Gorse, GJ, Keitel, W, Keyserling, H, Taylor, DN, Lock, M, Alves, K et al.. Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: a randomized, double-blinded, controlled, multicenter trial. Vaccine 24: 5950-5959

Baylor College of Medicine, Houston, Texas, United States
Vaccine (Impact Factor: 3.62). 09/2006; 24(33-34):5950-9. DOI: 10.1016/j.vaccine.2006.05.044
Source: PubMed


We report the results of a phase I dose escalation, safety and immunogenicity trial of a new recombinant protective antigen (rPA102) anthrax vaccine.
Hundred healthy volunteers were randomized in a 4:1 ratio to receive intramuscular doses of rPA102 in the following formulations: 5, 25, 50, or 75 microg of rPA102 in 82.5 microg aluminum hydroxide adjuvant at 0, 4, and 8 weeks; or the US licensed Anthrax Vaccine Adsorbed (AVA) at weeks 0 and 4.
Local reactogenicity (mostly pain) was more common with AVA than with rPA102 following the first (94.7% versus 44.4%; p < 0.001) and the second (84.2% versus 35.4%; p < 0.001) vaccinations. Systemic reactogenicity (mostly headache) was more common among rPA102 vaccinees, but only following the first vaccination (49.4% versus 15.8%; p = 0.025). A dose-response relationship for anti-PA antibodies was present after the 2nd and 3rd vaccinations. Two weeks following the 2nd vaccination, the geometric mean titers (GMT) for lethal toxin neutralization activity (TNA), for the 5, 25, 50 and 75 microg rPA102 and AVA groups were 38.6, 75.4, 373.9, 515.3, and 855.2, respectively. The geometric mean concentrations (GMC) measured by anti-PA IgG ELISA were 3.7, 11.5, 25.9, 44.1, and 171.6, respectively. Two weeks following the 3rd vaccination, TNA GMTs for the four rPA102 groups, were: 134.7, 719.7, 2116.6, 2422.4; and ELISA GMCs were: 22.9, 104.7, 196.4, and 262.6, respectively.
No clinically serious or dose-related toxicity or reactogenicity was observed. The TNA response after two injections of the 75 microg dose of rPA102 was similar to the response after two injections of AVA. The third rPA102 vaccination substantially increased the antibody response.

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    • "The major protective immunogen in these vaccines is PA [10] [11]. Recombinant PA vaccines are currently in clinical trials [12] [13] [14]. Antibody responses measured by an anti-PA IgG enzyme linked immunosorbent assay (ELISA) and an in vitro LeTx neutralizing antibody (TNA) assay, in which the functional activity of antisera are evaluated in a macrophage cytolysis assay, have been identified as serological correlates of immunity in non-human primates, rabbits, and guinea pigs [15– 20]. "
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    ABSTRACT: Abstract Serological memory after inoculation of protective antigen (PA) combined with Alhydrogel adjuvant (PA/Alhydrogel) was examined in New Zealand white rabbits, an animal model for anthrax. A threshold dose of 0.1 μg of PA/Alhydrogel was identified which resulted in an ELISA titer 2 weeks after a primary immunization of only 0.168 μg anti-PA IgG per ml and a toxin-neutralizing antibody titer (TNA ED50) of 1.8 (n = 40). A significant increase in anti-PA IgG and TNA ED50 titers were measured (p < 0.0001) 2 weeks after a booster immunization with 0.1 μg of PA/Alhydrogel at 14 days (n = 10; 40.9 μg anti-PA IgG per ml; 522 TNA ED50) and 28 days (n = 10; 63.8 μg anti-PA IgG per ml; 501 TNA ED50). At this threshold dose of PA/Alhydrogel, protection against an aerosol exposure to Bacillus anthracis Ames spores improved as the booster immunization was administered from 4 days (40% survival), to 8 days (50% survival), and to 12 days (80% survival) before challenge. The partial protection of rabbits, even in the absence of protective antibody titers (0.9 μg anti-PA IgG per ml and 26 TNA ED50) when the booster immunization was administered 4 days before challenge, suggested a protective potential for serologic memory.
    Preview · Article · Jul 2015 · Trials in Vaccinology
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    • "Since PA is known to be the primary protective component of the AVA vaccine, efforts are underway to explore the use of recombinant PA as the active component of a new vaccine. Initial studies in rabbits [17] and nonhuman primates [18] showed a high level of PA-mediated protection against aerosol infection, and Phase I trials indicated that while recombinant PA is safe, important features such as optimal formulation and dosing schedule require further development [19] [20]. Other studies have sought to combine the purified, recombinant PA with other B. anthracis proteins that elicit protective responses and could thus enhance the protection afforded by PA alone. "
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    ABSTRACT: The current standard for Bacillus anthracis vaccination is the Anthrax Vaccine Adsorbed (AVA, BioThrax). While effective, the licensed vaccine schedule requires five intramuscular injections in the priming series and yearly boosters to sustain protection. One potential approach to maintain or improve the protection afforded by an anthrax vaccine, but requiring fewer doses, is through the use of purified proteins to enhance an antibody response, which could be used on their own or in combination with the current vaccine. This study describes a novel, high-throughput system to amplify and clone every gene in the B. anthracis pXO1 and pXO2 virulence plasmids. We attempted to express each cloned gene in Escherichia coli, and obtained full-length expression of 57% of the proteins. Expressed proteins were then used to identify immunogens using serum from three different mammalian infection models: Dutch-belted rabbits, BALB/c mice, and rhesus macaque monkeys. Ten proteins were detected by antibodies in all of these models, eight of which have not been identified as immunoreactive in other studies to date. Serum was also collected from humans who had received the AVA vaccine, and similar screens showed that antigens that were detected in the infection models were not present in the serum of vaccinated humans, suggesting that antibodies elicited by the current AVA vaccine do not react with the immunoreactive proteins identified in this study. These results will contribute to the future selection of targets in antigenicity and protection studies as one or more of these proteins may prove to be worthy of inclusion in future vaccine preparations.
    Full-text · Article · Sep 2012 · Microbial Pathogenesis
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    • "Due to the long duration of the CDC study together with the public health impact of modifying the vaccine schedule it was necessary to develop a precise, accurate, specific, and sensitive serological assay with sustained performance, robustness and stability such that data generated early in the study were directly comparable to those generated in the later stages of enrollment. To address these needs, we developed, characterized and validated a quantitative enzyme-linked immunosorbent assay (ELISA) and a comprehensive set of serological reagents for assessment of anthrax toxin protective antigen (PA) specific immunoglobulin G (IgG) antibody levels in human serum (Quinn et al., 2002, 2004; Semenova et al., 2004; Gorse et al., 2006). We have previously reported the primary performance characteristics of the quantitative anti-PA IgG ELISA (Quinn et al., 2002). "
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    ABSTRACT: Accurate, reliable and standardized quantification of anti-protective antigen (PA) IgG antibody levels is essential for comparative analyses of anti-toxin immune responses in anthrax cases, recipients of PA-based anthrax vaccines and for evaluation of anti-PA based immunotherapies. We have previously reported the early performance characteristics and application of a quantitative anti-PA IgG enzyme linked immunosorbent assay. The principal application of this assay was in a Phase 4 human clinical trial of anthrax vaccine adsorbed (AVA, BioThrax), the central component of the CDC Anthrax Vaccine Research Program (AVRP) and in humans following bioterrorism associated Bacillus anthracis infection (Quinn et al., 2002; Quinn et al., 2004; Marano et al., 2008). The objective of the AVRP was to determine the feasibility of reducing the number of priming series and booster doses of the licensed Anthrax Vaccine Adsorbed (AVA) (BioThrax®; Emergent BioSolutions, Lansing, MI) and changing the route of administration from subcutaneous (SC) to intramuscular (IM) (Marano et al., 2008). In this paper we report the validation and long term performance characteristics of the assay during its six year application in the AVRP (2002-2008). The critical features are 1) extensive validation of the assay using two standard reference sera; 2) long term stability and 3) consistency of the data for quantitative analysis of human long term anti-PA IgG responses. The reportable value (RV) of the assay was expressed as anti-PA IgG concentration (μg/ml). Accuracy of the assay was high with a percent error (%ER) range of 1.6-11.4%. Overall intra-operator and intermediate precision were high with Coefficients of Variation (%CVs) of 2.5-15.4% and 6.3-13.2%, respectively. The assay demonstrated excellent dilutional linearity for human sera using log(10) transformed data with the slope=0.95 to 0.99, intercept=0.02 to 0.06 and r(2)=0.980-0.987. The assay was robust, tolerating changes in serum incubation temperatures from 35 to 39°C, serum incubation times from 55 to 65min and changes in key reagents. The long-term assay stability over 6years using consecutive reference sera AVR414 and AVR801 demonstrated sustained high accuracy and precision for the assay, confirming its suitability for long term studies of PA protein-based anthrax vaccines.
    Full-text · Article · Dec 2011 · Journal of immunological methods
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