key: cord-339709-49q2xxkw
authors: sermet, i.; temmam, s.; huon, c.; behillil, s.; gadjos, v.; bigot, t.; lurier, t.; chretien, d.; backovick, m.; Moisan-Delaunay, A.; donati, f.; albert, m.; foucaud, e.; Mesplees, B.; benoist, g.; fayes, a.; duval-arnould, m.; cretolle, c.; charbit, m.; aubart, m.; Auriau, J.; lorrot, m.; Kariyawasam, D.; fertita, l.; Orliaguet, G.; pigneur, b.; Bader-Meunier, B.; briand, c.; toubiana, j.; Guilleminot, T.; van der werf, s.; leruez-ville, m.; eloit, m.
title: Prior infection by seasonal coronaviruses does not prevent SARS-CoV-2 infection and associated Multisystem Inflammatory Syndrome in children
date: 2020-06-30
journal: nan
DOI: 10.1101/2020.06.29.20142596
sha: 
doc_id: 339709
cord_uid: 49q2xxkw

Background: Children have a lower rate of COVID-19, potentially related to cross-protective immunity conferred by seasonal coronaviruses (HCoVs). We tested if prior infections with seasonal coronaviruses impacted SARS-CoV-2 infections and related Multisystem Inflammatory Syndrome (MIS). Methods: This cross-sectional observational study in Paris hospitals enrolled 739 pauci or asymptomatic children (HOS group) plus 36 children with suspected MIS (MIS group). Prevalence, antigen specificity and neutralizing capability of SARS-CoV-2 antibodies were tested. Antibody frequency and titres against Nucleocapsid (N) and Spike (S) of the four seasonal coronaviruses (NL63, HKU1, 229E, OC43) were measured in a subset of seropositive patients (54 SARS-CoV-2 (HOS-P subgroup) and 15 MIS (MIS-P subgroup)), and in 118 matched SARS-CoV-2 seronegative patients (CTL subgroup). Findings: SARS-CoV-2 mean prevalence rate in HOSP children was 11.7% from April 1 to June 1. Neutralizing antibodies were found in 55.6% of seropositive children, and their relative frequency increased with time (up to 100 % by mid-May). A majority of MIS children (25/36) were SARS-CoV-2 seropositive, of which all tested (n=15) had neutralizing antibodies. On average, seropositive MIS children had higher N and S1 SARS-CoV-2 titres as compared to HOS children. Patients from HOS-P, MIS-P, and CTL subgroups had a similar prevalence of antibodies against the four seasonal HCoVs (66.9 -100%). The level of anti-SARS-CoV-2 antibodies was not significantly different in children who had prior seasonal coronavirus infection. Interpretation: Prior infection with HCoVs does not prevent SARS-CoV-2 infection and related MIS in children. Children develop neutralizing antibodies after SARS-CoV-2 infection.

COVID-19 is due to SARS-CoV-2, a betacoronavirus subgenus Sarbecovirus 1 , which has expanded 94 worldwide since its emergence in China at the end of 2019. Observations indicate that children are 95 less likely to develop the disease and that the clinical course of COVID-19 in children is less severe than 96 in adults 2-4 . Accordingly, children represent only 0.6-2.3% of confirmed cases in China and 0.8-5.2% 97 outside China outside context of household 2,5,6 . As asymptomatic or mildly symptomatic children are 98 underdiagnosed, and their viral loads are comparable to those of adults, children may act as an 99 asymptomatic reservoir for the spread of the virus to their adult and elderly relatives 7,8 , albeit with 100 low efficacy 9 . Children's susceptibility to infection might also be low 5 and the paediatric cohort may 101 represent a pool of "immune naïve" population. Differences in susceptibility profiles for children and 102 adults might be driven by infections with seasonal human coronaviruses (HCoVs), which are very 103 frequent at a very young age 10 , and could lead to cross-protective immunity in children. This may be 104 mediated either by cross-binding or cross-neutralizing antibodies 11 , or by T cell responses that target 105 epitopes shared by SARS-CoV-2 and HCoVs 12,13 . Indeed, it was recently shown that CD4+ T cells of 106 unexposed subjects (sampled before the pandemic) recognized SARS-CoV-2. 107

Despite a low frequency of respiratory symptoms, cases of Multisystem Inflammatory 108 Syndrome (MIS) have been reported in children that were infected by SARS-CoV-2 or were in contact 109 with COVID-19 patients 14, 15 . MIS shares similarities with classic Kawasaki disease but displays different 110 prominent clinical signs including cardiogenic shock or myocarditis 15 . As for other post infectious 111 diseases 16 , it is possible that a low antibody response to SARS-CoV-2, or cross-reactive antibodies 112 without any neutralizing capability, facilitate immune-dependent enhancement following re-113 exposure, potentiated by a specific genetic background 17,18 . Interestingly, a domain of the SARS-CoV-114 2 spike protein which binds with high affinity to T cells may act as a super antigen, and trigger 115 excessive adaptive immune responses 19 . 116

The aim of this study was to analyse the impact of endemic seasonal coronaviruses on SARS-117

CoV-2 infection in children. This was performed in a large cohort of children aged 0 -18 years, 118 6 hospitalized in Paris. To measure if prior infections with HCoVs (detected by antibody responses 119 against two major antigens, S and N) conferred protection towards SARS-CoV-2 infection, we analysed 120 their frequency in SARS-CoV-2 positive children as compared to SARS-CoV-2 negative matched 121 controls. We also analysed SARS-CoV-2 and seasonal HCoVs humoral responses of patients with MIS 122 regarding antibody targets and functional neutralizing activity. Our study is the first to analyse in depth 123 the typology of humoral responses to SARS-CoV-2 in children, and provides evidence that prior 124 infections by seasonal coronaviruses has no significant impact on SARS-CoV-2 infection or related MIS 125 disease in children. 126 127 128 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We recorded the history of suspected COVID-19 cases based on a standardized study-specific form. 140

We collected data on clinical symptoms consistent with COVID-19 occurring from December 2019 until 141 up to 7 days before enrolment. Demographic information, relevant epidemiological history (e.g. 142 international travel or contact with an infected person or a suspected case), comorbidities, reasons 143 for hospitalization were collected. 144

The local Ethics (CERAPHP Paris V) approved this study (IRB registration: #00011928). Patients and/or 146 their parents/guardians were informed about the study 147

For SARS-CoV-2 prevalence, we used a LIPS (Luciferase Immunoprecipitation System) test as 149 previously reported 22 , which identifies antibodies (Ab) targeted to the S1 and S2 domains of the Spike 150 (S) and to the Nucleoprotein (N). For the neutralization assay we used a viral pseudotype-based assay 151 and a neutralization test using live SARS-CoV-2. In a fraction of samples, we assessed by LIPS tests, 152 antibodies to the nucleoprotein and to the full spike ectodomain in a pre-fusion conformation for 153 SARS-CoV-2, and the four human coronaviruses (HKU1, NL63, OC43, and 229E). Detailed technical 154 8 information together with sensitivity and specificity evaluations are given respectively in 155

Supplementary Material S1 and S2. 156

We did not detect any difference in terms of age, sex ratio, and main comorbidities between patients 158 recruited in March (n=133; single centre study) and afterwards (n=642; multicentric seroprevalence 159 study) (Supplemental Table 1 ). We therefore present the demographic and clinical data of the whole 160 cohort of children enrolled. Cases were grouped based on the results of serology testing and clinical 161 presentation. Data were assessed for normal distribution using the Kolmogorov-Smirnov test. 162

Continuous variables were presented as mean (SD) and compared using the Student t test. Categorical 163 variables were compared using Chi2 or Fisher's exact tests, as appropriate. Statistical analyses were 164 conducted with Excel or GraphPad Prism 8 (GraphPad Software, LLC). Principal Component Analysis 165 was performed to identify the serological profile according to SARS-CoV-2 Abs and seasonal HCoV Abs. 166

Data were processed with R 3.6.3 using GGPlot2 with GGally for matrices of plots, and ggfortify for 167 PCA plots packages. Two-sided p value of <0.05 was considered significant. 168 169 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.29.20142596 doi: medRxiv preprint Results 170

In total, 775 children, mean (SD) age 8 (5·6) years were enrolled in the study (Figure 1 ). One hundred 172 six (13·6%) were below 15 years of age. The reason for consultation or hospitalization was regular 173 follow-up for 58%, surgery for 11·7% and medical emergency for 15% (HOS population). Among those, 174 17 patients (2·1%) were hospitalized for neurological disorders including encephalitis (n=4), 175 cerebellitis (n=5), polyradiculoneuritis (n=7), and labyrinthitis (n=1). Thirty-six other patients (4·6%) 176 presented with a MIS and among those, 25 were hospitalized in Intensive Care Unit because of signs 177 of shock, and 28 developed myocarditis. 178

The apparent prevalence of seropositive children was in the range 10% -15% between 6 th April and 179 1 st June, except on the week starting 11 th May where it reached 27%. The patients with MIS were 180 mainly detected from the last week of April to mid-May (Figure 2) . The seropositive patients with 181 neurological disorders were hospitalized over the whole study period. 182 Table 1 The seropositive children (HOS-P and MIS-P) did not show an age-dependent specific distribution 194 (Supplemental Figure S3 ). More than 70% of them (121 out of the 172) did not report any history 195 consistent with COVID-19 during the preceding weeks. The only symptoms that were marginally but 196 significantly reported in the previous months in seropositive children were headache, shortness of 197 breath and rhino-pharyngitis. Neurological disorders were significantly more frequent in the 198 seropositive group (13 children out of 17). 199

HOS-P patients Ab profile was characterized by a dominant S2 response compared to responses to S1, 201 N and to the full S ectodomain (Figure 3) . The HOS-P children with neurological symptoms showed N, 202 S1 and S2 responses similar to those of the HOS-P group without neurological symptoms 203 (Supplemental Figure S4 ) and were analysed together. 204 MIS-P patients showed a distinct Ab profile directed against N, S1 and S2 altogether (Figure 4 ). Levels 205 of N and S1 Abs to SARS-CoV-2 were significantly higher in the MIS-P than in the HOS-P group ( Figure  206 3C-D). 207

To investigate the neutralization activity, we first performed a pseudo-neutralization assay in the 209 subset of 54 HOS-P and 15 MIS-P patients (Figure 1) . Overall, 55·6% of HOS-P and 100% of MIS-P 210 children showed a neutralizing activity. Interestingly, the fraction of HOS-P children whose Abs 211 displayed a pseudo-neutralizing activity (PNT+) increased with time ( Figure 2B) , from 18% to 38% 212 during March and April to 100% at the beginning of May. For a fraction of these children, we 213 investigated the correspondence between PNT and live SARS-CoV-2 neutralizing activity determined 214 in a plaque reduction test (PRNT) ( Table S6) . All tested sera positive in PNT (n=28) were PRNT+ and 2 215 out of the 11 PNT-negative sera were also PRNT+. In total, 73·7% of HOS-P tested sera showed a 216 neutralizing activity. Neutralizing titres of PNT+ and PRNT+ sera of MIS-P patients were similar to those 217 of HOS-P patients (Figure 3) . 218 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 30, 2020. .

We compared the prevalence of anti-N and -S antibodies against the four seasonal HCoVs in a 220 subpopulation of children among the HOS-P (n=54), MIS-P (n=15) and CTL (n=118) groups (Figure 1) . 221

Prevalence rates for the two betacoronaviruses (HKU1 and OC43) and the two alphacoronaviruses 222 (229E and NL63) were similar for all viruses between the CTL and HOS-P groups. They were also similar 223 for HKU-1, 229E and NL63 in the MIS-P group, whereas Abs to OC43 N were more frequent in the MIS-224 P group (73%) than in the CTL group (39.4%), which was not paralleled by the anti-S response that was 225 near 100% in the two groups ( Table 2) . patients. There was no significant difference between HOS-P and CTL patients regarding antibody 233 levels to the four seasonal HCoVs (Figure 3) . This demonstrates that humoral responses between 234 seasonal coronaviruses and SARS-CoV-2 were not related. This is confirmed by the PCA analysis which 235 showed that the patient groups (HOS-P, MIS-P and CTL) were only clustered by SARS-COV-2 Abs and 236 not by seasonal HCoV Abs. (Figure 4 ). This suggests that the risk of SARS-CoV-2 infection and of related 237 MIS disease were not influenced by prior seasonal HCoV infection. In support to this observation, there 238 was an association, for each virus, between all S and N antibody titres within each of the three groups 239 of patients (CTL, HOS-P and MIS-P). This correlation was stronger for SARS-CoV-2 than for seasonal 240

HCoVs. (Supplemental Figures S5 and S6 ) Importantly, there was no significant association between 241 SARS-CoV-2 and seasonal HCoV quantitative Ab responses (Supplemental Figures S5 and S6) . MIS-P 242 and HOS-P groups did not differ for Abs titers against seasonal HCoVs, except for OC43-N Abs that 243 were increased in MIS-P children, but this tendency was not confirmed by the OC43-S Ab response 244 ( Figure 3A-B) . This was coherent with the Abs prevalence study (Table 2) . . 245 All rights reserved. No reuse allowed without permission.

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This cross-sectional prospective multicentric study provides to the best of our knowledge the largest 248 report on COVID-19 in the paediatric population outside of China. We enrolled nearly 800 children 249 during the first three months of the COVID-19 epidemic in Paris. From April to May, the prevalence 250 rate of Abs against SARS-CoV-2 was in the range of 10-15%. We noticed an outlier peak of incidence 251 during the week of 11 May, which was likely associated with an increase of vigilance of physicians 252 following the information of severe clinical presentations in children. This prevalence rate is in 253 contrast with previous epidemiological cohort studies, based on RT-PCR, where children represent 254 less than 2% of diagnosed cases 24-23 . These numbers are compatible with the prevalence estimated in 255

Paris 24 despite the specificity of the population of children recruited in university hospitals. Here, in a 256 large cohort of children less than 15 years old, we demonstrate that (i) a substantial proportion of 257 children can become infected and (ii) the risk is not related to age. In nearly 15% of the cases, a contact 258 with a parent suspected of COVID-19 was identified, which increased by 2·5 fold the risk to be infected. 259

Very importantly, more than 50% of the seropositive children did not report any symptoms, a 260 proportion similar to that recently reported in adults 25 . The reminders reported mild and non-specific 261 symptoms such as headache, rhino-pharyngitis and shortness of breath. This confirms previously 262 published data showing that COVID-19 is less severe in children than in adults 26 . The largest study in 263 children published so far that described SARS-CoV-2 infection in 2,143 Chinese children also reported 264 asymptomatic infection or mild symptoms such as fever, cough, a sore throat, sneezing, myalgia and 265 fatigue 27 . Altogether, these results and ours underline that most children remain undiagnosed 266 because of asymptomatic infections, which makes them potential drivers of virus spread 28 . 267 This is to our knowledge the first study profiling the humoral immune response in children 268 experiencing pauci-symptomatic infection by SARS-CoV-2. We showed that around half of SARS-CoV-269 2 positive sera present a significant neutralizing activity based on two independent assays (based on 270 lentivirus pseudo-typed with the SARS-CoV-2 spike or based on live virus). Interestingly, this rate 271 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 30, 2020. . https://doi.org/10.1101/2020.06.29.20142596 doi: medRxiv preprint 13 increased up to 100% at the end of the observation period on mid-May, almost 2 months after the 272 peak of the epidemic. As reported by others 29 , this suggests that appearance of neutralizing antibodies 273 is delayed relative to initial seroconversion. This is in contrast to severe COVID-19 forms 22,30 , where 274 neutralizing antibody responses against the immunodominant S viral protein are elicited as soon as 275 after two weeks of infection at higher frequency and titres. Importantly, considering these data, it 276 must be underlined that quantitative correlates of protection are currently unknown, which makes it 277 difficult to relate the neutralizing titres to a clinically relevant effect. have an impact on SARS-CoV-2 replication. Indeed, antibodies are unlikely to act as primary effectors 290 of protection, as there is no or very low 11 cross neutralization between these coronaviruses, but 291 antibodies serve as an indicator of underlying cellular responses. We found no evidence of cross-292 protective immunity linked to previous infection by seasonal HCoVs. First, similar seasonal HCoV 293 prevalence was found in SARS-CoV-2 positive versus negative patients. Second, on a quantitative side, 294 there was no significant correlation between SARS-CoV-2 and any HCoV antibody titres, whatever the 295 antigen considered (S or N). On the contrary, the level of SARS-CoV-2 antibodies to N and S were 296 correlated, which corresponds to a good internal control. This was also the case for the N and S 297 responses for each HCoV, but to a lesser extent. We hypothesized that multiple infections by seasonal 298 All rights reserved. No reuse allowed without permission.

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14 HCoVs would boost Ab responses against shared epitopes that are more frequent in the nucleoprotein 299 than in the spike, and that this would lead to a decrease of correlation between N and S responses 300 over time. When analysing the S and N responses to HCoVs, we found no obvious difference in N to S 301 correlations in CTL patients as compared to the HOS-P group, suggesting that infection with SARS-CoV-302 2 did not significantly boost pre-existing antibody responses to HCoVs N and S. 303

This lack of HCoV/SARS-CoV-2 cross-protection contrasts with the recent demonstration of pre-304 existing immune effectors recognizing SARS-CoV-2 in subjects sampled before the SARS-CoV-2 305 pandemic. Moreover, a very sensitive cytometric assay reported frequent low levels of cross-reacting 306 anti-S IgGs, mainly targeting the SARS-CoV-2 S2 domain of the spike 11 . Although those Abs neutralized 307 entry of SARS-CoV-2 S-pseudo-typed lentiviruses in HEK-293T cells mediated by the spike protein, the 308 clinical relevance of the SARS-CoV-2 pseudo-neutralisation test is questionable, because the 309 mechanism of entry did not involve the ACE2 receptor of the virus. Moreover, T-helper cells detected 310 in healthy subjects also recognized the C-terminal part of S (that contains the S2 subunit) but not the 311 receptor-binding domain (RBD) which belongs to S1 13 . In contrast, our results clearly show that cross-312 reactive antibodies directed against endemic seasonal HCoVs and underlying cross-reacting CD4+ T-313 cells do not seem to confer any significant protection against SARS-CoV-2 infection. This could be 314 explained by low identity between coronaviruses of important targets such as the RBD. Importantly, 315 this also suggests that potentially cross-reactive CD8+ T cells, which should be elicited upon seasonal 316

HCoV infections as is the case following SARS-CoV-2 infection 39 , are not able to significantly contribute 317 to protection against SARS-CoV-2 infection. 318

We analysed the SARS-CoV-2 Ab profile in 25 MIS cases associated with a positive SARS-CoV-2 Ab 319 response. We found higher S1 and N responses, but not an increased neutralizing capacity as 320 compared to HOS-P patients who experienced an asymptomatic or pauci-symptomatic infection 321 (Figure 2A) . This was not the case for the beta-(OC43) or alpha-(229E and NL63) coronaviruses Ab 322 responses, suggesting that the increased SARS-CoV-2 response is not a non-specific feature triggered 323 by inflammation. Furthermore, the lack of cross-reactivity between anti-S1 Abs of the different 324 All rights reserved. No reuse allowed without permission.

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viruses 40 does not favour the hypothesis of SARS-CoV-2 infection boosting pre-existing HCoV immunity 325 in MIS patients. As a whole, our data do not support that previous HCoV infection facilitates CoV-2 infection and MIS-related disease. 327

Neutralizing tests for the four seasonal HCoVs were not available but some extrapolation can be done 328 based on SARS-CoV-2 neutralization and LIPS results, because equivalent LIPS tests were used for all 329 viruses. As the SARS-CoV-2 results show that up to 100% of LIPS positive sera sampled one to two 330 months post-infection had neutralizing activity, it can be anticipated that most HCoV positive sera 331 would also neutralize corresponding HCoVs. This means that, in a perspective of herd immunity, most 332 of the general population would have antibodies neutralizing seasonal HCoVs, among other immune 333 effectors. As common colds due to seasonal HCoVs are experienced repeatedly, this leads to 334 questioning whether coronavirus immune responses induce a long-term clinically protective response. 335

Our results therefore pose a doubt regarding the humoral protective response against SARS-CoV-2 in 336 a perspective of herd immunity, even when the prevalence of antibodies will be high in the population. 337

The strengths of the study are the high number of well documented paediatric cases including MIS 338 cases and the extensive exploration of Ab responses to SARS-CoV-2, their neutralizing activity, and the 339 correlation with seasonal HCoV immune responses. We acknowledge that infection rates are probably 340 biased in this cohort of hospitalized children, despite the fact that we focused as much as possible on 341 regular follow-up or COVID-19 unrelated emergencies. In this cohort, we observed no correlation 342 between the Ab responses against SARS-CoV-2 and seasonal HCoVs. Although cellular and local 343

immune defenses were not directly tested, our results do not provide evidence for cross-protective 344 immunity or facilitation linked to previous infections by seasonal HCoVs on the risk of developing a 345 SARS-CoV-2 infection or a MIS disease once infected. 346

In conclusion, our results show that 11.7 % of children admitted in Parisian hospitals have Abs against 347 SARS-CoV-2 and that these Abs are able to neutralize SARS-CoV-2 in vitro. As seasonal HCoVs circulate 348 efficiently in the human population despite very high antibody prevalence, our results point to the 349 limits of herd immunity applied to seasonal coronaviruses and maybe SARS-CoV-2. 350 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted June 30, 2020. . and Dr Emeline Roy who helped for data collection. We thank Simon Cauchemez for critical lecture of 375 the manuscript. 376 377 All rights reserved. No reuse allowed without permission.

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