Last data update: Jun 24, 2024. (Total: 47078 publications since 2009)
Records 1-9 (of 9 Records) |
Query Trace: Schiffer JM [original query] |
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Evaluation of early immune response-survival relationship in cynomolgus macaques after anthrax vaccine adsorbed vaccination and Bacillus anthracis spore challenge
Sivko GS , Stark GV , Tordoff KP , Taylor KL , Glaze E , VanRaden M , Schiffer JM , Hewitt JA , Quinn CP , Nuzum EO . Vaccine 2016 34 (51) 6518-6528 Anthrax vaccine adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen. |
Recent developments in the understanding and use of anthrax vaccine adsorbed: Achieving more with less
Schiffer JM , McNeil MM , Quinn CP . Expert Rev Vaccines 2016 15 (9) 1151-62 Anthrax Vaccine Adsorbed (AVA, BioThrax) is the only Food and Drug Administration (FDA) approved vaccine for the prevention of anthrax in humans. Recent improvements in pre-exposure prophylaxis (PrEP) use of AVA include intramuscular (IM) administration and simplification of the priming series to three doses over six months. Administration IM markedly reduced the frequency, severity and duration of injection site reactions. Refinement of animal models for inhalation anthrax, identification of immune correlates of protection and cross-species modeling have created opportunities for reductions in the PrEP booster schedule and were pivotal in FDA approval of a post-exposure prophylaxis (PEP) indication. Clinical and nonclinical studies of accelerated PEP schedules and divided doses may provide prospects for shortening the PEP antimicrobial treatment period. These data may assist in determining feasibility of expanded coverage in a large-scale emergency when vaccine demand may exceed availability. Enhancements to the AVA formulation may broaden the vaccine's PEP application. |
Humoral and cell mediated immune responses to alternate booster schedules of anthrax vaccine adsorbed in humans
Quinn CP , Sabourin CL , Schiffer JM , Niemuth NA , Semenova VA , Li H , Rudge TL , Brys AM , Mittler RS , Ibegbu CC , Wrammert J , Ahmed R , Parker SD , Babcock J , Keitel W , Poland GA , Keyserling HL , Sahly HE , Jacobson RM , Marano N , Plikaytis BD , Wright JG . Clin Vaccine Immunol 2016 23 (4) 326-38 Protective antigen (PA)-specific antibody and cell mediated immune (CMI) responses to annual and alternate booster schedules of Anthrax Vaccine Adsorbed (AVA, BioThrax(R)) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: 3-dose intramuscular (IM) priming series (0, 1, 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30 and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, 18 months) and two annual boosters (30, 42 months) administered either subcutaneous (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time-points.Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of IFN-gamma and IL-4 secreting cells and memory B cells (MBCs), lymphocyte proliferation indices (SI) and induction of IFN-gamma, IL-2, IL-4, IL-6, IL-1beta and TNF-alpha mRNA levels.All active schedules elicited high avidity PA-specific IgG, TNA, MBCs and T cell responses with a mixed Th1/Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g. Month 7, r2 = 0.86, p < 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated faster and statistically superior antibody responses to the final Month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 Months. |
Bridging non-human primate correlates of protection to reassess the anthrax vaccine adsorbed booster schedule in humans
Schiffer JM , Chen L , Dalton S , Niemuth NA , Sabourin CL , Quinn CP . Vaccine 2015 33 (31) 3709-16 Anthrax vaccine adsorbed (AVA, BioThrax(R)) 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. |
Comprehensive analysis and selection of anthrax vaccine adsorbed immune correlates of protection in rhesus macaques
Chen L , Schiffer JM , Dalton S , Sabourin CL , Niemuth NA , Plikaytis BD , Quinn CP . Clin Vaccine Immunol 2014 21 (11) 1512-20 Humoral and cell mediated immune correlates of protection (COP) for inhalation anthrax in a rhesus macaque (Macaca mulatta) model were determined. Immunological and survival data were from 114 vaccinated and 23 control animals exposed to Bacillus anthracis spores at 12, 30 or 52 months after the first vaccination. Vaccinated animals received a 3-dose intramuscular priming series (0, 1, 6 months; 3-IM) of anthrax vaccine adsorbed (AVA, BioThrax). Immune responses were modulated by administering a range of vaccine dilutions. Together with vaccine dilution dose and the interval between first vaccination and challenge, each of 80 immune response variables to anthrax toxin protective antigen (PA) at every available study time point was analyzed as a potential COP by logistic regression penalized by Least Absolute Shrinkage and Selection Operator (LASSO) or elastic net. Anti-PA IgG at the last available time point before challenge ('Last') and lymphocyte stimulation index (SI) at months 2 and 6 were identified consistently as COP. Anti-PA IgG and lethal toxin neutralization activity (TNA) at month 6 and month 7 ('Peak') and the frequency of IFN-gamma secreting cells at month 6 also had statistically significant positive correlations with survival. The ratio of IL-4 mRNA to IFN-gamma mRNA at month 6 also had a statistically significant correlation with survival. TNA had lower COP accuracy than anti-PA IgG. Following 3-IM priming with AVA, the anti-PA IgG responses at the time of exposure or at month 7 were practicable and accurate metrics for correlating vaccine induced immunity with protection against inhalation anthrax. |
Detection of anthrax protective antigen (PA) using europium labeled anti-PA monoclonal antibody and time-resolved fluorescence
Stoddard RA , Quinn CP , Schiffer JM , Boyer AE , Goldstein J , Bagarozzi DA , Soroka SD , Dauphin LA , Hoffmaster AR . J Immunol Methods 2014 408 78-88 Inhalation anthrax is a rare but acute infectious disease following adsorption of Bacillus anthracis spores through the lungs. The disease has a high fatality rate if untreated, but early and correct diagnosis has a significant impact on case patient recovery. The early symptoms of inhalation anthrax are, however, non-specific and current anthrax diagnostics are primarily dependent upon culture and confirmatory real-time PCR. Consequently, there may be a significant delay in diagnosis and targeted treatment. Rapid, culture-independent diagnostic tests are therefore needed, particularly in the context of a large scale emergency response. The aim of this study was to evaluate the ability of monoclonal antibodies to detect anthrax toxin proteins that are secreted early in the course of B. anthracis infection using a time-resolved fluorescence (TRF) immunoassay. We selected monoclonal antibodies that could detect protective antigen (PA), as PA83 and also PA63 and LF in the lethal toxin complex. The assay reliable detection limit (RDL) was 6.63 x 10-6muM (0.551ng/ml) for PA83 and 2.51 x 10-5muM (1.58ng/ml) for PA63. Despite variable precision and accuracy of the assay, PA was detected in 9 out of 10 sera samples from anthrax confirmed case patients with cutaneous (n=7), inhalation (n=2), and gastrointestinal (n=1) disease. Anthrax Immune Globulin (AIG), which has been used in treatment of clinical anthrax, interfered with detection of PA. This study demonstrates a culture-independent method of diagnosing anthrax through use of monoclonal antibodies to detect PA and LF in the lethal toxin complex. |
Quantitative assessment of anthrax vaccine immunogenicity using the dried blood spot matrix
Schiffer JM , Maniatis P , Garza I , Steward-Clark E , Korman LT , Pittman PR , Mei JV , Quinn CP . Biologicals 2012 41 (2) 98-103 The collection, processing and transportation to a testing laboratory of large numbers of clinical samples during an emergency response situation present significant cost and logistical issues. Blood and serum are common clinical samples for diagnosis of disease. Serum preparation requires significant on-site equipment and facilities for immediate processing and cold storage, and significant costs for cold-chain transport to testing facilities. The dried blood spot (DBS) matrix offers an alternative to serum for rapid and efficient sample collection with fewer on-site equipment requirements and considerably lower storage and transport costs. We have developed and validated assay methods for using DBS in the quantitative anti-protective antigen IgG enzyme-linked immunosorbent assay (ELISA), one of the primary assays for assessing immunogenicity of anthrax vaccine and for confirmatory diagnosis of Bacillus anthracis infection in humans. We have also developed and validated high-throughput data analysis software to facilitate data handling for large clinical trials and emergency response. |
Anthrax vaccine-induced antibodies provide cross-species prediction of survival to aerosol challenge
Fay MP , Follmann DA , Lynn F , Schiffer JM , Stark GV , Kohberger R , Quinn CP , Nuzum EO . Sci Transl Med 2012 4 (151) 151ra126 Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's kappa ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans. |
A two-stage, multilevel quality control system for serological assays in anthrax vaccine clinical trials
Soroka SD , Schiffer JM , Semenova VA , Li H , Foster L , Quinn CP . Biologicals 2010 38 (6) 675-83 A two-stage, multilevel assay quality control (QC) system was designed and implemented for two high stringency QC anthrax serological assays; a quantitative anti-PA IgG enzyme-linked immunosorbent assay (ELISA) and an anthrax lethal toxin neutralization activity (TNA) assay. The QC system and the assays were applied for the congressionally mandated Centers for Disease Control and Prevention (CDC) Phase 4 human clinical trial of anthrax vaccine adsorbed (AVA, BioThrax). A total of 57,284 human serum samples were evaluated by anti-PA enzyme-linked immunosorbent assay (ELISA) and 11,685 samples by anthrax lethal toxin neutralization activity (TNA) assay. The QC system demonstrated overall sample acceptance rates of 86% for ELISA and 90% for the TNA assays respectively. Monitoring of multiple assay and test sample variables showed no significant long term trends or degradation in any of the critical assay reagents or reportable values for both assays. Assay quality control data establish the functionality of the quality control system and demonstrates the reliability of the serological data generated using these assays. |
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