Insufficient Anthrax Lethal Toxin Neutralization Is Associated with Antibody Subclass and Domain Specificity in the Plasma of Anthrax-Vaccinated Individuals

Anthrax vaccine adsorbed (AVA) is a significant line of defense against bioterrorist attack from Bacillus anthracis spores. However, in a subset of individuals, this vaccine may produce a suboptimal quantity of anti-protective antigen (PA), antibodies that are poorly neutralizing, and/or antibody titers that wane over time, necessitating annual boosters. To study individuals with such poor responses, we examine the properties of anti-PA in a subset of vaccinated individuals that make significant quantities of antibody but are still unable to neutralize toxin. In this cohort, characterized by poorly neutralizing antibody, we find that increased IgG4 to IgG1 subclass ratios, low antibody avidity, and insufficient antibody targeting domain 4 associate with improper neutralization. Thus, future vaccines and vaccination schedules should be formulated to improve these deficiencies

A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.

Although myocarditis/pericarditis (MP) has been identified as an adverse event following smallpox vaccine (SPX), the prospective incidence of this reaction and new onset cardiac symptoms, including possible subclinical injury, has not been prospectively defined.The study's primary objective was to determine the prospective incidence of new onset cardiac symptoms, clinical and possible subclinical MP in temporal association with immunization.New onset cardiac symptoms, clinical MP and cardiac specific troponin T (cTnT) elevations following SPX (above individual baseline values) were measured in a multi-center prospective, active surveillance cohort study of healthy subjects receiving either smallpox vaccine or trivalent influenza vaccine (TIV).New onset chest pain, dyspnea, and/or palpitations occurred in 10.6% of SPX-vaccinees and 2.6% of TIV-vaccinees within 30 days of immunization (relative risk (RR) 4.0, 95% CI: 1.7-9.3). Among the 1081 SPX-vaccinees with complete follow-up, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. This indicates a post-SPX incidence rate more than 200-times higher than the pre-SPX background population surveillance rate of myocarditis/pericarditis (RR 214, 95% CI 65-558). Additionally, 31 SPX-vaccinees without specific cardiac symptoms were found to have over 2-fold increases in cTnT (>99th percentile) from baseline (pre-SPX) during the window of risk for clinical myocarditis/pericarditis and meeting a proposed case definition for possible subclinical myocarditis. This rate is 60-times higher than the incidence rate of overt clinical cases. No clinical or possible subclinical myocarditis cases were identified in the TIV-vaccinated group.Passive surveillance significantly underestimates the true incidence of myocarditis/pericarditis after smallpox immunization. Evidence of subclinical transient cardiac muscle injury post-vaccinia immunization is a finding that requires further study to include long-term outcomes surveillance. Active safety surveillance is needed to identify adverse events that are not well understood or previously recognized

Pericarditis case definition for surveillance of adverse events after smallpox vaccination in the United States, 2003¹³.

<p>*<b>ECG findings</b>: Electrocardiogram findings not previously documented.</p><p>Pericarditis case definition for surveillance of adverse events after smallpox vaccination in the United States, 2003¹³.</p

Subject enrollment, exclusions and outcomes for two prospective cohorts, post-smallpox and annual trivalent influenza vaccine.

<p>Subject enrollment, exclusions and outcomes for two prospective cohorts, post-smallpox and annual trivalent influenza vaccine.</p

Prospective Cases of New Onset Myocarditis/Pericarditis or cTnT Elevation Following Immunization with Either Smallpox or Trivalent Influenza Vaccine.

<p>*<b>Healthy 2002</b>: DoD Defense Medical Surveillance System pre-SPX MP incidence data.³</p><p>^‡<b>Prospective clinical myocarditis/pericarditis</b> cases included 4 Caucasian male cases of probable myocarditis (new onset cardiac symptoms (chest pain, dyspnea on exertion and/or at rest, palpitations) and cTnT elevations ≥0.02 ng/ml with the pre-vaccine level <0.01 ng/ml). The 5^th case (female) was acute suspect pericarditis presenting with characteristic chest pain and no cTnT elevations or ECG changes. There were no cases in the TIV prospective study cohort.</p><p>^§<b>Comparison of Prospective Smallpox Vaccine Cohort with published historic retrospective epidemiologic estimate of myocarditis/pericarditis disease incidence in comparable population pre-SPX vaccine</b>: P<0.001.</p><p>^ǁSubclinical myocarditis is defined by increases in cTnT (above pre-immunization levels) without classic new onset cardiac symptoms. The comparison cohort does not reflect a dynamic change but a single level in time in healthy population subsequently followed for mortality relative risk. <b>Possible subclinical pericarditis</b>: There were no cases of possible subclinical pericarditis identified through the blinded ECG series review process.</p><p>Prospective Cases of New Onset Myocarditis/Pericarditis or cTnT Elevation Following Immunization with Either Smallpox or Trivalent Influenza Vaccine.</p