Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Circulating effector γδ T cell populations are associated with acute coronavirus disease 19 in unvaccinated individuals.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe coronavirus disease 2019 (COVID-19) in a small proportion of infected individuals. The immune system plays an important role in the defense against SARS-CoV-2, but our understanding of the cellular immune parameters that contribute to severe COVID-19 disease is incomplete. Here, we show that populations of effector γδ T cells are associated with COVID-19 in unvaccinated patients with acute disease. We found that circulating CD27neg CD45RA+ CX3CR1+ Vδ1effector cells expressing Granzymes (Gzms) were enriched in COVID-19 patients with acute disease. Moreover, higher frequencies of GzmB+ Vδ2+ T cells were observed in acute COVID-19 patients. SARS-CoV-2 infection did not alter the γδ T cell receptor repertoire of either Vδ1+ or Vδ2+ subsets. Our work demonstrates an association between effector populations of γδ T cells and acute COVID-19 in unvaccinated individuals.

SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity.

Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

COVID-Care – a safe and successful digital self-assessment tool for outpatients with proven and suspected coronavirus-2019

Introduction The coronavirus-2019 (COVID-19) pandemic and restrictions placed on movement to prevent its transmission have led to a surge in demand for remote medical care. We investigated whether COVID-Care, a patient-reported, telehealth, symptom monitoring system, was successful at delivering safe monitoring and care for these patients leading to decreased hospital presentations. Methods We performed a single centre, prospective, interventional cohort study with symptomatic outpatients who presented for COVID-19 screening at Austin Health, Australia. Participants were invited to take part in the COVID-Care programme, entering common COVID-19 symptoms on a purpose-built, online survey monitored by infectious diseases physicians, and matched with clinical data including date of symptom onset, hospital admission, and screening clinic presentations. Results 42,158 COVID-19 swabs were performed in 31,626 patients from March to October 2020, with 414 positive cases. 20,768 people used the COVID-Care survey at least once. COVID-Care users were significantly younger than non-users. Of the 414 positive cases, 254 (61.3%) used COVID-Care, with 160 (38.6%) non-users. Excluding presentations on the same day or prior to the COVID-19 swab, of the positive cases there were 56 hospital presentations. 4.3% (11) of COVID-Care users and 28.1% (45) non-users were admitted to hospital or the emergency department (p < 0.001), with 3.9% (10) versus 22.5% (36) requiring inpatient admission (p < 0.001). There were no deaths in COVID-Care users versus 2 deaths in non-users. Conclusion COVID-Care, a digitally integrated, outpatient, symptom tracking and telemedical service for patients with COVID-19, was safe and successful at reducing hospital and emergency department admissions, suggesting a strong role for telemedicine for future healthcare delivery in this logistically challenging setting.

Defective Severe Acute Respiratory Syndrome Coronavirus 2 Immune Responses in an Immunocompromised Individual With Prolonged Viral Replication.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2-specific antibody responses were absent and SARS-CoV-2-specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.

Staff to staff transmission as a driver of healthcare worker infections with COVID-19.

BACKGROUND: High rates of healthcare worker (HCW) infections due to COVID-19 have been attributed to several factors, including inadequate personal protective equipment (PPE), exposure to a high density of patients with COVID-19, and poor building ventilation. We investigated an increase in the number of staff COVID-19 infections at our hospital to determine the factors contributing to infection and to implement the interventions required to prevent subsequent infections. METHODS: We conducted a single-centre retrospective cohort study of staff working at a tertiary referral hospital who tested positive for SARS-CoV-2 between 25 January 2020 and 25 November 2020. The primary outcome was the source of COVID-19 infection. RESULTS: Of 45 staff who returned a positive test result for SARS-CoV-2, 19 were determined to be acquired at our hospital. Fifteen (15/19; 79% [95% CI: 54-94%]) of these were identified through contact tracing and testing following exposures to other infected staff and were presumed to be staff-to-staff transmission, including an outbreak in 10 healthcare workers (HCWs) linked to a single ward that cared for COVID-19 patients. The staff tearoom was identified as the likely location for transmission, with subsequent reduction in HCW infections and resolution of the outbreak following implementation of enhanced control measures in tearoom facilities. No HCW contacts (0/204; 0% [95% CI: 0-2%]) developed COVID-19 infection following exposure to unrecognised patients with COVID-19. CONCLUSION: Unrecognised infections among staff may be a significant driver of HCW infections in healthcare settings. Control measures should be implemented to prevent acquisition from other staff as well as patient-staff transmission.

Identifying patterns in unplanned hospital admissions during the COVID-19 pandemic: a single-centre retrospective study.

BACKGROUND: Countries with a high prevalence of COVID-19 have identified a reduction in crude hospital admission rates for non-COVID-19 conditions during the pandemic. There remains a paucity of such data from lower prevalence countries, including Australia. AIMS: To describe the patterns of unplanned hospital daily admission rates during the COVID-19 pandemic in a major Australian metropolitan hospital, with a focus on acute medical presentations including acute coronary syndrome (ACS), stroke and falls. METHODS: This single-centre retrospective analysis analysed hospital admission episodes between 1 March and 30 April 2020 (COVID-19-era) and compared this to a historical cohort during the same period between 2017 and 2019 (pre-COVID-19). Information collected included total admission rates and patient characteristics for ACS, stroke and falls patients. RESULTS: A total of 12 278 unplanned admissions was identified across the study period. The daily admission rate was lower in the COVID-19-era compared with pre-COVID-19 (46.59 vs 51.56 days, P < 0.001). There was also a reduced average daily admission rate for falls (7.79 vs 9.95 days, P < 0.001); however, similar admission rates for ACS (1.52 vs 1.49 days, P = 0.83) and stroke (1.56 vs 1.76 days, P = 0.33). CONCLUSIONS: Public health interventions have been effective in reducing domestic cases of COVID-19 in Australia. At our tertiary metropolitan hospital, we have observed a significant reduction in unplanned hospital admission rates during the COVID-19-era, particularly for falls. Public health messaging needs to focus on educating the public how to seek medical care safely and promptly in the context of the ongoing COVID-19 crisis.

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity.

To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαß repertoires and promiscuous αß-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαß diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.

The Role of Immunological and Clinical Biomarkers to Predict Clinical COVID-19 Severity and Response to Therapy-A Prospective Longitudinal Study.

Background: The association of pro-inflammatory markers such as interleukin-6 (IL-6) and other biomarkers with severe coronavirus disease 2019 (COVID-19) is of increasing interest, however their kinetics, response to current COVID-related treatments, association with disease severity and comparison with other disease states associated with potential cytokine storm (CS) such as Staphylococcus aureus bacteraemia (SAB) are ill-defined. Methods: A cohort of 55 hospitalized SARS-CoV-2 positive patients was prospectively recruited - blood sampling was performed at baseline, post-treatment and hospital discharge. Serum IL-6, C-reactive protein (CRP) and other laboratory investigations were compared between treatment groups and across timepoints. Acute serum IL-6 and CRP levels were then compared to those with suspected COVID-19 (SCOVID) and age and sex matched patients with SAB and patients hospitalized for any non-infectious condition (NIC). Results: IL-6 was elevated at admission in the SARS-CoV-2 cohort but at lower levels compared to matched SAB patients. Median (IQR) IL-6 at admission was 73.89 pg/mL (30.9, 126.39) in SARS-CoV-2 compared to 92.76 pg/mL (21.75, 246.55) in SAB (p=0.017); 12.50 pg/mL (3.06, 35.77) in patients with NIC; and 95.51 pg/mL (52.17, 756.67) in SCOVID. Median IL-6 and CRP levels decreased between admission and discharge timepoints. This reduction was amplified in patients treated with remdesivir and/or dexamethasone. CRP and bedside vital signs were the strongest predictors of COVID-19 severity. Conclusions: Knowledge of the kinetics of IL-6 did not offer enhanced predictive value for disease severity in COVID-19 over common investigations such as CRP and vital signs.

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.

Clinical evaluation of four commercial immunoassays for the detection of antibodies against established SARS-CoV-2 infection.

A comparison of the clinical performance of the Elecsys Anti-SARS-CoV-2, Liaison SARS-CoV-2 S1/S2 IgG, Access SARS-CoV-2 IgG and Vitros Immunodiagnostic Products Anti-SARS-CoV-2 IgG immunoassays for the diagnosis of COVID-19 infection was performed. Patient sera were collected at least 6 weeks following onset of COVID-19 infection symptoms. Negative control specimens were stored specimens from those without COVID-19, collected in April-May 2019. Sensitivity and specificity with 95% confidence intervals (CI) were calculated. Linear regression was used to examine the relationship between the magnitude of serological response and clinical characteristics. There were 80 patients from whom 86 sera specimens were collected; six patients had duplicate specimens. There were 95 negative control specimens from 95 patients. The clinical sensitivity of the Elecsys assay was 98.84% (95% CI 93.69-99.97), specificity was 100% (95% CI 96.19-100.00); the Liaison assay clinical sensitivity was 96.51% (95% CI 90.14-99.27), specificity was 97.89% (95% CI 92.60-99.74); the Access assay clinical sensitivity was 84.88% (95% CI 75.54-91.70), specificity was 98.95% (95% CI 94.27-99.97); and the Vitros assay clinical sensitivity was 97.67% (95% CI 91.85-99.72), specificity was 100% (95% CI 96.15-100.00). A requirement for hospitalisation for COVID-19 infection was associated with a larger Vitros, Liaison and Access IgG response whilst fever was associated with a larger Elecsys response. All assays evaluated with the exception of the Access assay demonstrated similar performance. The Elecsys assay demonstrated the highest sensitivity and specificity.

Complete recovery from COVID-19 of a kidney-pancreas transplant recipient: potential benefit from everolimus?

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.

COVID-MATCH65-A prospectively derived clinical decision rule for severe acute respiratory syndrome coronavirus 2.

OBJECTIVES: We report on the key clinical predictors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and present a clinical decision rule that can risk stratify patients for COVID-19. DESIGN, PARTICIPANTS AND SETTING: A prospective cohort of patients assessed for COVID-19 at a screening clinic in Melbourne, Australia. The primary outcome was a positive COVID-19 test from nasopharyngeal swab. A backwards stepwise logistic regression was used to derive a model of clinical variables predictive of a positive COVID-19 test. Internal validation of the final model was performed using bootstrapped samples and the model scoring derived from the coefficients, with modelling performed for increasing prevalence. RESULTS: Of 4226 patients with suspected COVID-19 who were assessed, 2976 patients underwent SARS-CoV-2 testing (n = 108 SARS-CoV-2 positive) and were used to determine factors associated with a positive COVID-19 test. The 7 features associated with a positive COVID-19 test on multivariable analysis were: COVID-19 patient exposure or international travel, Myalgia/malaise, Anosmia or ageusia, Temperature, Coryza/sore throat, Hypoxia-oxygen saturation < 97%, 65 years or older-summarized in the mnemonic COVID-MATCH65. Internal validation showed an AUC of 0.836. A cut-off of ≥ 1.5 points was associated with a 92.6% sensitivity and 99.5% negative predictive value (NPV) for COVID-19. CONCLUSIONS: From the largest prospective outpatient cohort of suspected COVID-19 we define the clinical factors predictive of a positive SARS-CoV-2 test. The subsequent clinical decision rule, COVID-MATCH65, has a high sensitivity and NPV for SARS-CoV-2 and can be employed in the pandemic, adjusted for disease prevalence, to aid COVID-19 risk-assessment and vital testing resource allocation.