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Vaccine Comparison

Anthrax Vaccine Adsorbed (AVA) Anthrax vaccine adsorbed with Squalene adjuvant B. anthracis DNA vaccine pCPA B. anthracis DNA vaccine pLAMP1-PA63 B. anthracis DNA vaccine pTPA-P B. anthracis DNA vaccine pTPA-PA63 DAAV using PA and PGA DNA vaccine encoding PA (PA63) pCLF4 pCMV/ER-PA83 pSecTag-PA83 Recombinant PA domain 4 Recombinant PA with Poly(I:C) Adjuvant rLAG- PA-DCpep rPA with adjuvant Nanoemulsion Typhi strain Ty21a-PA (Bacillus anthracis)
Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information
  • 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: Alhydrogel
  • 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).
  • Vaccine Ontology ID: VO_0004246
  • Type: Toxoid vaccine
  • Status: Research
  • Adjuvant: squalene
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0004480
  • Type: DNA vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • pagA gene engineering:
    • Type: DNA vaccine construction
    • Description: The gene fragment encoding amino acids 175 to 764 of a B. anthracis PA protein was PCR amplified using the forward primer 5′-ACA AGT CTC GAG ACC ATG GTT CCA GAC CGT GAC-3′ and the reverse primer 3′-CTC TAT CCT ATT CCA TTA AGA TCT ACT AAA-5′, with the pYS2 template. The PA gene fragment expressed corresponds to the biologically active, protease-cleaved PA63 fragment of the full-length 83-kDa protein. The PCR product was then digested with two restriction enzymes XhoI and XbaI and ligated into the eucaryotic expression plasmid pCI (Promega, Inc., Madison, Wis.) (Price et al., 2001).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Gene gun
  • Vaccine Ontology ID: VO_0004477
  • Type: DNA vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • PA63-LAMP1 gene engineering:
    • Type: DNA vaccine construction
    • Description: This DNA vaccine expressed C-terminal LAMP1 membrane anchor and 63 kDa mature protein (Midha and Bhatnagar, 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0004478
  • Type: DNA vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • TPA-PA63-LAMP1 gene engineering:
    • Type: DNA vaccine construction
    • Description: This DNA vaccine expressed A63-LAMP1 N-terminal TPA signal, C-terminal LAMP1 membrane anchor and 63 kDa mature protein (Midha and Bhatnagar, 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0004476
  • Type: DNA vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • TPA-PA63 gene engineering:
    • Type: DNA vaccine construction
    • Description: This DNA vaccine expressed the N-terminal TPA signal, and 63 kDa mature protein (Midha and Bhatnagar, 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0000522
  • Type: Conjugate vaccine
  • Antigen: Two antigens: PA-B and capsular poly-γ-d-glutamate. Both antigens are conjugated.
  • PagA from B. anthracis str. 'Ames Ancestor' gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Adjuvant: Alhydrogel
    • VO ID: VO_0001241
    • Description: Anthrax involves a dual process of bacterial replication and toxin production. The dually active anthrax vaccine (DAAV) confers simultaneous protection against both bacilli and toxins was highly sought after through research. The weakly immunogenic and antiphagocytic PGA capsule disguises the bacilli from immune surveillance in a similar manner to the role of capsular polysaccharides in protecting pathogens, such as pneumococci and meningococci. Encapsulated B. anthracis strains grow unimpeded in the infected host, whereas isolates lacking the capsule are phagocytized and are virtually avirulent. Anthrax toxins are formed by PA, lethal factor (LF), and edema factor (EF), which are secreted separately as nontoxic monomers. The binding of LF or EF to PA results in the formation of active lethal toxin (LT) or edema toxin (ET), respectively. Because of its ability to elicit a protective immune response against both anthrax toxins, PA is the target antigen of existing anthrax vaccine. However, a vaccine based on both PGA and PA might allow direct targeting of bacillar growth, as well as inhibiting toxin activity, making it more effective than a vaccine based on PA alone. PGA is an attractive antigen because it consists of d-glutamic acid residues linked by γ peptide bonds, and thus bears no resemblance to mammalian host molecules (Rhie et al., 2003).
  • Preparation: This conjugate vaccine is constructed by conjugating two major virulence factors of B. anthracis, the capsular poly-γ-D-glutamic acid (PGA) and the essential toxin component and protective antigen (PA). This is a DAAV that confers simultaneous protection against both bacilli and toxins. Two sets of conjugates with 1:2 and 1:1 (wt/wt) PGA-to-PA ratios, designated DAAV-1 and DAAV-2, respectively (Rhie et al., 2003).
  • Virulence: (Rhie et al., 2003)
  • Description: Anthrax involves a dual process of bacterial replication and toxin production. The dually active anthrax vaccine (DAAV) confers simultaneous protection against both bacilli and toxins was highly sought after through research. The weakly immunogenic and antiphagocytic PGA capsule disguises the bacilli from immune surveillance in a similar manner to the role of capsular polysaccharides in protecting pathogens, such as pneumococci and meningococci. Encapsulated B. anthracis strains grow unimpeded in the infected host, whereas isolates lacking the capsule are phagocytized and are virtually avirulent. Anthrax toxins are formed by PA, lethal factor (LF), and edema factor (EF), which are secreted separately as nontoxic monomers. The binding of LF or EF to PA results in the formation of active lethal toxin (LT) or edema toxin (ET), respectively. Because of its ability to elicit a protective immune response against both anthrax toxins, PA is the target antigen of existing anthrax vaccine. However, a vaccine based on both PGA and PA might allow direct targeting of bacillar growth, as well as inhibiting toxin activity, making it more effective than a vaccine based on PA alone. PGA is an attractive antigen because it consists of d-glutamic acid residues linked by γ peptide bonds, and thus bears no resemblance to mammalian host molecules (Rhie et al., 2003).
  • Vaccine Ontology ID: VO_0000518
  • Type: DNA vaccine
  • Antigen: B. anthracis PA (Gu et al., 1999)
  • PagA from B. anthracis str. 'Ames Ancestor' gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Vector: pJW4303 (Gu et al., 1999)
  • Preparation: The gene fragment encoding AAs 173–764 of PA was PCR amplified. The PCR product was digested with NheI and BamHI and ligated into the pJW4303 vector, which was cut with the same two restriction enzymes. Both PA plasmid and control DNA were purified from E. coli DH5a using Endo-free plasmid preparation kits (Qiagen) and resuspended in PBS before use (Gu et al., 1999).
  • Virulence: Virulent strains of B. anthracis are characterized by their expression of a polyglutamic acid capsule and the production of a protein toxin. In vivo studies to determine whether cell mediated immunity provided protection against virulent B. anthracis could not be performed, since such studies require BL3 con-tainment facilities (Gu et al., 1999).
  • Storage: Not virulent.
  • Description: There have been many attempts to improve the safety and immunogenicity of the current licensed anthrax vaccine, including the formulation of PA in different adjuvants, the use of recombinant, mutant PA, expression of PA by attenuated salmonellae, and the generation of attenuated B. anthracis strains lacking one or more toxin components. Current studies have examined the possibility of inducing protection against anthrax toxin by immunizing with a DNA vaccine encoding PA. Studies in other model systems indicate that antigen-encoding DNA plasmids can stimulate strong cellular and humoral immune responses against proteins from pathogens (Gu et al., 1999).
  • Vaccine Ontology ID: VO_0000880
  • Type: DNA vaccine
  • Antigen: B. anthracis lethal factor (LF)
  • Lef gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • PagA from B. anthracis str. 'Ames Ancestor' gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Vector: pCl (Price et al., 2001)
  • Preparation: Plasmid pCLF4 contains the N-terminal region (amino acids [aa] 10-254) of Bacillus anthracis LF cloned into the pCI expression plasmid. Plasmid pCPA contains a biologically active portion (aa 175-764) of B. anthracis PA cloned into the pCI expression vector. PA, LF, and LFE687C (LF7) were expressed and purified. LFE687C is the full-length enzymatically inactive LF protein containing the indicated aa substitution within the zinc-binding active site (Price et al., 2001).
  • Vaccine Ontology ID: VO_0000876
  • Type: DNA vaccine
  • Antigen: B. anthracis PA
  • pagA gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • Vector: pCMV/myc/ER (Hahn et al., 2004)
  • Preparation: For the pCMV/ER PA83 construct, PA83 was cloned into the eukaryotic expression plasmid pCMV/myc/ER. A gene fragment coding for PA83 was amplified by PCR, and the resulting 2205-bp PCR fragment was digested with Pau I and Not I and ligated into the plasmid pCMV/myc/ER (Hahn et al., 2004).
  • Vaccine Ontology ID: VO_0000875
  • Type: DNA vaccine
  • Status: Research
  • Antigen: Protective antigen
  • Preparation: The vector pSecTag PA83, encoding the full-length PA protein, has a signal sequence for secretion of the expressed protein. For the pSecTag PA83 construct, DNA encoding the full-length B. anthracis PA83 was cloned into the eukaryotic expression plasmid pSecTag 2B. A gene fragment coding for the PA83 protein, without its own signal sequence, was amplified by PCR from DNA of a pXO2 strain of B. anthracis. The resulting 2204-bp PCR fragment was digested with Apa I and Kpn I and ligated into the vector pSecTag 2B (Hahn et al., 2004).
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0000629
  • Type: Subunit vaccine
  • Antigen: PA domain 4 from B. anthracis strain Sterne
  • PagA from B. anthracis str. 'Ames Ancestor' gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Adjuvant: Alhydrogel
    • VO ID: VO_0001241
    • Description: Domain 4 contains the dominant protective epitopes of PA and comprises amino acids 596-735 of the carboxy terminus of the PA polypeptide. Cell intoxication is thought to occur when full-length PA (PA83) binds to the cell surface receptor via domain 4, which contains the host cell receptor binding site. After binding to the host cell receptor, the N-terminal amino acids (1-167, i.e. domain 1a) of domain 1, which contains a furin protease cleavage site, are cleaved off, exposing the LF or EF binding site located in domain 1b and the adjacent domain 3. Domains 2 and 3 then form part of a heptameric pore on the cell surface, the LF or EF binds to its receptor, and the whole toxin complex undergoes receptor-mediated endocytosis into the cell. After acidification of the endosome, the toxin is translocates into the cell cytosol, where it exerts its cytotoxic effect. Therefore, inhibition of the binding and entry of the toxin complex, particularly lethal toxin, into the host cell is clearly important for the prevention of infection. The crystal structure of PA shows domain 4 to be more exposed than the other three domains, which are closely associated with each other. This structural arrangement may make the epitopes in domain 4 the most prominent for recognition by immune effector cells (Flick-Smith et al., 2002).
  • Preparation: DNA encoding the PA domains, which comprise amino acids 1-258, 168-487, 1-487, 168-595, 1-595, 259-735, 488-735, 596-735, and 1-735 (fusion proteins GST1, GST1b-2, GST1-2, GST1b-3, GST1-3, GST2-4, GST3-4, GST4, and GST1-4, respectively), was PCR amplified from B. anthracis strain Sterne DNA and cloned into the XhoI and BamHI sites of the expression vector pGEX-6-P3. Proteins produced by this system were expressed as fusion proteins with an N-terminal glutathione S-transferase (GST) protein. Immunization was done with rPA, with recombinant GST control protein, or with fusion proteins comprising domains 1, 4, and 1 to 4, which had the GST tag removed by incubation with PreScission Protease and removal of the GST on a glutathione Sepharose column (Flick-Smith et al., 2002).
  • Virulence: (Flick-Smith et al., 2002)
  • Description: Domain 4 contains the dominant protective epitopes of PA and comprises amino acids 596-735 of the carboxy terminus of the PA polypeptide. Cell intoxication is thought to occur when full-length PA (PA83) binds to the cell surface receptor via domain 4, which contains the host cell receptor binding site. After binding to the host cell receptor, the N-terminal amino acids (1-167, i.e. domain 1a) of domain 1, which contains a furin protease cleavage site, are cleaved off, exposing the LF or EF binding site located in domain 1b and the adjacent domain 3. Domains 2 and 3 then form part of a heptameric pore on the cell surface, the LF or EF binds to its receptor, and the whole toxin complex undergoes receptor-mediated endocytosis into the cell. After acidification of the endosome, the toxin is translocates into the cell cytosol, where it exerts its cytotoxic effect. Therefore, inhibition of the binding and entry of the toxin complex, particularly lethal toxin, into the host cell is clearly important for the prevention of infection. The crystal structure of PA shows domain 4 to be more exposed than the other three domains, which are closely associated with each other. This structural arrangement may make the epitopes in domain 4 the most prominent for recognition by immune effector cells (Flick-Smith et al., 2002).
  • Vaccine Ontology ID: VO_0004255
  • Type: Subunit vaccine
  • Status: Research
  • Antigen: Recombinant PA (Sloat and Cui, 2006).
  • Adjuvant: poly(I:C) vaccine adjuvant
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0004715
  • Type: Recombinant vector vaccine
  • Status: Research
  • Host Species for Licensed Use: Mouse
  • pagA gene engineering:
    • Type: Recombinant vector construction
    • Detailed Gene Information: Click Here.
  • Preparation: Targeted B. anthracis protective antigen (PA) genetically fused to a DC-binding peptide (DCpep) was delivered by Lactobacillus acidophilus (Mohamadzadeh et al., 2010)
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0000526
  • Type: Toxoid vaccine
  • Antigen: For this vaccine, recombinant Bacillus anthracis protective antigen was used (Bielinska et al., 2007).
  • Adjuvant: nanoemulsion vaccine adjuvant
  • Preparation: The NE was manufactured by the emulsification of cetyl pyridum chloride, Tween 20, and ethanol in water with hot-pressed soybean oil, using a high-speed emulsifier. Every rPA-NE formulation was prepared by mixing rPA protein solution with NE, using saline as a diluent 30 to 60 min prior to immunization. For immunization with immunostimulants, 20 μg rPA was mixed with either 5 μg of MPL A or 10 μg CpG oligonucleotides in saline (Bielinska et al., 2007).
  • Vaccine Ontology ID: VO_0004702
  • Type: Recombinant vector vaccine
  • Status: Research
  • Host Species for Licensed Use: Mouse
  • Preparation: Anthrax protective antigen was delivered by Salmonella enterica serovar Typhi Ty21a (Osorio et al., 2009)
  • Immunization Route: Intramuscular injection (i.m.)
Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response

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).

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).

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).

Mouse Response

  • Host Strain: Hartley
  • Vaccination Protocol: Mice were immunized intramuscularly (i.m.) at 0 and 4 weeks (Ivins et al., 1995).
  • Challenge Protocol: Animals were challenged at 10 weeks post vaccination with an aerosol of spores of B. anthracis Ames strain (Ivins et al., 1995).
  • Efficacy: The vaccine adjuvanted with SLT (squalene) was more protective than the vaccine without the squalene adjuvant (Ivins et al., 1995).

Mouse Response

  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: All mice immunized with pCLF4, pCPA, or the combination of both survived the challenge, whereas all unimmunized mice did not survive (Price et al., 2001).

Mouse Response

  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Highest survival was elicited by all groups when they were challenged at week 12 and 14. Challenge was 100% fatal in control mice immunized with vector and PBS. Time-to-death analysis revealed that DNA vaccination with constructs pTPA-PA63, pPA63-LAMP1 and pTPA-PA63- LAMP1 was more protective than the native PA encoding construct (Midha and Bhatnagar, 2009).

Mouse Response

  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Highest survival was elicited by all groups when they were challenged at week 12 and 14. Challenge was 100% fatal in control mice immunized with vector and PBS (Midha and Bhatnagar, 2009).

Mouse Response

  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Highest survival was elicited by all groups when they were challenged at week 12 and 14. Challenge was 100% fatal in control mice immunized with vector and PBS. Time-to-death analysis revealed that DNA vaccination with constructs pTPA-PA63, pPA63-LAMP1 and pTPA-PA63- LAMP1 was more protective than the native PA encoding construct (Midha and Bhatnagar, 2009).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Groups of female BALB/c mice at 6–8 weeks of age were immunized by i.p. injection on days 0, 14, and 28. DAAV-1 was tested at 10- and 20-µg doses, and DAAV-2 was tested at 2-, 10-, and 20-µg doses (doses refer to PA content). Controls include PA and PGA at 20-µg doses, unconjugated PGA–PA mixture including 20 µg of PGA and 20 µg of PA. Each dose was dissolved in 50 µl of PBS and adsorbed to an equal volume of Al(OH)3 gel adjuvant (equivalent to 0.187 mg per dose). PBS/Al(OH)3 was used as a negative control (Rhie et al., 2003).
  • Persistence: (Rhie et al., 2003)
  • Side Effects: None were noted (Rhie et al., 2003).
  • Efficacy: After three immunizations in mice, DAAV-1 induced high levels of serum anti-PGA IgG, and booster injections significantly enhanced the IgG response. PGA-specific antibodies bound to encapsulated bacilli and promoted the killing of bacilli by complement. PA-specific antibodies neutralized toxin activity and protected immunized mice against lethal challenge with anthrax toxin. Thus, DAAV combines both antibacterial and antitoxic components in a single vaccine against anthrax (Rhie et al., 2003).
  • Description: PGA-specific antibodies bound to encapsulated bacilli and promoted the killing of bacilli by complement. PA-specific antibodies neutralized toxin activity and protected immunized mice against lethal challenge with anthrax toxin. Thus, DAAV combines both antibacterial and antitoxic components in a single vaccine against anthrax. DAAV introduces a vaccine design that may be widely applicable against infectious diseases and provides additional tools in medicine and biodefense (Rhie et al., 2003).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: BALB/c mice were immunized at 6–8 weeks of age by bilateral injection into the gastrocnemius muscle three times at 3-week intervals with 50 μg of purified plasmid in 50 μl of saline. Mice were bled two weeks after each vaccination. Some mice were challenged by tail vein injection of PA (60 μg/mouse) and LF (25–30 μg/mouse), a combination equivalent to approximately five LD50 (Gu et al., 1999).
  • Persistence: (Gu et al., 1999)
  • Side Effects: none (Gu et al., 1999)
  • Efficacy: The PA DNA vaccine protects against lethal challenge with a combination of anthrax PA + LF (Gu et al., 1999).
  • Description: Splenocytes from immunized BALB/c mice were stimulated to secrete IFNγ and IL-4 when exposed to PA in vitro. Immunized mice also mounted a humoral immune response dominated by IgG1 anti-PA antibody production. A 1:100 dilution of serum from these animals protected cells in vitro against cytotoxic concentrations of PA. Moreover, 7/8 mice immunized three times with the PA DNA vaccine were protected against lethal challenge with a combination of anthrax PA plus LF (Gu et al., 1999).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Micrometer-diameter gold particles were coated with plasmid pCLF4, pCPA, or a 1:1 mixture of both. Separate groups of female BALB/c mice at 4-5 weeks of age were immunized i.d. in the abdomen via biolistic particle injection on d 0, 14, and 28 with approximately 1 µg of plasmid DNA-coated gold particles for each injection. Immunization groups included mice injected with the same microparticles coated with pCPA, pCLF4, a 1:1 mixture of the pCPA and pCLF4 plasmids, or, as a vector control, the pCI plasmid. For the prime-boost immunization experiments, groups of BALB/c mice were first immunized twice with plasmid DNA as described above and then with a third and final boost of purified antigen emulsified in Freund's incomplete adjuvant. The protein immunizations were administered i.m. Blood samples were obtained 2 weeks following each vaccination, and the sera were pooled and stored at -20°C until analyzed (Price et al., 2001).
  • Immune Response: Titers of anti-LF antibody remain at high levels for much longer periods of time than do titers of anti-PA antibody. The LF antigen appears to be much more immunogenic and produces an immune response which lasts much longer than the response to the PA antigen. Co-administration of the pCPA and pCLF4 plasmids followed by a final protein booster immunization with the recombinant PA and LF7 antigens produced a substantially higher endpoint titer against either PA or LF at the same time-point than the antibody titers resulting from DNA-based immunization alone (Price et al., 2001).
  • Challenge Protocol: Plasmid-immunized BALB/c mice that had received a total of three injections were challenged with purified Letx 2 weeks following the third and final injection. The challenge was conducted by tail vein injection of a previously mixed combination of purified PA and LF proteins (60 μg of PA and 25 to 30 μg of LF per mouse), the equivalent of approximately 5 50% lethal doses (LD50) of Letx (Price et al., 2001).
  • Efficacy: All mice immunized with pCLF4, pCPA, or the combination of both survived the challenge, whereas all unimmunized mice did not survive. A significant antibody response is generated using DNA-based immunization alone and the levels of antibody produced are sufficient to protect animals against an Letx challenge that is 5 times the LD50. Also, co-administration of the pCPA and pCLF4 plasmids followed by a final protein booster immunization with the recombinant PA and LF7 antigens produced a substantially higher endpoint titer against either PA or LF at the same time point than the antibody titers resulting from DNA-based immunization alone (Price et al., 2001).

Mouse Response

  • Host Strain: BALB/c and A/J
  • Vaccination Protocol: In the first vaccination trial, groups of 5 BALB/c mice were vaccinated on days 0, 14 and 28, with one of the three different PA-expressing plasmid constructs. A fourth group of five negative control mice received pCMV/ myc/ER vector DNA without insert. Each immunization consisted of a dose of approximately 1 mg plasmid DNA, precipitated onto 1.6 mm gold carriers per mouse. The DNA was applied to the shaved abdomen of anesthetized mice using a Helios gene gun. DNA-coated gold particles were discharged with 250 psi helium pressure. In the second vaccination trial, A/J mice were immunized according to the same vaccination protocol, except that the helium pressure for discharge of the DNA-coated gold carriers was increased to 400 psi. The treatment groups in this trial were pSecTag PA83 (13 mice), pCMV/ER PA83 (14 mice), and pCMV/myc/ER as a negative control group (10 mice). In the third vaccination trial, A/J mice were immunized with two shots per immunization using an increased DNA dose of 2.5 mg per shot, which were discharged with 400 psi. Six mice were vaccinated with pCMV/ER PA83 and eight with pSecTag PA83 (Hahn et al., 2004).
  • Immune Response: 26 d after the final immunization, the mice were killed, bled, and the serum samples analyzed for PA-specific antibody titers. All three plasmids induced anti-PA Ig and IgG1 antibody titers. Sera from mice vaccinated with pCMV/ER PA83 had significantly higher anti-PA total immunoglobulin titers than sera from mice vaccinated with pSecTag PA83, or pCMV/ER PA63. The GMT for PA-specific IgG1 of mice immunized with pCMV/ER PA83 was higher but not significantly different than PA-specific IgG1 responses of mice vaccinated with pSecTag PA83 or pCMV/ER PA63. There were no statistically significant differences between the titers of A/J mice immunized with pSecTag PA83 and A/J mice that received the pCMV/ER PA83 plasmid (Hahn et al., 2004).
  • Side Effects: Commercial anthrax vaccines can cause transient side effects, such as local pain and edema, which are probably due to trace amounts of LF and EF. None of these were noted in conjunction with the use of vaccine candidates studied here (Hahn et al., 2004).
  • Challenge Protocol: 14 A/J mice were vaccinated with pCMV/ER PA83, and 13 A/J mice with pSecTag PA83. The negative control group (10 A/J mice) received pCMV/myc/ER plasmid DNA without insert. Ten days after the third immunization, all mice were bled and their individual anti-PA titers were determined by ELISA. The mice of each treatment group were then marked to be challenged with either 10 LD50 of B. anthracis STI spores or 100 LD50 of STI spores. A/J mice immunized with the increased amount of plasmid DNA were all challenged with 100 LD50. After injection with B. anthracis spores, mice were observed for a period of 14 days.Surviving mice were killed and bled. The post-challenge serum samples were also analyzed by anti-PA ELISA and for toxin neutralization titers (Hahn et al., 2004).
  • Efficacy: Vaccination with either pSecTag PA83 or pCMV/ER PA83 showed significant protection of A/J mice against infection with B. anthracis STI spores (Hahn et al., 2004).

Mouse Response

  • Host Strain: BALB/c and A/J
  • Vaccination Protocol: In the first vaccination trial, groups of 5 BALB/c mice were vaccinated on days 0, 14 and 28, with one of the three different PA-expressing plasmid constructs. A fourth group of five negative control mice received pCMV/ myc/ER vector DNA without insert. Each immunization consisted of a dose of approximately 1 mg plasmid DNA, precipitated onto 1.6 mm gold carriers per mouse. The DNA was applied to the shaved abdomen of anesthetized mice using a Helios gene gun. DNA-coated gold particles were discharged with 250 psi helium pressure. In the second vaccination trial, A/J mice were immunized according to the same vaccination protocol, except that the helium pressure for discharge of the DNA-coated gold carriers was increased to 400 psi. The treatment groups in this trial were pSecTag PA83 (13 mice), pCMV/ER PA83 (14 mice), and pCMV/myc/ER as a negative control group (10 mice). In the third vaccination trial, A/J mice were immunized with two shots per immunization using an increased DNA dose of 2.5 mg per shot, which were discharged with 400 psi. Six mice were vaccinated with pCMV/ER PA83 and eight with pSecTag PA83 (Hahn et al., 2004).
  • Immune Response: 26 d after the final immunization, the mice were killed, bled, and the serum samples analyzed for PA-specific antibody titers. All three plasmids induced anti-PA Ig and IgG1 antibody titers. Sera from mice vaccinated with pCMV/ER PA83 had significantly higher anti-PA total immunoglobulin titers than sera from mice vaccinated with pSecTag PA83, or pCMV/ER PA63. The GMT for PA-specific IgG1 of mice immunized with pCMV/ER PA83 was higher but not significantly different than PA-specific IgG1 responses of mice vaccinated with pSecTag PA83 or pCMV/ER PA63. There were no statistically significant differences between the titers of A/J mice immunized with pSecTag PA83 and A/J mice that received the pCMV/ER PA83 plasmid (Hahn et al., 2004).
  • Side Effects: Commercial anthrax vaccines can cause transient side effects, such as local pain and edema, which are probably due to trace amounts of LF and EF. None of these were noted in conjunction with the use of vaccine candidates studied here (Hahn et al., 2004).
  • Challenge Protocol: 14 A/J mice were vaccinated with pCMV/ER PA83, and 13 A/J mice with pSecTag PA83. The negative control group (10 A/J mice) received pCMV/myc/ER plasmid DNA without insert. Ten days after the third immunization, all mice were bled and their individual anti-PA titers were determined by ELISA. The mice of each treatment group were then marked to be challenged with either 10 LD50 of B. anthracis STI spores or 100 LD50 of STI spores. A/J mice immunized with the increased amount of plasmid DNA were all challenged with 100 LD50. After injection with B. anthracis spores, mice were observed for a period of 14 days.Surviving mice were killed and bled. The post-challenge serum samples were also analyzed by anti-PA ELISA and for toxin neutralization titers (Hahn et al., 2004).
  • Efficacy: Vaccination with either pSecTag PA83 or pCMV/ER PA83 showed significant protection of A/J mice against infection with B. anthracis STI spores (Hahn et al., 2004).
  • Host Ifng (Interferon gamma) response
    • Description: Spleen cells collected from plasmid-vaccinated BALB/c mice 26 days after the third immunization produced PA-specific interleukin-4, interleukin-5, and interferon-gamma in vitro. All levels were significantly higher than those from negative control mice immunized with pCMV/myc/ER, a eukaryotic expression plasmid without the insert (Hahn et al., 2004).
    • Detailed Gene Information: Click Here.
  • Host Ighg1 response
    • Description: pSecTag PA83 induced PA-specific humoral immune responses, predominantly IgG1 antibodies, in mice (Hahn et al., 2004).
    • Detailed Gene Information: Click Here.
  • Host Il4 (interleukin 4) response
    • Description: Spleen cells collected from plasmid-vaccinated BALB/c mice 26 days after the third immunization produced PA-specific interleukin-4, interleukin-5, and interferon-gamma in vitro. All levels were significantly higher than those from negative control mice immunized with pCMV/myc/ER, a eukaryotic expression plasmid without the insert (Hahn et al., 2004).
    • Detailed Gene Information: Click Here.
  • Host Il5 response
    • Description: Spleen cells collected from plasmid-vaccinated BALB/c mice 26 days after the third immunization produced PA-specific interleukin-4, interleukin-5, and interferon-gamma in vitro. All levels were significantly higher than those from negative control mice immunized with pCMV/myc/ER, a eukaryotic expression plasmid without the insert (Hahn et al., 2004).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Host Strain: Female A/J mice
  • Vaccination Protocol: Mice were vaccinated with 10 µg of protein adsorbed to a 20% (vol/vol) solution of 1.3% Alhydrogel on days 1 and 28 of the study. Also included were groups of mice that were immunized with rPA (expressed and purified from B. subtilis), with recombinant GST control protein, or with fusion proteins comprising domains 1, 4, and 1-4, which had the GST tag removed by incubation with PreScission Protease and removal of the GST on a glutathione Sepharose column. Blood samples from mice were collected 37 days after primary immunization for serum antibody analysis by enzyme-linked immunosorbent assay. Mice were challenged i.p. with either 105 or 106 spores of the B. anthracis STI strain (equivalent to 102 or 103 minimum lethal doses [MLDs], respectively) on day 70 of the immunization regimen and were monitored for 14 days postchallenge to determine their protected status (Flick-Smith et al., 2002).
  • Persistence: (Flick-Smith et al., 2002)
  • Side Effects: No side effects noted (Flick-Smith et al., 2002).
  • Efficacy: At the lower challenge level of 102 MLDs, mice in the GST1-2-, GST4-, and cleaved 4-immunized groups were all fully protected. All mice in the groups immunized with fusion proteins containing domain 4 were fully protected against challenge with 103 MLDs of STI spores (Brey, 2005).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Mice were lightly anesthetized and given a total volume of 20 mL of rPA/pI:C solution in two 10-mL doses, with 10-15 min between each dose, half in each nare. As controls, mice (n = 5) were subcutaneously (s.c.) injected with rPA (5 mg/mouse) admixed with aluminum hydroxide gel, nasally dosed with rPA admixed with cholera toxin as a mucosal adjuvant, or left untreated. Mice were dosed on days 0, 7, and 14 (Sloat and Cui, 2006).
  • Immune Response: Mice nasally immunized with rPA adjuvanted with pI:C developed strong systemic and mucosal anti-PA responses with lethal toxin neutralization activity. These immune responses compared favorably to that induced by nasal immunization with rPA adjuvanted with cholera toxin. Poly(I:C) enhanced the proportion of DCs in local draining lymph nodes and stimulated DC maturation (Sloat and Cui, 2006).

Mouse Response

  • Vaccination Protocol: Groups of mice were orally vaccinated with 100 µl (108 CFU) L. gasseri expressing PA–DCpep, PA–Ctrlpep, or cells harboring the empty vector. Oral vaccination was administered four times on a weekly basis (Mohamadzadeh et al., 2010).
  • Vaccine Immune Response Type: VO_0003057
  • Challenge Protocol: The groups of mice were challenged intraperitoneally with B. anthracis Sterne pXO1+/pXO2- (5 × 104 CFU/mouse) (Mohamadzadeh et al., 2010).
  • Efficacy: L. gasseri expressing PA–DCpep fusion was 100% efficacious in protection of the mice compared with 30% survival when vaccinated with L. gasseri expressing PA–Ctrl pep (Figure 3A & B). Additionally, vaccinated mice with recombinant PA plus alhydrogel were fully protected from Sterne lethal challenge (Mohamadzadeh et al., 2010).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Groups of mice were immunized intranasally with either one or two administrations of experimental vaccine 3 weeks apart. rPA-NE mixes were applied to the nares with a pipette tip administering 10 μl per nare, and the animals were then allowed to inhale the material (Bielinska et al., 2007).
  • Immune Response: rPA-NE immunization was effective in inducing both serum anti-PA IgG and bronchial anti-PA IgA and IgG antibodies after either one or two mucosal administrations. Serum anti-PA IgG2a and IgG2b antibodies and PA-specific cytokine induction after immunization indicate a Th1-polarized immune response. rPA-NE immunization also produced high titers of lethal-toxin-neutralizing serum antibodies in mice (Bielinska et al., 2007).
  • Challenge Protocol: The immune responses of mice were not challenged.

Mouse Response

  • Vaccination Protocol: Control mice received three doses of Ty21a alone. Mice that were immunized i.n. received 5 × 108 CFU per dose, and mice that were immunized i.p. received 5 × 107 CFU per dose. i.n. immunization was performed by administering 20 μl of a bacterial solution to the nares (Osorio et al., 2009).
  • Vaccine Immune Response Type: VO_0003057
  • Challenge Protocol: Mice were exposed for 90 min to aerosolized spores (5 × 109 spores per ml in deionized water with 0.01% Tween 80) prepared from B. anthracis strain 7702(pXO1+, pXO2−) (Osorio et al., 2009).
  • Efficacy: Vaccinated mice demonstrated 100% protection against a lethal intranasal challenge with aerosolized spores of B. anthracis 7702 (Osorio et al., 2009).

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).

Rabbit Response

  • Host Strain: NZW
  • Vaccination Protocol: Groups of rabbits were immunized with various vaccine preparations. The first group was immunized (i.m.) twice using the needleless Biojector device with 500 ug of plasmid DNA (pCPA and/or pCLF4) resuspended in 0.5 ml of sterile phosphate buffered saline (PBS) at 4-week intervals. These animals were boosted by needle (i.m.) 4 weeks later with 200 ug of purified full-length rPA protein or full-length recombinant lethal factor (LF) protein LF7 with a point mutation resuspended in incomplete Freund’s adjuvant. The second group was immunized three times by gene gun with 10 ug plasmid DNA containing the PA63 gene fragment and/or the LF4 gene fragment bound to gold beads, at 4-week intervals. The third group of animals was immunized (s.c.) at 4-week intervals with AVA (lot FAV059), 800 ug rPA protein with Alum, or a mixture of 400 ug rPA and 400 ug rLF7 protein with Alum. Controls consisted of either non-immunized animals or a plasmid vector control not containing the PA and/or LF genes. All rabbits were aerosol challenged with B. anthracis spores, Ames strain, with an average dose of 50 LD50s with a range of 18-169 LD50s. Rabbit sera were collected prior to and following aerosol challenge and titrated for PA antibodies by indirect ELISA (Galloway et al., 2004).
  • Persistence: (Galloway et al., 2004)
  • Side Effects: None were noted (Galloway et al., 2004).
  • Efficacy: The results of this study indicate that DNA-based immunization against PA and LF followed by protein boosting induces significant protective immunity against aerosol challenge in the rabbit model and compares favorably with protein-based immunization (Galloway et al., 2004).
  • Description: None of the rabbits immunized with the DNA vaccines i.d. survived the challenge. Of the 5 vaccinated rabbits that survived, 2 were immunized i.m. with DNA followed with a protein boost and 3 were immunized subcutaneously (s.q.) with recombinant protein. DNA prime-boosted animals mount a protective response against aerosol challenge more than 1 year following the final immunization. Priming immunizations with plasmid DNA appear to set up a substantial memory response which is recalled upon protein boosting. A major factor predicting survival was the ability of the animal to mount a lasting antibody response to PA (Galloway et al., 2004).

Guinea pig Response

  • Host Strain: Hartley
  • Vaccination Protocol: Hartley guinea pigs were vaccinated intranasally with one or two administrations of vaccine, each about 50 μl per nare, 4 weeks apart (Bielinska et al., 2007).
  • Immune Response: serum anti-PA immunoglobulin G and bronchial anti-PA IgA and IgG antibodies were produced following either one of two mucosal immunizations of rPA-NE. The anti-PA IgG2a and IgG2b antibodies and PA-specific cytokine induction found in the serum indicated a Th-1-polarized immune response. High titers of lethal-toxin-neatralizing antibodies were also found after rPA-NE immunization (Bielinska et al., 2007).
  • Challenge Protocol: The guinea pigs were challenged intradermaly with ~1,000 times the 50% lethal dose of B. anthracis Ames strain spores, which was about 1.38 × 103 spores (Bielinska et al., 2007).
  • Efficacy: Nasal immunization resulted in 70% and 40% survival rates against intranasal challenge with 1.2 × 106 and 1.2 × 107 Ames strain spores (Bielinska et al., 2007).
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