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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.

•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.

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

•The anti-PA IgG antibody response and B. anthracis lethal toxin neutralization activity of a cohort delayed as long as 7 years in receiving an anthrax vaccine dose was robust and non-inferior to the responses of the on-schedule cohort.•Non-inferiority of anti-PA IgG antibody levels and B. anthracis lethal toxin neutralization activity persisted until the next dose.•Racial categories “African American or Black” and “Asian or Pacific Islander” had lower anti-PA IgG antibody levels than “Whites”. The clinical relevance of this finding is unknown.•Although there were differences in anti-PA IgG antibody response and B. anthracis lethal toxin neutralization activity by age and gender, these differences were not statistically significant in this study. Whether to restart or continue the series when anthrax vaccine doses are missed is a frequent medical management problem. We applied the noninferiority analysis model to this prospective study comparing the Bacillus anthracis protective antigen (PA) IgG antibody response and lethal toxin neutralization activity at day 28 to the anthrax vaccine adsorbed (AVA) (Biothrax®) administered on schedule or delayed. A total of 600 volunteers were enrolled: 354 in the on-schedule cohort; 246 in the delayed cohort. Differences were noted in immune responses between cohorts (p<0.0001) and among the racial categories (p<0.0001). Controlling for covariates, the delayed cohort was non-inferior to the on-schedule cohort for the rate of 4-fold rise in both anti-PA IgG concentration (p<0.0001) and TNA ED50 titers (p<0.0001); as well as the mean log10-transformed anti-PA IgG concentration (p<0.0001) and the mean log10-transformed TNA ED50 titers (p<0.0001). Providing a missed AVA dose after a delay as long as 5–7 years, elicits anti-PA IgG antibody and TNA ED50 responses that are robust and non-inferior to the responses observed when the 6-month dose is given on-schedule. These important data suggest it is not necessary to restart the series when doses of the anthrax vaccine are delayed as long as 5 or more years.

•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. We describe the Bacillus anthracis protective antigen IgG antibody response and the B. anthracis lethal toxin neutralization activity to a delayed dose of anthrax vaccine adsorbed (AVA, BioThrax®) using validated assays. 373 individuals received 1, 2, or 3 priming doses, 18–24 months afterward, they received a delayed dose of AVA. Overall, 23.6% of subjects showed detectable anti-PA IgG before the boost, compared to 99.2% (P<0.0001) 28 days after the boost. Geometric mean anti-PA IgG concentration (GMC) was 1.66μg/mL before and 887.82μg/mL after the boost (P<0.0001). The proportion of individuals with four-fold increase in GMC following the boost ranged from 93.8% to 100%. Robust anti-PA IgG levels and B. anthracis lethal toxin neutralization activity are induced when an AVA dose is delayed as long as two years. These data support continuing with the vaccination schedule when a dose is delayed as long as two years rather than restarting the series.

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.

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.

•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.

•Correlates of protection were identified from NHP B. anthracis challenge studies.•The most accurate correlates have been used to predict protection in vaccinated humans.•Results predict high levels of protection from current and potential reduced booster schedules.•The three dose priming series with no additional boosters provided 86.8% predicted survival at 3 years. 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.

•BioThrax was well tolerated.•The primary success criterion at Day 63 was met.•Key secondary success criteria at Day 70 and Days 63–100 were met. This study was conducted to support licensure of a post-exposure prophylaxis indication for BioThrax® (anthrax vaccine adsorbed) concurrent with antimicrobials for individuals exposed to aerosolized anthrax spores. The immunogenicity and safety of a three-dose regimen (0, 2, and 4 weeks) of BioThrax administered subcutaneously (SC) were evaluated in 200 healthy adults 18–65 years of age. Toxin-neutralizing antibody (TNA) was expressed as 50% neutralization factor (NF50) at predetermined time points through Day 100. Safety was assessed by physical examinations, vital signs, solicited local and systemic reactions using web-enabled subject diaries, in-clinic solicited reactions, and unsolicited adverse events (AEs). The prospectively defined success criteria for the primary and secondary endpoints were met. This required the lower bound of the 95% confidence interval (CI) for the proportion of subjects with a TNA NF50 value to be greater than 40% at Day 63 (primary), Day 70 (secondary) and Days 63–100 (secondary). At Day 63, 71% of subjects achieved a TNA NF50 threshold value ≥0.56, with a lower bound of the 95% CI ≥40% (64%). The percentage of subjects achieving a TNA NF50 threshold value ≥0.56 at Day 70 was 58% (95% CI: 50%, 65%), and the mean value on Days 63–100 (inclusive) was 53% (95% CI: 41%, 55%). The threshold TNA NF50 value of 0.56 was developed from previous rabbit challenge and human immunogenicity studies. No related serious AEs occurred during the study, and no subjects withdrew from the study because of an AE. Tenderness and pain at the injection site were recorded most often in subject diaries following vaccination. BioThrax, administered as three SC doses at 0, 2, and 4 weeks, was well tolerated. The prospectively defined success criteria for TNA levels on Days 63, 70, and 63–100 were achieved.