA) is believed to be an effective prophylactic medical countermeasure against this threat. Our objective in this report was to expand the safety database for this vaccine by assessing data on self-reported, short-term safety of AVA during more than 25 years of use, measured by local and systemic adverse events temporally associated with the administration of AVA. A minority of AVA recipients reported systemic and injection site reactions. Females reported a higher incidence of injection site and systemic adverse events than males. Data show a difference in incidence of local reactions between lots. A prospective, randomized, placebo-controlled study to actively examine reactogenicity is needed to more completely define the extent and nature of reactions associated with receipt of AVA in humans as well as to confirm the gender lot differences in local reaction rates.