Longitudinal viscosity of blood plasma for rapid COVID-19 prognostics (preprint)

Blood Plasma Viscosity (PV) is an established biomarker for numerous diseases. While PV colloquially refers to the shear viscosity, there is a second viscosity component--the bulk viscosity--that describes the irreversible fluid compressibility on short time scales. The bulk viscosity is acutely sensitive to solid-like suspensions, and obtainable via the longitudinal viscosity from acoustic attenuation measurements. Whether it has diagnostic value remains unexplored yet may be pertinent given the association of diverse pathologies with the formation of plasma suspensions, such as fibrin-microstructures in COVID-19 and long-COVID. Here we show that the longitudinal PV measured using Brillouin Light Scattering (BLS) can serve as a proxy for the shear PV of blood plasma, and exhibits a temperature dependence consistent with increased suspension concentrations in severe COVID-patient plasma. Our results open a new avenue for PV diagnostics based on the longitudinal PV, and show that BLS can provide a means for its clinical implementation.

Respiratory syncytial virus surge in 2022 caused by lineages already present before the COVID-19 pandemic.

In 2022, Austria experienced a severe respiratory syncytial virus (RSV) epidemic with an earlier-than-usual start (Weeks 35/2021-45/2022) and increased numbers of pediatric patients in emergency departments. This surge came 2 years after a season with no cases detected as a result of coronavirus disease 2019 nonpharmaceutical interventions. We analyzed epidemiologic patterns and the phylodynamics of RSV based on approximately 30 800 respiratory specimens collected year-round over 10 years from ambulatory and hospitalized patients from 248 locations in Austria. Genomic surveillance and phylogenetic analysis of 186 RSV-A and 187 RSV-B partial glycoprotein sequences collected from 2018 to 2022 revealed that the 2022/2023 surge was driven by RSV-B in contrast to the surge in the 2021/2022 season that was driven by RSV-A. Whole-genome sequencing and phylodynamic analysis indicated that the RSV-B strain GB5.0.6a was the predominant genotype in the 2022/2023 season and emerged in late 2019. The results provide insight into RSV evolution and epidemiology that will be applicable to future monitoring efforts with the advent of novel vaccines and therapeutics.

After COVID-19 vaccinations: what does living and working in nursing homes look like?

BACKGROUND: Nursing homes were disproportionally affected by the COVID-19 pandemic. Vaccination was considered critical for the normalization of daily live of nursing home residents. The present study investigates the impact of the prolonged COVID-19 pandemic and the effect of vaccinations on the daily lives of residents and staff in Dutch nursing homes. SETTING AND PARTICIPANTS: The sample consisted of 78 nursing homes that participated in the Dutch national pilot on nursing home visits after the COVID-19 pandemic. One contact person per nursing home was approached for participation in this mixed-methods cross-sectional study. METHODS: Data was collected twice through questionnaires in April and December 2021. Quantitative questions focused on recent COVID-19 outbreaks, progress of vaccination, effects of vaccination on daily living in the nursing home and burden experienced by staff. Open-ended questions addressed the prolonged effect of the pandemic on residents, family members and staff. RESULTS: The overall vaccination rate of residents across nursing homes appeared to be high among both residents and staff. However, daily living in the nursing home had not returned to normal concerning personal interactions, visits, the use of facilities and work pressure. Nursing homes continued to report a negative impact of the pandemic on residents, family members and staff. CONCLUSIONS: Restrictions to the daily lives of residents in nursing homes were stricter than restrictions imposed on society as a whole. Returning to a normal daily living and working was found to be complex for nursing homes. With the emergence of new variants of the virus, policies strongly focusing on risk aversion were predominantly present in nursing homes.

The impact of COVID-19 related adversity on the course of mental health during the pandemic and the role of protective factors: a longitudinal study among older adults in The Netherlands.

PURPOSE: Many studies report about risk factors associated with adverse changes in mental health during the COVID-19 pandemic while few studies report about protective and buffering factors, especially in older adults. We present an observational study to assess protective and buffering factors against COVID-19 related adverse mental health changes in older adults. METHODS: 899 older adults (55 +) in the Netherlands were followed from 2018/19 to two pandemic time points (June-October 2020 and March-August 2021). Questionnaires included exposure to pandemic-related adversities ("COVID-19 exposure"), depressive and anxiety symptoms, loneliness, and pre-pandemic functioning. Linear regression analyses estimated main effects of COVID-19 exposure and protective factors on mental health changes; interaction effects were tested to identify buffering factors. RESULTS: Compared to pre-pandemic, anxiety symptoms, depression symptoms and loneliness increased. A higher score on the COVID-19 adversity index was associated with stronger negative mental health changes. Main effects: internet use and high mastery decreased depressive symptoms; a larger network decreased anxiety symptoms; female gender, larger network size and praying decreased loneliness. COVID-19 vaccination buffered against COVID-19 exposure-induced anxiety and loneliness, a partner buffered against COVID-19 exposure induced loneliness. CONCLUSION: Exposure to COVID-19 adversity had a cumulative negative impact on mental health. Improving coping, finding meaning, stimulating existing religious and spiritual resources, network interventions and stimulating internet use may enable older adults to maintain mental health during events with large societal impact, yet these factors appear protective regardless of exposure to specific adversities. COVID-19 vaccination had a positive effect on mental health.

Safety and immunogenicity of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases compared with healthy controls.

OBJECTIVES: A third COVID-19 vaccination is recommended for immunosuppressed patients. However, data on immunogenicity and safety of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are sparse and therefore addressed within this clinical trial. METHODS: 60 immunosuppressed patients and 48 healthy controls (HCs) received a third vaccination with an mRNA vaccine. The primary endpoint was defined as the presence of antibody levels against the receptor-binding domain (RBD)>1500 BAU/mL in patients with IMIDs versus HCs. Further endpoints included differences in neutralising antibodies and cellular immune responses after the third vaccination. Reactogenicity was recorded for 7 days, and safety was evaluated until week 4. RESULTS: Rate of individuals with anti-RBD antibodies>1500 BAU/mL was not significantly different after the third vaccination between patients with IMIDs and HCs (91% vs 100% p=0.101). Anti-RBD and neutralising antibody levels were significantly lower in patients with IMIDs after the third vaccination than in HCs (p=0.002 and p=0.016, respectively). In contrast, fold increase in antibody levels between week 0 and 4 was higher in patients with IMIDs. Treatment with biological (b) disease-modifying anti-rheumatic drugs (DMARD) or combination of bDMARDs and conventional synthetic DMARDs was associated with reduced antibody levels. Enhanced cellular immune response to wild type and Omicron peptide stimulation was observed after the third vaccination. No serious adverse event was attributed to the third vaccination. CONCLUSION: Our clinical trial data support the immunogenicity and safety of a third COVID-19 vaccination in patients with IMIDs. However, effects of DMARD therapy on immunogenicity should be considered. TRIAL REGISTRATION NUMBER: EudraCT No: 2021-002693-10.

Bivalent COVID-19 mRNA booster vaccination (BA.1 or BA.4/BA.5) increases neutralization of matched Omicron variants (preprint)

We report SARS-CoV-2 neutralizing antibody titers in sera of triple-vaccinated individuals who received a booster dose of an original monovalent or a bivalent BA.1- or BA.4/BA.5-adapted vaccine, or had a breakthrough infection with Omicron variants BA.1, BA.2 or BA.4/BA.5. A bivalent BA.4/BA.5 booster or Omicron-breakthrough infection induced increased Omicron-neutralization titers compared with the monovalent booster. The XBB.1.5 variant effectively evaded neutralizing-antibody responses elicited by current vaccines and/or infection with previous variants.

Disparities in patient engagement with video telemedicine among high-video-use providers during the COVID-19 pandemic.

Aims: Known racial, ethnic, age, and socioeconomic disparities in video telemedicine engagement may widen existing health inequities. We assessed if telemedicine disparities were alleviated among patients of high-video-use providers at a large cardiovascular practice. Methods and results: All telemedicine visits from 16 March to 31 October 2020 and patient demographics were collected from an administrative database. Providers in the upper quintile of video use were classified as high-video-use providers. Descriptive statistics and a multivariable logistic model were calculated to determine the distribution and predictors of a patient ever having a video visit vs. only phone visits. A total of 24 470 telemedicine visits were conducted among 18 950 patients by 169 providers. Video visits accounted for 48% of visits (52% phone). Among telemedicine visits conducted by high-video-use providers (n = 33), ever video patients were younger (P < 0.001) and included 78% of Black patients vs. 86% of White patients (P < 0.001), 74% of Hispanic patients vs. 86% of non-Hispanic patients (P < 0.001), and 79% of public insurance patients vs. 91% of private insurance patients (P < 0.001). High-video-use provider patients had 9.4 (95% confidence interval 8.4-10.4) times the odds of having video visit compared to low-video-use provider patients. Conclusion: These results suggest that provider-focused solutions alone, including promoting provider adoption of video visits, may not adequately reduce disparities in telemedicine engagement. Even in the presence of successful clinical infrastructure for telemedicine, individuals of Black race, Hispanic ethnicity, older age, and with public insurance continue to have decreased engagement. To achieve equity in telemedicine, patient-focused design is needed.

The respiratory syncytial virus surge in Austria, 2022, was caused by lineages present before the COVID-19 pandemic (preprint)

In 2022, Austria experienced a severe respiratory syncytial virus (RSV) epidemic with an earlier-than-usual start and increased numbers of paediatric patients in emergency departments. Nationwide multiyear genomic surveillance revealed that the surge was driven by RSV-B, however genotypes consisted of multiple lineages that were circulating prior to the pandemic.

The systemic renin-angiotensin system in COVID-19.

SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.

Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections.

Background and Methods: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct variant to date. As the heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after Omicron BA.1 or BA.2 sub-lineage infections in live virus neutralization tests with Omicron BA.1, Omicron BA.2, wildtype (WT, B1.1), and Delta (B.1.617.2) strains. Serum samples obtained after WT infections and three-dose mRNA vaccinations with and without prior infection were included as controls. Results: Primary BA.1 infections yielded reduced neutralizing antibody levels against WT, Delta, and Omicron BA.2, while samples from BA.2-infected individuals showed almost no cross-neutralization against the other variants. Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested. Conclusions: Our study demonstrates that although Omicron variants are able to enhance cross-neutralizing antibody levels in pre-immune individuals, primary infections with BA.1 or BA.2 induced mostly variant-specific neutralizing antibodies, emphasizing the differently shaped humoral immunity induced by the two Omicron variants. These data thus contribute substantially to the understanding of antibody responses induced by primary Omicron infections or multiple exposures to different SARS-CoV-2 variants and are of particular importance for developing vaccination strategies in the light of future emerging variants.

Changes in dispensing of anti-osteoporotic drugs during COVID-19 pandemic

Care of osteoporosis patients during COVID-19 pandemic is challenging. Due to lockdowns and restrictions, the management of osteoporosis has changed. Diagnosis of osteoporosis decreased and the influence of COVID-19 on drug prescriptions and dispensing is currently unclear. Therefore, the aim of the study was to assess the dispensing of anti-osteoporotic drugs during the Covid19 pandemic. Methods This study was a nationwide retrospective register-based observational study which included all patients in Austria aged >= 50 who received at least one prescription for anti-osteoporotic drug between January 2016 and November 2020. Pseudonymized individual-level patients' data were obtained from social insurance authorities and the Federal Ministry of Labour, Social Affairs, Health and Consumer Protection in Austria. Anti-osteoporotic agents were divided into: (i) oral bisphosphonates, (ii) intravenous bisphosphonates, (iii) selective estrogen receptor modulators (SERMs), (iv) teriparatide (TPTD) and (v) Denosumab (DMAB). We used interrupted time series analysis with autoregressive integrated moving average models (ARIMA) for the prediction of drug dispensing. Results There were 2,884,627 dispensing of anti-osteoporotic drugs by 318,573 patients between 2016-2020. The mean monthly prescriptions for oral bisphosphonates (-14.5 %) and SERMs (-12.9 %) decreased during COVID-19 pandemic, compared to the non-COVID-19 period. The dispensing for intravenous bisphosphonates (1.7 %) and teriparatide (9.5 %) increased during COVID- 19. The prescriptions for DMAB decreased during the first lock-down in March and April 2020 (24 %), however increased by 29.1 % for the total observation time. The ARIMA model for alendronate showed, that the estimated step change was minus 1443 dispensing (95 % CI - 2870 to - 17), while the estimated change in slope was minus 29 dispensing per month (95 % CI - 327 to 270). Thus, there were 1472 (1443 + 29) fewer dispensing in March 2020 than predicted had the lockdown not occurred. Discussion The total number of prescriptions dispensed to patients treated with anti-osteoporotic medications declined rapidly during the first COVID-19 lockdown. The largest drops in absolute terms were observed for ibandronate, followed by alendronate, denosumab, zolendronic acid and risendronate. The observed decrease of DMAB during the first lockdown, was compensated in the following months. Current evidence suggests no need for discontinuation of anti-osteoporotic drugs during COVID-19 pandemic, nor because of vaccination. Taking into account the massive treatment gap for osteoporosis, and the related fracture risk, clinicians should continue treatment, even in times of pandemics.

Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial.

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.

Immunogenicity and safety of a fourth COVID-19 vaccination in rituximab-treated patients: an open-label extension study.

OBJECTIVES: Patients under rituximab therapy are at high risk for a severe COVID-19 disease course. Humoral immune responses to SARS-CoV-2 vaccination are vastly diminished in B-cell-depleted patients, even after a third vaccine dose. However, it remains unclear whether these patients benefit from a fourth vaccination and whether continued rituximab therapy affects antibody development. METHODS: In this open-label extension trial, 37 rituximab-treated patients who received a third dose with either a vector or mRNA-based vaccine were vaccinated a fourth time with an mRNA-based vaccine (mRNA-1273 or BNT162b2). Key endpoints included the humoral and cellular immune response as well as safety after a fourth vaccination. RESULTS: The number of patients who seroconverted increased from 12/36 (33%) to 21/36 (58%) following the fourth COVID-19 vaccination. In patients with detectable antibodies to the spike protein's receptor-binding domain (median: 8.0 binding antibody units (BAU)/mL (quartiles: 0.4; 13.8)), elevated levels were observed after the fourth vaccination (134.0 BAU/mL (quartiles: 25.5; 1026.0)). Seroconversion and antibody increase were strongly diminished in patients who received rituximab treatment between the third and the fourth vaccination. The cellular immune response declined 12 weeks after the third vaccination, but could only be slightly enhanced by a fourth vaccination. No unexpected safety signals were detected, one serious adverse event not related to vaccination occurred. CONCLUSIONS: A fourth vaccine dose is immunogenic in a fraction of rituximab-treated patients. Continuation of rituximab treatment reduced humoral immune response, suggesting that rituximab affects a second booster vaccination. It might therefore be considered to postpone rituximab treatment in clinically stable patients. TRIAL REGISTRATION NUMBER: 2021-002348-57.

Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections

Background and Methods The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct variant to date. As the heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after Omicron BA.1 or BA.2 sub-lineage infections in live virus neutralization tests with Omicron BA.1, Omicron BA.2, wildtype (WT, B1.1), and Delta (B.1.617.2) strains. Serum samples obtained after WT infections and three-dose mRNA vaccinations with and without prior infection were included as controls. Results Primary BA.1 infections yielded reduced neutralizing antibody levels against WT, Delta, and Omicron BA.2, while samples from BA.2-infected individuals showed almost no cross-neutralization against the other variants. Serum neutralization of Omicron BA.1 and BA.2 variants was detectable after three-dose mRNA vaccinations, but with reduced titers. Vaccination-breakthrough infections with either Omicron BA.1 or BA.2, however, generated equal cross-neutralizing antibody levels against all SARS-CoV-2 variants tested. Conclusions Our study demonstrates that although Omicron variants are able to enhance cross-neutralizing antibody levels in pre-immune individuals, primary infections with BA.1 or BA.2 induced mostly variant-specific neutralizing antibodies, emphasizing the differently shaped humoral immunity induced by the two Omicron variants. These data thus contribute substantially to the understanding of antibody responses induced by primary Omicron infections or multiple exposures to different SARS-CoV-2 variants and are of particular importance for developing vaccination strategies in the light of future emerging variants.

Immune Response after mRNA COVID-19 Vaccination in Lung Transplant Recipients: A 6-Month Follow-Up.

BACKGROUND AND OBJECTIVE: This prospective cohort study analyzed the immune response to COVID-19 mRNA vaccines in lung transplant recipients (LuTRs) compared to healthy controls (HCs) at a 6-month follow-up. METHODS: After the first two doses of either BNT162b2 or mRNA-1273, SARS-CoV-2 antibodies were measured in LuTRs (n = 57) and sex- and age-matched HCs (n = 57). Antibody kinetics during a 6-month follow-up and the effect of a third vaccine dose were evaluated. Humoral responses were assessed using the Elecsys® Anti-SARS-CoV-2 S immunoassay. In 16 LuTRs, SARS-CoV-2-specific T cell responses were quantified using IFN-γ ELISpot assays. RESULTS: Seroconversion rates were 94% and 100% after the first and second vaccine dose, respectively, in HCs, while only 19% and 56% of LuTRs developed antibodies. Furthermore, 22 of 24 LuTRs who received the third vaccine dose showed seroconversion (five of seven primary non-responders and 17 of 17 primary responders). A T cell response against SARS-CoV-2-spike S1 and/or S2 was detected in 100% (16/16) of HCs and 50% (8/16) of LuTRs. CONCLUSIONS: The data suggest that LuTRs have reduced humoral and cellular immune responses after two doses of COVID-19 mRNA vaccination when compared to HCs. A third dose may be of substantial benefit.

Long-Lived Immunity in SARS-CoV-2-Recovered Children and Its Neutralizing Capacity Against Omicron.

SARS-CoV-2 infection is effectively controlled by humoral and cellular immune responses. However, the durability of immunity in children as well as the ability to neutralize variants of concern are unclear. Here, we assessed T cell and antibody responses in a longitudinal cohort of children after asymptomatic or mild COVID-19 over a 12-month period. Antigen-specific CD4 T cells remained stable over time, while CD8 T cells declined. SARS-CoV-2 infection induced long-lived neutralizing antibodies against ancestral SARS-CoV-2 (D614G isolate), but with poor cross-neutralization of omicron. Importantly, recall responses to vaccination in children with pre-existing immunity yielded neutralizing antibody activities against D614G and omicron BA.1 and BA.2 variants that were 3.9-fold, 9.9-fold and 14-fold higher than primary vaccine responses in seronegative children. Together, our findings demonstrate that SARS-CoV-2 infection in children induces robust memory T cells and antibodies that persist for more than 12 months, but lack neutralizing activity against omicron. Vaccination of pre-immune children, however, substantially improves the omicron-neutralizing capacity.

Heterogeneous SARS-CoV-2-Neutralizing Activities After Infection and Vaccination.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with different resistance levels to existing immunity have recently emerged. Antibodies that recognize the SARS-CoV-2 spike (S) protein and exhibit neutralizing activities are considered the best correlate of protection and an understanding of humoral immunity is crucial for controlling the pandemic. We thus analyzed such antibodies in individuals recovered from infection in 2020 as well as vaccinees after two doses of an mRNA vaccine. Methods: Neutralizing antibody responses against three SARS-CoV-2 variants (D614G, VOCs Beta and Delta) were determined in serum samples from 54 infected individuals (24 non-hospitalized, 30 hospitalized) and 34 vaccinees shortly after symptom onset or second vaccination, respectively, as well as six months later. In addition, the effect of the S sequence of the infecting strain on neutralization was studied. Results: Non-hospitalized patients had the lowest neutralization titers against all variants, while those of hospitalized patients equaled or exceeded those of vaccinees. Neutralizing activity was lower against the two VOCs and declined significantly in all cohorts after six months. This decrease was more pronounced in hospitalized and vaccinated individuals than in non-hospitalized patients. Of note, the specific neutralizing activity (NT titer/ELISA value ratio) was higher in the infected cohorts than in vaccinees and did not differ between non-hospitalized and hospitalized patients. Patients infected with viral strains carrying mutations in the N-terminal domain of the spike protein were impaired in Beta VOC neutralization. Conclusions: Specific neutralizing activities were higher in infected than in vaccinated individuals, and no difference in the quality of these antibodies was observed between hospitalized and non-hospitalized patients, despite significantly lower titers in the latter group. Additionally, antibody responses of infected individuals showed greater heterogeneity than those of vaccinees, which was associated with mutations in the spike protein of the infecting strain. Overall, our findings yielded novel insights into SARS-CoV-2-specific neutralizing antibodies, evolving differently after virus infection and COVID-19 vaccination, which is an important issue to consider in ongoing vaccine strategy improvements.