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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

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