Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members.

OBJECTIVES: To evaluate the rates of myopericarditis (primary objective) and rates of cardiovascular and neurological adverse events (secondary objectives) in temporal association with ACAM2000® smallpox vaccine. METHODS: Observational cohort study conducted through monthly surveillance from 2009 to 2017 of electronic medical records of military service members (SM) for pre-specified cardiac and neurological International Classification of Diseases (ICD) codes reported in the 30 days following smallpox vaccination. ICD codes potentially predictive of myopericarditis and codes for encephalitis, Guillain-Barré syndrome, and sudden death were classified into Group 1. All other cardiovascular and neurological ICD codes were classified into Group 2. Medical records containing Group 1 codes were individually reviewed to confirm coding accuracy and to seek additional data in support of myopericarditis adjudication, which was performed by an independent clinical panel. Chart reviews were not performed for Group 2 codes, which were reported in aggregate only. RESULTS: 897,227 SM who received ACAM2000 smallpox vaccine and 450,000 SM who received Dryvax smallpox vaccine were included in the surveillance population. The rate of adjudicated myopericarditis among ACAM2000 smallpox vaccine recipients was 20.06/100,000 and was significantly higher for males (21.8/100,000) than females (8.5/100,000) and for those < 40 years of age (21.1/100,000) than for those 40 years or older (6.3/100,000). Overall rates for any cardiovascular event (Group 1 plus Group 2) were 113.5/100,000 for ACAM2000 vaccine and 439.3/100,000 for Dryvax vaccine; rate ratio, 0.26 (95% CI, 0.24-0.28). The rates of subjects with one or more defined neurological events were 2.12/100,000 and 1.11/100,000 for ACAM2000 and Dryvax vaccines respectively; rate ratio, 1.91 (95% CI, 0.71-5.10). CONCLUSIONS: Electronic records surveillance of the entire vaccinated SM population over a ten-year period found rates of myopericarditis, of defined neurological events, and of overall cardiac events that were consistent with those of prior passive surveillance studies involving Dryvax or ACAM2000 smallpox vaccines. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00927719.

Post-licensure surveillance of trivalent live attenuated influenza vaccine in adults, United States, Vaccine Adverse Event Reporting System (VAERS), July 2005-June 2013.

BACKGROUND: Trivalent live attenuated influenza vaccine (LAIV3) was licensed and recommended for use in 2003 in children and adults 2-49 years of age. Post-licensure safety data have been limited, particularly in adults. METHODS: We searched Vaccine Adverse Event Reporting System (VAERS) for US reports after LAIV3 from July 1, 2005-June 30, 2013 (eight influenza seasons) in adults aged ≥ 18 years old. We conducted descriptive analyses and clinically reviewed serious reports (i.e., death, life-threatening illness, hospitalization, prolonged hospitalization, or permanent disability) and reports of selected conditions of interest. We used empirical Bayesian data mining to identify adverse events (AEs) that were reported more frequently than expected. We calculated crude AE reporting rates to VAERS by influenza season. RESULTS: During the study period, VAERS received 1207 LAIV3 reports in adults aged 18-49 years old; 107 (8.9%) were serious, including four death reports. The most commonly reported events were expired drug administered (n=207, 17%), headache (n=192, 16%), and fever (n=133, 11%). The most common diagnostic categories for non-fatal serious reports were neurological (n=40, 39%), cardiovascular (n=14, 14%), and other non-infectious conditions (n=20, 19%). We noted a higher proportion of Guillain-Barré syndrome (GBS) and cardiovascular reports in the Department of Defense (DoD) population compared to the civilian population. Data mining detected disproportional reporting of ataxia (n=15); clinical review revealed that ataxia was a component of diverse clinical entities including GBS. CONCLUSIONS: Review of VAERS reports are reassuring, the only unexpected safety concern for LAIV3 identified was a higher than expected number of GBS reports in the DoD population, which is being investigated. Reports of administration of expired LAIV3 represent administration errors and indicate the need for education, training and screening regarding the approved indications.

Evaluation of the effects of exposure to organic solvents and hazardous noise among US Air Force Reserve personnel.

Hearing loss affects many workers including those in the military and may be caused by noise, medications, and chemicals. Exposures to some chemicals may lead to an increase in the incidence of hearing loss when combined with hazardous noise. This retrospective study evaluated the risk for hearing loss among Air Force Reserve personnel exposed to occupational noise with and without exposures to toluene, styrene, xylene, benzene, and JP-8 (jet fuel). Risk factors associated with hearing loss were determined using logistic and linear regression. Stratified analysis was used to evaluate potential interaction between solvent and noise exposure. The majority of the subjects were male (94.6%) and 35 years or older on the date of their first study audiogram (66%). Followed for an average of 3.2 years, 9.2% of the study subjects had hearing loss in at least one ear. Increasing age (odds ratio [OR] = 1.03 per year of age) and each year of follow-up time (OR = 1.23) were significantly associated with hearing loss. Low and moderate solvent exposures were not associated with hearing loss. Linear regression demonstrated that hearing loss was significantly associated with age at first study audiogram, length of follow-up time, and exposure to noise. Hearing decreased by 0.04 decibels for every decibel increase in noise level or by almost half a decibel (0.4 dB) for every 10 decibel increase in noise level.

International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines.

BACKGROUND: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. METHODS: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. RESULTS: We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach. CONCLUSIONS: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines.

Disability among US Army Veterans vaccinated against anthrax.

CONTEXT: To protect troops against the use of anthrax as a biological weapon, the US Department of Defense began an anthrax vaccination program in 1998. 14 years after the inception of the vaccination program, there is no evidence suggesting vaccination against anthrax carries long-term health risks for Active Duty Soldiers. OBJECTIVE: To investigate the association between Anthrax Vaccine Adsorbed (AVA) received while on Active Duty and subsequent disability determined by the Veterans Benefits Administration. DESIGN, SETTING AND PARTICIPANTS: Case-control study nested in the cohort of all Active Duty personnel known to have separated from the US Army between December 1, 1997 and December 31, 2005. Cases were ≥10% disabled, determined either by the Army prior to separation (N=5846) or by the Veterans Benefits Administration (VBA) after separation (N=148,934). Controls (N=937,705) separated from the Army without disability, and were not receiving pensions from the VBA as of April 2007. Data were from the Total Army Injury and Health Outcomes Database and the VBA Compensation and Pension and Benefits database. MAIN OUTCOMES: Disability status (yes/no); for primary disability, percent disabled (≥10%, 20%, >20%) and type of disability. RESULTS: Vaccination against anthrax was four times more likely among disabled Veterans with hostile fire pay records (HFP, a surrogate for deployment). Vaccinated Soldiers with HFP had lower odds of disability separation from the Army 0.89 (0.80, 0.98); there was no association between vaccine and receiving Army disability benefits among those without HFP (OR=1.05, CI: 0.96, 1.14). Vaccination was negatively associated with receiving VA disability benefits for those with HFP (OR=0.66, CI: 0.65, 0.67), but there was little or no association between vaccine and receipt of VA disability benefits for those without HFP (OR=0.95, CI: 0.93, 0.97). CONCLUSIONS: Risk of disability separation from the Army and receipt of disability compensation from the VA were not increased in association with prior exposure to AVA. This study provides evidence that vaccination against anthrax is not associated with long term disability.

The yellow fever 17D vaccine and risk of malignant melanoma in the United States military.

Previous studies show that the tuberculosis and smallpox vaccine protect against melanoma because of sequence homologies they have with the melanoma antigen, HERV-K-MEL. The yellow fever 17D (YF 17D) vaccine is thought to have this property, so there is a possibility that the YF17D vaccine is able to protect against melanoma. This nested case-control study used the Defense Medical Surveillance System to assess the association between the YF17D vaccine and risk of malignant melanoma in active members of the United States military. Although point estimates hinted at a protective effect, none of the values reached a significant level. Therefore, this study concluded that in the ten year period following vaccination there is no association between the yellow fever 17D vaccine and risk of malignant melanoma in active members of the US armed forces.

Cost-minimization analysis of the U.S. Army accession screening and immunization program.

OBJECTIVES: Significant Army resources are utilized to identify nonimmune recruits for targeted vaccinations against hepatitis A, hepatitis B, measles, rubella, and varicella. Therefore, a cost-minimization analysis between the Accession Screening and Immunization Program (ASIP) and the previously utilized universal vaccination program will assist military public health policy makers in decisions that enhance force health protection. METHODS: Serological immunity data on 41,146 Fort Leonard Wood, Missouri, Army basic training recruits aged 17 to 42 years from October 1, 2007 to September 30, 2009 were utilized. Vaccination, serology, and other direct and indirect costs were determined using the Federal Supply Schedule and local base immunization data. TreeAge Pro 2009 version 1.0.2 was used for the analysis. RESULTS: The cumulative annual cost for the universal vaccination program totaled $1,504,587, whereas the cumulative costs for the ASIP totaled $1,094,025, for a cost-savings of $410,561 annually at this basic training site. CONCLUSIONS: Over $400,000 of annual savings was realized from the ASIP compared to universal vaccination at Fort Leonard Wood, thus confirming the cost-savings theorized by the implementation of the ASIP.

Risk of disability for US army personnel vaccinated against anthrax, 1998-2005.

To evaluate the potential for long-term or delayed onset health effects, we extended a previous cohort study of disability separation from the army associated with vaccination against anthrax. Analyses included stratified Cox proportional hazards and multiple logistic regression models. Forty-one percent of 1,001,546 soldiers received at least one anthrax vaccination; 5.21% were evaluated for disability. No consistent patterns or statistically significant differences in risk of disability evaluation, disability determination, or reason for disability were associated with anthrax vaccination. There was a dose-related trend in risk of disability for soldiers with 2 years' service, limited to those entering service in 2000 or later. Divergent patterns in risk suggest confounding by temporal or occupational risks of disability.

Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members.

Limited effectiveness data are available comparing live attenuated influenza vaccine (LAIV) to inactivated influenza vaccine (TIV) among adults. To compare the incidence of influenza-like illness following immunization of adults with LAIV vs. TIV, we conducted a retrospective cohort analysis of active component U.S. military personnel for the 2005-2006 and 2006-2007 influenza seasons. Recruits experienced a much higher burden of disease compared to non-recruits, with crude incidence rates of influenza-like illness 2-16 times higher than non-recruits depending on the season and cohort. For both seasons, a slightly greater protection from influenza-like illness was found for non-recruits who received TIV compared to LAIV (adjusted incidence rate ratio, 1.17 (95% CI, 1.14-1.20) and 1.33 (95% CI, 1.30-1.36), 2005-2006 and 2006-2007 influenza seasons, respectively). However, for Army and Air Force recruits, LAIV was found to provide significantly greater protection from influenza-like illnesses compared to TIV, with adjusted incidence rates of influenza-like illness 22-51% and 18-47% lower among LAIV compared to TIV recipients for the 2005-2006 and 2006-2007 influenza seasons, respectively. Possible reasons for differences in recruit and non-recruit findings include differences in pre-existing influenza antibody levels, differing respiratory disease burden, and/or unmeasured confounding. Consideration of these findings should be made when developing influenza immunization policies.

Streptococcus pneumoniae-related illnesses in young children: secular trends and regional variation.

BACKGROUND: Children <2 years old have been targeted for routine pneumococcal conjugate vaccine. Laboratory-confirmed illnesses represent a minority of all medical care utilization for pneumococcal disease. OBJECTIVES: To evaluate trends in medical care utilization for Streptococcus pneumoniae-related illnesses before introduction of pneumococcal conjugate vaccine (1995 to 1999) and to evaluate regional variation in utilization. METHOD: Retrospective cohort analysis with the use of computerized billing data of children <2 years old enrolled in Tennessee (Medicaid program) and the Rochester, NY area (commercial and Medicaid managed care plans). Secular trends (1995 to 1999) analysis included 316 519 person-years in Tennessee Medicaid. Regional variation (1998 to 1999) analysis included 130 525 person-years in Tennessee and 26 140 and 3184 person-years in commercial and Medicaid plans, respectively, in the Rochester, NY area. RESULTS: From 1995 to 1999 in Tennessee, the net increase in medical care visits was 12% for pneumococcal and nonspecific pneumonia and invasive disease, 11% for otitis media and 11% for other acute respiratory conditions. Analysis of trends indicated that a significant vaccine effect could be detected if utilization rates declined by 32, 9 and 21%, respectively. In the Tennessee Medicaid population, rates of pneumococcal and nonspecific pneumonia and invasive disease were 60% higher than in either the New York Medicaid or the commercial populations. Children with commercial insurance had the highest medical care utilization for otitis media. CONCLUSIONS: Geographic variation and large population differences in medical care utilization among children < 2 years old in three study populations suggest that the benefits of vaccination may vary by region and by population. In the Tennessee Medicaid population, temporal trends and year-to-year variability of pneumococcal-related outcomes were observed from 1995 to 1999. In this population a 10% decline in otitis media visits after the introduction of pneumococcal conjugate vaccine could be detected by trend analysis.