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•AV7909 is a combination of BioThrax® (Anthrax Vaccine Absorbed) and CPG 7909 adjuvant.•AV7909 vaccine is being developed for anthrax post-exposure prophylaxis.•The safety and immunogenicity of 2 doses and 3 vaccine schedules were evaluated.•Immunogenicity results indicate further study of a two dose schedule is warranted.•Both doses and all vaccine schedules were well tolerated. AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax® (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1–2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2–4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.

GC1109, a novel recombinant protective antigen (PA) anthrax vaccine, has demonstrated promising immunogenicity in previous dose-finding trials. This study evaluated the immunogenicity and safety of four intramuscular doses of GC1109 in healthy adults. This randomized, double-blind, placebo-controlled phase 2 trial enrolled healthy volunteers aged 19 to 65 years. Participants were assigned in a 3: 1 ratio to receive either GC1109 (1.0 mL) or placebo at weeks 0, 4, 8, and 32. Immunogenicity was assessed using toxin neutralization antibody (TNA) titers and anti-PA IgG levels. The primary endpoint was the proportion of vaccine recipients achieving a TNA 50 % neutralization factor (NF50) ≥ 0.56 at week 36. Safety was evaluated through solicited and unsolicited adverse events (AEs). All participants in the GC1109 group achieved TNA NF50 ≥ 0.56 at week 36 (100 %, 95 % confidence interval: 97.6–100.0) and the predefined criterion for the primary endpoint was met. TNA and anti-PA IgG levels peaked at week 36 but declined thereafter. Pruritus was the only solicited AE significantly more frequent in the GC1109 group; serious AEs were rare and unrelated to vaccination. Four doses of GC1109 were immunogenic and generally well-tolerated. Further studies are needed to explore appropriate boosting strategies and evaluate safety in larger populations.

This double-blinded randomized Phase 3 study evaluated the immunogenicity and safety of CYFENDUS® vaccine (AV7909; Anthrax Vaccine Adsorbed, Adjuvanted) to support licensure for post-exposure prophylaxis following suspected or confirmed Bacillus anthracis exposure when administered with the recommended antibacterial drugs. Healthy adult participants (n = 3689) aged 18 to 65 were randomized to receive CYFENDUS vaccination (intramuscularly at 0, 2 weeks) or BioThrax® (Anthrax Vaccine Absorbed) [subcutaneously at 0, 2, 4 weeks]. Immunogenicity at Day 64 (seven weeks after the last CYFENDUS vaccine dose; five weeks after the last BioThrax vaccine dose) was evaluated using a 50 % neutralizing factor (NF50) threshold of protective immunogenicity generated by a toxin neutralizing antibody (TNA) assay, and by evaluating non-inferiority of CYFENDUS to BioThrax vaccination. Safety was assessed by physical exams, vital signs, solicited local injection site and systemic reactogenicity, and unsolicited adverse events (AEs). The prospectively defined success criteria were met for the primary immunogenicity endpoints. The lower bound of the two-sided 95 % confidence interval (CI) for the proportion of CYFENDUS participants with TNA NF50 ≥ 0.56 was above the pre-defined criterion of ≥40 % (95 % CI: 64.5 %, 68.1 %). The lower bound of the two-sided 95 % CI of the difference in the proportion of participants with TNA NF50 ≥ 0.29 in the CYFENDUS versus the BioThrax vaccine group was greater than the pre-defined non-inferiority criterion of −15 % as well as demonstrating statistical superiority (95 % CI: 20.0, 29.2 %), a closed hypothesis test supported by regulatory agencies in well-controlled clinical trials. The most common adverse events (AE) were injection site-related; most reported solicited reactogenicities and AEs were either Grade 1 or 2 severity. The study met the pre-defined endpoint criteria, demonstrating protective level of immune response and non-inferiority of CYFENDUS to BioThrax vaccination. The CYFENDUS vaccine was well-tolerated in healthy adults. Trial Registration:ClinicalTrials.gov Identifier: NCT03877926 •CYFENDUS has comparable safety profile to Anthrax Vaccine Absorbed (BioThrax) in healthy adults•CYFENDUS achieved protective antibody levels up to seven weeks after second vaccination•CYFENDUS-elicited immune response was non-inferior to that of BioThrax•Equivalent immunogenicity was observed across three consecutively manufactured CYFENDUS vaccine lots

Immunization with BioThrax® (Anthrax Vaccine Adsorbed) is a safe and effective means of preventing anthrax. Animal studies have demonstrated that the addition of CpG DNA adjuvants to BioThrax can markedly increase the immunogenicity of the vaccine, increasing both serum anti-protective antigen (PA) antibody and anthrax toxin-neutralizing antibody (TNA) concentrations. The immune response to CpG-adjuvanted BioThrax in animals was not only stronger, but was also more rapid and led to higher levels of protection in spore challenge models. The B-class CpG DNA adjuvant CPG 7909, a 24-base synthetic, single-strand oligodeoxynucleotide, was evaluated for its safety profile and adjuvant properties in a Phase 1 clinical trial. A double-blind study was performed in which 69 healthy subjects, age 18–45 years, were randomized to receive three doses of either: (1) BioThrax alone, (2) 1mg of CPG 7909 alone or (3) BioThrax plus 1mg of CPG 7909, all given intramuscularly on study days 0, 14 and 28. Subjects were monitored for IgG to PA by ELISA and for TNA titers through study day 56 and for safety through month 6. CPG 7909 increased the antibody response by 6–8-fold at peak, and accelerated the response by 3 weeks compared to the response seen in subjects vaccinated with BioThrax alone. No serious adverse events related to study agents were reported, and the combination was considered to be reasonably well tolerated. The marked acceleration and enhancement of the immune response seen by combining BioThrax and CPG 7909 offers the potential to shorten the course of immunization and reduce the time to protection, and may be particularly useful in the setting of post-exposure prophylaxis.

•AV7909 was safe and immunogenic when administered IM on Days 0 and 14.•AV7909 elicited a greater TNA response than BioThrax after 2 IM doses.•No significant difference was seen in immunogenicity of four AV7909 formulations.•Immunogenicity and reactogenicity of AV7909 will be studied further. A new anthrax vaccine that could accelerate the immune response and possibly reduce the number of injections needed for protection would be desirable in a post-exposure setting. This Phase 1 study compared the safety and immunogenicity of 2 IM doses (Days 0 and 14) of 4 formulations of AV7909 (AVA plus CPG 7909) with 2 IM doses of BioThrax® (Anthrax Vaccine Adsorbed) and 2 IM doses of saline placebo administered on Days 0 and 14. A total of 105 healthy adults 18–50 years of age were randomized to 1 of 6 study groups: BioThrax (0.5mL), AV7909 Formulation 1 (0.5mL AVA+0.5mg CPG 7909), AV7909 Formulation 2 (0.5mL AVA+0.25mg CPG 7909), AV7909 Formulation 3 (0.25mL AVA+0.5mg CPG 7909), AV7909 Formulation 4 (0.25mL AVA+0.25mg CPG 7909), or saline placebo (0.5mL). All randomized subjects received at least 1 vaccination, and 100 subjects completed the trial. After 2 doses, mean peak normalized toxin neutralizing antibody responses (TNA NF50) in the AV7909 groups were higher than in the BioThrax group. Differences among the 4 AV7909 groups were not statistically significant. Subjects who received AV7909 reached peak titers on Day 28 vs. Day 35 in the BioThrax group. The most common adverse events (AEs) in the BioThrax and AV7909 groups assessed as related to vaccination were injection site reactions. Transient lymphopenia was observed after the first dose in each AV7909 group. Frequencies of injection site and systemic reactions recorded by subjects in diaries for 7 days after each injection were highest with AV7909 Formulation 1. No AEs of special interest (autoimmune events) were observed in the study. Further studies of doses and dosing regimens are planned to assess the immunogenicity and reactogenicity of AV7909.

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.

CYFENDUS® vaccine (Anthrax Vaccine Adsorbed, Adjuvanted) with the recommended antibacterial drugs is licensed for post-exposure prophylaxis (PEP) following suspected or confirmed Bacillus anthracis exposure. This pre-licensure study examined potential interaction of CYFENDUS vaccine with ciprofloxacin and doxycycline when administered concomitantly. In this Phase 2, open-label study, healthy adult participants (18 to 45 years of age; n = 210) were randomized to receive either ciprofloxacin+CYFENDUS vaccine, doxycycline+CYFENDUS vaccine, or CYFENDUS vaccine only. Pharmacokinetic (PK) parameters of antibacterials such as steady-state maximum concentration (Cmax) and area under the curve from 0 to 12 h (AUC0-12h) were assessed. Immunogenicity of the vaccine was evaluated using 50 % neutralizing factor (NF50) values generated by toxin neutralizing antibody (TNA) assay. Solicited reactogenicity and adverse events (AEs) were collected for safety evaluation. The PK endpoint was met for ciprofloxacin. The vaccine had no effect on PK with 90 % confidence intervals (CIs) of the mean ratios for AUC0-12h [90 % CI: 0.8895,1.0718] and Cmax [90 % CI: 0.8693,1.0838] contained within the predefined equivalence criteria [0.80, 1.25]. The PK endpoint was not met for doxycycline, wherein the 90 % of the mean ratios for AUC0-12h [90 % CI: 0.8187,1.0278] was within the equivalence criteria, but the lower bound of the 90 % CI for Cmax [90 % CI: 0.7841,1.0271] was below the equivalence limits [0.80, 1.25]; this impact on Cmax may be negligible to the extent that doxycycline efficacy is correlated with AUC. The immunogenicity endpoint was met, wherein the lower bound 95 % CIs for geometric mean ratio of TNA NF50 for the vaccine with ciprofloxacin (0.78) or doxycycline (0.81) to vaccine alone were above the non-inferiority margin (0.5). Most solicited reactogenicities and AEs were Grade 1 or 2 in severity. CYFENDUS vaccination with or without ciprofloxacin or doxycycline had an acceptable safety profile and co-administration did not affect the relevant PK and immunogenicity parameters. ClinicalTrials.gov Identifier: NCT04067011

•BioThrax® Plus CPG 7909 (0.25mg) in 2 vaccinations was sufficient to induce IFNγ+ cells.•IP-10 is a successful serum marker of CPG 7909 in vaccines delivered intramuscularly.•Absolute lymphocyte count was confirmed as a marker of CPG 7909 in this vaccine.•A pool of HLA class II PA-derived peptides were suitable T cell recall antigens.•CPG 7909 was confirmed to increase antigen-specific humoral immunity. NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24–48h after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALCs), correlated with transiently increased IP-10. Cellular recall responses to anthrax protective antigen (PA) or PA peptides were assessed by IFN-γ ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48h (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

Bacillus anthracis is a deadly pathogen that under unfavourable conditions forms highly resistant spores which enable them to survive for a long period of time. Spores of B. anthracis are transmitted through the contaminated soil or animal products and enter to the host through the skin, lungs or oral route and can cause cutaneous, injection, inhalation and gastrointestinal anthrax, respectively. The disease is caused by the toxin which is produced by them once they germinate within the host cell. Anthrax toxin is the major virulence factor which has the ability to kill the host cell. The role of protein kinases and phosphatases of B. anthracis in toxin production and other virulence related properties have also been reported. There are two vaccines, BioThrax and CYFENDUSTM, which are approved by the FDA-USA to prevent anthrax disease. Recently, anthrax toxin has also been shown to be a potential candidate for cancer therapeutics. Through present review, we aim to provide insights into sporulation, transmission and pathogenesis of B. anthracis as well as the current state of its prevention, treatment, vaccines and possible therapeutic uses in cancer.