• Vaccine Name: Anthrax Vaccine Adsorbed (AVA)
• Target Pathogen: Bacillus anthracis
• Target Disease: Anthrax
• Product Name: Anthrax Vaccine Adsorbed
• Tradename: Biothrax
• Manufacturer: BioPort Corp
• Vaccine Ontology ID: VO_0000014
• CDC CVX code: 24
• Type: Subunit vaccine
• Status: Licensed
• Location Licensed: USA (License #1260)
• Host Species for Licensed Use: Human
• Antigen: A cell-free filtrate of B. anthracis culture
• Adjuvant:
  • Adjuvant name:
  • VO adjuvant ID: VO_0001241
• Preservative: benzethonium chloride,formaldehyde
• Preparation: This vaccine is prepared by adsorbing filtered culture supernatants of an attenuated strain (V770-NP1-R) to aluminum hydroxide (Alhydrogel) as an adjuvant (Brey, 2005). The strain V770-NP1-R used for AVA preparation is a toxigenic, nonencapsulated strain. The filtrate contains a mix of cellular products including all three toxin components (LF, EF, and PA) (Amphogel, Wyeth Laboratories) (CDC, 2000).
• Immunization Route: Intramuscular injection (i.m.)
• Virulence: Most studies show that AVA only induces localized, minor, and self-limited adverse effects. No studies have definitively documented any occurrence of chronic diseases (e.g. cancer or infertility) following anthrax vaccination (CDC, 2000).
• Storage: Vaccine should be stored at 2°C TO 8°C (36 TO 46°F). Do not freeze.
• Approved Age for Licensed Use: Ages 18-65 (FDA: Anthrax Vaccine Adsorbed).
• Contraindication: The use of BioThrax is contraindicated in subjects with a history of anaphylactic or anaphylactic-like reaction following a previous dose of BioThrax, or any of the vaccine components.
• Description: AVA is the only licensed human anthrax vaccine in the United States. This vaccine was developed in the early 1950s and was licensed by the FDA in 1970. AVA has been shown to have a 92.5% efficacy for protection in both cutaneous and inhalational anthrax cases (Brey, 2005).

Human Response

• Host Strain: Most of the study subjects were male (70.9%) and Caucasian (83.7%; 11.6% were African–American). The median age of study subjects was 33 years (range 19–61).
• Vaccination Protocol: The vaccinations followed a minimal-risk protocol reviewed and administratively approved by the institutional review board at USAMRIID and the Human Subjects Research Review Board at the U.S. Army Surgeon General's office. Overall, AVA was given in a 6-dose series (subcutaneous injections at 0, 2, and 4 weeks and 6, 12, and 18 months with subsequent yearly boosters). Specifically, Vaccinations occurred within defined time intervals after receipt of the initial AVA injection (day 0 [dose #1], day 14 [range 11–21], day 28 [range 25–35], day 182 [range 154–216], day 364 [range 336–413], day 546 [range 518–609]) (Pittman et al., 2006).
• Immune Response: A total of 671 sera were analyzed for IgG to PA. All subjects seroconverted after receiving AVA, as defined by a fourfold or greater increase over baseline in dilutional IgG to PA titer. The mean time after receipt of the initial AVA injection to seroconversion was 27.7 days (range = 14–63 days). The mean number of days after the first vaccine dose needed to reach a serum concentration of IgG to PA of 3 μg/mL was 24.2 days (Pittman et al., 2006).
• Side Effects: No side effects were noted in this study (Pittman et al., 2006). In another independent report, AVA was linked to the development of adverse side effects including joint pain, gastrointestinal disorders, and pneumonia, leading many U.S. soldiers to refuse vaccination (Xie et al., 2005).
• Efficacy: A serum concentration of IgG to PA ≥ 3 μg/mL was observed in all subjects after vaccination. This level of antibody was reached by 39.5% of subjects after the first injection, by a total of 96.5% after the second injection, and by 100% after the third injection. The analysis confirms that AVA is an effective immunogen, and significant increases in antibody concentration occurred after each injection, with peak responses achieved after the fourth (6-month) dose. No cases of anthrax disease have been observed among individuals receiving the 6-month dose of AVA (Pittman et al., 2006).
• Description: The antibody profile during and after the six-dose primary vaccination series with anthrax vaccine adsorbed (AVA) was characterized in 86 human volunteers. The present study describes the kinetics of IgG antibodies to Bacillus anthracis protective antigen (PA) in AVA vaccinees receiving the entire six-dose primary series using sera obtained as part of the occupational health program and stored in the USAMRIID archive (Pittman et al., 2006).
  

Mouse Response

• Host Strain: Male A/J mice obtained from the National Cancer Institute
• Vaccination Protocol: Mice were immunized with AVA formulated with and without CpG ODN, PLG, or CpG ODN adsorbed onto PLG (CpG ODN-PLG). The mice were bled weekly, and their serum was stored at –20°C until use. Mice were challenged intraperitoneally with 3 x 102 to 9 x 103 50% lethal doses (LD50) of STI spores suspended in 0.5 ml of sterile phosphate-buffered saline (1 LD50 = 1.1 x 103 STI spores). Survival was monitored for 21 days (Xie et al., 2005).
  
• Persistence: 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 (Xie et al., 2005).
• Side Effects: No side effects noted.
• Efficacy: Coadministering CpG ODN-PLG with 8 to 25 µl of AVA boosted the resultant IgG anti-PA antibody response by nearly 50-fold compared to AVA alone (Xie et al., 2005).
• Description: 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 AVA. 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 (Xie et al., 2005).

Monkey Response

• Host Strain: Rhesus Macaques
• Vaccination Protocol: In the first experiment, rhesus macaques were immunized at 0 and 6 weeks with 0.5 ml of AVA plus 250 μg of an equimolar mixture of 3 CpG ODN, and then challenged with 105 Sterne strain anthrax spores when serum anti-PA titers returned to baseline at week 26.
  In the second experiment, macaques were immunized with 0.5 ml of AVA plus 500 ug of ODN 7909 or the above mixture of 3 CpG ODN (Klinman et al., 2004).
• Persistence: The results show that co-administering CpG ODN with AVA generates high levels of toxin neutralizing antibodies very rapidly, exceeding AVA alone by 17-fold at 11 days post-immunization (Klinman et al., 2004).
• Side Effects: No serious local or systemic adverse reactions were observed in any of the macaques treated with CpG ODN plus AVA (Klinman et al., 2004).
• Efficacy: Macaques immunized with AVA+ODN 7909 had on average a 17-fold higher toxin neutralizing titer than those immunized with AVA alone (Klinman et al., 2004).
• Description: Synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs can improve the immune response to co-administered antigens. In mice, CpG ODN have been shown to boost the protective efficacy of vaccines against bacterial, viral and parasitic pathogens. However, due to evolutionary divergence in CpG recognition between species, ODNs that are highly active in rodents may be less efficacious in primates. Thus, pre-clinical studies to examine whether CpG ODN can accelerate and boost the immune response elictied by AVA must be conducted in a pertinent primate model. This study shows that co-administering GMP-grade CpG ODN with AVA to rhesus macaques does indeed increase rapidity, titer, affinity, and protective efficacy of their resultant IgG anti-PA response (Klinman et al., 2004).

Human Response

• Vaccination Protocol: This study included 1,249 workers [379 received anthrax vaccine, 414 received placebo, 116 received incomplete inoculations (with either vaccine or placebo) and 340 were in the observational group (no treatment)] in four mills in the northeastern United States that processed imported animal hides (FDA: Anthrax Vaccine Adsorbed).
• Immune Response: During the trial, there were 26 cases of anthrax reported across the four mills - five inhalation and 21 cutaneous.
• Side Effects: Side effects after vaccination were mostly limited to local site reactions, fever, chills, nausea and general body aches.
• Efficacy: In a comparison of anthrax cases between the placebo and vaccine groups, including only those who were completely vaccinated, the calculated vaccine efficacy level against all reported cases of anthrax combined was 92.5% (FDA: Anthrax Vaccine Adsorbed).