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BioThrax

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BioThrax

CLINICAL PHARMACOLOGY

Mechanism of Action

Anthrax is a zoonotic disease caused by the gram-positive, spore-forming bacterium Bacillus anthracis. The spore form of Bacillus anthracis is the predominant phase of the bacterium in the environment and anthrax disease is contracted largely through the uptake of spores. Spores are markedly resistant to heat, cold, drought, UV light, and gamma radiation. Following germination at the site of infection, the bacilli can also enter the blood and lead to septicemia.

Virulence components of Bacillus anthracis include an antiphagocytic polypeptide capsule and three proteins known as protective antigen (PA), lethal factor (LF) and edema factor (EF). Individually these proteins are not cytotoxic but the combination of PA with LF or EF results in the formation of the cytotoxic lethal toxin and edema toxin, respectively. Although an immune correlate of protection is unknown, antibodies raised against PA may contribute to protection by neutralizing the activities of these toxins.3 Bacillus anthracis proteins other than PA may be present in BioThrax (anthrax vaccine adsorbed emergent biosolutions) , but their contribution to protection has not been determined.

Clinical Studies

A controlled field study using an earlier version of a protective antigen-based anthrax vaccine, developed in the 1950's, that consisted of an aluminum potassium sulfate-precipitated cell-free filtrate from an aerobic culture, was conducted from 1955-1959.4 This study included 1,249 workers [379 received anthrax vaccine, 414 received placebo, 116 received incomplete inoculations (with either vaccine or placebo) and 340 were in the observational group (no treatment)] in four mills in the northeastern United States that processed imported animal hides. Prior to vaccination, the yearly average number of human anthrax cases (both cutaneous and inhalational) was 1.2 cases per 100 employees in these mills. During the trial, 26 cases of anthrax were reported across the four mills – 5 inhalation and 21 cutaneous. Of the five inhalation cases (four of which were fatal), two received placebo and three were in the observational group. Of the 21 cutaneous cases, 15 received placebo, three were in the observational group, and three received anthrax vaccine. Of those three cases in the vaccine group, one case occurred just prior to administration of the scheduled third dose, one case occurred 13 months after an individual received the third of the scheduled 6 doses (but no subsequent doses), and one case occurred prior to receiving the scheduled fourth dose of vaccine. Because the comparison of anthrax cases between the placebo and vaccine groups included both inhalation and cutaneous cases, the calculated efficacy of the vaccine to prevent all types of anthrax disease combined was 92.5% (lower 95% CI = 65%). The efficacy analysis in this study included all cases of anthrax disease, regardless of the route of exposure or manifestation of the disease.

Between 1962 and 1974, the Centers for Disease Control and Prevention (CDC) collected surveillance data on the occurrence of anthrax disease in mill workers or those living near mills in the United States.5, 6 In that time period, individuals received either BioThrax or the earlier protective antigen-based anthrax vaccine used in the field trial described above. Of the 27 cases of anthrax identified by CDC, 24 cases occurred in unvaccinated individuals. In vaccinated individuals one case occurred after the person had been given one dose of anthrax vaccine and two cases occurred after individuals had been given two doses of anthrax vaccine. No documented cases of anthrax were reported for individuals who had received at least three doses of the recommended six doses of anthrax vaccine.

Between 2002 and 2008, the CDC sponsored a prospective double-blinded, randomized, placebo-controlled study to evaluate the impact on safety and immunogenicity of changing the administration route from SQ to IM, and reducing the number of doses (i.e. omitting the week 2 dose) [NCT00119067]. This study enrolled a total of 1,564 healthy civilian men and women between the ages of 18 and 61. Subjects were randomized to one of six groups. A planned analysis of the first 1005 subjects enrolled with 7 month follow-up was conducted to compare safety and immunogenicity of study groups at Week 8 (four weeks after the Week-4 dose) and Month 7 (one month after the Month-6 dose). These designations are used when referring to the data analyses of study groups:

Group A (N=165) received BioThrax (anthrax vaccine adsorbed emergent biosolutions) via the SQ route of administration at Weeks 0, 2, 4 and Months 6, 12, 18 followed by 2 annual boosters (initial U.S. licensed route/schedule). Group A served as the active control in this study.

Group B (N=170) received BioThrax (anthrax vaccine adsorbed emergent biosolutions) via the IM route of administration at Weeks 0, 2, 4 and Months 6, 12, 18 followed by 2 annual boosters.

Group C (N=501) received BioThrax (anthrax vaccine adsorbed emergent biosolutions) via the IM route of administration at Weeks 0, 4 (no Week 2 dose) and Month 6 with various schedules thereafter. (Group C represents data from 3 randomized groups combined for the analysis because the schedules are identical through the Month 6 dose.)

The placebo group (N=169) received saline administered by the IM or SQ route, respectively, using the Weeks 0, 2, 4 and Months 6, 12, 18 schedule, followed by 2 annual boosters.

Immune responses were assessed using an ELISA and were reported as the serum geometric mean concentration (GMC) and geometric mean titers (GMT) of IgG antibodies directed against anthrax protective antigen (PA). Non-inferiority analyses of Group B vs. Group A and Group C vs. Group A were performed. The three immunogenicity endpoints were: (1) Geometric Mean Concentration (GMC) (µg/mL), (2) Geometric Mean Titer (GMT), and (3) percentage with 4-fold rise in anti-PA titer from baseline. These immunogenicity endpoints were assessed at the Week 8 and Month 7 time points. Group B (IM route) was shown to be non-inferior to Group A (SQ route) for all 3 primary endpoints at the Week 8 and Month 7 time points (Tables 5 and 6). Group C (abbreviated IM route) at the Week 8 time point (Table 7) was shown to be non-inferior to Group A for the percentage with 4-fold rise in titer but not non-inferior to Group A for GMCs and GMTs. However, by the Month 7 time point (Table 8). Group C was non-inferior to Group A for all 3 primary endpoints. The elimination of the Week 2 dose did not impact the immune response following the Month 6 vaccination.

The level of protection against Bacillus anthracis prior to completion of the full vaccination series is unknown.

In an exploratory subgroup analysis, a diminished immune response was noted in male subjects in Group B (IM route) at the 8 week time point compared to male subjects vaccinated via the SQ route (Group A). The diminished immune response in males was not, however, seen by 7 months (i.e. after the fourth dose of vaccine). At the 7 month time point, non-inferiority was observed between the IM and SQ routes in male subjects. A summary of the gender-by-treatment interaction findings for the three immunogenicity endpoints at the week 8 and month 7 time point is provided in Table 9.

Table 5: Immune Responses at Week 8 - Group A vs. Group B

Endpoint Group A BioThrax (anthrax vaccine adsorbed emergent biosolutions) SQ Weeks-0-2-4-26
N=153 point estimate
(2-sided 95% CI)
Group B BioThrax (anthrax vaccine adsorbed emergent biosolutions) IM Weeks 0-2-4-26
N=154 point estimate
(2-sided 95% CI)
Comparisons Non-Inferiority Criteria Passed?
      Ratios
(2-sided 97.5% CI)
1
Antibody Concentration GMC (µg/mL) 101.92
(88.34, 117.58)
87.78
(74.99, 102.76 )
1.161
(0.911, 1.480)
Yes*
Antibody Titer GMT 1250.12
(1079.55, 1447.63)
1080.96
(926.08, 1261.74)
1.156
(0.907, 1.475)
Yes**
      Difference of rates
(2-sided 97.5% CI)
 
Titer 4-fold increase frombaseline+ (Proportion of Responders) 98.69%
(95.36, 99.85 )
97.40%
(93.49, 99.30 )
0.013
(-0.031, 0.062)
Yes***
*Criteria for non-inferiority of comparisons based on ratios of GMCs: Mean antibody concentration ratio (GMCGroup A/GMCGroup B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
**Criteria for non-inferiority of comparisons based on ratios of GMTs: Mean antibody titer ratio (GMTGroup A/GMTGroup B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
***Criteria for non-inferiority of comparisons based on differences in rates of 4-fold rise in antibody titer: 4-fold rise in antibody titer (Group A – Group B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 0.10.
+Baseline values below LLOQ set to ½-empirical LLOQ to calculate post-vaccination 4-fold rise in titer.

Table 6: Immune Responses at Month 7 - Group A vs. Group B

Endpoint Group A BioThrax (anthrax vaccine adsorbed emergent biosolutions) SQ Weeks-0-2-4-26
N=139 point estimate
(2-sided 95% CI)
Group B BioThrax (anthrax vaccine adsorbed emergent biosolutions) IM Weeks 0-2-4-26
N=145 point estimate
(2-sided 95% CI)
Comparisons Non- Inferiority Criteria Passed?
      Ratios
(2-sided 97.5% CI)
 
Antibody Concentration GMC (µg/mL) 218.32
(187.52, 254.17 )
262.61
(228.81, 301.41)
0.831
(0.658, 1.050)
Yes*
Antibody Titer GMT 2614.95
(2251.57, 3036.98)
3065.95
(2678.19, 3509.86)
0.853
(0.678, 1.073)
Yes**
      Difference of rates
(2-sided 97.5% CI)
 
Titer 4-fold increase from baseline+ (Proportion of Responders) 99.28%
(96.06, 99.98)
100%
(97.49, 100.0 )
-0.007
(-0.048, 0.027)
Yes***
*Criteria for non-inferiority of comparisons based on ratios of GMCs: Mean antibody concentration ratio (GMCGroup A/GMCGroup B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
**Criteria for non-inferiority of comparisons based on ratios of GMTs: Mean antibody titer ratio (GMTGroup A/GMTGroup B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5. ***Criteria for non-inferiority of comparisons based on differences in rates of 4-fold rise in antibody titer: 4-fold rise in antibody titer (Group A – Group B). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 0.10.
+Baseline values below LLOQ set to ½-empirical LLOQ to calculate post-vaccination 4-fold rise in titer.

Table 7: Immune Responses at Week 8 – Group A vs. Group C

Endpoint Group A BioThrax (anthrax vaccine adsorbed emergent biosolutions) SQ Weeks-0-2-4-26
N=153 point estimate
(2-sided 95% CI)
Group C BioThrax (anthrax vaccine adsorbed emergent biosolutions) IM Weeks 0-4-26
N=446 point estimate
(2-sided 95% CI)
Comparisons Non- Inferiority Criteria Passed?
      Ratios
(2-sided 97.5% CI)
 
Antibody Concentration GMC (µg/mL) 101.92
(88.34, 117.58 )
54.21
(49.40, 59.50 )
1.880
(1.531, 2.308)
No*
Antibody Titer GMT 1250.12
(1079.55,1447.63)
662.09
(601.13, 729.23)
1.888
(1.527, 2.335)
No**
      Difference of rates
(2-sided 97.5% CI)
 
Titer 4-fold increase from baseline+ (Proportion of Responders) 98.69 %
(95.36, 99.85)
92.83%
(90.02, 95.04)
0.059
(0.014, 0.094)
Yes***
*Criteria for non-inferiority of comparisons based on ratios of GMCs: Mean antibody concentration ratio (GMCGroup A/GMCGroup C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
**Criteria for non-inferiority of comparisons based on ratios of GMTs: Mean antibody titer ratio (GMTGroup A/GMTGroup C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
***Criteria for non-inferiority of comparisons based on differences in rates of 4-fold rise in antibody titer: 4-fold rise in antibody titer (Group A – Group C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 0.10.
+ Baseline values below LLOQ set to ½-empirical LLOQ to calculate post-vaccination 4-fold rise in titer.

Table 8: Immune Responses at Month 7 - Group A vs. Group C

Endpoint Group A BioThrax (anthrax vaccine adsorbed emergent biosolutions) SQ Weeks-0-2-4-26
N=139 point estimate
(2-sided 95% CI)
Group C BioThrax (anthrax vaccine adsorbed emergent biosolutions) IM Weeks 0-4-26
N=410 point estimate
(2-sided 95% CI)
Comparisons Non-Inferiority Criteria Passed?
      Ratios
(2-sided 97.5% CI)
 
Antibody Concentration GMC (µg/mL) 218.32
(187.52, 254.17 )
258.13
(232.96, 286.02 )
0.846
(0.675, 1.059)
Yes*
Antibody Titer GMT 2614.95
(2251.57, 3036.98)
3087.00
(2785.20, 3421.51)
0.847
(0.676, 1.061)
Yes**
      Difference of rates
(2-sided 97.5% CI)
 
Titer 4-fold increase frombaseline+ (Proportion of Responders) 99.28%
(96.06,99.98)
99.27%
(97.88, 99.85)
0.000
(-0.041, 0.019)
Yes***
*Criteria for non-inferiority of comparisons based on ratios of GMCs: Mean antibody concentration ratio (GMCGroup A/GMCGroup C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
**Criteria for non-inferiority of comparisons based on ratios of GMTs: Mean antibody titer ratio (GMTGroup A/GMTGroup C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 1.5.
***Criteria for non-inferiority of comparisons based on differences in rates of 4-fold rise in antibody titer: 4-fold rise in antibody titer (Group A – Group C). Non-inferiority is achieved (passed) when the upper 97.5% confidence limit is ≤ 0.10.
+ Baseline values below LLOQ set to ½-empirical LLOQ to calculate post-vaccination 4-fold rise in titer.

Table 9: Immune Response by Gender: Group A (SQ) vs. Group B (IM)

Immunogenicity Endpoints Group A BioThrax SQ Weeks-0-2-4-26 Group B BioThrax IM Weeks 0-2-4-26 Ratio (of GMCs, GMTs) or Difference (of rates of 4-fold rise) 2-sided 97.5% CIs of ratios of GMCs, GMTs, or 2-sided 97.5% CI of Difference of rates of 4-fold rise
  N
(Point Estimate) (95% Cl)
N
(Point Estimate) (95% Cl)
  Lower Limit Upper Limit
Antibody Concentration GMC (µg/ml): Males: week 8 7994.41
(79.43, 112.21)
7369.54
(52.92, 91.37)
Ratio of GMCs 1.358 0.946 1.949
Log Antibody Concentration GMC (µg/ml): Males: month 7 70216.66
(177.89, 263.87)
68263.11
(210.39, 329.05)
Ratio of GMCs 0.823 0.587 1.155
Antibody Concentration GMC (µg/ml): Females: week 8 74110.59
(87.52, 139.74)
81108.29
(91.96, 127.51)
Ratio of GMCs 1.021 0.742 1.406
Antibody Concentration GMC (µg/ml): Females: month 7 69220.01
(173.56, 278.90)
77262.17
(220.47, 311.76)
Ratio of GMCs 0.839 0.604 1.166
Antibody Titer GMT: Males: week 8 791159.35
(974.45, 1379.34)
73873.23
(670.54, 1137.19)
Ratio of GMTs 1.328 0.932 1.892
Antibody Titer GMT: Males: month 7 702586.05
(2128.41, 3142.09)
683093.38
(2484.02, 3852.21)
Ratio of GMTs 0.836 0.599 1.166
Antibody Titer GMT: Females: week 8 741354.88
(1062.53, 1727.66)
811310.19
(1108.37, 1548.76)
Ratio of GMTs 1.034 0.743 1.439
Antibody Titer GMT: Females: month 7 692644.60
(2095.66, 3337.32)
773041.94
(2566.20, 3605.87)
Ratio of GMTs 0.869 0.630 1.201
4-fold rise in Titer (Proportion of responders): Males: week 8 79100%
(95.44, 100.00)
7394.52%
(86.56, 98.51)
0.055 -0.007 0.148
4-fold rise in Titer (Proportion of responders): Males: month 7 70100%
(94.87, 100.00)
68100%
(94.72, 100.00)
0.000 -0.067 0.069
4-fold rise in Titer (Proportion of responders): Females: week 8 7497.30%
(90.58, 99.69)
81100%
(95.55, 100.0)
-0.027 -0.108 0.033
4-fold rise in Titer (Proportion of responders): Females: Month 7 6998.55%
(92.20, 99.96)
77100%
(95.32, 100.00)
-0.014 -0.093 0.048
Criteria for non-inferiority based on the ratio of GMCs and GMTs and differences in the rate of 4-fold rise in antibody titer. Mean antibody concentration ratio (GMCGroup A/GMCGroup B): Non-inferiority criteria met when the upper 97.5% confidence limit is ≤ 1.5
Mean antibody titer ratio (GMTGroup A/GMTGroup B): Non-inferiority criteria met when the upper 97.5% confidence limit is ≤ 1.5 4-fold rise in antibody titer (Group A)-(Group B): Non-inferiority criteria met when the upper 97.5% confidence limit is ≤ 0.10.

REFERENCES

1. Ryan, M.A.D., et al. 2008. Birth defects among infants born to women who received anthrax vaccine in pregnancy. Am J Epidimiol, 168:434-442.

2. Catherino, W., et al., 2005. The anthrax vaccine does not affect semen parameters, embryo quality, or pregnancy outcome in couples with a vaccinated male military service member. Fertility and Sterility, 83:480-483

3. Brachman, P.; Friedlander, A.; Grabenstein, J., 2008. Anthrax Vaccine. In: Vaccines, Fifth Edition, Plotkin, S.A.: Orenstein W.A. and Offit P.A. (eds.), 111-126

4. Brachman, P., et al., 1962. Field evaluation of a human anthrax vaccine. Amer. J. Public Health, 52:632-645.

5. Food and Drug Administration, 2005, Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review; Anthrax Vaccine Adsorbed; Final Order. FDA Federal Register 2005; 70(242): 75180-75198.

6. Food and Drug Administration. Biological Products; Bacterial vaccines and toxoids; Implementation of efficacy review. Federal Register (December 13, 1985), 50(240):51002-51117.

Last reviewed on RxList: 10/28/2009
This monograph has been modified to include the generic and brand name in many instances.

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