Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis.

BACKGROUND: The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a person's own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome. METHODS: Data were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design. FINDINGS: Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42-4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated. INTERPRETATION: The modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks. FUNDING: US Federal Government.

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.

Glucose dysregulation among veterans living with schizophrenia-related disorders after switching second-generation antipsychotics.

OBJECTIVES: To compare (1) blood glucose and glycosylated hemoglobin (A1C) laboratory results and (2) longitudinal trends in blood glucose levels among veterans switched from one second-generation antipsychotic (SGA) to another. DESIGN: Retrospective, naturalistic, nonequivalent control group. SETTING: United States between April 1, 2003, and September 30, 2003. PATIENTS: 1,776 U.S. Veterans Health System beneficiaries living with schizophrenia-related disorders switching (1) from olanzapine to another SGA, (2) to olanzapine from another SGA, and (3) among nonolanzapine SGAs. INTERVENTION: Data were retrieved from the laboratory results (LAR) database for a maximum of 180 days before and 365 days after the index date. MAIN OUTCOME MEASURES: Mean blood glucose, A1C, and change in blood glucose. RESULTS: Blood glucose (36.0 mg/dL, paired t test109 = -4.87, P < 0.001) and A1C (1.0%, paired t143 = -4.84, P < 0.001) declined among veterans switched from olanzapine who were taking a blood glucose-lowering agent before the switch but was unchanged for those who were not. Adjusting for age, gender, and race, addition of the switch-type variables improved prediction of blood glucose change (F-ratio = 3.76, P = 0.03). Linear mixed-effects models confirmed that blood glucose levels declined for veterans switched from olanzapine with glucose dysregulation before the switch (Est(beta2 - beta1) = -34.5 mg/dL, t424 = -5.05, P < 0.001). CONCLUSION: Blood glucose and A1C were significantly improved among veterans switched from olanzapine with evidence of glucose dysregulation before the switch. They were stable among those without evidence of preexisting glucose dysregulation. Therapeutic switches from one SGA to another should be monitored as a risk factor for changes in glucose regulation.

Metabolic monitoring in veterans with schizophrenia-related disorders and treated with second-generation antipsychotics: findings from a Veterans Affairs-based population.

OBJECTIVES: To describe the proportions of veterans living with schizophrenia-related disorders monitored for dyslipidemia and hyperglycemia and to investigate whether the likelihood of metabolic dysregulation monitoring was influenced by veterans' sociodemographic characteristics, preswitch pharmacologic treatment, and monitoring before the switch from one second-generation antipsychotic (SGA) to another. DESIGN: Retrospective, observational, descriptive study. SETTING: Veterans Affairs (VA) Healthcare System between October 1, 2001, and December 31, 2003. PATIENTS: 1,826 veterans with schizophrenia-related disorders. INTERVENTION: Veterans who were dispensed two or more prescriptions for one of five SGAs (i.e., clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) on the VA Healthcare System formulary were identified. Of these veterans, a subset that was switched from one SGA to another was identified. From this subset, veterans were identified who were on the first SGA continuously for at least 90 days before the index date and the new SGA for 180 or more days after. Finally, among these veterans, ICD-9 codes were used to identify veterans with a schizophrenia or schizoaffective disorder diagnosis (ICD-9 code 295.xx or 296). MAIN OUTCOME MEASURES: Proportions of veterans with lipid (i.e., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) and blood glucose (i.e., fasting blood glucose [FBG], glycosylated hemoglobin [A1C]) laboratory results. RESULTS: Nearly 39% of the veterans had at least one of three lipid fractions monitored 6 months or less before their SGA switch and 59% during the 12 months after. The corresponding proportions of veterans monitored were 57% and 80% for FBG and 19% and 31% for A1C. Pharmacologic agent for metabolic dysregulation, monitoring during the 6 months before the switch, and age 50 years or older were significant predictors of monitoring after the SGA switch for all three laboratory parameters. CONCLUSION: These findings serve as a benchmark for lipid and blood glucose monitoring among patients who switch SGA therapy. Veterans' metabolic dysregulation was more likely to be monitored after SGA switch for those receiving pharmacologic treatment for metabolic dysregulation, monitored before the switch, and aged 50 years or older. Implementation of monitoring guidelines in daily practice is emphasized to ensure that individuals living with schizophrenia-related disorders and taking SGAs achieve optimal physical health.

Weight and blood pressure changes after switching second-generation antipsychotics in a population of veterans with schizophrenia-related disorders.

OBJECTIVES: To describe (1) the association between systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes and weight change and (2) weight, SBP, and DBP changes attributable to the medication following a switch from one second-generation antipsychotic (SGA) to another. DESIGN: Retrospective, naturalistic, nonequivalent control group study. SETTING: United States between April 1, 2002, and September 30, 2002. PATIENTS: 1,425 U.S. Veterans Healthcare System enrollees with diagnoses of schizophrenia or schizoaffective disorders. INTERVENTION: Analysis of data from the Veterans Integrated System Technology Architecture. MAIN OUTCOME MEASURES: Veterans' weight, SBP, and DBP. RESULTS: Weight change and change in SBP (r = 0.19) and DBP (r = 0.15) were significant (P < 0.001), even after adjusting for obesity status (body mass index <30 or > or = 30 kg/m2). Veterans who were switched from olanzapine to another SGA lost weight (P < 0.001), whereas those switched from another SGA to olanzapine gained weight (P < 0.05). Weight change remained significant after controlling for preswitch obesity status (P < 0.001). Blood pressure was not associated with switch type after adjusting for preswitch obesity status. CONCLUSION: Monitoring and aggressively treating weight change is an evidence-based and relatively inexpensive strategy that primary care practitioners and psychiatrists can use in working in tandem toward reducing the already greater cardiovascular risk of patients with schizophrenia.

Effect on lipid profiles of switching from olanzapine to another second-generation antipsychotic agent in veterans with schizophrenia.

OBJECTIVE: To compare (1) mean low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride differences after switching from olanzapine to quetiapine, risperidone, or ziprasidone and (2) the mean lipid change between switch patterns. DESIGN: Retrospective, naturalistic, nonequivalent control group design. SETTING: United States between April 1, 2002, and September 30, 2002. PATIENTS: 1,826 U.S. Veterans Healthcare System enrollees with diagnoses of schizophrenia or schizoaffective disorders and receiving a second-generation antipsychotic (SGA) medication. INTERVENTIONS: Analysis of data from the Veterans Information Systems and Technology Architecture. MAIN OUTCOME MEASURES: Differences in LDL-C, HDL-C, and triglycerides and mean differences between switch patterns. Predictors were the type of switch (e.g., olanzapine to quetiapine) and switch patterns (e.g., olanzapine to quetiapine versus olanzapine to risperidone). Data were analyzed using Pearson's X2 and multivariate analysis of covariance with planned comparisons. RESULTS: After adjusting for age, gender, and race/ethnicity, LDL-C decreased significantly among patients switched from olanzapine to ziprasidone (-16.9 mg/dL, P <0.01) and olanzapine to quetiapine (-7.6 mg/dL, P = 0.04) and trended upward in patients switched from olanzapine to risperidone (+6.6 mg/dL, P = 0.12). Triglyceride levels decreased among those switched from olanzapine to ziprasidone (-62.9 mg/dL, P <0.01) and olanzapine to risperidone (-48.5 mg/dL, P <0.01) but not among veterans switched from olanzapine to quetiapine (+7.8 mg/dL, P = 0.54). HDL-C levels did not change significantly when veterans were switched from olanzapine to quetiapine, risperidone, or ziprasidone. CONCLUSION: Switching SGAs can increase or decrease cardiovascular risk depending on the clinician's follow-on SGA choice. LDL-C and triglyceride levels decreased significantly among veterans switched from olanzapine to ziprasidone. Switching to quetiapine was associated with a reduction in LDL-C, while switching to risperidone resulted in lower triglyceride levels. Clinicians should use these results when building a patient care plan that includes switching of SGAs.

Deployment of the 1st Area Medical Laboratory in a Split-Based Configuration During the Largest Ebola Outbreak in History.

BACKGROUND: The U.S. Army 1st Area Medical Laboratory (1st AML) is currently the only deployable medical CBRNE (Chemical, Biological, Radiological, Nuclear, and Explosives) laboratory in the Army's Forces Command. In support of the United States Agency for International Development Ebola response, the U.S. military initiated Operation United Assistance (OUA), and deployed approximately 2,500 service members to support the Government of Liberia's Ebola control efforts. Due to its unique molecular diagnostic and expeditionary capabilities, the 1st AML was ordered to deploy in October of 2014 in support of OUA via establishment of Ebola testing laboratories. To meet the unique mission requirements of OUA, the unit was re-organized to operate in a split-based configuration and sustain four separate Ebola testing laboratories. METHODS: This article is a review of the 1st AML's OUA participation in a split-based configuration. Topics highlighted include pre-deployment planning/training, operational/logistical considerations in fielding/withdrawing laboratories, laboratory testing results, disease and non-battle injuries, and lessons learned. FINDINGS: Fielding the 1st AML in a split-based configuration required careful pre-deployment planning, additional training, optimal use of personnel, and the acquisition of additional laboratory equipment. Challenges in establishing and sustaining remote laboratories in Liberia included: difficulties in transportation of equipment due to poor road infrastructure, heavy equipment unloading, and equipment damage during transit. Between November 26, 2014 and February 18, 2015 the four 1st AML labs successfully tested blood samples from patients and oral swabs collected by burial teams in rural Liberia. The most significant equipment malfunction during laboratory operations was generators powering the labs, with the same problem impacting headquarters. Generator failures delayed laboratory operations/result reporting, and put temperature sensitive reagents at risk. None of the 22 1st AML soldiers (at remote labs or headquarters) had an Ebola exposure, none were infected with malaria or other tropical diseases, and none required evacuation from the time deployed to remote sites. The primary medical condition encountered was acute gastroenteritis, and within the first week of arrival to Liberia, 19 (86%) soldiers were affected. DISCUSSION/IMPACT/RECOMMENDATIONS: With proper planning and training, the 1st AML can successfully conduct split-based operations in an outbreak setting, and this capability can be utilized in future operations. The performance of the 1st AML during the current Ebola outbreak highlights the value of this asset, and the need to continue its evolution to support U.S. military operations.

Smallpox vaccine, ACAM2000: Sites and duration of viral shedding and effect of povidone iodine on scarification site shedding and immune response.

The U.S. Department of Defense vaccinates personnel deployed to high-risk areas with the vaccinia virus (VACV)-based smallpox vaccine. Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections. The objectives of this study were to investigate, in naïve smallpox vaccinees, (a) whether the vaccination site can remain contagious after the scab separates and (b) whether the application of povidone iodine ointment (PIO) to the vaccination site inactivates VACV without affecting the immune response. These objectives were tested in 60 individuals scheduled to receive smallpox vaccine. Thirty individuals (control) did not receive PIO; 30 subjects (treatment) received PIO starting on post-vaccination day 7. Counter to current dogma, this study showed that VACV continues to shed from the vaccination site after the scab separates. Overall viral shedding levels in the PIO group were significantly lower than those in the control group (p=0.0045), and PIO significantly reduced the duration of viral shedding (median duration 14.5 days and 21 days in the PIO and control groups, respectively; p=0.0444). At least 10% of control subjects continued to shed VACV at day 28, and 3.4% continued to shed the virus at day 42. PIO reduced the proportion of subjects shedding virus from the vaccination site from day 8 until days 21-23 compared with control subjects. Groups did not differ significantly in the proportion of subjects mounting an immune response, as measured by neutralizing antibodies, IgM, IgG, and interferon-gamma enzyme-linked immunospot assay. When applied to the vaccination site starting on day 7, PIO reduced viral shedding without altering the immune response. The use of PIO in addition to a semipermeable dressing may reduce the rates of autoinoculation and contact transmission originating from the vaccination site in smallpox-vaccinated individuals.

Computational modeling of interventions and protective thresholds to prevent disease transmission in deploying populations.

Military personnel are deployed abroad for missions ranging from humanitarian relief efforts to combat actions; delay or interruption in these activities due to disease transmission can cause operational disruptions, significant economic loss, and stressed or exceeded military medical resources. Deployed troops function in environments favorable to the rapid and efficient transmission of many viruses particularly when levels of protection are suboptimal. When immunity among deployed military populations is low, the risk of vaccine-preventable disease outbreaks increases, impacting troop readiness and achievement of mission objectives. However, targeted vaccination and the optimization of preexisting immunity among deployed populations can decrease the threat of outbreaks among deployed troops. Here we describe methods for the computational modeling of disease transmission to explore how preexisting immunity compares with vaccination at the time of deployment as a means of preventing outbreaks and protecting troops and mission objectives during extended military deployment actions. These methods are illustrated with five modeling case studies for separate diseases common in many parts of the world, to show different approaches required in varying epidemiological settings.

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.

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.

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.

Immunization-safety monitoring systems for the 2009 H1N1 monovalent influenza vaccination program.

The effort to vaccinate the US population against the 2009 H1N1 influenza virus hinged, in part, on public confidence in vaccine safety. Early in the vaccine program, >20% of parents reported that they would not vaccinate their children. Concerns about the safety of the vaccines were reported by many parents as a factor that contributed to their intention to forgo vaccination (see www.hsph.harvard.edu/news/press-releases/2009-releases/survey-40-adults-absolutely-certain-h1n1-vaccine.html and www.med.umich.edu/mott/npch/reports/h1n1.htm). The safety profiles of 2009 H1N1 monovalent influenza vaccines were anticipated to be (and have been) similar to those of seasonal influenza vaccines, for which an excellent safety profile has been demonstrated. Here we describe steps taken by the US government to (1) assess the key federal systems in place before 2009 for monitoring the safety of vaccines and (2) integrate and upgrade those systems for optimal vaccine-safety monitoring during the 2009 H1N1 monovalent influenza vaccination program. These efforts improved monitoring of 2009 H1N1 vaccine safety, hold promise for enhancing future national monitoring of vaccine safety, and may ultimately help improve public confidence in vaccines.