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Effects of a Reduced Dose Schedule and Intramuscular Administration of Anthrax Vaccine Adsorbed on Immunogenicity and Safety at 7 Months: A Randomized Trial [JAMA]
Effects of a Reduced Dose Schedule and Intramuscular Administration of Anthrax Vaccine Adsorbed on Immunogenicity and Safety at 7 Months - A Randomized Trial
Nina Marano, DVM; Brian D. Plikaytis, MSc; Stacey W. Martin, MSc; Charles Rose, PhD; Vera A. Semenova, PhD; Sandra K. Martin, BS; Alison E. Freeman, MPH; Han Li, PhD; Mark J. Mulligan, MD; Scott D. Parker, MD; Janiine Babcock, MD; Wendy Keitel, MD; Hana El Sahly, MD; Gregory A. Poland, MD; Robert M. Jacobson, MD; Harry L. Keyserling, MD; Stephen D. Soroka, MPH; Sarah P. Fox, BS; John L. Stamper, BS; Michael M. McNeil, MD; Bradley A. Perkins, MD; Nancy Messonnier, MD; Conrad P. Quinn, PhD; for the Anthrax Vaccine Research Program Working Group
JAMA. 2008;300(13):1532-1543.
Context
In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA).
Objective
To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (SQ) to intramuscular (IM) and omitting the week 2 dose from the licensed schedule.
Design, Setting, and Participants
Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002).
Intervention
Healthy adults received AVA by the SQ (reference group) or IM route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals.
Main Outcome Measures
Noninferiority at week 8 and month 7 of anti?protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4xR). Reactogenicity outcomes were proportions of injection site and systemic AEs.
Results
At week 8, the 4-IM group (GMC, 90.8 ?g/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 ?g/mL; GMT, 1315.4; %4xR, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4xR (GMC, 52.2 ?g/mL; GMT, 650.6; %4xR, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs.
Conclusions
The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs.
Trial Registration
clinicaltrials.gov Identifier: NCT00119067
Author Affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Marano, Plikaytis, S. W. Martin, Rose, Semenova, Li, McNeil, Perkins, Messonnier, and Quinn; Mss S. K. Martin, Freeman, and Fox; and Messrs Soroka and Stamper); University of Alabama at Birmingham (Drs Mulligan and Parker); Walter Reed Army Institute for Research, Silver Spring, Maryland (Dr Babcock); Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas (Drs Keitel and El Sahly); Mayo Clinic, Rochester, Minnesota (Drs Poland and Jacobson); and Emory University School of Medicine, Atlanta, Georgia (Dr Keyserling). Dr Mulligan is now with Emory Vaccine Center, Emory University.
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<cite cite="http://jama.ama-assn.org/cgi/content/abstract/300/13/1532?etoc">JAMA -- Abstract: Effects of a Reduced Dose Schedule and Intramuscular Administration of Anthrax Vaccine Adsorbed on Immunogenicity and Safety at 7 Months: A Randomized Trial, October 1, 2008, Marano et al. 300 (13): 1532</cite>
Nina Marano, DVM; Brian D. Plikaytis, MSc; Stacey W. Martin, MSc; Charles Rose, PhD; Vera A. Semenova, PhD; Sandra K. Martin, BS; Alison E. Freeman, MPH; Han Li, PhD; Mark J. Mulligan, MD; Scott D. Parker, MD; Janiine Babcock, MD; Wendy Keitel, MD; Hana El Sahly, MD; Gregory A. Poland, MD; Robert M. Jacobson, MD; Harry L. Keyserling, MD; Stephen D. Soroka, MPH; Sarah P. Fox, BS; John L. Stamper, BS; Michael M. McNeil, MD; Bradley A. Perkins, MD; Nancy Messonnier, MD; Conrad P. Quinn, PhD; for the Anthrax Vaccine Research Program Working Group
JAMA. 2008;300(13):1532-1543.
Context
In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA).
Objective
To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (SQ) to intramuscular (IM) and omitting the week 2 dose from the licensed schedule.
Design, Setting, and Participants
Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002).
Intervention
Healthy adults received AVA by the SQ (reference group) or IM route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals.
Main Outcome Measures
Noninferiority at week 8 and month 7 of anti?protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4xR). Reactogenicity outcomes were proportions of injection site and systemic AEs.
Results
At week 8, the 4-IM group (GMC, 90.8 ?g/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 ?g/mL; GMT, 1315.4; %4xR, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4xR (GMC, 52.2 ?g/mL; GMT, 650.6; %4xR, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs.
Conclusions
The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs.
Trial Registration
clinicaltrials.gov Identifier: NCT00119067
Author Affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Marano, Plikaytis, S. W. Martin, Rose, Semenova, Li, McNeil, Perkins, Messonnier, and Quinn; Mss S. K. Martin, Freeman, and Fox; and Messrs Soroka and Stamper); University of Alabama at Birmingham (Drs Mulligan and Parker); Walter Reed Army Institute for Research, Silver Spring, Maryland (Dr Babcock); Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas (Drs Keitel and El Sahly); Mayo Clinic, Rochester, Minnesota (Drs Poland and Jacobson); and Emory University School of Medicine, Atlanta, Georgia (Dr Keyserling). Dr Mulligan is now with Emory Vaccine Center, Emory University.
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