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9 september 2020: Bron: NEJM, September 1, 2020 DOI: 10.1056/NEJMoa2026116

Antistoffen bij ex-coronapatienten (COVID-19) blijven lang aanwezig in het lichaam van patiënten die besmet zijn geweest met het coronavirus.  91 procent had nog steeds meetbare antistofffen in het bloed 4 maanden na de besmetting. Nog interessanter is dat bij 44 procent van de mensen die nooit waren getest op het coronavirus en blijkbaar te lichte klachten hadden gehad om getest te worden of te denken aan corona -antilichamen, ook immuniteit en antistoffen werden gevonden. Dat blijkt uit een kwalitatief uitstekend opgezette IJslandse studie naar de immuniteit van het coronavirus.

De auteurs van het onderzoek analyseerden meer dan 30.000 mensen in IJsland, waar ongeveer 15% van de bevolking was getest op het coronavirus.
Meer dan 90% van de mensen die positief waren getest door een laboratorium PCR-test (bijna 2.000 van de geteste mensen ), testten twee keer positief op antistoffen en bleven 120 dagen na de coronainfectie nog steeds antistoffen te hebben, aldus schrijven de onderzoekers. Een positief resultaat werd bepaald door twee positieve antilichamen testen.
Belangrijk is dat mensen die in het ziekenhuis waren opgenomen voor COVID-19 met ernstiger klachten, sneller antistoffen ontwikkelden.
De immuniteit leek twee maanden na de coronavirus-diagnosetest toe te nemen, zeiden onderzoekers, en de immuniteit bleef op een stabiel niveau voor de rest van het onderzoek.

De wetenschappers in Reykjavik gaven ook schattingen over de omvang van de uitbraak in IJsland.
Ze schatten dat bijna 1% van de bevolking van het land besmet is geraakt met het coronavirus. Het risico op sterfte door infectie was 0,33%, lager dan schattingen in andere landen.
De onderzoekers schrijven ook dat ongeveer 44% van de mensen die besmet zijn met het coronavirus tijdens de uitbraak niet zijn getest door laboratorium-PCR-tests.
De resultaten pleiten voor het gebruik van antistoffentests als permanente controle - surveillance om virusuitbraken snel te herkennen en op te sporen, schrijven de onderzoekers in hun commentaar.

Wel denken zij dat omdat IJsland voornamelijk bestaat uit blanke mensen hun onderzoek ook gedaan zou moeten worden bij een bevolking die een grotere diversiteit laat zien dan de IJslandse bevolking. Maar de resutlaten zijn natuurlijk wel bijzonder hoopgevend en geeft vertrouwen dat veel meer mensen dan gedacht immuniteit opbouwen tegen het coronavirus zonder dat ze daar heel veel last van hebben. 

De studie Humoral Immune Response to SARS-CoV-2 in Iceland is volledig in te zien of te downloaden.

Hier het abstract van de studie:

Humoral Immune Response to SARS-CoV-2 in Iceland

List of authors.

  • Daniel F. Gudbjartsson, Ph.D., 
  • Gudmundur L. Norddahl, Ph.D., 
  • Pall Melsted, Ph.D., 
  • Kristbjorg Gunnarsdottir, M.Sc., 
  • Hilma Holm, M.D., 
  • Elias Eythorsson, M.D., Ph.D., 
  • Asgeir O. Arnthorsson, M.Sc., 
  • Dadi Helgason, M.D., Ph.D., 
  • Kristbjorg Bjarnadottir, Ph.D., 
  • Ragnar F. Ingvarsson, M.D., 
  • Brynja Thorsteinsdottir, B.Sc., 
  • Steinunn Kristjansdottir, B.Sc., 

Abstract

BACKGROUND

Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

METHODS

We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin [pan-Ig] assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay. We measured antibodies in 4222 quarantined persons who had been exposed to SARS-CoV-2 and in 23,452 persons not known to have been exposed.

RESULTS

Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR.

CONCLUSIONS

Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR.

Discussion

We estimate that during the first wave of the SARS-CoV-2 pandemic, the incidence of infection in Iceland was 0.9% (95% CI, 0.8 to 0.9) and the infection fatality risk was 0.3% (95% CI, 0.2 to 0.6). Our estimate of the infection fatality risk is lower than but consistent with estimates described by others.6-8 We estimate that of the infected persons, 56% had cases previously diagnosed by qPCR, 14% had been in quarantine (but either had not been qPCR-tested or had tested negative), and 30% neither were known to be qPCR-positive nor had been placed in quarantine. We therefore conclude that, despite extensive screening by qPCR, a substantial fraction of infections were not detected, which indicates that many infected persons did not have substantial symptoms.

The case fatality risk is straightforward to estimate but may differ across countries and over time. An accurate calculation of infection fatality risk requires an accurate estimate of the number of infections, both diagnosed and undiagnosed. In Iceland, the high percentage of infections identified through qPCR (56%) as compared with that of other countries (for example, approximately 9% in Spain4) renders a commensurately accurate estimate of the total number of infections.

Each of the pan-Ig SARS-CoV-2 antibody assays that we used has high specificity (99.8%, according to the manufacturers’ literature), which raises the question of whether using a single pan-Ig assay would have sufficed. One sample obtained in 2017 was positive on only one pan-Ig antibody assay, a finding that supports the use of two separate assays to determine seroprevalence, if the infection rate is below 1%, as in Iceland.

By April 30, a total of 20,766 Icelanders had been placed in quarantine. Of the 1797 Icelanders who tested positive by qPCR, 1088 (61%) were in quarantine when tested. Despite substantial qPCR testing of persons in quarantine, 2.3% of persons in quarantine who did not receive qPCR-positive result (i.e., a diagnosis of infection) developed SARS-CoV-2 antibodies. Household exposure was more likely to lead to infection than other types of exposure, which suggests that people who share a household with an infected person should not have contact during quarantine and that contacts of household members should be quarantined. Seroprevalence in the two regional hot spots (Vestfirdir and Vestmannaeyjar) was absent or low outside quarantine, which indicates that most infections were detected by qPCR screening and that quarantine, social distancing, contact tracing, and limits on public gatherings were effective in limiting spread.

Over 90% of qPCR-positive persons tested positive with both pan-Ig SARS-CoV-2 antibody assays and remained seropositive 120 days after diagnosis, with no decrease of antibody levels as detected by the two pan-Ig assays. We observed some diminution of antibody titer with some of the single-Ig assays. Previous smaller studies reported reduction of IgG antibodies against the N protein and a peptide representing the S protein within 21 to 28 days5 and against trimeric S protein within 56 days14 after a positive test by qPCR. These discrepancies may be explained partly by differences in the specificity and sensitivity of the assays used as well as differences in the design and performance of the semiquantitative assays used, including the antigen targeted and the analytic sensitivity and range, as well as differences in the study populations. For example, because of widespread qPCR testing and screening, it is likely that the Icelandic qPCR-positive persons were healthy, as compared with the participants in other studies. Repeated SARS-CoV-2 exposure is unlikely to affect the persistence of antibody levels in Iceland, given the low prevalence of infection. Comparative studies using validated quantitative SARS-CoV-2 antibody assays are needed; those described in the published literature are based on small sample sizes.9-12

Of the 22 recovered persons who had a negative result (using the combined pan-Ig antibody tests) for an early sample and who had another sample tested at least a month later, 19 (86%) received a second negative result. Thus, either some persons infected by SARS-CoV-2 produce no antibodies or undetectable levels of antibodies reactive to the S1 and N proteins, even 3 months after infection, or some qPCR delivered false positive results.

Among recovered persons, antibody levels are higher in older persons and in those more severely affected by SARS-CoV-2 infection. Women, who tend to become less sick than men, had lower antibody levels in two spike protein antibody assays. SARS-CoV-2 antibody levels were lower in smokers. Smoking increases the probability of severe Covid-19 illness among young adults,15 and smoking has been reported to increase the expression of ACE2,16 the receptor for cellular entry of the SARS-CoV-2 virus.

The humoral immune response is critical for the clearance of cytopathic viruses and is generally important for the prevention of viral reinfection.17 A relationship between a humoral immune response to SARS-CoV-2 infection and protection against reinfection by this virus has been shown in rhesus macaques18 but has yet to be established in humans. Regardless of the relationship or lack thereof between seropositivity against SARS-CoV-2 and protection against reinfection, the low SARS-CoV-2 antibody seroprevalence in Iceland indicates that the Icelandic population is vulnerable to a second wave of infection.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on September 1, 2020, at NEJM.org.

Author Affiliations

From deCODE Genetics/Amgen (D.F.G., G.L.N., P.M., K.G., H.H., A.O.A., K. Bjarnadottir, B. Thorsteinsdottir, S.K., K. Birgisdottir, A.M.K., G.A.A., E.V.I., M.A., F.J., A.B.A., J.B., B.E., R.F., E.E.G., S.G., K.R.G., A.G., A.H., B.O.J., A.J., H.J., T.K., D.N.M., O.T.M., S.R., L.R., A.S., G. Sveinbjornsson, K.E.S., E.A.T., B. Thorbjornsson, J.S., G.M., G.G., U.T., I.J., P.S., K.S.), the School of Engineering and Natural Sciences (D.F.G., P.M.), the Department of Anthropology (A.H.), the BioMedical Center (K.G.K.), and the Faculty of Medicine, School of Health Sciences (M.I.S., M.G., K.G.K., R.P., U.T., I.J., K.S.), University of Iceland, Internal Medicine and Rehabilitation Services (E.E., D.H., R.F.I., M.G., L.B.O., M.K., R.P.), the Division of Anesthesia and Intensive Care Medicine (M.I.S.), and the Department of Clinical Microbiology (O.S.G., T.R.G., K.G.K., M.S.), Landspitali–the National University Hospital, and the Directorate of Health (G. Sigmundsdottir, M.T., K.S.J., A.M., T.G.), Reykjavik, and the Health Care Institution of South Iceland, Selfoss (S.H.K.) — all in Iceland.

Address reprint requests to Dr. Stefansson at deCODE Genetics–Amgen, Sturlugata 8, Reykjavik 102, Iceland, or at .

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