Seroprevalence as an Indicator of Undercounting of COVID-19 Cases in a Large Well-Described Cohort.

Introduction: Reported confirmed cases represent a small portion of overall true cases for many infectious diseases. The undercounting of true cases can be considerable when a significant portion of infected individuals are asymptomatic or minimally symptomatic, as is the case with COVID-19. Seroprevalence studies are an efficient way to assess the extent to which true cases are undercounted during a large-scale outbreak and can inform efforts to improve case identification and reporting. Methods: A longitudinal seroprevalence study of active duty U.S. military members was conducted from May 2020 through June 2021. A random selection of service member serum samples submitted to the Department of Defense Serum Repository was analyzed for the presence of antibodies reactive to SARS-CoV-2. The monthly seroprevalence rates were compared with those of cumulative confirmed cases reported during the study period. Results: Seroprevalence was 2.3% in May 2020 and increased to 74.0% by June 2021. The estimated true case count based on seroprevalence was 9.3 times greater than monthly reported cases at the beginning of the study period and fell to 1.7 by the end of the study. Conclusions: In our sample, confirmed case counts significantly underestimated true cases of COVID-19. The increased availability of testing over the study period and enhanced efforts to detect asymptomatic and minimally symptomatic cases likely contributed to the fall in the seroprevalence to reported case ratio.

Post-vaccination serum cytokines levels correlate with breakthrough influenza infections.

Post-vaccination cytokine levels from 256 young adults who subsequently suffered breakthrough influenza infections were compared with matched controls. Modulation within the immune system is important for eliciting a protective response, and the optimal response differs according to vaccine formulation and delivery. For both inactivated influenza vaccine (IIV) and live attenuated influenza vaccines (LAIV) lower levels of IL-8 were observed in post-vaccination sera. Post-vaccination antibody levels were higher and IFN-γ levels were lower in IIV sera compared to LAIV sera. Subjects who suffered breakthrough infections after IIV vaccination had higher levels of sCD25 compared to the control group. There were differences in LAIV post-vaccination interleukin levels for subjects who subsequently suffered breakthrough infections, but these differences were masked in subjects who received concomitant vaccines. Wide variances, sex-based differences and confounders such as concomitant vaccines thwart the establishment of specific cytokine responses as a correlate of protection, but our results provide real world evidence that the status of the immune system following vaccination is important for successful vaccination and subsequent protection against disease.

Effectiveness of mRNA-1273, BNT162b2, and JNJ-78436735 COVID-19 Vaccines Among US Military Personnel Before and During the Predominance of the Delta Variant.

Importance: No studies to date have evaluated the effectiveness of 3 COVID-19 vaccines in the US military population, especially during the circulation of the SARS-CoV-2 Delta (B.1.617.2) variant. Objective: To estimate the effectiveness of the mRNA-1273, BNT162b2, and JNJ-78436735 vaccines among US military personnel before and during the predominance of the Delta variant in the US. Design, Setting, and Participants: This case-control study was conducted among all unvaccinated and fully vaccinated US military personnel who had a documented SARS-CoV-2 test performed in the US between January 1 and September 24, 2021. Individuals were identified using Department of Defense (DOD) electronic medical, laboratory, and surveillance databases. The pre-Delta period was defined as January 1 to May 31, 2021, and the Delta period as June 19 to September 24, 2021. Case individuals were defined by a positive polymerase chain reaction SARS-CoV-2 test result or a positive antigen test result with symptoms. Control individuals had at least 1 negative SARS-CoV-2 test result. Exposures: COVID-19 vaccination with the mRNA-1273, BNT162b2, or JNJ-78436735 vaccine, assessed from DOD electronic vaccination records. Main Outcomes and Measures: COVID-19 vaccine effectiveness overall, by vaccine type, and by outcome stratified by the pre-Delta and Delta periods in the US. Vaccine effectiveness was estimated as 100 × (1 - odds ratio) in a logistic regression model with adjustment for potential confounders. Results: The cohort included 441 379 individuals, with 290 256 in the pre-Delta period (236 555 [81%] male; median age, 25 years [range, 17-68 years]) and 151 123 in the Delta period (120 536 [80%] male; median age, 26 years [range, 17-70 years]). Adjusted vaccine effectiveness of all vaccines was significantly higher during the pre-Delta period (89.2%; 95% CI, 88.1%-90.1%) compared with the Delta period (70.2%; 95% CI, 69.3%-71.1%) for all outcomes, an overall decrease of 19%. mRNA-1273 vaccine effectiveness was highest in the pre-Delta (93.5%; 95% CI, 91.9%-94.7%) and Delta (79.4%; 95% CI, 78.3%-80.4%) periods for all outcomes, whereas the JNJ-78436735 vaccine had the lowest effectiveness during the pre-Delta (81.8%; 95% CI, 74.2%- 87.1%) and Delta (38.3%; 95% CI, 34.5%-41.9%) periods. Effectiveness for all vaccines during both periods was higher for symptomatic infection and hospitalization among individuals with SARS-CoV-2 infection. Conclusions and Relevance: In this case-control study, among US military personnel, COVID-19 vaccine effectiveness was significantly lower during the period when the Delta variant predominated compared with the period before Delta variant predominance; this was especially true for the JNJ-78436735 vaccine. These findings were confounded by time since vaccination; this and the change in effectiveness support the need for booster doses and continued evaluation of vaccine effectiveness as new variants of SARS-CoV-2 emerge.

Hepatitis B seroprevalence in the U.S. military and its impact on potential screening strategies.

INTRODUCTION: Knowledge of the contemporary epidemiology of hepatitis B virus (HBV) infection among military personnel can inform potential Department of Defense (DoD) screening policy and infection and disease control strategies. MATERIALS AND METHODS: HBV infection status at accession and following deployment was determined by evaluating reposed serum from 10,000 service members recently deployed to combat operations in Iraq and Afghanistan in the period from 2007 to 2010. A cost model was developed from the perspective of the Department of Defense for a program to integrate HBV infection screening of applicants for military service into the existing screening program of screening new accessions for vaccine-preventable infections. RESULTS: The prevalence of chronic HBV infection at accession was 2.3/1,000 (95% CI: 1.4, 3.2); most cases (16/21, 76%) identified after deployment were present at accession. There were 110 military service-related HBV infections identified. Screening accessions who are identified as HBV susceptible with HBV surface antigen followed by HBV surface antigen neutralization for confirmation offered no cost advantage over not screening and resulted in a net annual increase in cost of $5.78 million. However, screening would exclude as many as 514 HBV cases each year from accession. CONCLUSIONS: Screening for HBV infection at service entry would potentially reduce chronic HBV infection in the force, decrease the threat of transfusion-transmitted HBV infection in the battlefield blood supply, and lead to earlier diagnosis and linkage to care; however, applicant screening is not cost saving. Service-related incident infections indicate a durable threat, the need for improved laboratory-based surveillance tools, and mandate review of immunization policy and practice.

Summary of the 2018-2019 influenza season among Department of Defense service members and other beneficiaries.

The Armed Forces Health Surveillance Branch conducts weekly surveillance of influenza activity among Department of Defense (DoD) populations each influenza season. This report provides a summary of the data from the 2018-2019 influenza season. Ambulatory data for influenza-like illnesses (ILIs), influenza hospitalization data, and lab data for influenza-confirmed cases were used for the surveillance. The 2018-2019 season differed from past seasons in that it was much longer, had a later peak, and the predominant strain of influenza changed from influenza A(H1N1)pdm09 at the beginning of the season to influenza A(H3N2) in the middle of the season. Non-service member beneficiaries accounted for the majority of ILI-related encounters and hospitalizations. However, there were still 149 influenza-related hospitalizations among service members during the 2018- 2019 season. Continued weekly surveillance of influenza among DoD populations is crucial to track increases in activity each season and the potential emergence of new and/or severe influenza subtypes.

Tick-borne encephalitis surveillance in U.S. military service members and beneficiaries, 2006-2018.

The risk of tick-borne encephalitis (TBE) among U.S. military service members and beneficiaries residing in or traveling to Europe has not been assessed since the 1990s. The primary objective of this study was to assess the current risk of TBE in this population. Records of reportable medical events, inpatient and outpatient care, and laboratory test results were searched for TBE cases between 2006 and 2018. There were 8 individuals who met the case definition for TBE over the 13-year interval; 7 cases occurred during 2017 or 2018. Outpatient records did not identify any additional verified cases of TBE but revealed a large number of misclassified diagnoses. The risk of TBE among U.S. military service members and beneficiaries is low but may have increased in recent years. Military members and their dependents residing in Europe or Asia generally have a risk for TBE similar to that of other residents of the host nation. Additionally, there may be locations or activities that place certain individuals or units at increased risk for TBE, thus warranting additional control measures such as active surveillance, enhanced personal protective measures, and vaccination.

The Effects of Birth Year, Age and Sex on Hemagglutination Inhibition Antibody Responses to Influenza Vaccination.

The first exposure to influenza is thought to impact subsequent immune responses later in life. The consequences of this can be seen during influenza epidemics and pandemics with differences in morbidity and mortality for different birth cohorts. There is a need for better understanding of how vaccine responses are affected by early exposures to influenza viruses. In this analysis of hemagglutination inhibition (HI) antibody responses in two cohorts of military personnel we noticed differences related to age, sex, prior vaccination, deployment and birth year. These data suggest that HI antibody production, in response to influenza vaccination, is affected by these factors. The magnitude of this antibody response is associated with, among other factors, the influenza strain that circulated following birth.

Department of Defense end-of-season influenza vaccine effectiveness estimates for the 2017-2018 season.

The Department of Defense (DoD) generates influenza vaccine effectiveness (VE) estimates each season. The Armed Forces Health Surveillance Branch Air Force (AFHSB-AF) satellite, Naval Health Research Center Operational Infectious Disease Directorate at the Naval Health Research Center (NHRCOID), and the Armed Forces Health Surveillance Branch (AFHSB) all conduct influenza surveillance and perform test-negative case-control analyses to estimate seasonal influenza VE for DoD populations. The mid-season estimates contribute to the aggregate data utilized by the Food and Drug Administration's Vaccine and Related Biological Products Advisory Committee to select the composition of the influenza vaccine for the next influenza season. The full season data provide DoD with direct estimates for force health protection decisions. The 2017-2018 DoD influenza season was predominated by influenza A(H3N2) with varying levels of adjusted overall VE estimates. AFHSB-AF satellite's VE for dependents was moderate at 49% (95% confidence interval [CI]: 42%-55%) for all strains. NHRC-OID's VE among dependents was moderate-high at 63% (95% CI: 50%-73%) for all strains. AFHSB service member VE was low at 18% (95% CI: 4%-30%). These estimates highlight the need for continued influenza surveillance and VE estimate calculations each season among the different DoD populations as circulating strains and VE may change annually.

Different Repeat Annual Influenza Vaccinations Improve the Antibody Response to Drifted Influenza Strains.

Seasonal influenza vaccine formulas change almost every year yet information about how this affects the antibody repertoire of vaccine recipients is inadequate. New vaccine virus strains are selected, replacing older strains to better match the currently circulating strains. But even while the vaccine is being manufactured the circulating strains can evolve. The ideal response to a seasonal vaccine would maintain antibodies toward existing strains that might continue to circulate, and to generate cross-reactive antibodies, particularly towards conserved influenza epitopes, potentially limiting infections caused by newly evolving strains. Here we use the hemagglutination inhibition assay to analyze the antibody repertoire in subjects vaccinated two years in a row with either identical vaccine virus strains or with differing vaccine virus strains. The data indicates that changing the vaccine formulation results in an antibody repertoire that is better able to react with strains emerging after the vaccine virus strains are selected. The effect is observed for both influenza A and B strains in groups of subjects vaccinated in three different seasons. Analyses include stratification by age and sex.

Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members.

Mefloquine was widely prescribed to U.S. military service members until 2009 when use was limited to personnel with contraindications to doxycycline and no contraindications to mefloquine. The need to estimate the occurrence of neuropsychiatric outcomes (NPOs) in service members prescribed mefloquine warranted a comprehensive evaluation of this issue. Active component service members filling a prescription for mefloquine, doxycycline, or atovaquone/proguanil (A/P) between January 1, 2008 and June 30, 2013, were included in the analysis. The risk of developing incident NPOs and the risk of subsequent NPOs among subjects with a history of the condition were assessed. A total of 367,840 individuals were evaluated (36,538 received mefloquine, 318,421 received doxycycline, and 12,881 received A/P). Among deployed individuals prescribed mefloquine, an increased risk of incident anxiety was seen when compared with doxycycline recipients (incidence rate ratio [IRR] = 1.12 [1.01-1.24]). Among nondeployed mefloquine recipients, an increased risk of posttraumatic stress disorder (PTSD) was seen when compared with A/P recipients (IRR = 1.83 [1.07-3.14]). An increased risk of tinnitus was seen for both deployed and nondeployed mefloquine recipients compared with A/P recipients (IRR = 1.81 [1.18-2.79]), 1.51 (1.13-2.03), respectively). Six percent of the mefloquine cohort had an NPO in the year before receiving mefloquine. When comparing individuals with a prior neuropsychiatric history to those without, the ratio of relative risks for adjustment disorder, anxiety, insomnia, and PTSD were higher (not statistically significant) for mefloquine compared with doxycycline. These findings emphasize the continued need for physicians prescribing mefloquine to conduct contraindication screening.

Incidence and recent trends in functional gastrointestinal disorders, active component, U.S. Armed Forces, 2005-2014.

Functional gastrointestinal disorders (FGIDs) are common chronic conditions with an unknown pathophysiology and etiology. FGIDs elevate healthcare costs and cause substantial burden to public health and the military, including diminished readiness, productivity, and quality of life. This retrospective cohort study of active component U.S. military personnel covered a 10-year surveillance period, 2005-2014. The Defense Medical Surveillance System (DMSS) was the data source. Incident cases were identified and rates were calculated and stratified by important covariates. Trends were described over the surveillance period. Incidence rates among deployed personnel were compared to rates in non-deployed personnel, stratified by age and sex. An increasing trend in functional constipation was observed during 2005-2012. Being female, black, in the Army or Air Force, and younger than 20 years of age or 40 years of age or older was associated with higher incidence rates. Deployment-exposed personnel had incidence rates that were 53% higher than those of non-deployed personnel. Elevated rates in personnel younger than 20 years of age and deployed personnel evoke interest concerning readiness and cost implications for the Military Health System. These subgroups should be examined in future studies.

Post-refractive surgery complications and eye disease, active component, U.S. Armed Forces, 2005-2014.

Refractive surgery (RS) is a common procedure in the U.S. military population. This report provides an estimation of incident RS for vision correction purposes in the active component of the U.S. military from 1 January 2005 through 31 December 2014 and the prevalence of post-RS complications and eye disease in the 1-year period after RS. During the surveillance period, a total of 121,571 subjects without a diagnosis of eye disease other than hyperopia, myopia, or astigmatism in the previous year received a single incident RS procedure. In the 1-year period after RS, 5.3% of subjects with preoperative hyperopia or myopia had treatment-persistent (unresolved) hyperopia or myopia; 2.0% of subjects with preoperative astigmatism had treatment-persistent (unresolved) astigmatism; and 3.8% were diagnosed with tear film insufficiency. In general, most outcomes showed higher prevalences in Army and Air Force personnel versus Navy and Marine Corps personnel, in women versus men, in officer versus enlisted personnel, and in aviation and Special Forces personnel. A wide variation in outcome prevalences was noted by procedural military treatment facility.

Intra-Weekly Variations of Influenza-Like Illness in Military Populations.

In this report, we describe and analyze a periodic pattern in influenza-like illness within active military populations, derived from the Defense Medical Surveillance System data set. We find that there is a well-defined pattern with peak incidence on Monday, decaying to Friday, and remaining roughly constant over the weekend. Moreover, we find that the pattern systematically changes in response to public holidays. We quantitatively describe the effect of this modulation, and show how these results may be used to detrend military and, by extension, civilian data sets. As medical data streams become more timely, these results may be used to infer near-real-time daily estimates of influenza-like illness incidence, which may form the basis of a forecasting tool for imminent outbreaks.

Costs and consequences: Hepatitis C seroprevalence in the military and its impact on potential screening strategies.

UNLABELLED: Knowledge of the contemporary epidemiology of hepatitis C viral (HCV) infection among military personnel can inform potential Department of Defense screening policy. HCV infection status at the time of accession and following deployment was determined by evaluating reposed serum from 10,000 service members recently deployed to combat operations in Iraq and Afghanistan in the period 2007-2010. A cost model was developed from the perspective of the Department of Defense for a military applicant screening program. Return on investment was based on comparison between screening program costs and potential treatment costs avoided. The prevalence of HCV antibody-positive and chronic HCV infection at accession among younger recently deployed military personnel born after 1965 was 0.98/1000 (95% confidence interval 0.45-1.85) and 0.43/1000 (95% confidence interval 0.12-1.11), respectively. Among these, service-related incidence was low; 64% of infections were present at the time of accession. With no screening, the cost to the Department of Defense of treating the estimated 93 cases of chronic HCV cases from a single year's accession cohort was $9.3 million. Screening with the HCV antibody test followed by the nucleic acid test for confirmation yielded a net annual savings and a $3.1 million dollar advantage over not screening. CONCLUSIONS: Applicant screening will reduce chronic HCV infection in the force, result in a small system costs savings, and decrease the threat of transfusion-transmitted HCV infection in the battlefield blood supply and may lead to earlier diagnosis and linkage to care; initiation of an applicant screening program will require ongoing evaluation that considers changes in the treatment cost and practice landscape, screening options, and the epidemiology of HCV in the applicant/accession and overall force populations.

Risk factors for severe outcomes among members of the United States military hospitalized with pneumonia and influenza, 2000-2012.

BACKGROUND: The progression from hospitalization for a respiratory infection to requiring substantial supportive therapy is a key stage of the influenza severity pyramid. Respiratory infections are responsible for 300,000-400,000 medical encounters each year among US military personnel, some of which progress to severe acute respiratory infections. METHODS: We obtained data on 11,086 hospitalizations for pneumonia and influenza (P&I) among non-recruit US military service members during the period of 1 January 2000 through 31 December 2012. From these, we identified 512 P&I hospitalizations that progressed to severe episodes using standard case definitions. We evaluated the effect of demographic and occupational characteristics, co-morbid conditions, and history of influenza vaccination on the risk of a hospitalized P&I case becoming a severe case. We also evaluated the risk of a severe outcome and the length of time since influenza vaccination (within 180, 60, and 30 days). RESULTS: The median age of subjects at the time of the P&I episode was 32 years (range, 28-40) and subjects were predominantly male (89.5%). In a univariate analysis, demographic risk factors for a severe episode included service in the US Air Force (RR=1.6 relative to US Army, 95%CI 1.3-2.1), US Coast Guard (RR=2.1, 1.2-3.7) or US Navy (RR=1.4, 1.1-1.8). Being born in the US and recent influenza vaccination (within 180 days of episode) were protective against developing severe disease. Among co-morbid conditions, univariate risk factors for severe disease included chronic renal or liver disease (RR=4.98, 95%CI 4.1-6.1), diseases of the circulatory system (RR=3.1, 95%CI 2.6-3.7), diabetes mellitus (RR=2.3, 95%CI 1.5-3.6), obesity (RR=1.6, 95%CI 1.2-2.1), cancer (RR=1.6, 95%CI 1.3-2.0), and chronic obstructive pulmonary disease (RR=1.4, 95%CI 1.1-1.7). Although many of the risk factors found to be significant in univariate analysis were no longer significant under a multivariate analysis, receipt of any influenza vaccine within 180 days of episode remained protective (RR=0.81, 95%CI 0.67-0.99), while serving in the US Coast Guard (RR=1.9, 95%CI 1.1-3.4) or US Air Force (RR=1. 5, 95%CI 1.2-2.0), presence of renal or liver disease (RR=3.6, 95%CI 2.9-4.6), and diseases of the circulatory system (RR=2.2, 95%CI 1.8-2.8), remained significantly associated with a higher risk of developing severe disease. CONCLUSIONS: In a large cohort, after adjusting for many possible risk factors, influenza vaccination was protective against severe episodes among P&I hospitalizations. The service-specific (US Coast Guard or US Air Force) increased risk may represent some differences in data (e.g., coding or reporting practices) as opposed to genuine differences in physiological outcome. Our findings suggest that renal and liver disease as well as diseases of the circulatory system may contribute to influenza severity in this population independently of age and other potential comorbidities. These findings provide additional evidence for the prioritization of specific risk groups within the US military for influenza vaccination.