Anthrax Vaccines

Saile, Elke; Quinn, Conrad P.

doi:10.1002/9780470891193.ch14

Cited by 7 publications

(6 citation statements)

References 168 publications

(195 reference statements)

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“…As the anthrax protective antigen (PA) is known to be an important component of an effective anthrax vaccine, antibodies to PA (AbPA) are commonly used as the primary measure of AVA immunogenicity. Although lethal toxin-neutralizing antibodies may also be relevant, studies in humans and mice have generally indicated a strong correlation between AbPA and toxin-neutralizing antibody levels (46). Accordingly, AbPA was measured by ELISA as anti-PA specific immunoglobulin G in comparison to reference samples of known AbPA concentrations in a quantitative enzyme-linked immunosorbent assay, with an empirical reactivity threshold of 3.7 μg ml −1 (29, 47).…”

Section: Methodsmentioning

confidence: 99%

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Ptacek

et al. 2013

Sci. Transl. Med.

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B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.

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Section: Methodsmentioning

confidence: 99%

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Ptacek

et al. 2013

Sci. Transl. Med.

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“…Anti-PA antibody levels have been an accepted serological indicator for protection against anthrax since acellular vaccines for human use were first developed (1,(30)(31)(32)(33)(34). More recently, serum TNA has been the focal point for correlates of protection in animal models and estimates of survival probability in humans (4,27,35).…”

Section: Discussionmentioning

confidence: 99%

“…Anthrax toxin protective antigen (PA) is the primary immunogen in licensed anthrax vaccines in the United States and the European Union, as well as in many of the second-generation anthrax vaccines in current development (1). Consequently, the quantitative analysis of anti-PA IgG antibody levels and lethal toxin neutralization activity (TNA) in serum are generally accepted as immunological correlates of protection (COP) for vaccine efficacy in animal models (2).…”

mentioning

confidence: 99%

Comprehensive Analysis and Selection of Anthrax Vaccine Adsorbed Immune Correlates of Protection in Rhesus Macaques

Chen

Schiffer

Dalton

et al. 2014

Clin. Vaccine Immunol.

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T o date, there has not been a systematic evaluation of the relationship between anthrax vaccine-stimulated humoral and cell-mediated immune responses, their relative contributions to protection, or their comparative importance when used singly or in combination to predict the probability of survival in animal models or in humans.Anthrax toxin protective antigen (PA) is the primary immunogen in licensed anthrax vaccines in the United States and the European Union, as well as in many of the second-generation anthrax vaccines in current development (1). Consequently, the quantitative analysis of anti-PA IgG antibody levels and lethal toxin neutralization activity (TNA) in serum are generally accepted as immunological correlates of protection (COP) for vaccine efficacy in animal models (2). Anti-PA IgG levels and TNA are also considered pivotal for cross-species predictions of anthrax vaccine efficacy in humans, for whom clinical efficacy studies are either impractical or ethically infeasible (3, 4) (http://www.fda .gov/AdvisoryCommittees/CommitteesMeetingMaterials/Blood VaccinesandOtherBiologics/VaccinesandRelatedBiologicalProducts AdvisoryCommittee/ucm239733.htm). Anti-PA IgG and TNA levels, however, are but one part of the spectrum of humoral and cell-mediated immune responses that may contribute to protection. The COP for anthrax may differ depending on vaccine formulations, schedules, and routes of administration (5-10).The U.S.-licensed anthrax vaccine adsorbed (AVA) (BioThrax) was approved in 1970 for the prevention of anthrax in humans (11)(12)(13)(14). The original regimen for AVA was a subcutaneous (s.c.) six-dose primary schedule at 0, 0.5, 1, 6, 12, and 18 months, with subsequent annual boosters. In May 2012, the U.S. Food and Drug Administration (FDA) approved the AVA regimen as an intramuscular (i.m.) three-dose priming schedule at 0, 1, and 6 months, with boosters at 12 and 18 months and annually thereafter (http://www .fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts /ucm304758.htm). These recent changes in the schedule and administration route were based on data from the Centers for Disease Control and Prevention Anthrax Vaccine Research Program (AVRP) (12, 13). The goals of the AVRP were to improve the AVA safety profile and ensure efficacy while minimizing the number of doses required. The study objectives included determining immunological correlates of protection, documenting vaccine efficacy, and optimizing the vaccination schedule and route of administration (14). Due to the low prevalence of inhalation anthrax and the ethical concerns of conducting an efficacy trial in humans, vaccine efficacy and duration of protection were evaluated in rhesus macaques (Macaca mulatta) (15).The AVRP nonhuman primate (NHP) study used the 0-, 1-, and 6-month intramuscular priming series (3-i.m.) with a full human dose or saline dilutions of AVA to modulate the immune response. The NHP were challenged with high-dose (median, 504ϫ the 50% lethal dose [LD 50 ]) aerosolized Bacillus anthracis spores at m...

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“…The US licensed anthrax vaccine adsorbed (AVA, BioThrax®) was approved in 1970 for prevention of anthrax in humans [1–3]. The primary immunogen in AVA is anthrax toxin protective antigen (PA) [4]. The 1970 regimen for AVA was a subcutaneous (s.c.) six-dose primary schedule at 0, 0.5, 1, 6, 12 and 18 months with subsequent annual boosters.…”

Section: Introductionmentioning

confidence: 99%

Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans

Schiffer

Chen

Dalton

et al. 2015

Vaccine

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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.

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Anthrax Vaccines

Cited by 7 publications

References 168 publications

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Comprehensive Analysis and Selection of Anthrax Vaccine Adsorbed Immune Correlates of Protection in Rhesus Macaques

Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans

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