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Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of commercially available high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. In this work, we leverage repeated serological measurements between April 2020 and December 2021 on 1083 participants of a population-based cohort in Geneva, Switzerland, to evaluate anti-Spike RBD antibody levels as a correlate of protection against Omicron BA.1/BA.2 infections during the December 2021-March 2022 epidemic wave. We do so by first modeling antibody dynamics in time with kinetic models. We then use these models to predict antibody trajectories into the time period where Omicron BA.1/BA.2 were the predominant circulating sub-lineages and use survival analyses to compare the hazard of having a positive SARS-CoV-2 test by antibody level, vaccination status and infection history. We find that antibody kinetics in our sample are mainly determined by infection and vaccination history, and to a lesser extent by demographics. After controlling for age and previous infections (based on anti-nucleocapsid serology), survival analyses reveal a significant reduction in the hazard of having a documented positive SARS-CoV-2 infection during the Omicron BA.1/BA.2 wave with increasing antibody levels, reaching up to a three-fold reduction for anti-S antibody vels above 800 IU/mL (HR 0.30, 95% CI 0.22-0.41). However, we did not detect a eduction in hazard among uninfected participants. Taken together these results indicate that nti-Spike RBD antibody levels, as quantified by the immunoassay used in this study, are an direct correlate of protection against Omicron BA.1/BA.2 for individuals with a history of revious SARS-CoV-2 infection. Despite the uncertainty in what SARS-COV-2 variant will me next, these results provide reassuring insights into the continued interpretation of ARS-CoV-2 binding antibody measurements as an independent marker of protection at both the individual and population levels.
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BackgroundMore than two years into the COVID-19 pandemic, it is generally assumed that most of the population has developed anti-SARS-CoV-2 antibodies from infection and/or vaccination. However, public health decision-making is hindered by the lack of up-to-date and precise characterization of the immune landscape in the population. We thus aimed to estimate anti-SARS-CoV-2 antibodies seroprevalence and cross-variant neutralization capacity after Omicron became dominant in Geneva, Switzerland. MethodsWe conducted a population-based serosurvey between April 29th and June 9th, 2022, recruiting children and adults of all ages from age-stratified random samples of the Geneva general population. Anti-SARS-CoV-2 antibody presence was assessed using commercial immunoassays targeting either the spike (S) or nucleocapsid (N) protein. Antibodies neutralization capacity against different SARS-CoV-2 variants was evaluated using a cell-free Spike trimer-ACE2 binding-based surrogate neutralization assay. Seroprevalence of anti-SARS-CoV-2 antibodies and neutralization capacity were estimated using Bayesian modeling frameworks accounting for the demographics, vaccination, and infection statuses of the Geneva population. ResultsAmong the 2521 individuals included in the analysis (55.2% women; 21.4% aged <18 years and 14.2% aged [≥] 65 years), overall seroprevalence of antibodies was 93.8% (95% credible interval: 93.1-94.5), including 72.4% (70.0-74.7) for infection-induced antibodies. Estimates of neutralizing antibodies based on a representative subsample of 1160 participants ranged from 79.5% (77.1-81.8) against the Alpha variant to 46.7% (43.0-50.4) against the Omicron BA.4/BA.5 subvariants. Despite having high seroprevalence of infection-induced antibodies (76.7% [69.7-83.0] for ages 0-5 years, 90.5% [86.5-94.1] for ages 6-11 years), children aged <12 years had substantially lower neutralizing activity than older participants, particularly against Omicron subvariants. In general, higher levels of neutralization activity against pre-Omicron variants were associated with vaccination, particularly having received a booster dose. Higher levels of neutralization activity against Omicron subvariants were associated with booster vaccination alongside recent infection. ConclusionMore than nine in ten individuals in the Geneva population have developed anti-SARS-CoV-2 antibodies through vaccination and/or infection, but less than half of the population has antibodies with neutralizing activity against the currently circulating Omicron BA.5 subvariant. Hybrid immunity obtained through booster vaccination and infection appears to confer the greatest neutralization capacity, including against Omicron.
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BackgroundUp-to-date seroprevalence estimates are critical to describe the SARS-CoV-2 immune landscape in the population and guide public health measures. We aimed to estimate the seroprevalence of anti-SARS-CoV-2 antibodies 15 months into the COVID-19 pandemic and six months into the vaccination campaign. MethodsWe conducted a population-based cross-sectional serosurvey between June 1 and July 7, 2021, recruiting participants from age- and sex-stratified random samples of the general population. We tested participants for anti-SARS-CoV-2 antibodies targeting the spike (S) or nucleocapsid (N) proteins (Roche Elecsys immunoassays). We estimated the anti-SARS-CoV-2 antibodies seroprevalence following vaccination and/or infection (anti-S antibodies), or infection only (anti-N antibodies). ResultsWe included 3355 individuals, of which 1814 (54.1%) were women, 697 (20.8%) were aged <18 years and 449 (13.4%) were aged [≥]65 years, 2161 (64.4%) tested positive for anti-S antibodies, and 906 (27.0%) tested positive for anti-N antibodies. The total seroprevalence of anti-SARS-CoV-2 antibodies was 66.1% (95% credible interval, 64.1-68.0). We estimated that 29.9% (28.0-31.9) of the population developed antibodies after infection; the rest having developed antibodies only via vaccination. Seroprevalence estimates were similar across sexes, but differed markedly across age groups, being lowest among children aged 0-5 years (20.8% [15.5-26.7]) and highest among older adults aged [≥]75 years (93.1% [89.6-96.0]). Seroprevalence of antibodies developed via infection and/or vaccination was higher among participants with a higher educational level. ConclusionsMost adults have developed anti-SARS-CoV-2 antibodies, while most teenagers and children remain vulnerable to infection. As the SARS-CoV-2 Delta variant spreads and vaccination rates stagnate, efforts are needed to address vaccine hesitancy, particularly among younger individuals and socioeconomically disadvantaged groups, and to minimize spread among children.
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ObjectivesThis cohort study including essential workers, assessed the{square}risk and incidence of SARS-CoV-2{square}infection during the second surge of COVID-19 according to baseline serostatus and occupational sector. MethodsEssential workers were selected from a seroprevalence survey cohort in Geneva, Switzerland and were linked to a state centralized registry compiling SARS-CoV-2 infections. Primary outcome was the number of virologically-confirmed infections from serological assessment (between May and September 2020) to January 25, 2021, according to baseline antibody status and stratified by three pre-defined occupational groups (occupations requiring sustained physical proximity, involving brief regular contact or others). Secondary outcomes included the incidence of infection. Results10457 essential workers were included (occupations requiring sustained physical proximity accounted for 3057 individuals, those involving regular brief contact, 3645, and 3755 workers were classified under "Other essential occupations"). After a follow-up period of over 27 weeks, 5 (0.6%) seropositive and 830 (8.5%) seronegative individuals had a positive SARS-CoV-2 test, with an incidence rate of 0.2 (95% CI 0.1 to 0.6) and 3.2 (95% CI 2.9 to 3.4) cases per person-week, respectively. Incidences were similar across occupational groups. Seropositive essential workers had a 93% reduction in the hazard (HR of 0.07, 95% CI 0.03 to 0.17) of having a positive test during follow-up with no significant between-occupational group difference. ConclusionsA ten-fold reduction in the hazard of being virologically tested positive was observed among anti-SARS-CoV-2 seropositive essential workers regardless of their sector of occupation, confirming the seroprotective effect of a previous SARS-CoV2 exposure at least six months after infection. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSRisk of SARS-CoV-2 reinfection is low in the general population and among healthcare workers. What are the new findings?A ten-fold reduction of risk of being virologically tested positive reinfection is observed among anti-SARS-CoV-2 seropositive essential workers of different activity sectors, regardless of their occupation-related risk of exposure. How might this impact on policy or clinical practice in the foreseeable future?Vaccination could be delayed in individuals with previous history of SARS-CoV-2 infection with serologic confirmation, regardless of their occupational exposure. These observations need to be confirmed for new SARS-CoV-2 variants.
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ImportanceSerological assays detecting specific IgG antibodies generated against the Spike protein following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection are being widely deployed in research studies and clinical practice. However, the duration and the effectiveness of the protection conferred by the immune response against future infection remains to be assessed in a large population. ObjectiveTo estimate the incidence of newly acquired SARS-CoV-2 infections in seropositive individuals from a population-based sample as compared to seronegative controls. DesignRetrospective longitudinal propensity-score matched cohort study. SettingA seroprevalence survey including a population-based representative sample of the population from the canton of Geneva (Switzerland) was conducted between April and June 2020, immediately after the first pandemic wave. Each individual included in the seroprevalence survey was linked to a state centralized registry compiling virologically confirmed SARS-CoV-2 infections since the beginning of the pandemic. ParticipantsParticipants aged twelve years old and over, who developed anti-spike IgG antibodies were matched one-to-two to seronegative controls, using a propensity-score including age, gender, immunodeficiency, body mass index, smoking status and education level. ExposureSARS-CoV-2 seropositivity. Main outcomes and measuresOur primary outcome was virologically confirmed SARS-CoV-2 infections which occurred from serological status assessment in April-June 2020 to the end of the second pandemic wave (January 2021). Additionally, incidence of infections, rate of testing and proportion of positive tests were analysed. ResultsAmong 8344 serosurvey participants, 498 seropositive individuals were selected and matched with 996 seronegative controls. After a mean follow-up of 35.6 (Standard Deviation, SD: 3.2) weeks, 7 out of 498 (1.4%) seropositive subjects had a positive SARS-CoV-2 test, of which 5 (1.0%) were considered as reinfections. By contrast, infection rate was significantly higher in seronegative individuals (15.5%, 154/996) during a similar mean follow-up of 34.7 (SD 3.2) weeks, corresponding to a 94% (95%CI 86% to 98%, P<0.001) reduction in the hazard of having a positive SARS-CoV-2 test for seropositive subjects. Conclusions and relevanceSeroconversion after SARS-CoV-2 infection confers protection to successive viral contamination lasting at least 8 months. These findings could help global health authorities establishing priority for vaccine allocation. Key points QuestionDo SARS-CoV-2 antibodies confer protection against future infection? FindingsIn this retrospective matched cohort study nested in a representative sample of the general population of Geneva, Switzerland, we observed a 94% reduction in the hazard of being infected among participants with antibodies against SARS-CoV-2, when compared to seronegative controls, >8 months after initial serology assessment. MeaningSeroconversion to SARS-CoV-2 is associated with a large and sustained protection against reinfection.
ABSTRACT
Serologic studies have been critical in tracking the evolution of the COVID-19 pandemic. The reliability of serologic studies for quantifying the proportion of the population that have been infected depends on the extent of antibody decay as well as on assay performance in detecting both recent and older infections. Data on anti-SARS-CoV-2 antibodies persistence remain sparse, especially from infected individuals with few to no symptoms. In a cohort of mostly mild/asymptomatic SARS-CoV-2-infected individuals tested with three widely-used immunoassays, antibodies persisted for at least 8 months after infection, although detection depended on immunoassay choice, with one of them missing up to 40% of past infections. Simulations reveal that without appropriate adjustment for time-varying assay sensitivity, seroprevalence surveys may underestimate infection rates. As the immune landscape becomes more complex with naturally-infected and vaccinated individuals, assay choice and appropriate assay-performance-adjustment will become even more important for the interpretation of serologic studies.
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AimsUnravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights in the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We aimed at determining i) the association between anti-SARS-CoV-2 and anti-apoA-1 humoral response, ii) their relationship to prognosis, and iii) the degree of linear homology between SARS-CoV-2, apoA-1, and Toll-like receptor-2 (TLR2) epitopes. Methods and ResultsImmunoreactivity against different engineered peptides as well as cytokines were assessed by immunoassays, on a case-control (n=101), an intensive care unit (ICU; n=126) with a 28-days follow-up, and a general population cohort (n=663) with available samples in the pre and post-pandemic period. Using bioinformatics modelling a linear sequence homologies between apoA-1, TLR2, and Spike epitopes were identified. Overall, anti-apoA-1IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (p<0.0001). Significant and similar associations were noted between anti-apoA-1, anti-SARS-CoV-2IgG, cytokines, and lipid profile. In ICU patients, anti-SARS-CoV-2 and anti-apoA-1 seroconversion rates displayed similar 7-days kinetics, reaching 82% for anti-apoA-1 seropositivity. C-statistics (CS) indicated that anti-Spike/TLR2 mimic-peptide IgGs displayed a significant prognostic accuracy for overall mortality at 28 days (CS: 0.64; p=0.02). In the general population, SARS-CoV-2 exposure increased baseline anti-apoA-1 IgG levels. ConclusionCOVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic.
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BackgroundPopulation-based serological surveys provide a means for assessing the immunologic landscape of a community, without the biases related to health-seeking behaviors and testing practices typically associated with rt-PCR testing. This study assesses SARS-CoV-2 seroprevalence over the first epidemic wave in Canton Geneva, Switzerland, as well as biological and socio-economic risk factors for infection and symptoms associated with IgG seropositivity. Methods and findingsBetween April 6 and June 30, 2020, former participants of a yearly representative cross-sectional survey of the 20-75-year-old population of the canton of Geneva were invited to participate in a seroprevalence study, along with household members five years and older. We collected blood and tested it for anti-SARS-CoV-2 immunoglobulins G (IgG). Questionnaires were self-administered. We estimated seroprevalence with a Bayesian model accounting for test performance and sampling design. We included 8344 participants (53.5% women, mean age 46.9 years). The population-level seroprevalence over the 12-week study period was 7.8 % (95% Credible Interval (CrI) 6.8-8.9), accounting for sex, age and household random effects. Seroprevalence was highest among 18-49 year olds (9.5%, 95%CrI 8.1-10.9), with young children (5-9 years) and those >65 years having significantly lower seroprevalence (4.3% and 4.7-5.4% respectively). Men were more likely to be seropositive than women (relative risk 1.2, 95%CrI 1.1-1.4). Odds of seropositivity were reduced for female retirees (0.46, 95%CI 0.23-0.93) and unemployed men (0.35, 95%CI 0.13-1.0) compared to employed individuals, and for current smokers (0.36, 95%CI 0.23-0.55) compared to never-smokers. We found no significant association between occupation, level of education, neighborhood income and the risk of being seropositive. Symptoms most strongly associated with seropositivity were anosmia/dysgeusia, loss of appetite, fever, fatigue and myalgia and/or arthralgia. Thirteen percent of seropositive participants reported no symptoms. ConclusionsOur results confirm a low population seroprevalence of anti-SARS-CoV-2 antibodies after the first wave in Geneva, a region hard hit by the COVID-19 pandemic. Socioeconomic factors were not associated with seropositivity in this sample. The elderly and young children were less frequently seropositive, though it is not clear how biology and behaviors shape these differences. These specificities should be considered when assessing the need for targeted public health measures.
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BackgroundKnowing the transmissibility of asymptomatic infections and risk of infection from household- and community-exposures is critical to SARS-CoV-2 control. Limited previous evidence is based primarily on virologic testing, which disproportionately misses mild and asymptomatic infections. Serologic measures are more likely to capture all previously infected individuals. ObjectiveEstimate the risk of SARS-CoV-2 infection from household and community exposures, and identify key risk factors for transmission and infection. DesignCross-sectional household serosurvey and transmission model. SettingGeneva, Switzerland Participants4,524 household members [≥]5 years from 2,267 households enrolled April-June 2020. MeasurementsPast SARS-CoV-2 infection confirmed through IgG ELISA. Chain-binomial models based on the number of infections within households used to estimate the cumulative extra-household infection risk and infection risk from exposure to an infected household member by demographics and infectors symptoms. ResultsThe chance of being infected by a SARS-CoV-2 infected household member was 17.3% (95%CrI,13.7-21.7%) compared to a cumulative extra-household infection risk of 5.1% (95%CrI,4.5-5.8%). Infection risk from an infected household member increased with age, with 5-9 year olds having 0.4 times (95%CrI, 0.07-1.4) the odds of infection, and [≥]65 years olds having 2.7 (95%CrI,0.88-7.4) times the odds of infection of 20-49 year olds. Working-age adults had the highest extra-household infection risk. Seropositive asymptomatic household members had 69.6% lower odds (95%CrI,33.7-88.1%) of infecting another household member compared to those reporting symptoms, accounting for 14.7% (95%CrI,6.3-23.2%) of all household infections. LimitationsSelf-reported symptoms, small number of seropositive kids and imperfect serologic tests. ConclusionThe risk of infection from exposure to a single infected household member was more than three-times that of extra-household exposures over the first pandemic wave. Young children had a lower risk of infection from household members. Asymptomatic infections are far less likely to transmit than symptomatic ones but do cause infections. Funding SourceSwiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), Fondation de Bienfaisance du Groupe Pictet, Fondation Ancrage, Fondation Privee des Hopitaux Universitaires de Geneve, and Center for Emerging Viral Diseases.
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Novel technologies are needed to facilitate large-scale detection and quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies in human blood samples. Such technologies are essential to support seroprevalence studies, vaccine clinical trials, and to monitor quality and duration of immunity. We developed a microfluidic nano-immunnoassay for the detection of anti-SARS-CoV-2 IgG antibodies in 1024 samples per device. The method achieved a specificity of 100% and a sensitivity of 98% based on the analysis of 289 human serum samples. To eliminate the need for venipuncture, we developed low-cost, ultra-low volume whole blood sampling methods based on two commercial devices and repurposed a blood glucose test strip. The glucose test strip permits the collection, shipment, and analysis of 0.6 {micro}L whole blood easily obtainable from a simple fingerprick. The nano-immunoassay platform achieves high-throughput, high sensitivity and specificity, negligible reagent consumption, and a decentralized and simple approach to blood sample collection. We expect this technology to be immediately applicable to current and future SARS-CoV-2 related serological studies and to protein biomarker diagnostics in general.
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To understand SARS-CoV-2 immunity after natural infection or vaccination, functional assays such as virus neutralizing assays are needed. So far, assays to determine SARS-CoV-2 neutralizing antibodies rely on cell-culture based infection assays either using wild type SARS-CoV-2 or pseudotyped viruses. Such assays are labour-intensive, require appropriate biosafety facilities and are difficult to standardize. Recently, a new surrogate virus neutralisation assay (sVNT) was described that uses the principle of an ELISA to measure the neutralization capacity of anti-SARS-CoV-2 antibodies directed against the receptor binding domain. Here, we performed an independent evaluation of the robustness, specificity and sensitivity on an extensive panel of sera from 269 PCR-confirmed COVID-19 cases and 259 unmatched samples collected before 2020 and compared it to cell-based neutralization assays. We found a high specificity of 99.2 (95%CI: 96.9-99.9) and overall sensitivity of 80.3 (95%CI: 74.9-84.8) for the sVNT. Clinical sensitivity increased between early (<14 days post symptom onset or post diagnosis, dpos/dpd) and late sera (>14 dpos/dpd) from 75.0 (64.7-83.2) to 83.1 (76.5-88.1). Also, higher severity was associated with an increase in clinical sensitivity. Upon comparison with cell-based neutralisation assays we determined an analytical sensitivity of 74.3 (56.4-86.9) and 98.2 (89.4-99.9) for titres [≥]10 to <40 and [≥]40 to <160, respectively. Only samples with a titre [≥]160 were always positive in the sVNT. In conclusion, the sVNT can be used as an additional assay to determine the immune status of COVID-19 infected of vaccinated individuals but its value needs to be assessed for the specific context of use.
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A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) is the source of a current pandemic (COVID-19) with devastating consequences in public health and economic stability. Using a peptide array to map the antibody response of plasma from healing patients, we identified immunodominant linear epitopes corresponding to key proteolytic sites on the spike protein.
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BackgroundAssessing the burden of COVID-19 based on medically-attended case counts is suboptimal given its reliance on testing strategy, changing case definitions and the wide spectrum of disease presentation. Population-based serosurveys provide one avenue for estimating infection rates and monitoring the progression of the epidemic, overcoming many of these limitations. MethodsTaking advantage of a pool of adult participants from population-representative surveys conducted in Geneva, Switzerland, we implemented a study consisting of 8 weekly serosurveys among these participants and their household members older than 5 years. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available enzyme-linked immunosorbent assay (Euroimmun AG, Lubeck, Germany). We estimated seroprevalence using a Bayesian regression model taking into account test performance and adjusting for the age and sex of Genevas population. ResultsIn the first three weeks, we enrolled 1335 participants coming from 633 households, with 16% <20 years of age and 53.6% female, a distribution similar to that of Geneva. In the first week, we estimated a seroprevalence of 3.1% (95% CI 0.2-5.99, n=343). This increased to 6.1% (95% CI 2.69.33, n=416) in the second, and to 9.7% (95% CI 6.1-13.11, n=576) in the third week. We found that 5-19 year-olds (6.0%, 95% CI 2.3-10.2%) had similar seroprevalence to 20-49 year olds (8.5%, 95%CI 4.99-11.7), while significantly lower seroprevalence was observed among those 50 and older (3.7%, 95% CI 0.99-6.0, p=0.0008). InterpretationAssuming that the presence of IgG antibodies is at least in the short-term associated with immunity, these results highlight that the epidemic is far from burning out simply due to herd immunity. Further, no differences in seroprevalence between children and middle age adults are observed. These results must be considered as Switzerland and the world look towards easing restrictions aimed at curbing transmission.
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ObjectivesTo validate the diagnostic accuracy of a Euroimmun SARS-CoV-2 IgG and IgA immunoassay for COVID-19. MethodsIn this unmatched (1:1) case-control validation study, we used sera of 181 laboratory-confirmed SARS-CoV-2 cases and 176 controls collected before SARS-CoV-2 emergence. Diagnostic accuracy of the immunoassay was assessed against a whole spike protein-based recombinant immunofluorescence assay (rIFA) by receiver operating characteristic (ROC) analyses. Discrepant cases between ELISA and rIFA were further tested by pseudo-neutralization assay. ResultsCOVID-19 patients were more likely to be male and older than controls, and 50.3% were hospitalized. ROC curve analyses indicated that IgG and IgA had high diagnostic accuracies with AUCs of 0.992 (95% Confidence Interval [95%CI]: 0.986-0.996) and 0.977 (95%CI: 0.963-0.990), respectively. IgG assays outperformed IgA assays (p=0.008). Taking an assessed 15% inter-assay imprecision into account, an optimized IgG ratio cut-off > 1.5 displayed a 100% specificity (95%CI: 98-100) and a 100% positive predictive value (95%CI: 97-100). A 0.5 cut-off displayed a 97% sensitivity (95%CI: 93-99) and a 97% negative predictive value (95%CI: 93-99). Substituting these thresholds for the manufacturers, improved assay performance, leaving 12% of IgG ratios indeterminate between 0.5-1.5. ConclusionsThe Euroimmun assay displays a nearly optimal diagnostic accuracy using IgG against SARS-CoV-2 in patient samples, with no obvious gains from IgA serology. The optimized cut-offs are fit for rule-in and rule-out purposes, allowing determination of whether individuals in our study population have been exposed to SARS-CoV-2 or not. IgG serology should however not be considered as a surrogate of protection at this stage.