Unique Inflammatory Mediators and Specific IgE Levels Distinguish Local from Systemic Reactions after Anthrax Vaccine Adsorbed Vaccination

Abstract

Although the U.S. National Academy of Sciences concluded that anthrax vaccine adsorbed (AVA) has an adverse event (AE) profile similar to those of other adult vaccines, 30 to 70% of queried AVA vaccinees report AEs. AEs appear to be correlated with certain demographic factors, but the underlying immunologic pathways are poorly understood. We evaluated a cohort of 2,421 AVA vaccinees and found 153 (6.3%) reported an AE. Females were more likely to experience AEs (odds ratio [OR] = 6.0 [95% confidence interval {CI} = 4.2 to 8.7]; P < 0.0001). Individuals 18 to 29 years of age were less likely to report an AE than individuals aged 30 years or older (OR = 0.31 [95% CI = 0.22 to 0.43]; P < 0.0001). No significant effects were observed for African, European, Hispanic, American Indian, or Asian ancestry after correcting for age and sex. Additionally, 103 AEs were large local reactions (LLRs), whereas 53 AEs were systemic reactions (SRs). In a subset of our cohort vaccinated 2 to 12 months prior to plasma sample collection (n = 75), individuals with LLRs (n = 33) had higher protective-antigen (PA)-specific IgE levels than matched, unaffected vaccinated individuals (n = 50; P < 0.01). Anti-PA IgE was not associated with total plasma IgE, hepatitis B-specific IgE, or anti-PA IgG in individuals who reported an AE or in matched, unaffected AVA-vaccinated individuals. IP-10 was also elevated in sera of individuals who developed LLRs (P < 0.05). Individuals reporting SRs had higher levels of systemic inflammation as measured from C-reactive protein (P < 0.01). Thus, LLRs and SRs are mediated by distinct pathways. LLRs are associated with a vaccine-specific IgE response and IP-10, whereas SRs demonstrate increased systemic inflammation without a skewed cytokine profile.

FIG 1

AVA-related AEs are associated with female sex and increased age. Self-reported demographic data were analyzed for associations with the prevalence of AEs. In individual comparisons of sex, ethnicity, and age, males (A), Hispanic individuals (B), and individuals less than 30 years of age (C) were less likely to experience AEs than other demographic groups. Conversely, females (A); individuals of Asian descent (B); and individuals 30 to 39, 40 to 49, and 50 or more years of age (C) were more likely to experience an adverse event. The numbers within the bars indicate the number of unaffected VIs within each demographic group. **, P < 0.01; *, P < 0.05 versus all other demographic groups by chi-square test with Yates' correction. In multivariate analysis, sex and age, but not race, remained significantly associated with AEs. EA, European American; AA, African American; H, Hispanic; A, Asian.

FIG 2

AVA-related LLRs are associated with anti-PA IgE. PA-specific IgE (A) was assessed by ELISA, along with anti-PA IgG (B), total plasma IgE (D), and IgG (E). The ability of plasma to neutralize LT (C) was assessed by in vitro assay, and the percentages of leukocytes that were basophils (F) and eosinophils (G) were assessed in blood smears by a trained medical technician. Individuals who reported an LLR had higher levels of anti-PA IgE than their unaffected, matched, vaccinated counterparts. There were no significant differences between the groups in any other measure. Each symbol represents a single individual; the horizontal bars indicate means, and the error bars indicate standard deviations. **, P < 0.01 between the indicated groups by Mann-Whitney U test.