Clusters of post-acute COVID-19 symptoms: a latent class analysis across 9 databases and 7 countries (preprint)

Prior evidence has suggested the multisystem symptomatic manifestations of post-acute COVID-19 condition (PCC). Here we conducted a network cluster analysis of 24 WHO proposed symptoms to identify potential latent subclasses of PCC. Individuals with a positive test of or diagnosed with SARS-CoV-2 after 09/2020 and with at least one symptom within ≥ 90 to 365 days following infection were included. Sub-analyses were conducted among people with ≥ 3 different symptoms. Summary characteristics were provided for each cluster. All analyses were conducted separately in 9 databases from 7 countries, including data from primary care, hospitals, national health claims and national health registries, allowing to validate clusters across the different healthcare settings. 787,078 persons with PCC were included. Single-symptom clusters were common across all databases, particularly for joint pain, anxiety, depression and allergy. Complex clusters included anxiety-depression and abdominal-gastrointestinal symptoms. Substantial heterogeneity within and between PCC clusters was seen across healthcare settings. Current definitions of PCC should be critically reviewed to reflect this variety in clinical presentation.

Post-COVID-19 Condition Patients’ Utilisation of Healthcare Resources after Implementation of an Integrated Care Unit: A Retrospective and Case-Control Observational Study (preprint)

Background: While the clinical factors of the post-COVID-19 condition (PCC) are becoming clearer, the economic implications remain uncertain, posing a challenge to healthcare professionals in terms of understanding and managing this emerging phenomenon. This article aims to investigate the demographic and clinical characteristics of PCC patients and quantify the economic impact of their healthcare resource utilisation. Methods: A retrospective and case-control observational study was conducted, comparing the case group of PCC population before and after diagnosis with a control group. Demographic and clinical variables were analysed with the objective of describing the population. Economic analysis was performed to evaluate the resource costs in procedures and primary, secondary (both outpatient and inpatient) and emergency care. Findings: PCC patients (N=341) exhibited older age and elevated cardiovascular risk factors compared to controls (N=49,078). There were differences in the socio-economic distribution between male and female patients in the PCC patients. Hypertension and diabetes mellitus type 2 were the most common chronic diseases observed among the case patients. Economic analysis revealed that PCC patients were approximately four times as costly as control patients, with increased utilisation of healthcare resources. However, post-diagnosis PCC patients showed a reduction in costs, primarily driven by decreased primary care visits and hospitalisations. Conclusion: Coordinated care management for PCC patients is associated with reduced costs and improved healthcare resource utilisation. Further research is warranted to investigate long-term health outcomes and establish causal relationships between COVID-19 sequelae and healthcare resource utilisation.

Healthy lifestyle for the prevention of post-COVID-19 multisystem sequelae, hospitalization, and death: a prospective cohort study (preprint)

Abstract Background Post-COVID complications are emerging as a global public health crisis. Effective prevention strategies are needed to inform patients, clinicians and policy makers, and to reduce their cumulative burden. We aimed to investigate whether a habitual healthy lifestyle predated pandemic is associated with lower risks of multisystem sequelae and other adverse outcomes of COVID-19, and whether the potential protective effects are independent of pre-existing comorbidities. Methods The prospective population-based cohort study enrolled participants with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction test result between March 1, 2020, and March 1, 2022. Participants with no history of the related outcome one year before infection were included and followed up for 210 days. Exposures included ten modifiable healthy lifestyle factors including past or never smoking, moderate alcohol intake ([≤]4 times week), body mass index <30 kg/m2, at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, less sedentary time (<4 hours per day), healthy sleep duration (7-9 hours per day), adequate intake of fruit and vegetables ([≥]400 g/day), adequate oily fish intake ([≥]1 portion/week), moderate intake of red meat ([≤]4 portions week) and processed meat ([≤]4 portions week). Outcomes included multisystem COVID-19 sequelae (consisting of 75 diseases/symptoms in 10 organ systems), death, and hospital admission following SARS-CoV-2 infection, confirmed by hospital inpatient and death records. Risk was reported in relative scale (hazard ratio [HR]) and absolute scale (absolute risk reduction [ARR]) during both the acute (the first 30 days) and post-acute (30-210 days) phases of infection using Cox models. Findings A total of 68,896 participants (mean [SD] age, 66.6 [8.4]; 32,098 women [46.6%]) with COVID-19 were included. A favorable lifestyle (6-10 healthy lifestyle factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae of COVID-19 (HR, 0.64; 95% CI, 0.58-0.69; ARR, 7.08%; 95% CI, 5.98-8.09), compared with unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions were observed across all 10 prespecified organ systems including cardiovascular, coagulation, metabolic and endocrine, gastrointestinal, kidney, mental health, musculoskeletal, neurologic, and respiratory disorders, and general symptoms of fatigue and malaise. This beneficial effect was largely attributable to direct effects of healthy lifestyle, with mediation proportion ranging from 44% to 93% across organ systems. A favorable lifestyle was also associated with lower risk of post-COVID death (HR, 0.59; 95% CI, 0.52-0.66; ARR, 1.99%; 95% CI, 1.61-2.32) and hospitalization (HR, 0.78; 95% CI, 0.73-0.84; ARR, 6.14%; 95% CI, 4.48-7.68). These associations were observed after accounting for potential misclassification of lifestyle factors, and during acute and post-acute infection, in those tested positive in the hospital and community setting, and independent of vaccination status or SARS-CoV-2 variant. Interpretation Adherence to a healthy lifestyle predated pandemic was associated with substantially lower risk of complications across organ systems, death, and hospitalization following COVID-19, regardless of phases of infection, vaccination status, test setting, and SARS-CoV-2 variants, and independent of comorbidities. These findings illustrate the benefits of adhering to a healthy lifestyle to reduce the long-term adverse health consequences following SARS-CoV-2 infection.

The burden of long COVID: a multinational cohort analysis of Spanish and UK data including SARS-CoV-2 infections, reinfections, and matched contemporaneous test negative controls (preprint)

As limited data was available on the effect of persisting COVID-19 symptoms, we characterised long COVID and identified key symptoms associated with persistent disease. Using primary care data from Spain and UK, we estimated incidence rates of long COVID in the population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential for long COVID by comparing their frequency in COVID-19 patients vs matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections. Fortunately, the proportion of COVID-19 cases resulting in long COVID declined over the study period.  Risk for altered smell/taste, dyspnoea, and fatigue were consistently higher in long COVID patient vs controls [RR between 5.97-1.09]. All persistent symptoms were less common after reinfection than first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.

Time from symptoms onset to remdesivir is associated with the risk of ICU admission: a multicentric analyses (preprint)

Background: shorter duration of symptoms before remdesivir has been associated with better outcomes. Our goal was to evaluate variables associated with the need of ICU admission in a cohort of hospitalized patients for COVID-19 under remdesivir including the period from symptoms onset to remdesivir. Methods: We conducted a retrospective multicentric study analysing all patients admitted with COVID-19 in 9 Spanish hospitals who received treatment with remdesivir in October 2020. The main outcome was the need of ICU admission after 24 hours of the first dose of remdesivir. Results: In our cohort of 497 patients, the median of days from symptom onset to remdesivir was 5 days, and 70 of them (14.1%) were later admitted into ICU. The clinical outcomes associated with ICU admission were days from symptoms onset (5 vs. 6; p=0.023), clinical signs of severe disease (respiratory rate, neutrophil count, ferritin levels and very-high mortality rate in SEIMC-Score) and the use of corticosteroids and anti-inflammatory drugs before ICU. The only variable significatively associated with risk reduction in the Cox-regression analyses was ≤5 days from symptoms onset to RDV (HR: 0.54, CI95%: 0.31-0.92; p=0.024). Conclusion: For patients admitted to the hospital with COVID-19, the prescription of remdesivir within 5 days from symptoms onset diminishes the need of ICU admission.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Venous Thromboembolism in Ambulatory Covid-19 patients: Clinical and Genetic Determinants (preprint)

Background Substantial evidence suggests that severe Covid-19 leads to an increased risk of Venous Thromboembolism (VTE). We aimed to quantify the risk of VTE associated with ambulatory Covid-19, study the potential protective role of vaccination, and establish key clinical and genetic determinants of post-Covid VTE. Methods We analyzed a cohort of ambulatory Covid-19 patients from UK Biobank, and compared their 30-day VTE risk with propensity-score-matched non-infected participants. We fitted multivariable models to study the associations between age, sex, ethnicity, socio-economic status, obesity, vaccination status and inherited thrombophilia with post-Covid VTE. Results Overall, VTE risk was nearly 20-fold higher in Covid-19 vs matched non-infected participants (hazard ratio [HR] 19.49, 95% confidence interval [CI] 11.50 to 33.05). However, the risk was substantially attenuated amongst the vaccinated (HR: 2.79, 95% CI 0.82 to 9.54). Older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 2.00 (1.61 to 2.47) per 10 years, 1.66 (1.28 to 2.15), and 1.85 (1.29 to 2.64), respectively. Further, inherited thrombophilia led to an HR 2.05, 95% CI 1.15 to 3.66. Conclusions Ambulatory Covid-19 was associated with a striking 20-fold increase in incident VTE, but no elevated risk after breakthrough infection in the fully vaccinated. Older age, male sex, and obesity were clinical determinants of Covid-19-related VTE. Additionally, inherited thrombophilia doubled risk further, comparable to the effect of 10-year ageing. These findings reinforce the need for vaccination, and call for targeted strategies to prevent VTE during outpatient care of Covid-19

Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis (preprint)

This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV; or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N=5,245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2 patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2 patients (RR 0.21, 95%CI 0.09-0.46; RR 0.24, 95%CI 0.11-0.48); no improvement was observed among HFO2 patients. Improved early and late recovery was observed among LFO2 patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2 and LFO2 patients.

Unraveling the antiviral activity of plitidepsin by subcellular and morphological analysis (preprint)

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation factor 1 alpha 1) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin completely blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.

Clinical course impacts early kinetics and long-term magnitude and amplitude of SARS-CoV-2 neutralizing antibodies beyond one year after infection (preprint)

Background Understanding the determinants of long-term immune responses to SARS-CoV-2 and the concurrent impact of vaccination and emerging variants of concern will guide optimal strategies to achieve global protection against the COVID-19 pandemic. Methods A prospective cohort of 332 COVID-19 patients was followed beyond one year. Plasma neutralizing activity was evaluated using HIV-based reporter pseudoviruses expressing different SARS-CoV-2 spikes and was longitudinally analyzed using mixed-effects models. Findings Long-term neutralizing activity was stable beyond one year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while outpatient responses were dominated by long-lived B cells. In both groups, vaccination boosted responses to natural infection, although viral variants, mainly B.1.351, reduced the efficacy of neutralization. Importantly, despite showing higher neutralization titers, hospitalized patients showed lower cross-neutralization of B.1.351 variant compared to outpatients. Multivariate analysis identified severity of primary infection as the factor that independently determines both the magnitude and the inferior cross-neutralization activity of long-term neutralizing responses. Conclusions Neutralizing response induced by SARS-CoV-2 is heterogeneous in magnitude but stable beyond one year after infection. Vaccination boosts these long-lasting natural neutralizing responses, counteracting the significant resistance to neutralization of new viral variants. Severity of primary infection determines higher magnitude but poorer quality of long-term neutralizing responses.

Characterization of long-term patient-reported symptoms of COVID-19: an analysis of social media data (preprint)

As the SARS-CoV-2 virus (COVID-19) continues to affect people across the globe, there is limited understanding of the long term implications for infected patients. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually designed by clinicians, and not granular enough to understand the natural history or patient experiences of "long COVID". In order to get a complete picture, there is a need to use patient generated data to track the long-term impact of COVID-19 on recovered patients in real time. There is a growing need to meticulously characterize these patients' experiences, from infection to months post-infection, and with highly granular patient generated data rather than clinician narratives. In this work, we present a longitudinal characterization of post-COVID-19 symptoms using social media data from Twitter. Using a combination of machine learning, natural language processing techniques, and clinician reviews, we mined 296,154 tweets to characterize the post-acute infection course of the disease, creating detailed timelines of symptoms and conditions, and analyzing their symptomatology during a period of over 150 days.

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization. (preprint)

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.

Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses (preprint)

COVID-19 pandemic is not yet under control by vaccination, and effective antivirals are critical for preparedness. Here we report that macrophages and dendritic cells, key antigen presenting myeloid cells (APCs), are largely resistant to SARS-CoV-2 infection. APCs effectively captured viruses within cellular compartments that lead to antigen degradation. Macrophages sense SARS-CoV-2 and released higher levels of cytokines, including those related to cytokine storm in severe COVID-19. The sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) present on APCs, which interacts with sialylated gangliosides on membranes of retroviruses or filoviruses, also binds SARS-CoV-2 via GM1. Blockage of Siglec-1 receptors by monoclonal antibodies reduces SARS-CoV-2 uptake and transfer to susceptible target cells. APCs expressing Siglec-1 and carrying SARS-CoV-2 are found in pulmonary tissues of non-human primates. Single cell analysis reveals the in vivo induction of cytokines in those macrophages. Targeting Siglec-1 could offer cross-protection against SARS-CoV-2 and other enveloped viruses that exploit APCs for viral dissemination, including those yet to come in future outbreaks.

Economic Analysis of the Impact of Mass Workplace COVID-19 Testing on Health and Healthcare Resource Savings: A Case Study of SEAT in Catalonia (preprint)

Background: The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe a line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity.Objective: To evaluate the economic impact of mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings.Methodology: Analysis of health costs and impacts based on the estimation of mortality and morbidity avoided because of screening and the resulting savings in healthcare costs.Results: The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5,575.49 per positive detected. 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected).Conclusion: In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.Funding Statement: This research received no external funding.Declaration of Interests: None declared.

Impact of Mass Workplace COVID-19 Rapid Testing on Health and Healthcare Resource Savings (preprint)

Background: The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe a line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity. Objective: To evaluate the economic impact of mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings. Methodology: Analysis of health costs and impacts based on the estimation of mortality and morbidity avoided because of screening and the resulting savings in healthcare costs. Results: The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5,575.49 per positive detected. 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected). Conclusion: In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.

Highly functional Cellular Immunity in SARS-CoV-2 Non-Seroconvertors is associated with immune protection (preprint)

The role of T cells in the control of SARS-CoV-2 infection has been underestimated in favor of neutralizing antibodies. However, cellular immunity is essential for long-term viral control and protection from disease severity. To understand T-cell immunity in the absence of antibody generation we focused on a group of SARS-CoV-2 Non-Seroconvertors (NSC) recovered from infection. We performed an immune comparative analysis of SARS-CoV-2 infected individuals stratified by the absence or presence of seroconversion and disease severity. We report high levels of total naive and low effector CD8+ T cells in NSC. Moreover, polyfunctional Nucleocapsid (NP)-specific CD8+ T-cell responses, as well as reduced levels of T-cell activation monitored by PD-1 and activation-induced markers, were distinctive immunological traits in NSC. Longitudinal data support the stability of the NSC phenotype over three months. Our results implicate highly functional SARS-CoV-2 Spike and NP T-cell responses with low immune activation in protection from disease severity in the absence of seroconversion.