Effects of a Reduced Dose Schedule and Intramuscular Administration of Anthrax Vaccine Adsorbed on Immunogenicity and Safety at 7 Months: A Randomized Trial

• Published in: JAMA : the journal of the American Medical Association Vol. 300; no. 13; pp. 1532 - 1543
• Main Authors: Marano, Nina, Plikaytis, Brian D, Martin, Stacey W, Rose, Charles, Semenova, Vera A, Martin, Sandra K, Freeman, Alison E, Li, Han, Mulligan, Mark J, Parker, Scott D, Babcock, Janiine, Keitel, Wendy, El Sahly, Hana, Poland, Gregory A, Jacobson, Robert M, Keyserling, Harry L, Soroka, Stephen D, Fox, Sarah P, Stamper, John L, McNeil, Michael M, Perkins, Bradley A, Messonnier, Nancy, Quinn, Conrad P, Anthrax Vaccine Research Program Working Group, for the
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 01.10.2008
• Subjects: Adult; Anthrax; Anthrax Vaccines - administration & dosage; Anthrax Vaccines - adverse effects; Anthrax Vaccines - immunology; Antibodies, Bacterial - immunology; Bacillus anthracis - immunology; Bacterial diseases; Biological and medical sciences; Double-Blind Method; Drug Administration Schedule; Drug dosages; Female; General aspects; Genes; Human bacterial diseases; Humans; Immunoglobulin G - immunology; Immunology; Infectious diseases; Injections, Intramuscular; Injections, Subcutaneous; Male; Medical sciences; Middle Aged; Miscellaneous; Muscular system; Vaccines; Infection; Medicine; Randomization; Immune response; Immunogenicity; Anthrax; Low dose; Bacteriosis; Clinical trial; Pharmacovigilance; Intramuscular administration
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.300.13.1532

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 (%4×R). Reactogenicity outcomes were proportions of injection site and systemic AEs. RESULTS At week 8, the 4-IM group (GMC, 90.8 μg/mL; GMT, 1114.8; %4×R, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 μg/mL; GMT, 1315.4; %4×R, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4×R (GMC, 52.2 μg/mL; GMT, 650.6; %4×R, 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