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, Brian D. Plikaytis, Stacey W. Martin, Charles Rose, Vera A. Semenova, Sandra K. Martin, Alison E. Freeman, Han Li, Mark J. Mulligan, Scott D. Parker, Janiine Babcock, Wendy Keitel, Hana El Sahly, Gregory A. Poland, Robert M. Jacobson, Harry L. Keyserling, Stephen D. Soroka, Sarah P. Fox, John L. Stamper, Michael M. McNeilBradley A. Perkins, Nancy Messonnier, Conrad P. Quinn

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

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 μg/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 μg/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 μg/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.

Original languageEnglish (US)
Pages (from-to)1532-1543
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume300
Issue number13
DOIs
StatePublished - Oct 1 2008

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Anthrax Vaccines
Appointments and Schedules
Safety
Injections
Phase IV Clinical Trials
Centers for Disease Control and Prevention (U.S.)
Immunoglobulin G
Odds Ratio
Outcome Assessment (Health Care)
Antigens
Pain
Control Groups

ASJC Scopus subject areas

  • Medicine(all)

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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. / 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.

In: JAMA - Journal of the American Medical Association, Vol. 300, No. 13, 01.10.2008, p. 1532-1543.

Research output: Contribution to journalArticle

Marano, N, Plikaytis, BD, Martin, SW, Rose, C, Semenova, VA, Martin, SK, Freeman, AE, Li, H, Mulligan, MJ, Parker, SD, Babcock, J, Keitel, W, El Sahly, H, Poland, GA, Jacobson, RM, Keyserling, HL, Soroka, SD, Fox, SP, Stamper, JL, McNeil, MM, Perkins, BA, Messonnier, N & Quinn, CP 2008, 'Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: A randomized trial', JAMA - Journal of the American Medical Association, vol. 300, no. 13, pp. 1532-1543. https://doi.org/10.1001/jama.300.13.1532
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. / Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months : A randomized trial. In: JAMA - Journal of the American Medical Association. 2008 ; Vol. 300, No. 13. pp. 1532-1543.
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abstract = "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 μg/mL; GMT, 1114.8; {\%}4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 μg/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 μg/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 = "Nina Marano and Plikaytis, {Brian D.} and Martin, {Stacey W.} and Charles Rose and Semenova, {Vera A.} and Martin, {Sandra K.} and Freeman, {Alison E.} and Han Li and Mulligan, {Mark J.} and Parker, {Scott D.} and Janiine Babcock and Wendy Keitel and {El Sahly}, Hana and Poland, {Gregory A.} and Jacobson, {Robert M.} and Keyserling, {Harry L.} and Soroka, {Stephen D.} and Fox, {Sarah P.} and Stamper, {John L.} and McNeil, {Michael M.} and Perkins, {Bradley A.} and Nancy Messonnier and Quinn, {Conrad P.}",
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TY - JOUR

T1 - Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months

T2 - A randomized trial

AU - Marano, Nina

AU - Plikaytis, Brian D.

AU - Martin, Stacey W.

AU - Rose, Charles

AU - Semenova, Vera A.

AU - Martin, Sandra K.

AU - Freeman, Alison E.

AU - Li, Han

AU - Mulligan, Mark J.

AU - Parker, Scott D.

AU - Babcock, Janiine

AU - Keitel, Wendy

AU - El Sahly, Hana

AU - Poland, Gregory A.

AU - Jacobson, Robert M.

AU - Keyserling, Harry L.

AU - Soroka, Stephen D.

AU - Fox, Sarah P.

AU - Stamper, John L.

AU - McNeil, Michael M.

AU - Perkins, Bradley A.

AU - Messonnier, Nancy

AU - Quinn, Conrad P.

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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 μg/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 μg/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 μg/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.

AB - 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 μg/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 μg/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 μg/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.

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