Avidity in the 7-IM group (AI = 0.35) was not significantly different from those in the other groups at this time point. At month 42, when the antibody levels for group 4-IM were at their trough, the respective avidity was also least expensive. IL-1, and tumor necrosis factor alpha (TNF-) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, < 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior RGB-286638 to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.) INTRODUCTION Anthrax vaccine adsorbed (AVA; BioThrax; Emergent BioSolutions Inc., Lansing, MI) is the only Food and Drug Administration (FDA)-approved vaccine in the United States for prevention of anthrax in humans. The primary immunogen in AVA is usually anthrax toxin protective antigen (PA). Serum anti-PA antibody levels are accurate immune correlates of protection in nonhuman primate (NHP) models of inhalation anthrax and for predicted probability of survival in humans (1,C3). There is a significant lack of data in humans regarding the onset, duration, quantitative analysis, and functional activity of humoral antibody and cell-mediated immunity (CMI) responses following priming and improving with AVA. In 2012, the preexposure routine for AVA was approved as a priming series of three 0.5-ml intramuscular (IM) injections at 0, 1, and 6 months (3-IM) with subsequent boosters at 12 and 18 Rabbit Polyclonal to CARD6 months and annually thereafter for those at continued risk of contamination (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm304758.htm; http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/UCM074923.pdf). In 2013, AVA received market approval in the European Union (EU) using a 3-IM priming series and 3-yearly booster routine (http://emergentbiosolutions.com/sites/default/files/BioThrax_Germany.pdf). These recent changes in the FDA-approved priming routine and route of administration for AVA and EU approval of an alternate routine warranted detailed characterization of their immunological impact. Serological noninferiority analyses for peak anti-PA IgG and lethal toxin neutralization activity (TNA) in response to the 3-IM priming routine and option booster schedules were reported previously, and the security profile of AVA administered IM in humans was confirmed to be comparable to that for other alum-containing vaccines (4,C6). Less frequent AVA injection doses resulted in a reduction in some injection site adverse events (AEs), and IM administration resulted in reduced frequency, period, and severity of AEs (5,C11). The potential for increasing the intervals between booster doses requires an assessment of sustained antibody functional activity, CMI, and the ability to develop rapid protective anamnestic responses (5, 6, 12). In a rhesus macaque model of inhalation anthrax, the AVA 3-IM priming series diluted RGB-286638 up to 1/10 with no additional boosters provided significant levels of protection (60 to 100%) for up to 4 years after the first vaccination (13). The immunological characteristics of these long-term protective responses in NHPs have been reported previously, and anti-PA IgG was identified as the most accurate immune correlate of protection (COP) (1). Serum antibody levels decline in humans and NHPs in the absence of boosters. However, a COP RGB-286638 cross-walk analysis between NHPs and humans receiving only the 3-IM priming series estimated that even the lowest levels of anti-PA IgG provided significant probability of survival in RGB-286638 humans (86.8% to 95.8%) in a combined model for two alternate booster schedules (3). In the present COP substudy of the CDC Anthrax Vaccine Research Program (AVRP) human clinical trial, we conducted the first RGB-286638 detailed evaluation in humans of the earliest onset, magnitude, and period of PA-specific humoral and CMI profiles analogous to those providing long-term protection in NHPs (13). The objectives were to evaluate the potential immunological effects of route of vaccine administration and the feasibility of adopting alternate booster schedules. Characterization of the humoral antibody responses to AVA included serum anti-PA IgG levels and subclass distributions, antibody avidity, and TNA. Assessment of CMI in peripheral blood mononuclear cells (PBMCs) included lymphocyte activation indices (SI), frequencies of gamma interferon (IFN-)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), induction of IFN-, IL-2, IL-4, IL-6, IL-1, and tumor necrosis factor alpha (TNF-) gene transcription (mRNA), and overall Th1-Th2 disposition. The kinetics of anamnestic anti-PA IgG responses to the boosters at months 6 and 42.