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Anthrax Vaccine Adsorbed (AVA, BioThrax ® ) is approved for use in humans as a priming series of 3 intramuscular (i.m.) injections (0, 1, 6 months; 3-IM) with boosters at 12 and 18 months, and annually thereafter for those at continued risk of infection. A reduction in AVA booster frequency would lessen the burden of vaccination, reduce the cumulative frequency of vaccine associated adverse events and potentially expand vaccine coverage by requiring fewer doses per schedule. Because human inhalation anthrax studies are neither feasible nor ethical, AVA efficacy estimates are determined using cross-species bridging of immune correlates of protection (COP) identified in animal models. We have previously reported that the AVA 3-IM priming series provided high levels of protection in non-human primates (NHP) against inhalation anthrax for up to 4 years after the first vaccination. Penalized logistic regressions of those NHP immunological data identified that anti-protective antigen (anti-PA) IgG concentration measured just prior to infectious challenge was the most accurate single COP. In the present analysis, cross-species logistic regression models of this COP were used to predict probability of survival during a 43 month study in humans receiving the current 3-dose priming and 4 boosters (12, 18, 30 and 42 months; 7-IM) and reduced schedules with boosters at months 18 and 42 only (5-IM), or at month 42 only (4-IM). All models predicted high survival probabilities for the reduced schedules from 7 to 43 months. The predicted survival probabilities for the reduced schedules were 86.8% (4-IM) and 95.8% (5-IM) at month 42 when antibody levels were lowest. The data indicated that 4-IM and 5-IM are both viable alternatives to the current AVA pre-exposure prophylaxis schedule. [ABSTRACT FROM AUTHOR]

Background Epitope-focused immunogens can elicit antibody against the loop neutralizing determinant (LND), a neutralizing epitope found within the 2β2-2β3 loop of protective antigen (PA), which can protect rabbits from high-dose inhalation challenge with Bacillus anthracis Ames strain. Interestingly, data suggests that this epitope is relatively immunosilent in rabbits and non-human primates immunized with full length PA. Methods To determine whether the LND is immunosilent among humans vaccinated with PA, we screened antisera from AVA- or placebo-vaccinees from a clinical trial for antibody reactive with the LND. Results AVA-vaccinee sera had significant PA-specific antibody compared to placebo-vaccinee sera; however, sera from the two cohorts were indistinguishable with regard to the frequency of individuals with antibody specific for the LND. Conclusions AVA-vaccinees have a low frequency of antibody reactive with the LND. As with rabbits and non-human primates, the elicitation of LND-specific antibody in humans appears to require immunization with an epitope-focused vaccine. [ABSTRACT FROM AUTHOR]

Highlights: [•] The persistence of anti-PA IgG antibody in humans two years after partial priming doses of anthrax vaccine is described. [•] Human anti-PA IgG antibody response to delayed doses of anthrax vaccine adsorbed is described. [•] Comparison of antibody response by ELISA and lethal toxin neutralization activity. [•] Evidence is presented supporting continuing the anthrax vaccination series when a dose is missed for as long as two years rather than restarting the series. [Copyright &y& Elsevier]

Abstract: Background: In 2002 CDC initiated the Anthrax Vaccination Program (AVP) to provide voluntary pre-exposure vaccination with Anthrax Vaccine Adsorbed (AVA) for persons at high risk of exposure to Bacillus anthracis spores. There has been concern that AVA could be associated with long term impairment of physical and/or mental health. Objectives: To ascertain whether physical and mental functional status, as measured by the SF-36v2 health survey (Medical Outcomes Trust, Boston, MA), of AVA recipients and controls changed differently over time. Methods: We enrolled 437 exposed (received AVA) and 139 control subjects. The exposed group received AVA under then-current Advisory Committee on Immunization Practices (ACIP) recommendations. SF-36v2 surveys were completed at 0, 12, and 30 months. SF-36v2 physical and mental scores both range from 0 to 100 with an estimated national average of 50 points. Results: For physical scores, the average change from baseline was −0.53 for exposed vs. −0.67 for controls at 12 months (p =0.80) and −1.09 for exposed vs. −1.97 for controls at 30 months (p =0.23). For mental scores, the average change from baseline was −1.50 for exposed vs. −1.64 for controls at 12 months (p =0.86) and −2.11 for exposed vs. −0.24 for controls at 30 months (p =0.06). In multivariable analysis, the difference in mental score change between exposed vs. controls at 30 months was less pronounced (p =0.37) but other findings were similar to univariate analyses. Conclusions: These results do not favor an association between receipt of AVA and an altered health related quality of life over a 30-month period. [Copyright &y& Elsevier]

Abstract: Samples of human plasma from anthrax vaccine adsorbed (AVA, BioThrax™)-vaccinated individuals were used to demonstrate passive protection of A/J mice from a lethal challenge with the Sterne strain of anthrax bacteria. The maximum concentration of human anti-protective antigen IgG in mouse sera 24h after injection of 260μg of anti-PA IgG was 134μg/ml, declining to 91μg/ml at 72h (half-life=101.7h). Mice showed significant survival (p ≤0.001) after injection of serial dilutions up to 1:4 of the standard plasma and challenged with 100 LD50. Similarly, mice injected with the standard anti-AVA plasma and challenged up to 5 days post-treatment also survived (p ≤0.001). Using a cohort of human plasma to measure passive protection, the best correlation between passive protection and an in vitro assay was found to be with the quantitative toxin neutralization assay (minimum fold increase in odds of survival: 2.71, p =0.0062). These results demonstrate a reliable in vivo neutralization method that correlates with standard in vitro measures of neutralizing antibody levels in plasma from individuals vaccinated with the standard anthrax vaccine. This analytical method may provide additional opportunities to compare the efficacy of improved anthrax vaccines with the licensed vaccine. [Copyright &y& Elsevier]

Abstract: The anti-PA IgG1, IgG2, IgG3, and IgG4 subclass responses to clinical anthrax and to different numbers of anthrax vaccine adsorbed (AVA, BioThrax®) injections were determined in a cross-sectional study of sera from 63 vaccinees and 13 clinical anthrax patients. The data show that both vaccination with three AVA injections and clinical anthrax elicit anti-PA IgG1, IgG2, and IgG3 subclass responses. An anti-PA IgG4 response was detected in AVA recipients after the fourth injection. The anthrax lethal toxin (LTx) neutralization efficacy of sera from recipients who received 4 to ≥10 AVA injections did not vary significantly in relation to changes in distribution of anti-PA IgG1 and IgG4 subclasses. [Copyright &y& Elsevier]

Abstract: Anthrax, a disease of herbivores, only rarely infects humans. However, the threat of using Bacillus anthracis, the causative agent, to intentionally produce disease has been the impetus for development of next-generation vaccines. Two licensed vaccines have been available for human use for several decades. These are composed of acellular culture supernatants containing the protective antigen (PA) component of the anthrax toxins. In this review we summarize the various approaches used to develop improved vaccines. These efforts have included the use of PA with newer adjuvants and delivery systems, including bacterial and viral vectors and DNA vaccines. Attempts to broaden the protection afforded by PA-based vaccines have focused on adding other B. anthracis components, including spore and capsule antigens. [Copyright &y& Elsevier]

Objective: We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired., Methods: Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 "annual" boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs)., Results: The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at 42 months., Conclusions: A priming series of 3 intramuscular doses administered at m0, m1, and m6 with a triennial booster was non-inferior to more complex schedules for achieving antibody response., (Published by Elsevier Ltd.)