Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: A randomized, double-blinded, controlled, multicenter trial
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.
- SourceAvailable from: Conrad P Quinn
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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). "
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   . 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 . "
ABSTRACT: Bacillus anthracis is the causative agent of anthrax, a bacterial infection with a high mortality rate [1-3]. Although anthrax infection can be cutaneous, gastrointestinal or pulmonary, the pulmonary form is the most deadly [2,3]. Thus, the release of Bacillus anthracis spores that can be inhaled represents a potent bioterrorism threat; the capacity of B. anthracis spores to act as a bioterrorism weapon was demonstrated in 2001, with the intentional infection of 22 persons in the U.S.A. [2,4]. Until recently, the available vaccines were developed to confer protection against cutaneous infection; despite this, these vaccines demonstrated experimental efficacy against pulmonary infection in multiple animal models [1,2]. Nevertheless, there are many limitations for these vaccines to be considered successful and effective vaccine, including the intensity of the required vaccination schedule, the administration route and the presence of local adverse effects experienced after vaccination [1,3,5,6]. To develop more efficient vaccines against pulmonary anthrax, intranasal formulations with adjuvant have been studied. These formulations have advantages because they are easy to administer and because they are expected to induce both systemic and respiratory tract mucosal immune responses. Therefore, the main goal of this review is to compare the different experimental adjuvants used with anthrax antigens and the different approaches regarding the vaccination schedule and consecutive boosters.World Journal of Vaccines 08/2011; 1(3):79-91. DOI:10.4236/wjv.2011.13008
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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™ , , . We show here, as have others  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). "
ABSTRACT: The fatal disease caused by Bacillus anthracis is preventable with a prophylactic vaccine. The currently available anthrax vaccine requires a lengthy immunization schedule, and simpler and more immunogenic options for protection against anthrax are a priority for development. In this report we describe a phase I clinical trial testing the safety and immunogenicity of an anthrax vaccine using recombinant Escherichia coli-derived, B. anthracis protective antigen (rPA). A total of 73 healthy adults ages 18-40 were enrolled and 67 received 2 injections separated by 4 weeks of either buffered saline placebo, or rPA formulated with or without 704 µg/ml Alhydrogel® adjuvant in increasing doses (5, 25, 50, 100 µg) of rPA. Participants were followed for one year and safety and immunologic data were assessed. Tenderness and warmth were the most common post-injection site reactions. No serious adverse events related to the vaccine were observed. The most robust humoral immune responses were observed in subjects receiving 50 µg of rPA formulated with Alhydrogel® with a geometric mean concentration of anti-rPA IgG antibodies of 283 µg/ml and a toxin neutralizing geometric 50% reciprocal geometric mean titer of 1061. The highest lymphoproliferative peak cellular response (median Lymphocyte Stimulation Index of 29) was observed in the group receiving 25 µg Alhydrogel®-formulated rPA. The vaccine was safe, well tolerated and stimulated a robust humoral and cellular response after two doses. ClinicalTrials.gov NCT00057525.PLoS ONE 11/2010; 5(11):e13849. DOI:10.1371/journal.pone.0013849 · 3.23 Impact Factor