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Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: A randomized, double-blinded, controlled, multicenter trial

Saint Louis Veterans Affairs Medical Center and St. Louis University School of Medicine, St. Louis, MO, USA.
Vaccine (Impact Factor: 3.49). 09/2006; 24(33-34):5950-9. DOI: 10.1016/j.vaccine.2006.05.044
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ABSTRACT 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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    • "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.
    Journal of immunological methods 12/2011; 376(1-2):97-107. DOI:10.1016/j.jim.2011.12.002 · 2.01 Impact Factor
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    • "In fact, Phase I clinical trials of the injectable recombinant vaccine are underway, and the preliminary results for immunogenicity and tolerance have been encouraging [27] [28] [29]. Therefore, it is generally accepted that PA, a toxin component from vegetative cells, is central for the design of a human vaccine that targets toxaemia [30]. "
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    • "Vaccine formulations of rPA with and without Alhydrogel® were immunogenic. The humoral responses, as measured by ELISA for binding antibodies and TNA for neutralizing antibodies, follow similar patterns (Figure 5) and the values correlate well (Figure 6), which is in line with prior observations following natural infection and vaccination with Biothax™ [13], [16], [18]. We show here, as have others [14] that formulation with Alhydrogel® tended to enhance antibody responses, especially at 5 µg and the 25 µg dosage levels where, at 2 weeks post-second vaccination (near the presumed peak of immunogenicity), the GMCs of anti-rPA antibodies were nearly a log higher in the groups receiving Alhydrogel®-formulated rPA than those in groups receiving PBS-formulated rPA (Figure 4). "
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    PLoS ONE 11/2010; 5(11):e13849. DOI:10.1371/journal.pone.0013849 · 3.23 Impact Factor
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