key: cord-0968189-8wrdpmuz
authors: Anna, François; Goyard, Sophie; Lalanne, Ana Ines; Nevo, Fabien; Gransagne, Marion; Souque, Philippe; Louis, Delphine; Gillon, Véronique; Turbiez, Isabelle; Bidard, François‐Clément; Gobillion, Aline; Savignoni, Alexia; Guillot‐Delost, Maude; Dejardin, François; Dufour, Evelyne; Petres, Stéphane; Richard‐Le Goff, Odile; Choucha, Zaineb; Helynck, Olivier; Janin, Yves L.; Escriou, Nicolas; Charneau, Pierre; Perez, Franck; Rose, Thierry; Lantz, Olivier
title: High seroprevalence but short‐lived immune response to SARS‐CoV‐2 infection in Paris
date: 2020-12-01
journal: Eur J Immunol
DOI: 10.1002/eji.202049058
sha: c2722caf45df3ba6ca8d4c8a9ade32954a36bb62
doc_id: 968189
cord_uid: 8wrdpmuz

Although the COVID‐19 pandemic peaked in March/April 2020 in France, the prevalence of infection is barely known. Using high‐throughput methods, we assessed herein the serological response against the SARS‐CoV‐2 virus of 1847 participants working in three sites of an institution in Paris conurbation. In May‐July 2020, 11% (95% CI: 9.7–12.6) of serums were positive for IgG against the SARS‐CoV‐2 N and S proteins, and 9.5% (CI:8.2–11.0) were neutralizer in pseudo‐typed virus assays. The prevalence of seroconversion was 11.6% (CI:10.2–13.2) when considering positivity in at least one assays. In 5% of RT‐qPCR positive individuals, no systemic IgGs were detected. Among immune individuals, 21% had been asymptomatic. Anosmia (loss of smell) and ageusia (loss of taste) occurred in 52% of the IgG‐positive individuals and in 3% of the negative ones. In contrast, 30% of the anosmia‐ageusia cases were seronegative suggesting that the true prevalence of infection may have reached 16.6%. In sera obtained 4–8 weeks after the first sampling anti‐N and anti‐S IgG titers and neutralization activity in pseudo‐virus assay declined by 31%, 17% and 53%, resulting thus in half‐life of respectively 35, 87 and 28 days. The population studied is representative of active workers in Paris. The short lifespan of the serological systemic responses suggests an underestimation of the true prevalence of infection. This article is protected by copyright. All rights reserved

In May-July 2020, 11% (95% CI: 9.7-12.6) of serums were positive for IgG against the SARS-CoV-2 N and S proteins, and 9.5% (CI:8.2-11.0) were neutralizer in pseudo-typed virus assays. The prevalence of seroconversion was 11.6% (CI:10.2-13.2) when considering positivity in at least one assays. In 5% of RT-qPCR positive individuals, no systemic IgGs were detected. Among immune individuals, 21% had been asymptomatic. Anosmia (loss of smell) and ageusia (loss of taste) occurred in 52% of the IgG-positive individuals and in 3% of the negative ones. In contrast, 30% of the anosmia-ageusia cases were seronegative suggesting that the true prevalence of infection may have reached 16.6%.

In sera obtained 4-8 weeks after the first sampling anti-N and anti-S IgG titers and neutralization activity in pseudo-virus assay declined by 31%, 17% and 53%, resulting thus in half-life of respectively 35, 87 and 28 days.

The population studied is representative of active workers in Paris. The short lifespan of the serological systemic responses suggests an underestimation of the true prevalence of infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 emerged in 2019 in China [1] [2] [3] before being detected in a patient living in the Paris conurbation in December 2019 [4] . From January 2020, the virus spread exponentially leading to a risk of Paris conurbation intensive care units saturation. Accordingly, on March 17 th , a lockdown was imposed by the French authorities to slow down virus progression. To date, the exposure of the French population during that period remains poorly documented. In contrast with RT-qPCR assays which are positive for only 2-3 weeks after infection [5] , a more efficient way to monitor virus propagation is a serological study of representative populations since specific and lasting antibodies are generated in the great majority of infected subjects [6, 7] . However, studying the anti-SARS-CoV-2 serological response of large cohorts is challenging and require robustness, specificities, sensitivities and high-throughput capabilities of the measurement methods which are exceeding the performance of currently marketed serological assays.

Here, we developed original bioluminescence-based serological assays allowing a high throughput assessment of the specific antibody responses to the Spike (S) and Nucleoprotein (N) proteins of SARS-CoV-2 and their ability to neutralize the virus fusion with a permissive human cell line.

We monitored individual serology against SARS-CoV-2 in a large cohort of workers in three institution sites following the March-April 2020 peak of the COVID-19 pandemic in Paris (France) and over the next six months. More than half of Institut Curie workers (n=1847), a hospital and research center specialized in oncology, volunteered for this Curie-O-SA longitudinal serological study. The participants had only been marginally in contact with COVID-19 patients and are domiciled in the Paris conurbation and are thus representative of an urban population of healthy active adults living in a big metropolitan area. In the course of this survey, we found a high prevalence of immunization although endowed with a rather short-lived immune responses.

Blood samples were collected from 1847 volunteers at the three sites of the Institut Curie located in three cities of Paris conurbation (Ile-de-France): Paris, Saint Cloud and Orsay from April 28 th until July 31 th for the initial time-point. None of the individuals showed clinical signs of COVID-19 or had been subjected to a standard RNA detection of SARS-CoV-2, using RT-qPCR, within 14 days prior to blood sampling. All participants were invited to complete a web-based questionnaire which included demographic variables, symptom occurrences and whether these had led to a sick leave, treatment and/or hospitalization. The participant cohort had a strong (77.4%) female bias ( Table 1) ; the mean age was 38 and ranged between 19 and 75 years old. The hospital-working staff represented 72.7% of the volunteers, the rest being researchers and administrative staff.

Three serological assays were carried out on these 1847 sera samples in multi-well plates at the Institut Pasteur. Luciferase-linked immuno-sorbent assays (LuLISA) were used to assess specific IgG for SARS-CoV-2 Nucleoprotein (N) and Spike (S) proteins in these serum samples. LuLISA [10] is expanding the sensitivity, the dynamic range and the scalability in comparison with the gold standard ELISA [8] as detailed in Supporting Information (Figures S1 and S2) . A neutralization activity assay using pseudo-typed virus, also named pseudo-neutralization test (PNT), was undertaken [9] to assess in parallel of LuLISA, the ability of serum components to neutralize the fusion of a SARS-CoV-2 Spike pseudo-typed lentiviral vector encoding a luciferase gene using a permissive human cell line (HEK 293T) which is constitutively expressing the human ACE2 receptors (Supporting Information Figure S3 ). The specificity threshold of the three methods were established by using serum samples from 54 COVID-19 patients (March 2020, Institut Cochin), 234 prepandemic negative healthy donors from a blood bank (2014-2018, EFS/ICAReB) and 75 negative serums from prepandemic breast cancer patients (2012, Institut Curie) (Figure 1A, B, C) . The positivity thresholds were set to 98% specificity for LuLISA assay allowing the detection of anti-N IgG (10,400 RLU/s) and anti-S IgG (8,400 RLU/s) and to a confidence level of 99% in the case of PNT assay (28,783 RLU/s) established on prepandemic negative sera.

The robustness of the specificity thresholds and dynamic ranges were assessed using dilution series of COVID-19 positive sera (Supporting Information Figures S2 and S3) . The specificity for SARS-CoV-2 anti-N IgG was assessed against purified Nucleoproteins of SARS-CoV-1 as well as seasonal coronaviruses (HCoV) HKU, OC43, NL63, 229E (Supporting Information Figures S4 and S5 ).

For the Institut Curie workers, using a 98% specificity threshold, the seroprevalence of IgG directed against N and S proteins was 9.9% (183/1847, 95% CI: 8.6-11.4) and 9.8% (181/1847, 95% CI: 8.5-11.3), respectively ( Figure 1A -B and Table 1) . Amongst all the serums tested, 9.5% (176/1847, 95% CI: 8.2-11.0) displayed a pseudo-neutralization activity against the pseudo-virus ( Figure 1C ).

Considering each of these assays independently as a marker of specific immune response leads to a 11.6% (215/1847, 95% CI: 10.2-13.2) positivity of immunization.

The correlative plots ( Figure 1D ) indicates that the responses against the N and S are linked when both are above their respective threshold (R²=0.57). Correlation between PNT and LuLISA is mainly detectable when high levels of both IgG against N and S are detected (red dots in Figure 1D ).

Moreover, above the 98% specificity threshold, a higher correlation is observed between PNT and LuLISA IgG/S (R²=0.60) ( Figure 1F ) than between PNT and LuLISA IgG/N (R²=0.47) ( Figure 1E ).

Remarkably, out of the 215 seropositive samples, 72% are positive for the 3 assays (Figure 1G) , 9.7% are positive only for anti-N IgG (IgG/N), 5.6% for anti-S IgG (IgG/S) and 5.1% for PNT.

Based on the web-based survey, 54% (1007/1847) participants mentioned at least one symptom (Supporting Information Table S1 ). Symptomatic workers were more seropositive (16.8%, 170/1007, CI 95%: 14.6-19.3) than asymptomatic workers (5.3%, 45/840, CI 95%: 3.9-7.1) ( Table 2 and Figure   2A ). Hence, SARS-CoV-2 infection may have been asymptomatic in at least 20.9% (45/215, 95% CI: 16.5-28.2) of the cases ( Figure 2B) . The amount of anti-N IgG was higher in the symptomatic versus asymptomatic patients while the levels of anti-S or the neutralization capacity in pseudo-virus assay did not differ (Supporting Information Figure S6 ). This discrepancy suggests that anti-N IgG may be generated in the course of a mild infection.

A correlation between serological tests, RT-qPCR and symptoms was performed ( Figure 2C) . In the 171 individuals tested by RT-qPCR, 169 (99%) reported symptoms, only 76 (44.4%, CI 95%: 37.9-53.1) were positive in serological assays. Among these 171 RT-qPCR tested workers, 55% of them were RT-qPCR negative, seronegative for anti-N and anti-S IgG and PNT, but symptomatic whereas 35% were positive, seropositive and symptomatic. Moreover, no IgG antibodies were detected in 3 subjects out of 63 with a positive SARS-CoV-2 RT-qPCR indicating that a systemic anti-N or S IgG response may not always be present following a proven SARS-CoV-2 infection. However, low levels of anti-SARS-CoV-2 IgM, were detected using a commercial lateral flow assay, in one of these three subjects (data not shown). Except for one case, all anosmia/ageusia cases without detectable systemic IgG (n=48) were associated with other COVID-19 typical symptoms and occurred in late February, March or April suggesting that they represent true SARS-CoV-2 infections. Indeed, one of them was associated with a positive SARS-CoV-2 RT-qPCR test and, in 7 cases anti-SARS-CoV-2 IgM were detected using lateral flow assays (data not shown). Thus, in addition to the 215 SARS-CoV-2 immune cases detected by our survey, the cohort may feature an additional 48 infection cases devoid of detectable systemic IgG antibodies. Assuming that the incidence (52%) of the anosmia/ageusia symptom is similar in immune and non-immune individuals, the true prevalence of SARS-CoV-2 infection in this population would then be more than 11.6% (215/1847) and as high as The frequency of declared symptoms was significantly much higher in seropositive workers (79%) than in those devoid of COVID-19 specific IgG (51%) ( Table 2 ). If fever (66%, 142/215) was the most frequent symptoms in the seropositive population, it was also noted in individuals lacking antibodies (37%, 599/1632) suggesting a low correlation with a COVID-19 infection (chi-square scores 2E -16 ) ( Table 2 ). In contrast, anosmia/ageusia and myalgia symptoms were highly prevalent (52%, 111/215 and 48%, 103/215 respectively) in the seropositive group but were rare in the seronegative group 3% (48/1632) and 15.7% (256/1632) respectively ( Figure 2H -J), resulting in a high correlation with COVID-19 (chi-square scores 5E -76 and 3E -29 ) ( Table 2) . Only anosmia/ageusia symptoms were temporally correlated with the epidemic peak in March whereas other symptoms such as myalgia and rhinitis (Figure 2K -M) were declared by seronegative workers mainly before but also after this peak suggesting the consequences of other circulating infections.

To follow over time the antibody titers and neutralizing activity, a second blood sample (t 1 ) was obtained 4-8 weeks after the first one (t 0 ) from more than 1000 individuals. For the 120 samples of individuals previously found positive, the results are reported in Figure 3A , D, G according to the time interval between symptom onset and sampling. A clear decrease in the antibody titers and neutralization activity in pseudo-virus assay was observed. The half-lives of the antibody titers were 35, 87 and 28 days for anti-N, anti-S IgG and neutralization activity in pseudo-virus assay, respectively. A paired analysis showed a systematic decreased response (p<0.0005) (Figure 3B, E, H) .

The titers of antibodies decreased by 31% and 17% for anti-N and anti-S IgG, respectively for a majority of workers (>75%) and this correlated with a major decrease of the neutralization activity in pseudo-virus assay (53%) (Figure 3C, F, I) . Interestingly, some workers sera became negative in our assays: 15% (16/107) for LuLISA IgG/N ( Figure 3C ), 14% (10/71) for PNT ( Figure 3I ) and 5% (4/84) for LuLISA IgG/S ( Figure 3F) . Thus, past a few months, a serological-based survey of SARS-CoV-2 may run a risk of underestimating the number of formerly infected individuals.

We report here the longitudinal study Curie-O-SA describing the natural immune response against the SARS-CoV-2 in a large population of healthy subjects working in the Paris conurbation following the March 2020 peak. Three bioluminescence-based and sensitive high-throughput assays including a pseudo-typed virus neutralization activity assay allowed repeated measurements on a large number of samples. In contrast with other studies focusing on hospitalized patients or based on the occurrence of symptoms [11] [12] [13] [14] [15] [16] , this study included more than half of all the employees working at three distant locations of a non-especially COVID-exposed institution with a corresponding webbased questionnaire filled up by more than 96% of the participants.

This survey evidenced a high prevalence (11.6-16.6%) of previous infection by the SARS-CoV-2 in March/April 2020 along with the following points: 1) the levels of IgG/N and IgG/S were highly correlated beyond twice their positive thresholds as wells as with the viral pseudo-neutralization capacity beyond three times their positive thresholds. 2) 21% of infections had been asymptomatic. In accordance with recent studies 38/1847 individuals were RT-qPCR positive but negative for serological tests [17] and all subject among the 215/1847 did not display a common scheme of coordinated immune response [18] which included all the parameters studied. Indeed, the largest response was the sequential occurrence of anti-N IgG, followed by the anti-S IgG and then the pseudo-typed virus neutralizing activity. A few individuals were endowed with neutralizing sera without any detectable IgG against S, either because their S-specific IgG had high affinity and a very low concentration or because other Ig than IgG were responsible for the pseudo-typed virus neutralization activity as recently suggested for S-specific IgA or IgM [19] . The lower prevalence of the PNT activity could be either related to a lower sensitivity of the assay or to an immune response decrease of the as evidenced in Figure 3 . Indeed, although most of the symptoms occurred from March to early April, the blood samplings were performed between May and July, leading to a variable interval between an eventual infection and the antibody response study.

Our experiments pointed out a clear cross-recognition of IgG for SARS-CoV-1 and -2 Nucleoproteins but none with any of the seasonal HCoV, aside from samples displaying a very high IgG/N content (Supporting Information Figure S4 ). This may be expected in view of the relatively few short peptide patterns common to all the aligned antigens sequences (Supporting Information Figure S5 ).

Asian outbreak and afterward, we do not expect any bias of the seroprevalence for SARS-CoV-2 with SARS-CoV-1 or the seasonal HCoV in Paris from February to June.

The seroprevalence we observed for this population of active workers in Paris conurbation (11.6%) is much higher than the one we found in a nation-wide representative population in France in May (n= 3592, 4.9%) [20] but much lower than the response we saw in a population living in precarious conditions such as homeless (n=543, 50.5%) or people not born in France living in workers' residences (n=127, 88.7%) in Paris conurbation performed with the same LuLISA and PNT methods in July [21] . Our results are consistent with other large-scale serological studies (mostly with single time-point and no symptom reports) in conurbations that have been subjected to the SARS-CoV-2 epidemic. Higher seroprevalence was found in New-York City (USA, n=5129, 22.7%, March [22] ; n= 72 401, 41.5%, March [23] ), Madrid (Spain, n=2590, 31.6%, April) [24] , similar in Saint Petersburg (Russia, n=1038, 10.8%, May) [25] and lower in Geneva (Swiss, n= 2766, 8.5%, April) [26] , Wuhan (China, n=17368, 3.8%, March-April) [27] or nine cities of Rio Grande do Sul (Brazil, n=4500, 0.22%, May) [28] . Seroprevalence in healthcare workers (HCW) highly exposed to COVID is also contrasted.

It was high in London (n=2167, 31.6%, May-June 2020) [12] and Paris (n=154, 21.1%, March) [29] but lower in Essen (Germany, n=316, 1.6%, March) [13] ; Madrid (Spain, n=578, 9.3%, April) [11] ; Milano (Italia, n=789, 10.8%, March) [15] .

Among seropositive individuals, 20% had been asymptomatic in this study which is less than what has been mentioned in other studies reports although this is highly dependent on the recording and reporting methods: 40% in Madrid area [11] , 50% in Boston area [30] and up to 80% locally in France on September 2020. This last result where it is a likely consequence of reinforced mask wearing policies [31] since such efficacy was also observed in Wuhan with 86% of asymptomatic in January 2020 [32] , plausibly due to mask-attenuated infectious load [31] .

The pattern of symptoms displayed by the immune subjects are consistent with those reported elsewhere [33, 34] . Our results further emphasize the predictive value and specificity of the anosmia/ageusia symptoms. Aside from fatigue, only 51% of the studied individuals, 77% of the immunized individuals declared some symptoms. The higher prevalence of infection in the hospital workers (12.7%) than in the research center (8.7%) is certainly not related to difference in confinement since most contaminations occurred in March 2020 before or at the time of the lockdown. Because the hospital treated very few COVID patients, it is likely that the observed contaminations in the hospital staff are resulting from public transportation use as well as social encounters rather than work-related. The difference of the RT-qPCR number performed between the hospital and research center is mainly due to the health staff priority access to SARS-CoV-2 RT-qPCR assays in March and April 2020.

In this first report, we studied the immune response of 120 positive individuals 6-12 weeks after the first blood sampling. A majority of these individuals (>75%) displayed a diminishing anti-SARS Cov2 response. Notably, the anti-N IgG decreased faster (31%) than anti-S IgG (17%) suggesting that if anti-N IgG titration is a reliable marker for prevalence follow-up during the early stage of the COVID-19 pandemic, this assay may be less relevant for longer studies and should be seconded with an anti-S IgG assay. This observation emphasizes the difficulty to estimate the real seroprevalence in a large population. Interestingly, the very slow drop of anti-S IgG titer also reported in other studies [23, 35] did not correlate with the major decrease of neutralization activity on pseudo-typed viruses observed herein (53%). Since our pseudo-neutralization assay is exclusively associated with anti-S response, the neutralization activity we observed might be explained by the occurrence of other Ig isotypes, such as IgM or IgA, which would disappear much faster than the IgG from subsequent blood samples [19] . This illustrates again the serological complexity of any long-lasting immunity.

From an epidemiological perspective, the 11.6-16.6% seroprevalence results may still underestimate the number of individuals who have been infected by the SARS-CoV-2 because, as discussed earlier, we also observed a lack of systemic IgG response among the RT-qPCR positive individuals along with a gradual loss of the virus-specific IgG titer. In the present epidemic, the rather fast decrease in antibody titers is also hindering any retrospective assessment of its true extent. Since Paris may be considered as representative of the world hard-hit conurbations, such high prevalence of a SARS-CoV-2 previous infection along with a short-lived immune response are raising the issues of possible reinfection and virus persistence in a high-density population and may be important parameters to guide future public health policies. frozen. Sera to be tested were thawed and distributed into 96 well plates at the Institut Curie. An aliquot of a pool of positive (or negative) sera was distributed into 6 wells of each plate in a unique dispatching pattern allowing an unambiguous identification of plates.

These positive and negative wells were used to control for any drift of the measurements. The plates were then assessed at the Institut Pasteur. For the Figure 3 longitudinal analysis, the t 0 and t 1 samples were analyzed in the same experiment from frozen serum samples.

Development and validation of the LuLISA method are described in the methods section of the Supporting Information. Briefly, N-and S-specific IgG were assessed using an ELISA-based assays on sera incubated in antigen-coated wells (Supporting Information Figure S1 -2) [36] [37] [38] . Antigens have been produced as follow. Full-length N protein from SARS-CoV-2, SARS-CoV1, HCoV-HKU, HCoV-OC43, HCoV-NL63 and HCoV-229E (UniProtKB ID: P0DTC9, P59595, Q5MQC6, P33469, Q6Q1R8, P15130 respectively) were produced with a (His) 6 

Pseudo-typed vectors were produced and titrated as previously described [41] . Inhibition assay of neutralization of pseudo-typed virus--cell fusion by serum contents [9] are detailed in the methods section of the Supporting Information and Figure S3 . Briefly, sera were decomplemented at 56°C FCS (Gibco) + Pen/Strep (Gibco). After 48h incubation at 37°C 5% CO 2 , the medium is completely removed by aspiration and bioluminescence is measured using a Luciferase Assay System (Promega) on an EnSpire plate reader (PerkinElmer).

Seropositivity was defined as the presence of detectable anti-SARS-CoV-2 antibodies against N or S.

The proportion of seropositive samples was compared by time between onset of symptoms and collection of blood sample using chi-square test.

LuLISA, and pseudo-neutralization of sera were compared by delay since onset of symptoms using the Kruskall-Wallis non-parametric test. The chi-square test was used to evaluate the association between investigated factors and neutralization levels.

All analyses were performed using GraphPad Prism 8 (GraphPad Software, LLC). These results and the raw data of the LuLISA IgG/N and IgG/S and PNT are provided in the Supporting Information Table S1 . is indicated in %. 

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11% of workers at Institut Curie living in Paris conurbation were seropositive and 9.5% had detectable but short-living neutralizing antibodies of SARS-CoV-2. Some 21% of these neutralizing sera actually belong to asymptomatic individuals. Only 2% of the PCR-detected infections had not been followed by humoral immune response

Authors thank all the volunteers from Institut Curie for their participation to this study.