[This corrects the article DOI: 10.1371/journal.pone.0297481.].

Plasmodium vivax malaria is a threat to armed forces operating in the Korean Peninsula. Surges in malaria cases in the Republic of Korea entail increased risk. We report 6 cases from a cluster of P. vivax malaria cases in a non-endemic setting in active duty personnel who had redeployed from the Korean Peninsula. Demographics, disease course, and laboratory data were collected on 6 patients diagnosed with Plasmodium vivax malaria at Fort Bliss in 2022. All patients were males, with a mean age of 23 years (range 20-27 years), exposed in the Dagmar North training area in the Gyeonggi province in 2021, with an average time from symptom onset to diagnosis of 57 days (8-121 days). All had uncomplicated malaria. Laboratory findings included hemoglobin of 12.1g/dL (range 8.1-14.2 g/dL), platelets of 123 × 103/µL (range 40-171 × 103/µL), and parasitemia <1% (0.1%-0.9%) with diagnosis on peripheral smear and/or rapid antigen testing. No cases received chemoprophylaxis. Patients were treated with artemether/lumefantrine and primaquine. Clearance of parasitemia on peripheral smear was seen after an average of 2.8 days (range 2-4 days). Changing vector ecology and increased tempo of training exercises in the Dagmar North Region near the Demilitarized Zone are hypothesized to contribute to this cluster of cases. Malaria diagnosis post-deployment in non-endemic regions is challenging due to the long latency of illness onset and requires clinician vigilance. Preventive measures of pre-deployment should also be emphasized.

BACKGROUND:Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS:This analysis included 1988 SARS-CoV-2 positive U.S. Military Health System beneficiaries who had quantitative post-COVID symptom scores. Among participants who reported moderate-to-severe symptoms on surveys collected 6 months post-SARS-CoV-2 infection, principal component analysis followed by k-means clustering identified distinct clusters of symptoms. RESULTS:Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization than those with no/mild symptoms at 6 months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS:We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

ABSTRACT Antigen-based rapid diagnostic tests (Ag-RDTs) provide timely results, are simple to use, and are less expensive than molecular assays. Recent studies suggest that antigen-based testing aligns with virus culture-based results (a proxy of contagiousness at the peak viral phase of illness); however, the performance of Ag-RDTs for newer SARS-CoV-2 variants is unclear. In this study, we (i) assessed the performance of Ag-RDTs and diagnostic antibodies to detect a range of SARS-CoV-2 variants and (ii) determined whether Ag-RDT results correlated with culture positivity. We noted only minor differences in the limit of detection by variant for all assays, and we demonstrated consistent antibody affinity to the N protein among the different variants. We observed moderate to high sensitivity (46.8%–83.9%) for Ag-RDTs when compared to PCR positivity (100%), and all variants were assessed on each assay. Ag-RDT sensitivity and PCR Ct showed an inverse correlation with the detection of viable virus. Collectively, our results demonstrate that commercially available Ag-RDTs offer variable sensitivity compared to PCR, show similar diagnostic validity across variants, and may predict the risk of transmissibility. These findings may be used to support more tailored SARS-CoV-2 isolation strategies, particularly if other studies clarify the direct association between Ag-RDT positivity and transmission risk. The apparent trade-off between sensitivity in the detection of any PCR-positive infection and concordance with infectious virus positivity may also inform new RDT diagnostic development strategies for SARS-CoV-2 and other epidemic respiratory pathogens. IMPORTANCE Despite the availability of vaccines, COVID-19 continues to be a major health concern, and antigen-based rapid diagnostic tests (Ag-RDTs) are commonly used as point-of-care or at-home diagnostic tests. In this study, we evaluated the performance of two commercially available Ag-RDTs and a research Ag-RDT to detect multiple SARS-CoV-2 variants using upper respiratory tract swab samples from clinical COVID-19 cases. Furthermore, we determined whether Ag-RDT results correlated with culture positivity, a potential proxy of viral transmissibility. Our results have important implications to inform future testing and response strategies during periods of high COVID-19 transmission with new variants.

Background:Previous research has shown that vaccination reduces risk of post-coronavirus disease 2019 (COVID-19) venous thrombosis or embolism (VTE), but the effect of vaccine boosting on post-COVID-19 VTE risk reduction is unclear. We sought to estimate the effect of COVID-19 vaccination on the risk of post-COVID-19 VTE and to examine if the magnitude of this association differed among variant eras. Methods:We performed a case-control study of Military Health System (MHS) beneficiaries who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2022. Cases were defined as those with medically attended VTE within 90 days after their first positive SARS-CoV-2 test; controls were defined as SARS-CoV-2 infections without incident VTE by 90 days. Multivariate logistic regression estimated the odds of post-SARS-CoV-2 VTE based on pre-COVID-19 vaccine status, adjusting for other VTE risk factors. Results:A total of 4646 MHS beneficiaries were included in this analysis; 1370 received a primary vaccine series and a further 790 received at least 1 booster at time of infection; 71 had VTE within 90 days of SARS-CoV-2 infection. Those who were vaccinated had lower odds of VTE (adjusted odds ratio [95% confidence interval]) compared to the unvaccinated following infection (primary series: 0.28 [.13-.62]; booster dose: 0.06 [.01-.46]). Post-COVID-19 VTE risk was lowest during the Omicron era, but VTEs were too rare to examine for an interaction of variant era and vaccine effect. Conclusions:Among MHS beneficiaries, COVID-19 vaccination was associated with a reduced risk of post-COVID-19 VTE diagnosis; estimated risk reduction was larger among those who received a booster.

BACKGROUND:Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype. METHODS:The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores. RESULTS:The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant. CONCLUSIONS:Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes.

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials.

Abstract Background SARS-CoV-2 infections have been associated with self-reported impaired cognitive function, but research examining objective cognitive assessments is scant. Given the potential impact of long-term cognitive impairment, it is important to characterize this post-infection phenotype. Methods The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal cohort assessing the impact of SARS-CoV-2 infection in Military Health System (MHS) beneficiaries. A subset of EPICC enrollees consented to cognitive assessment using the Brain-Baseline Assessment of Cognition and Everyday Functioning app (BRACE; Digital Artefacts LLC, Iowa City, IA) and completed 4 tasks: Trails Making Tests A and B, Stroop task, and Visuospatial Short-term Memory task. Participants completed the tasks in August-September 2022 and were categorized as impaired if their mean completion time was >1 SD above the control sample mean. Results A total of 482 participants completed the cognitive assessments, 71% of whom had a known history of SARS-CoV-2 infection. Among those with a history of SARS-CoV-2 infection, the mean time between first positive SARS-CoV-2 test and module completion was 9 months (SD=5). Participants were primarily active duty service members (80%), male (65%), and non-Hispanic white (70%). SARS-CoV-2 infections were primarily mild or asymptomatic with only 14 (4.1%) hospitalized. Logistic regression models adjusted for sex, race/ethnicity, age, and education showed no difference in impairment in any of the BRACE tests comparing those with and without a history of SARS-CoV-2 infection (Figure 1). Age was a risk factor for impairment across all tests with each additional year increasing risk of impairment by 6-8% (95% CI: 1.04 – 1.11).Figure 1.Adjusted odds of scoring >1 SD above mean completion time of SARS-CoV-2 negative participantsLogistic regression adjusted for age, sex, race/ethnicity, and education Conclusion MHS beneficiaries with a history of SARS-CoV-2 infection did not demonstrate a long-term higher prevalence of objectively measured cognitive impairment compared to participants without SARS-CoV-2 infection after adjusting for demographic variables. Further study is needed to understand the incongruence between reported cognitive symptoms and objectively measured cognitive performance. Disclosures Julia Rozman, BS, AstraZeneca: TBD Mark P. Simons, PhD, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response Timothy Burgess, MD, MPH, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial Simon Pollett, MBBS, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial

Abstract Background SARS-CoV-2 most severely affects older age groups, while children experience minimal disease. We measured elements of adaptive immunity in children and adults with SARS-CoV-2 to define the age-dependent viral and host response. Methods Participants were enrolled in the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study. Eligibility required that individuals present with COVID-19-like symptoms between March 2020 to March 2022. Magnitude of viral RNA was determined by quantitative PCR. SARS-CoV-2-specific antibodies were measured from blood with multiplex microsphere immunoassays. Results Serologic responses against the spike protein were measured at early and convalescent time points and compared by age, predominant infecting SARS-CoV-2 variant, and vaccination status. In those with mild disease, the seropositivity rates did not differ based on age. The magnitude of the anti-spike IgG response differed by age at early time points. Only the oldest age group differed at convalescent time points. Conclusions The serologic response to SAR-CoV-2 differs with age, implicating host immunity in pathogenesis. Improved understanding of the host immune response has the potential to optimize vaccine design. Disclaimer:The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, Department of the Navy, the Department of the Air Force, the Department of Defense or the U.S. Government and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46. This work was supported by the Defense Health Program (grant number HU00012020067) and the National Institute of Allergy and Infectious Diseases (grant number HU00011920111).

Abstract Background The long-term duration of post COVID condition (PCC, “Long COVID”) remains unclear. In this study, we estimated the risk of healthcare encounters in Military Health System (MHS) beneficiaries for the 12 months post SARS-CoV-2 diagnosis, adjusting for prior healthcare use, and compared to those without known prior SARS-COV-2 diagnosis. Methods Follow up continues for the Epidemiology, Immunology and Clinical Characteristics of Emerging Infectious Diseases of Pandemic Potential (EPICC) COVID-19 cohort study MHS beneficiaries who were tested for SARS-COV-2 or vaccinated from March 2020 to April 2022. Participants with SARS-COV-2 diagnosis from 3/1/20 through 12/31/21 were matched 1:1 with participants in the same age group with no record of SARS-COV-2 diagnosis. We identified categories of ICD-10 diagnoses occurring from 3 months before through 12 months after first SARS-COV-2 diagnosis (or matched time point) from electronic medical records. Multivariable Poisson regression models were used to estimate the risk of ICD-10 diagnosis categories for those with past SARS-COV-2 diagnosis, compared to those with no SARS-COV-2 diagnosis, adjusting for age, sex, BMI, variant era, and prior healthcare use.Table 1.Characteristics of matched Epidemiology, Immunology and Clinical Characteristics of Emerging Infectious Diseases of Pandemic Potential (EPICC) participants included in analyses. Statistical comparisons are Pearson’s Chi squared tests, unless otherwise specified. Results Analyses included 1,819 matched pairs with a median age of 35 years. Participants were primarily male (63.0%) or white (57.3%) (Table 1) and severe acute COVID-19 was infrequent (9.6% hospitalized). Compared to those without a history of SARS-COV-2 diagnosis, medical encounters for all diagnosis groups (pulmonary, cardiovascular, diabetes, anxiety/depression, and neurology) were elevated in the first month after SARS-COV-2 diagnosis (Figures 1 and 2). Among the different diagnosis categories, only pulmonary diagnoses remained elevated at 9 months post-infection compared to those without a history of SARS-COV-2 diagnosis (risk ratio: 1.95 (95% CI 1.34, 2.83)). Percent of EPICC participants with medical encounters / diagnoses (by organ system or other domain) in health records. Participants without a history of SARS-CoV-2 infection were assigned the infection date of their matched case. Poisson regression analysis run using each category of healthcare encounters (pulmonary, cardiovascular, diabetes, neurology, and anxiety/depression) as the outcome. The models included time in 30-day periods around SARS-CoV-2 diagnosis date (or matched time point), SARS-CoV-2 diagnosis status, age, sex, BMI category, and variant/calendar period (calendar times with predominant Ancestral, Alpha, or Delta circulation), as well as a random effect for participant. Conclusion MHS beneficiaries with prior SARS-COV-2 diagnosis were at higher risk of pulmonary-associated healthcare encounters through 9 months post-infection compared to those without prior SARS-COV-2 diagnosis, even after adjusting for baseline characteristics and calendar time. Future work will assess the effect of vaccination and boosting on this relationship. Disclosures Michael Morris, MD, Janssen Pharmaceuticals: Paid speaker (unrelated to this project and COVID-19 in general) Ryan C. Maves, MD, Sound Pharmaceuticals: Grant/Research Support Mark Simons, PhD, AstraZeneca: TBD Timothy Burgess, MD, AstraZeneca: TBD Simon Pollett, MBBS, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial

Visceral leishmaniasis (VL) is a chronic infection caused by Leishmania (L.) donovani or L. infantum parasites. Despite having the infection, most individuals never develop the clinical disease and are able to control the parasite and remain asymptomatic. However, some progress to symptomatic VL, leading to death if untreated. The host immune response has a major role in determining the progression and severity of the clinical manifestations in VL; several immune biomarkers of symptomatic VL have been described with interferon-gamma release as a surrogate biomarker of host cellular immunity. However, new biomarkers to identify asymptomatic VL (AVL) are needed for the identification of people at risk for VL activation. In our study, levels of chemokine/cytokine in the supernatants of peripheral mononuclear blood cells (PBMC) from 35 AVL+ Iraq-deployed participants, stimulated in vitro with soluble Leishmania antigen for 72 h, were assessed by a bead-based assay that allows the measurement of multiple analytes. PBMC of AVL-negative military beneficiaries were used as controls. Monocyte Chemoattractant Protein-1, Monokine Induced by Gamma Interferon and Interleukin-8, were detected at high levels in AVL+ stimulated cultures from Iraq deployers compared to uninfected controls. Measurement of chemokine/cytokine levels can identify cellular immune responses in AVL+ asymptomatic individuals.

Abstract Background Prior studies suggest SARS-CoV-2 (SC2) infection and vaccination are risk factors for the development of Herpes Zoster (HZ). We performed a nested case-control study using data from the Epidemiology, Immunology and Clinical Characteristics of Emerging Infectious Diseases of Pandemic Potential (EPICC) cohort to evaluate the impact of SC2 exposure (positive SC2 test or COVID-19 vaccination) on the odds of HZ diagnosis. Methods The EPICC cohort is comprised primarily of younger (median age 34.6 years) Military Health System (MHS) beneficiaries who were either tested for SC2 and/or received COVID-19 vaccination. MHS Data Repository (MDR) records were evaluated for HZ diagnosis. Information about SC2 diagnosis and COVID-19 vaccination was aggregated from participant survey data and MDR records. Cases were defined as adult participants with an HZ ICD-10 code after 3/1/2020. Controls were selected randomly and matched individually to cases on age, race, sex, and time period. We defined exposure as ≥ 1 SC2 positive test or COVID-19 vaccination 0-365 days before HZ diagnosis. We used conditional logistic regression to explore the association between SC2 diagnosis, or COVID-19 vaccination, and HZ diagnosis, adjusting for comorbidities and HZ vaccination. Results Between 3/2020 and 12/2022, 7,394 were enrolled in the EPICC study, and a total of 94 HZ cases were identified. The median age at HZ diagnosis was 39 years (IQR: 33, 48). There was no difference between the median age of HZ cases with and without SC2 diagnosis (38.5 and 39.4 years respectively, p=0.96). Among HZ cases, 28 (30%) had ≥ 1 SC2 diagnosis in the year prior, compared to 12 controls (13%) (Table 1). Participants with a known history of SC2 diagnosis were more likely to be HZ cases (OR 2.7; 95% CI: 1.3, 5.8), adjusting for HZ vaccination and Charlson Comorbidity Index (Table 2). No significant association was found between COVID-19 vaccination and HZ (OR: 1.0; 95% CI: 0.4, 2.5). Sensitivity analyses (exposure 1-90 days prior to HZ diagnosis) found similar results (Table 2). Conclusion In a cohort primarily comprised of younger individuals, SC2 diagnosis, but not COVID-19 vaccination, was associated with increased risk for HZ diagnosis. Disclosures Mark P. Simons, PhD, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response Timothy Burgess, MD, MPH, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial Simon Pollett, MBBS, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial

Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10–20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto-Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) cohort collected demographic data, clinical data and sera from SARS-CoV-2 infected patients enrolled across 10 U.S. military treatment facilities. We screened sera collected <21 days post-symptom onset from 214 COVID-19 inpatients and 312 COVID-19 outpatients for IFN auto-Ab positivity and neutralizing activity using Luminex and intracellular flow cytometry, respectively. Similar to previous reports, we detected neutralizing auto-Abs against IFN-α and/or IFN-ω in a significantly higher frequency of inpatients (9 total, 4.2%) versus outpatients (1, 0.32%) (p=0.009). Remarkably, IFN auto-Abs persisted 6–12 months post-infection in most inpatients, including several with a prior history of autoimmune disease. Among inpatients, multivariate logistic regression analyses demonstrated that type I IFN auto-Abs were associated with a greater risk of severe and critical COVID-19 (adjusted odds ratio (aOR) = 16.40 and 6.44, respectively) after adjusting for age, sex and comorbidity burden. Our results confirm a robust association between critical COVID-19 and the presence of type I IFN auto-Abs, which may predispose to other severe respiratory viral infections that cause substantial morbidity and mortality in the MHS. This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111). The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF).

Background Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles. Methods 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations. Results We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 (“Nasal cluster”) is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 (“Sensory cluster”) is highly correlated with loss of smell or taste, and cluster 3 (“Respiratory/Systemic cluster”) is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01). Conclusions We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.

Background:The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain.Methods:We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health.Results:The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70).Conclusions:In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss.

Prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection followed by vaccination, or vice versa, provides a greater and more durable immunoglobulin G response than SARS-CoV-2 infection- or vaccine-induced immunity alone. The timing between SARS-CoV-2 infection and vaccination shapes the magnitude of post vaccine responses. Background Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity. Methods We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities. We excluded those with evidence of clinical or subclinical SARS-CoV-2 reinfection from all groups. Results Multivariable regression results indicated that vaccine-after-infection anti-spike-IgG responses were higher than infection-alone (P < .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P < .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P < .01) compared with infection-alone (P < .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P < .01), regardless of infection history. Those with vaccine-after-infection or vaccine-breakthrough-infection had a more durable anti-spike-IgG response compared to infection-alone (P < .01). Conclusions Vaccine-receipt elicited higher anti-spike-IgG responses than infection-alone, although IgG levels waned faster in those vaccinated (compared to infection-alone). Vaccine-after-infection elicits a greater humoral response compared with vaccine or infection alone; and the timing, but not disease severity, of prior infection predicted these post-vaccination IgG responses. While differences between groups were small in magnitude, these results offer insights into vaccine immunogenicity variations that may help inform vaccination timing strategies.

Abstract Background Predicting, preventing, and treating post-COVID condition (PCC; “Long COVID) is challenging due to a limited understanding of PCC mechanisms. To address this, we analyzed whole blood transcriptomic data using machine learning to identify candidate gene and gene expression pathways associated with the development of PCC. Figure 1 (A) Clinical and demographic characteristics of 222 military health system beneficiaries (COVI D, no PCC: SARS-CoV-2 positive subjects reported no or mild symptoms on 6-month survey; COVID, PCC: SARS-CoV-2 positive subjects reported moderate to severe symptoms on 6-month survey; and Control: SARS-CoV-2 negative subjects), (B) AUROC indicates the ability of leading genes (measured early after infection, TSSK4, TUFT1, and XBP1; which have known association with pulmonary fibrosis, lung cancer, and lymphoma, respectively) which can predict which participants develop PCC versus those who do not, and (C) Identification of biomarker candidates for PCC based on machine learning algorithms. Statistical significance was determined by Mann-Whitney U test. Asterisks indicate statistical significance: ns: p > 0.05, *: p ≤ 0.05 Methods The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal cohort study exploring the impact of SARS-CoV-2 infection in military health system beneficiaries. We collected demographic and clinical data through surveys, interviews and medical record reviews. We conducted transcriptome profiling (bulk RNA-seq) on early post-infection whole blood samples from unvaccinated individuals with and without PCC at 6-months, as well as uninfected, unvaccinated controls. These three groups were matched on sex, age, and comorbidities. We identified transcriptomic signatures associated with group classes using t-tests with correction for multiple comparisons. Molecular signatures and candidate markers for PCC were developed using gene set enrichment analysis (GSEA) and machine learning, including random forest (RF) and support vector machine (SVM) methods. Results Out of the 5289 SARS-CoV-2 positive Military Health System beneficiaries enrolled in EPICC, 814 participants had at least one sample with blood transcriptomic profiling data. Among these, 171 unvaccinated, SARS-CoV-2 positive participants completed a 6-month follow up survey and were included in the analysis. Ninety-one percent did not report any chronic symptoms, while 8% reported moderate to severe symptoms at six months and were classified as PCC group. A control group of 51 participants was also identified. Machine learning approaches (RF: AUROC = 0.90, CI = 0.79 to 1; and SVM: AUROC = 0.89, CI = 0.76 to 1) identified three candidate biomarkers (Figure 1), including TSSK4, TUFT1, and XBP1 genes, which could be a predictive or mechanistic marker for PCC with further validation. Conclusion Our study demonstrates the potential of using machine learning to translate transcriptomic data into precision medicine applications, specifically for predicting the development of PCC after COVID-19. Disclosures Mark P. Simons, PhD, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response Timothy Burgess, MD, MPH, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial Simon Pollett, MBBS, AstraZeneca: The IDCRP and the Henry M. Jackson Foundation (HJF) were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial

Importance Understanding the factors associated with post-COVID conditions is important for prevention. Objective To identify characteristics associated with persistent post–COVID-19 symptoms and to describe post–COVID-19 medical encounters. Design, Setting, and Participants This cohort study used data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) study implemented in the US military health system (MHS); MHS beneficiaries aged 18 years or older who tested positive for SARS-CoV-2 from February 28, 2020, through December 31, 2021, were analyzed, with 1-year follow-up. Exposures SARS-CoV-2 infection. Main Outcomes and Measures The outcomes analyzed included survey-reported symptoms through 6 months after SARS-CoV-2 infection and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis categories reported in medical records 6 months following SARS-CoV-2 infection vs 3 months before infection. Results More than half of the 1832 participants in these analyses were aged 18 to 44 years (1226 [66.9%]; mean [SD] age, 40.5 [13.7] years), were male (1118 [61.0%]), were unvaccinated at the time of their infection (1413 [77.1%]), and had no comorbidities (1290 [70.4%]). A total of 728 participants (39.7%) had illness that lasted 28 days or longer (28-89 days: 364 [19.9%]; ≥90 days: 364 [19.9%]). Participants who were unvaccinated prior to infection (risk ratio [RR], 1.39; 95% CI, 1.04-1.85), reported moderate (RR, 1.80; 95% CI, 1.47-2.22) or severe (RR, 2.25; 95% CI, 1.80-2.81) initial illnesses, had more hospitalized days (RR per each day of hospitalization, 1.02; 95% CI, 1.00-1.03), and had a Charlson Comorbidity Index score of 5 or greater (RR, 1.55; 95% CI, 1.01-2.37) were more likely to report 28 or more days of symptoms. Among unvaccinated participants, postinfection vaccination was associated with a 41% lower risk of reporting symptoms at 6 months (RR, 0.59; 95% CI, 0.40-0.89). Participants had higher risk of pulmonary (RR, 2.00; 95% CI, 1.40-2.84), diabetes (RR, 1.46; 95% CI, 1.00-2.13), neurological (RR, 1.29; 95% CI, 1.02-1.64), and mental health–related medical encounters (RR, 1.28; 95% CI, 1.01-1.62) at 6 months after symptom onset than at baseline (before SARS-CoV-2 infection). Conclusions and Relevance In this cohort study, more severe acute illness, a higher Charlson Comorbidity Index score, and being unvaccinated were associated with a higher risk of reporting COVID-19 symptoms lasting 28 days or more. Participants with COVID-19 were more likely to seek medical care for diabetes, pulmonary, neurological, and mental health–related illness for at least 6 months after onset compared with their pre-COVID baseline health care use patterns. These findings may inform the risk-benefit ratio of COVID-19 vaccination policy.

Abstract Background Nasopharyngeal (NP) swabs are the standard for SARS-CoV-2 diagnosis. If less invasive alternatives to NP swabs (eg, oropharyngeal [OP] or nasal swabs [NS]) are comparably sensitive, the use of these techniques may be preferable in terms of comfort, convenience, and safety. Methods This study compared the detection of SARS-CoV-2 in swab samples collected on the same day among participants with at least one positive PCR test. Results Overall, 755 participants had at least one set of paired swabs. Concordance between NP and other swab types was 75% (NS), 72% (OP), 54% (rectal swabs [RS]), and 78% (NS/OP combined). Kappa values were moderate for the NS, OP, and NS/OP comparisons (0.50, 0.45, and 0.54, respectively). Highest sensitivity relative to NP (0.87) was observed with a combination of NS/OP tests (positive if either NS or OP was positive). Sensitivity of the non-NP swab types was highest in the first week postsymptom onset and decreased thereafter. Similarly, virus RNA quantity was highest in the NP swabs as compared with NS, OP, and RS within two weeks postsymptom onset. OP and NS performance decreased as virus RNA quantity decreased. No differences were noted between NS specimens collected at home or in clinic. Conclusions NP swabs detected more SARS-CoV-2 cases than non-NP swabs, and the sensitivity of the non-NP swabs decreased with time postsymptom onset. While other swabs may be simpler to collect, NP swabs present the best chance of detecting SARS-CoV-2 RNA, which is essential for clinical care as well as genomic surveillance.

Abstract Background COVID-19 may have deleterious effects on the fitness of active duty US military service members. We seek to understand the long-term functional consequences of SARS-CoV-2 infection in this critical population, and in other military healthcare beneficiaries. Methods The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal cohort study to describe the outcomes of SARS-CoV-2 infection in US Military Health System beneficiaries. Subjects provided information about difficulties experienced with daily activities, exercise, and physical fitness performance via electronic surveys. Subjects completed surveys at enrollment and at 1, 3, 6, 9, and 12 months. Results 5,910 subjects completed survey fitness questions, 3,244 (55%) of whom tested SARS-CoV-2 positive at least once during the period of observation. Over 75% of subjects were young adults and over half were male (Table 1). 1,093 (34.3%) of SARS-CoV-2-positive subjects reported new or increased difficulty exercising compared to 393 (14.8%) SARS-CoV-2 negative subjects (p < 0.01) (Table 2). The most commonly reported symptoms related to problems with exercise and activities were dyspnea and fatigue. Among the active-duty members who answered the question about their service-mandated physical fitness test scores, 43.2% of SARS-CoV-2-positive participants reported that their scores had worsened in the study period, compared with 24.3% of SARS-CoV-2 negative participants. Among SARS-CoV-2-positive subjects, reports of difficulty exercising and performing daily activities were highest within one month of the first positive test, decreasing in prevalence among the cohort only slightly to 24% and 18%, respectively, at 12 months (Figure 1). Conclusion A substantial proportion of military service-members in this cohort have reported impairment of their service-mandated physical fitness scores after COVID-19; this proportion is significantly higher than those who are SARS-CoV-2 negative and persists to 12 months in many; similar complaints were reported among non-active duty. Further objective evaluation of post-COVID fitness impairment in this population is warranted. Disclosures Ryan C. Maves, MD, AiCuris: Grant/Research Support|Sound Pharmaceuticals: Grant/Research Support|Trauma Insights, LLC: Advisor/Consultant Julia S. Rozman, n/a, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Mark P. Simons, PhD, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.