June 28, 2016
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BioThrax

"FLUAD Pediatric™/FLUAD® is a trivalent, surface antigen, inactivated influenza virus vaccine adjuvanted with MF59C.1.

The influenza virus strains are individually grown in the allantoic cavity of embryonated hens' eggs inocula"...

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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. Although an immune correlate of protection is unknown, BioThrax induces antibodies raised against PA, which may contribute to protection by neutralizing the activities of the cytotoxic lethal toxin and edema toxin of Bacillus anthracis.3 Bacillus anthracis proteins other than PA may be present in BioThrax, 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 and supplied by G. G. Wright and associates of the U.S. Army Chemical Corps, Fort Detrick, Frederick, MD, 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. The anthrax vaccine was administered subcutaneously at 0, 2, 4 weeks, 6, 12, 18 months. 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. The calculated efficacy of the vaccine to prevent all types of anthrax disease, regardless of the route of exposure or clinical manifestations, was 92.5% (lower 95% CI = 65%).

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 reported cases of anthrax, 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 originally licensed six-dose series of anthrax vaccine.

Between 2002 and 2007, a prospective double-blinded, randomized, placebo-controlled and active-controlled study was conducted to evaluate the impact on safety and immunogenicity on changing the administration route from SC to IM, and reducing the number of doses [NCT00119067]. This study enrolled 1,564 healthy civilian men and women between the ages of 18 and 61. A total of 1,563 subjects received at least one dose (one subject withdrew consent prior to the first injection). Subjects were randomized to one of six groups. See Table 1.

Using an ELISA, IgG antibodies directed against anthrax protective antigen (PA) were measured at the Week 8 and Months 7, 13, 19, 31, and 43 time points. The three primary immunogenicity endpoints were: (1) Geometric Mean Concentration (GMC) (mcg/mL), (2) Geometric Mean Titer (GMT), and (3) percentage with 4-fold rise in anti-PA antibody titer from baseline.

The criteria for non-inferiority of comparisons based on ratios of GMCs and GMTs and differences in the rates of 4-fold rise in antibody titer were defined as follows:

Mean antibody concentration ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 1.5

Mean antibody titer ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 1.5

4-fold rise in antibody titer: non-inferiority was achieved when the upper bound of the 95% confidence limit was < 0.10

To compare the originally licensed 6-dose SC schedule (0, 2, 4 weeks and 6, 12, and 18 months) versus a 3-dose IM primary series (at 0, 1, and 6 months), non-inferiority analyses were performed for all three primary immunogenicity endpoints. This evaluation compared the immune response at Month 7 for Group C (COM, where COM is Combined, as described in 6.1) to Month 19 for Group A (TRT-8SC, where TRT is Treatment) and Group B (TRT-8IM). Non-inferiority was demonstrated for all analyses (See Table 3). These results support a 3 dose primary series of BioThrax administered IM at 0, 1 and 6 months, followed by booster doses at 12 and 18 months and at 1-year intervals thereafter to maintain protective immunity.

The Month 7 antibody levels of Group A (TRT-8SC) were non-inferior to Month 13 and 19 antibody levels after a 0, 2, 4 week and 6 month primary SC series followed by SC booster injections at 12 and 18 months (see Table 3). These results support a 4 dose SC primary series of BioThrax administered at weeks 0, 2, 4, and at 6 months followed by booster doses at 12 and 18 months after initiation of the series, and at 1-year intervals thereafter to maintain protective immunity.

Catch up Administration for Delayed or Missed Doses

In subjects who did not receive booster doses at 12, 18 and 30 months, PA antibody levels decline over time following the third dose of BioThrax administered intramuscularly at 6 months (Group F; 4IM; 0, 1, 6, and 42 months). In the absence of booster doses it is not known whether these individuals are adequately protected between 12 months and receipt of a booster dose at 42 months. One month following a dose of BioThrax at 42 months the immune response for Group F met the criteria for non-inferiority relative to Group A (8SC) for all three primary immunogenicity endpoints (see Table 3). The optimal schedule for further intramuscular booster doses among persons administered a single booster dose at 42 months following completion of a three-dose primary series at 0, 1, and 6 months is not known.

Table 3: Primary Immunogenicity Endpoints (According to Protocol†)

  Week 4 Week 8 Month 7 Month 13 Month 19 Month 31 Month 43
Anti-PA Specific IgG GMC, mcg/mL
  n GMC 95%CI n GMC 95%CI n GMC 95%CI n GMC 95%CI n GMC 95%CI n GMC 95%CI n GMC 95%CI
TRT-8SC 242 235 219 203 190 167 144
Group A 49.72 94.29 201.14 201.67 193.45 250.07 216.83
  (43.32, 57.06) (82.08, 108.31) (174.71, 231.56) (174.77, 232.71) (167.29, 223.69) (215.38, 290.34) (185.80, 253.05)
TRT-7IM*       203 192 169 139
Group D       229.86 (203.20, 260.02) 204.95 (180.82, 232.29) 263.13 (231.09, 299.61) 254.80 (222.03, 292.40)
TRT-5IM* 723 698 636 399 174 153 141
Group E 2.63 (2.39, 2.89) 46.39 (42.18, 51.01) 206.09 (187.14, 226.96) 28.64 (25.79, 31.81) 293.60 (258.30, 333.73) 33.68 (29.48, 38.48) 310.02 (270.49, 355.33)
TRT-4IM* Group F         193 179 157
13.71 (12.11, 15.53) 7.80 (6.87, 8.86) 433.20 (379.58, 494.40)
Anti-PA Specific IgG GMT
  n n n n n n n
  GMT GMT GMT GMT GMT GMT GMT
  95% CI 95% CI 95% CI 95% CI 95% CI 95% CI 95% CI
TRT-8SC 242 235 219 203 190 167 144
Group A 565.16 1048.50 2211.94 2184.59 2080.89 2677.97 2282.36
  (492.57, 648.45) (913.05, 1204.05) (1921.78, 2545.90) (1893.62, 2520.26) (1799.87, 2405.79) (2306.82, 3108.83) (1955.79, 2663.45)
TRT-7IM*       203 192 169 139
Group D       2546.81 (2251.11, 2881.35) 2254.56 (1988.85, 2555.75) 2867.88 (2518.14, 3266.19) 2760.35 (2404.66, 3168.64)
TRT-5IM* 723 698 636 399 174 153 141
Group E 36.61 514.57 2257.09 296.08 (266.67, 328.74) 3167.26 348.89 3286.41
  (33.32, 40.23) (468.08, 565.68) (2050.12, 2484.94)   (2785.88, 3600.85) (305.33, 398.66) (2866.50, 3767.83)
TRT-4IM* Group F         193 179 157
135.30 (119.44, 153.26) 79.63 (70.10, 90.44) 4683.79 (4102.99, 5346.80)
  Week 4 Week 8 Month 7 Month 13 Month 19 Month 31 Month 43
4-fold response
  n 4-fold response 95% CI n 4-fold response 95% CI n 4-fold response 95% CI n 4-fold response 95% CI n 4-fold response 95% CI n 4-fold response 95% CI n 4-fold response 95% CI
TRT-8SC Group A 242 80.99 (75.47, 85.73) 235 94.89 (91.25, 97.33) 219 98.63 (96.05, 99.72) 203 99.51 (97.29, 99.99) 190 98.95 (96.25, 99.87) 167 100.00 (97.82, 100.00) 144 100.00 (97.47, 100.00)
TRT-7IM* Group D 723 698 636 203 192 169 139
100.00 (98.20, 100.00) 98.96 (96.29, 99.87) 100.00 (97.84, 100.00) 100.00 (97.38, 100.00)
TRT-5IM* Group E 4.15 (2.82, 5.87) 78.80 (75.57, 81.77) 97.80 (96.33, 98.79) 399 174 99.43 (96.84, 99.99) 153 63.40 (55.24, 71.03) 141 99.29 (96.11, 99.98)
TRT-4IM* Group F       60.40 (55.41, 65.23) 193 37.82 (30.96, 45.07) 179 22.35 (16.47, 29.16) 157 99.36 (96.50, 99.98)
CI: Confidence Interval;
†According to Protocol (ATP): To be included in the ATP population at a particular timepoint, a participant must have: (a) received all injections up through that timepoint, (b) received these injections within the windows defined by protocol, (c) received the correct agent administered by the correct route according to subject's assigned study arm, (d) received the correct injection volume. A shot of 0.3 mL or greater is considered valid.
*Groups TRT-7IM, -5IM, and -4IM combined as group TRT-COM (combined) through Month 7 of the study, GMC: geometric mean concentration. GMT: geometric mean titer. IM: Intramuscular; SC: Subcutaneous, TRT: treatment.

REFERENCES

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: 11/2/2015
This monograph has been modified to include the generic and brand name in many instances.

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