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.

Evaluation of ICD-10-CM-based case definitions of ambulatory encounters for COVID-19 among Department of Defense health care beneficiaries.

SARS-CoV-2 ICD-10-CM-based case definitions are lacking in the literature. This analysis was conducted to evaluate the performance metrics of 3 COVID-19 case definitions among Department of Defense (DoD) beneficiaries. SARS-CoV-2 tested specimens collected from 1 March 2020 to 28 February 2021 were matched to ambulatory medical encounters (68% match). The COVID-19 case definition (ICD-10-CM: U07.1) had high specificity (99%) and positive predictive value (PPV) (94%) but low to moderate (29%-66%) sensitivity. The COVID-specific case definition (10 additional codes added), had moderate to high specificity (82-93%), moderate sensitivity (65-75%), and low to moderate PPV (23%-77%). The COVID-like illness case definition (19 additional codes added to the COVID-specific definition), had moderate specificity (65%-86%), moderate sensitivity (76%-79%), and low to moderate PPV (15%-62%). Regardless of the case definition, all metrics improved over the surveillance period. The COVID-19 case definition is ideal for studies that need to ensure all cases are true positives. However, for broad surveillance efforts, the COVID-specific case definition may be the best to maximize specificity without a large decrease in sensitivity and PPV.

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.

Department of Defense mid-season vaccine effectiveness estimates for the 2019-2020 influenza season.

This report provides mid-season vaccine effectiveness (VE) estimates from the Armed Forces Health Surveillance Division (AFHSD), the DoD Global Respiratory Pathogen Surveillance (DoDGRS) program, and the Naval Health Research Center (NHRC) for the 2019-2020 influenza season. Using a test negative case-control study design, the AFHSD performed a VE analysis for active component service members while the DoDGRS program and NHRC collaborated to perform a VE analysis for DoD beneficiaries and U.S.-Mexico border civilians. Among active component service members, there was low to moderate protection against influenza B, moderate protection against A(H3N2), and non-statistically significant low protection against influenza A overall and A(H1N1). Among DoD beneficiaries and U.S.-Mexico border civilians, there was statistically significant moderate protection against influenza B, influenza A overall, A(H1N1), and A(H3N2).

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.

Neutralizing and Neuraminidase Antibodies Correlate With Protection Against Influenza During a Late Season A/H3N2 Outbreak Among Unvaccinated Military Recruits.

BACKGROUND: Antibodies that inhibit hemagglutination have long been considered a correlate of protection against influenza, but these antibodies are only a subset of potentially protective antibodies. Neutralizing and neuraminidase antibodies may also contribute to protection, but data on their associations with protection are limited. METHODS: We measured preoutbreak hemagglutinin pseudovirus neutralization (PVN) and neuraminidase inhibition (NAI) antibody titers in unvaccinated military recruits who experienced an H3N2 influenza outbreak during training. We conducted a case-control study to investigate the association between titers and protection against influenza illness or H3N2-associated pneumonia using logistic regression. RESULTS: With every 2-fold increase in PVN titer, the odds of medically attended polymerase chain reaction-confirmed H3N2 infection (H3N2+) decreased by 41% (odds ratio [OR], 0.59; 95% confidence interval [CI], .45 to .77; P < .001). Among those who were H3N2+, the odds for pneumonia decreased by 52% (OR, 0.48; CI, .25 to .91; P = .0249). With every 2-fold increase in NAI titer, the odds of medically attended H3N2 infection decreased by 32% (OR, 0.68; 95% CI, .53 to .87; P = .0028), but there was no association between NAI titers and H3N2-associated pneumonia. There was also no synergistic effect of PVN and NAI antibodies. CONCLUSIONS: PVN and NAI titers were independently associated with reduced risk of influenza illness. NAI titers associated with protection had greater breadth of reactivity to drifted strains than PVN titers. These findings show that PVN and NAI titers are valuable biomarkers for assessing the odds of influenza infection.

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.

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.

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.

A Brief Description of the Operation of the DoD Serum Repository.

Beginning in 1985, the United States military has consistently maintained repositories of frozen human serum for force health protection reasons. The separate repositories created by the Army, Navy, and Air Force during the startup of their human immunodeficiency virus (HIV) screening programs were fully combined by 1996, along with the Defense Medical Surveillance System, to form the DoD Serum Repository (DoDSR). Currently comprised of 450,000 square feet of storage space at a constant -30 degrees Celsius, the DoDSR, operated by the Armed Forces Health Surveillance Center (AFHSC), receives approximately 2 million new serum specimens per year as a result of current HIV screening programs and pre- and post-deployment serum collection. Following initial testing for HIV when required, each specimen remains frozen until needed for clinical testing or a public health study, and its physical location is carefully tracked. Certain militarily-relevant research studies occur, though the serum from a specific individual is never allowed to be fully exhausted. AFHSC maintains careful control over the repository, utilizing a scientific review board to determine which requests for serum will be granted. As of 2012, only 0.42% of all of the frozen specimens in the DoDSR had been thawed for any type of use. The addition of new specimen processing capacity and significant changes to policy would be required if more of the specimens were to be used to answer relevant epidemiological, operational, or medical research questions.

Assessment of ICD-9-based case definitions for influenza-like illness surveillance.

Population-based surveillance of influenza routinely relies on administrative medical encounter databases and ICD-9 codes. However, an assessment of the ICD-9 codes used for the Department of Defense (DoD) influenza-like illness (ILI) case definition has not been conducted since 2007. As coding practices may have changed over time, this analysis was done to determine the sensitivity, specificity, and positive predictive value (PPV) of the current ILI case definition and three alternative case definitions for the 2014-2015 influenza season. Influenza laboratory tests conducted on specimens from DoD beneficiaries during the 2014-2015 season were matched to ambulatory and inpatient medical encounters. The current DoD ILI case definition had high sensitivity (92%) but low specificity (30%) and moderate PPV (63%). A more specific ILI case definition utilizing only codes with greater than 75% influenza positivity for the matched laboratory test had high specificity (96%) and PPV (96%) and moderate sensitivity (62%). The current ILI case definition is sufficient for broad, sensitive population-based surveillance; however, an alternative case definition may be more appropriate when there is a need to maximize specificity.