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SARS-CoV-2 Omicron lineages continue to emerge and evolve into new sublineages, causing infection waves throughout 2022 and 2023, which has been attributed to immune escape. We examined neutralizing antibody responses to the recently emerged SARS-CoV-2 JN.1 variant in comparison to ancestral D614G and Omicron BA.1, BA.2, BA.5, and XBB.1.5 variants. We tested 79 human sera from cohorts with different combinations of vaccinations and infections, including 23 individuals who had been repeatedly exposed to Omicron. Individuals with a monovalent XBB.1.5 vaccine booster or XBB.1.5 breakthrough infection had robust antibody levels against all variants tested; however, JN.1 evaded antibodies in individuals after single Omicron BA.1, BA.2 or BA.5 breakthrough infections. Moreover, in the non-vaccinated cohort, serum antibodies demonstrated almost no cross-neutralization activities against D614G, XBB.1.5 and JN.1. after infections with earlier Omicron variants. These findings show that SARS-CoV-2-immunity is heterogeneous, depending on different combinations of vaccinations and infections, and emphasize the importance of considering different immune-backgrounds when evaluating novel variants.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , SARS-CoV-2 , Humanos , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Anticuerpos Antivirales/sangre , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Femenino , Masculino , Adulto , Persona de Mediana Edad , Vacunación , Pruebas de Neutralización , AncianoRESUMEN
Primary infection with the Omicron variant of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) can be serologically identified with distinct profiles of neutralizing antibodies (nAbs), as indicated by high titers against the Omicron variant and low titers against the ancestral wild-type (WT). Here, we evaluated whether a novel surrogate virus neutralization assay (sVNT) that simultaneously quantifies the binding inhibition of angiotensin-converting enzyme 2 (ACE2) to the proteins of the WT- and Omicron-specific receptor-binding domains (RBDs) can identify nAb profiles after primary Omicron infection with accuracy similar to that of variant-specific live-virus neutralization tests (NTs). Therefore, we comparatively tested 205 samples from individuals after primary infection with the Omicron variant and the WT, and vaccinated subjects with or without Omicron breakthrough infections. Indeed, variant-specific RBD-ACE2 binding inhibition levels significantly correlated with respective NT titers (p < 0.0001, Spearman's r = 0.92 and r = 0.80 for WT and Omicron, respectively). In addition, samples from individuals after primary Omicron infection were securely identified with the sVNT according to their distinctive nAb profiles (area under the curve = 0.99; sensitivity: 97.2%; specificity: 97.84%). Thus, when laborious live-virus NTs are not feasible, the novel sVNT we evaluated in this study may serve as an acceptable substitute for the serological identification of individuals with primary Omicron infection.
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BACKGROUND: In October 2020, amidst the second COVID-19 epidemic wave and before the second-national lockdown, Austria introduced a policy of population-wide point-of-care lateral flow antigen testing (POC-LFT). This study explores the impact of this policy by quantifying the association between trends in POC-LFT-activity with trends in PCR-positivity (as a proxy for symptomatic infection), hospitalisations and deaths related to COVID-19 between October 22 and December 06, 2020. METHODS: We stratified 94 Austrian districts according to POC-LFT-activity (number of POC-LFTs performed per 100,000 inhabitants over the study period), into three population cohorts: (i) high(N = 24), (ii) medium(N = 45) and (iii) low(N = 25). Across the cohorts we a) compared trends in POC-LFT-activity with PCR-positivity, hospital admissions and deaths related to COVD-19; b) compared the epidemic growth rate before and after the epidemic peak; and c) calculated the Pearson correlation coefficients between PCR-positivity with COVID-19 hospitalisations and with COVID -19 related deaths. RESULTS: The trend in POC-LFT activity was similar to PCR-positivity and hospitalisations trends across high, medium and low POC-LFT activity cohorts, with association with deaths only present in cohorts with high POC-LFT activity. Compared to the low POC-LFT-activity cohort, the high-activity cohort had steeper pre-peak daily increase in PCR-positivity (2.24 more cases per day, per district and per 100,000 inhabitants; 95% CI: 2.0-2.7; p < 0.001) and hospitalisations (0.10; 95% CI: 0.02, 0.18; p = 0.014), and 6 days earlier peak of PCR-positivity. The high-activity cohort also had steeper daily reduction in the post-peak trend in PCR-positivity (-3.6; 95% CI: -4.8, -2.3; p < 0.001) and hospitalisations (-0.2; 95% CI: -0.32, -0.08; p = 0.001). PCR-positivity was positively correlated to both hospitalisations and deaths, but with lags of 6 and 14 days respectively. CONCLUSIONS: High POC-LFT-use was associated with increased and earlier case finding during the second Austrian COVID-19 epidemic wave, and early and significant reduction in cases and hospitalisations during the second national lockdown. A national policy promoting symptomatic POC-LFT in primary care, can capture trends in PCR-positivity and hospitalisations. Symptomatic POC-LFT delivered at scale and combined with immediate self-quarantining and contact tracing can thus be a proxy for epidemic status, and hence a useful tool that can replace large-scale PCR testing.
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COVID-19 , Humanos , Austria/epidemiología , SARS-CoV-2 , Sistemas de Atención de Punto , Control de Enfermedades Transmisibles , HospitalizaciónRESUMEN
The SARS-CoV-2 Omicron variant is characterized by substantial changes in the antigenic structure of the Spike (S) protein. Therefore, antibodies induced by primary Omicron infection lack neutralizing activity against earlier variants. In this study, we analyzed whether these antigenic changes impact the sensitivity of commercial anti-SARS-CoV-2 antibody assays. Sera from 37 unvaccinated, convalescent individuals after putative primary Omicron infection were tested with a panel of 20 commercial anti-SARS-CoV-2 immunoassays. As controls, we used samples from 43 individuals after primary infection with the SARS-CoV-2 ancestral wild-type strain. In addition, variant-specific live-virus neutralization assays were used as a reference for the presence of SARS-CoV-2-specific antibodies in the samples. Notably, in Omicron convalescents, there was a statistically significant reduction in the sensitivity of all antibody assays containing S or its receptor-binding-domain (RBD) as antigens. Furthermore, antibody levels quantified by these assays displayed a weaker correlation with Omicron-specific neutralizing antibody titers than with those against the wild type. In contrast, the sensitivity of nucleocapsid-protein-specific immunoassays was similar in wild-type and Omicron-infected subjects. In summary, the antigenic changes in the Omicron S lead to reduced immunoreactivity in the current commercial S- and RBD-specific antibody assays, impairing their diagnostic performance. IMPORTANCE This study demonstrates that the antigenic changes of the SARS-CoV-2 Omicron variant affect test results from commercial Spike- and RBD-specific antibody assays, significantly diminishing their sensitivities and diagnostic abilities to assess neutralizing antibodies.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Humanos , Pruebas de Neutralización , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/metabolismo , SARS-CoV-2 , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , COVID-19/diagnóstico , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
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.
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COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Anticuerpos ampliamente neutralizantes , Humanos , Glicoproteínas de Membrana , Pruebas de Neutralización , ARN Mensajero , Glicoproteína de la Espiga del Coronavirus/genética , Proteínas del Envoltorio ViralRESUMEN
OBJECTIVE: To increase knowledge of discrete symptoms shall help to avoid misinterpretation of test results and to gain better understanding of associations between early symptoms and severe disease to provide additional criteria for targeted early interventions. DESIGN: Retrospective observational study. SETTING: Austrian GP practices in the year 2020, patients above 18 years were included. PARTICIPANTS: We recruited 25 practices which included 295 participants with a positive SARS-CoV2 test. MAIN OUTCOME MEASURES: Data collection comprised basic demographic data, risk factors and the recording of symptoms at several points in time in the course of the illness. Descriptive analyses for possible associations between demographics and symptoms were conducted by means of cross tabulation. Group differences (hospitalized yes/no) were assessed using Fisher's exact test. The significance level was set to 0.05; due to the observational character of the study, no adjustment for multiplicity was performed. RESULTS: Only one third of patients report symptoms generally understood to be typical for COVID19. Most patients presented with unspecific complaints. We found symptoms indicating complicated disease, depending on when they appear. The number of symptoms may be a predictor for the need of hospital care. More than 50% of patients still experience symptoms 14 days after onset. CONCLUSION: Unspecific symptoms are valuable indicators in the detection of early COVID19 disease that practitioners and the general public should be aware of also in the interpretation of low sensitivity tests. Monitoring patients using the indicators we identified may help to identify patients who are likely to profit from early intervention.
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COVID-19 , COVID-19/diagnóstico , COVID-19/epidemiología , Hospitalización , Humanos , Atención Primaria de Salud , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Resultado del TratamientoRESUMEN
This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach.
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COVID-19 , COVID-19/complicaciones , Humanos , SARS-CoV-2 , Síndrome Post Agudo de COVID-19RESUMEN
OBJECTIVES: We explore the importance of SARS-CoV-2 sentinel surveillance testing in primary care during a regional COVID-19 outbreak in Austria. DESIGN: Prospective cohort study. SETTING: A single sentinel practice serving 22 829 people in the ski-resort of Schladming-Dachstein. PARTICIPANTS: All 73 patients presenting with mild-to-moderate flu-like symptoms between 24 February and 03 April, 2020. INTERVENTION: Nasopharyngeal sampling to detect SARS-CoV-2 using real-time reverse transcriptase-quantitative PCR (RT-qPCR). OUTCOME MEASURES: We compared RT-qPCR at presentation with confirmed antibody status. We split the outbreak in two parts, by halving the period from the first to the last case, to characterise three cohorts of patients with confirmed infection: early acute (RT-qPCR reactive) in the first half; and late acute (reactive) and late convalescent (non-reactive) in the second half. For each cohort, we report the number of cases detected, the accuracy of RT-qPCR, the duration and variety of symptoms, and the number of viral clades present. RESULTS: Twenty-two patients were diagnosed with COVID-19 (eight early acute, seven late acute and seven late convalescent), 44 patients tested SARS-CoV-2 negative and 7 were excluded. The sensitivity of RT-qPCR was 100% among all acute cases, dropping to 68.1% when including convalescent. Test specificity was 100%. Mean duration of symptoms for each group were 2 days (range 1-4) among early acute, 4.4 days (1-7) among late acute and 8 days (2-12) among late convalescent. Confirmed infection was associated with loss of taste. Acute infection was associated with loss of taste, nausea/vomiting, breathlessness, sore throat and myalgia; but not anosmia, fever or cough. Transmission clusters of three viral clades (G, GR and L) were identified. CONCLUSIONS: RT-qPCR testing in primary care can rapidly and accurately detect SARS-CoV-2 among people with flu-like illness in a heterogeneous viral outbreak. Targeted testing in primary care can support national sentinel surveillance of COVID-19.
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COVID-19 , SARS-CoV-2 , Austria , Estudios de Cohortes , Humanos , Atención Primaria de Salud , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Testing for COVID-19 with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) may result in delayed detection of disease. Antigen detection via lateral flow testing (LFT) is faster and amenable to population-wide testing strategies. Our study assesses the diagnostic accuracy of LFT compared to RT-PCR on the same primarycare patients in Austria. METHODS: Patients with mild to moderate flu-like symptoms attending a general practice network in an Austrian district (October 22 to November 30, 2020) received clinical assessment including LFT. All suspected COVID-19 cases obtained additional RT-PCR and were divided into two groups: Group 1 (true reactive): suspected cases with reactive LFT and positive RT-PCR; and Group 2 (false non-reactive): suspected cases with a non-reactive LFT but positive RT-PCR. FINDINGS: Of the 2,562 symptomatic patients, 1,037 were suspected of COVID-19 and 826 (79.7%) patients tested RT-PCR positive. Among patients with positive RT-PCR, 788/826 tested LFT reactive (Group 1) and 38 (4.6%) non-reactive (Group 2). Overall sensitivity was 95.4% (95%CI: [94%,96.8%]), specificity 89.1% (95%CI: [86.3%, 91.9%]), positive predictive value 97.3% (95%CI:[95.9%, 98.7%]) and negative predictive value 82.5% (95%CI:[79.8%, 85.2%]). Reactive LFT and positive RT-PCR were positively correlated (r = 0.968,95CI=[0.952,0.985] and κ = 0.823 , 95%CI=[0.773,0.866]). Reactive LFT was negatively correlated with Ct-value ( r = -0.2999, p < 0.001) and pre-test symptom duration (r = -0.1299,p = 0.0043) while Ct-value was positively correlated with pre-test symptom duration (r = 0.3733),p < 0.001). INTERPRETATION: We show that LFT is an accurate alternative to RT-PCR testing in primary care. We note the importance of administering LFT properly, here combined with clinical assessment in symptomatic patients. FUNDING: Thomas Czypionka received funding from the European Union's Horizon 2020 Research and Innovation Programe under the grant agreement No 101016233 (PERISCOPE). No further funding was available for this study.