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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335620

ABSTRACT

SARS-CoV-2 is a highly contagious respiratory virus and the causative agent for COVID-19. The severity of disease varies from mildly symptomatic to lethal and shows an extraordinary correlation with increasing age, which represents the major risk factor for severe COVID-19 1 . However, the precise pathomechanisms leading to aggravated disease in the elderly are currently unknown. Delayed and insufficient antiviral immune responses early after infection as well as dysregulated and overshooting immunopathological processes late during disease were suggested as possible mechanisms. Here we show that the age-dependent increase of COVID-19 severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) responses. To overcome the limitations of mechanistic studies in humans, we generated a mouse model for severe COVID-19 and compared the kinetics of the immune responses in adult and aged mice at different time points after infection. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Mimicking impaired type I IFN immunity in adult and aged mice, a second major risk factor for severe COVID-19 2–4 , we found that therapeutic treatment with IFN-λ in adult and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1 -/- mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity of COVID-19 and clarify the nonredundant antiviral functions of type I, II and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Based on our data, we suggest that highly vulnerable individuals combining both risk factors, advanced age and an impaired type I IFN immunity, may greatly benefit from immunotherapy combining IFN-γ and IFN-λ.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335502

ABSTRACT

Reports of waning immunity after COVID-19 vaccination (1-3) have recently led to large booster vaccination campaigns. Previous studies showed that basic immunization with two mRNA vaccine doses elicits a robust spike-specific CD8+ T cell response (4-6). The effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains, however, unclear. Indeed, very little is known about the efficacy, duration and effects on long-term immunity and recall responses in breakthrough infections. In this study, we show that spike-specific CD8+ T cells are immediately and vigorously activated and expanded in all tested individuals after the 3rd and 4th mRNA vaccine shots. However, this CD8+ T cell boost response is characterized by a steep contraction and lasts only for about 30-60 days compared to a prolonged contraction after natural infection. Booster vaccination did not affect long-term spike-specific CD8+ T cell immunity reflected by a stable stem cell memory pool that already reached maximum frequencies after basic immunization. Accordingly, rapid and full-fledged recall responses of boosted spike-specific CD8+ T cells were detectable after breakthrough infection with delta and omicron. Thus, in addition to the previously reported cross-reactivity (7-12) also a robust activation and effector response determines the efficacy of the CD8+ T cell response targeting emerging variants of concern. Neutralizing antibody responses displayed hardly any boost effect towards omicron, further highlighting the relevance of spike-specific CD8+ T cell immunity. In sum, these data will inform future vaccination strategies facing the next COVID-19 wave expected for late 2022/early 2023.

3.
Nat Microbiol ; 7(5): 675-679, 2022 May.
Article in English | MEDLINE | ID: covidwho-1815548

ABSTRACT

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , COVID-19 Vaccines , Epitopes, T-Lymphocyte/genetics , Humans , RNA, Messenger/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
4.
Nat Commun ; 13(1): 1152, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1730284

ABSTRACT

In spring 2021, an increasing number of infections was observed caused by the hitherto rarely described SARS-CoV-2 variant A.27 in south-west Germany. From December 2020 to June 2021 this lineage has been detected in 31 countries. Phylogeographic analyses of A.27 sequences obtained from national and international databases reveal a global spread of this lineage through multiple introductions from its inferred origin in Western Africa. Variant A.27 is characterized by a mutational pattern in the spike gene that includes the L18F, L452R and N501Y spike amino acid substitutions found in various variants of concern but lacks the globally dominant D614G. Neutralization assays demonstrate an escape of A.27 from convalescent and vaccine-elicited antibody-mediated immunity. Moreover, the therapeutic monoclonal antibody Bamlanivimab and partially the REGN-COV2 cocktail fail to block infection by A.27. Our data emphasize the need for continued global monitoring of novel lineages because of the independent evolution of new escape mutations.


Subject(s)
COVID-19/immunology , COVID-19/virology , Pandemics , SARS-CoV-2/immunology , Africa, Western/epidemiology , Amino Acid Substitution , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/immunology , Antiviral Agents/pharmacology , COVID-19/transmission , Drug Combinations , Germany/epidemiology , Global Health , Humans , Immune Evasion/genetics , Mutation , Phylogeography , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322709

ABSTRACT

SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as 10 days post prime vaccination, when specific antibodies are hardly detectable and still lack neutralizing activity. Vaccine-induced T cells, especially CD8+ T cells, may thus be the main mediators of protection at this early stage. The details of antigen-specific CD8+ T cell induction after prime/boost vaccination, their comparison to naturally induced CD8+ T cell responses and their association with other arms of vaccine-induced adaptive immunity remain, however, incompletely understood. Here, we show on a single epitope level that both, a stable memory precursor pool of spike-specific CD8+ T cells and fully functional spike-specific effector CD8+ T cell populations, are vigorously mobilized as early as one week after prime vaccination when CD4+ T cell and spike-specific antibody responses are still weak and neutralizing antibodies are lacking. Boost vaccination after 3 weeks induced a full-fledged recall expansion generating highly differentiated CD8+ effector T cells, however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared to natural infection, vaccine-induced early memory T cells exhibited similar frequencies and functional capacities but a different subset distribution dominated by effector memory T cells at the expense of self-renewing and multipotent central memory T cells. Our results indicate that spike-specific CD8+ T cells may represent the major correlate of early protection after SARS-CoV-2 mRNA/bnt162b2 prime vaccination that precede other effector arms of vaccine-induced adaptive immunity and are stably maintained after boost vaccination.

6.
EMBO Rep ; 23(2): e53865, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1579708

ABSTRACT

The ongoing COVID-19 pandemic and the emergence of new SARS-CoV-2 variants of concern (VOCs) requires continued development of effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nbs) specific for the receptor-binding domain (RBD) of SARS-CoV-2. Taking advantage of detailed epitope mapping, we generate two biparatopic Nbs (bipNbs) targeting a conserved epitope outside and two different epitopes inside the RBD:ACE2 interface. Both bipNbs bind all currently circulating VOCs with high affinities and are capable to neutralize cellular infection with VOC B.1.351 (Beta) and B.1.617.2 (Delta) in vitro. To assess if the bipNbs NM1267 and NM1268 confer protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice are treated intranasally before infection with a lethal dose of SARS-CoV-2 B.1, B.1.351 (Beta) or B.1.617.2 (Delta). Nb-treated mice show significantly reduced disease progression and increased survival rates. Histopathological analyses further reveal a drastically reduced viral load and inflammatory response in lungs. These data suggest that both bipNbs are broadly active against a variety of emerging SARS-CoV-2 VOCs and represent easily applicable drug candidates.


Subject(s)
COVID-19 , Single-Domain Antibodies , Animals , Antibodies, Neutralizing , Antibodies, Viral , Humans , Mice , Mice, Transgenic , Pandemics , SARS-CoV-2 , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus
7.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295926

ABSTRACT

We have identified camelid single-domain antibodies (VHHs) that cross-neutralize SARS-CoV-1 and −2, such as VHH72, which binds to a unique highly conserved epitope in the viral receptor-binding domain (RBD) that is difficult to access for human antibodies. Here, we establish a protein engineering path for how a stable, long-acting drug candidate can be generated out of such a VHH building block. When fused to human IgG1-Fc, the prototype VHH72 molecule prophylactically protects hamsters from SARS-CoV-2. In addition, we demonstrate that both systemic and intranasal application protects hACE-2-transgenic mice from SARS-CoV-2 induced lethal disease progression. To boost potency of the lead, we used structure-guided molecular modeling combined with rapid yeast-based Fc-fusion prototyping, resulting in the affinity-matured VHH72_S56A-Fc, with subnanomolar SARS-CoV-1 and −2 neutralizing potency. Upon humanization, VHH72_S56A was fused to a human IgG1 Fc with optimized manufacturing homogeneity and silenced effector functions for enhanced safety, and its stability as well as lack of off-target binding was extensively characterized. Therapeutic systemic administration of a low dose of VHH72_S56A-Fc antibodies strongly restricted replication of both original and D614G mutant variants of SARS-CoV-2 virus in hamsters, and minimized the development of lung damage. This work led to the selection of XVR011 for clinical development, a highly stable anti-COVID-19 biologic with excellent manufacturability. Additionally, we show that XVR011 is unaffected in its neutralizing capacity of currently rapidly spreading SARS-CoV-2 variants, and demonstrate its unique, wide scope of binding across the Sarbecovirus clades.

8.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294108

ABSTRACT

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. Clinical implications The identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression. Graphical abstract A vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs) . SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292291

ABSTRACT

In spring 2021, an increasing number of infections was observed caused by the hitherto rarely described SARS-CoV-2 variant A.27 in south-west Germany. From December 2020 to June 2021 this lineage has been detected in 31 countries. Phylogeographic analyses of A.27 sequences obtained from national and international databases reveal a global spread of this lineage through multiple introductions from its inferred origin in Western Africa. Variant A.27 is characterized by a mutational pattern in the spike gene that includes the L18F, L452R and N501Y spike amino acid substitutions found in various variants of concern but lacks the globally dominant D614G. Neutralization assays demonstrated an escape of A.27 from convalescent and vaccine-elicited antibody-mediated immunity. Moreover, the therapeutic monoclonal antibody Bamlanivimab and partially the REGN-COV2 cocktail failed to block infection by A.27. Our data emphasize the need for continued global monitoring of novel lineages because of the independent evolution of new escape mutations.

10.
Nat Commun ; 12(1): 6405, 2021 11 04.
Article in English | MEDLINE | ID: covidwho-1505001

ABSTRACT

The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient's escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.


Subject(s)
COVID-19/immunology , COVID-19/virology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Genome, Viral , Humans , Immune Evasion , Immunocompromised Host , Male , Middle Aged , Mutation , Neutralization Tests , Phylogeny , SARS-CoV-2/chemistry , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
11.
Sci Transl Med ; 13(621): eabi7826, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1450584

ABSTRACT

Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody-based therapeutics are also essential for pandemic preparedness against future Sarbecovirus outbreaks. Camelid-derived single domain antibodies (VHHs) exhibit potent antimicrobial activity and are being developed as SARS-CoV-2­neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 and SARS-CoV-2, including now circulating variants. We observed that the VHHs bound to a highly conserved epitope in the receptor binding domain of the viral spike protein that is difficult to access for human antibodies. Structure-guided molecular modeling, combined with rapid yeast-based prototyping, resulted in an affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule with subnanomolar neutralizing activity. This VHH-Fc fusion protein, produced in and purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication in prophylactic and therapeutic settings in mice expressing human angiotensin converting enzyme 2 and in hamsters infected with SARS-CoV-2. These data led to affinity-enhanced selection of the VHH, XVR011, a stable anti­COVID-19 biologic that is now being evaluated in the clinic.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Humans , Models, Animal , SARS-CoV-2
12.
Science ; 373(6557): 918-922, 2021 08 20.
Article in English | MEDLINE | ID: covidwho-1367378

ABSTRACT

Zoonotic avian influenza A virus (IAV) infections are rare. Sustained transmission of these IAVs between humans has not been observed, suggesting a role for host genes. We used whole-genome sequencing to compare avian IAV H7N9 patients with healthy controls and observed a strong association between H7N9 infection and rare, heterozygous single-nucleotide variants in the MX1 gene. MX1 codes for myxovirus resistance protein A (MxA), an interferon-induced antiviral guanosine triphosphatase known to control IAV infections in transgenic mice. Most of the MxA variants identified lost the ability to inhibit avian IAVs, including H7N9, in transfected human cell lines. Nearly all of the inactive MxA variants exerted a dominant-negative effect on the antiviral function of wild-type MxA, suggesting an MxA null phenotype in heterozygous carriers. Our study provides genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic IAV infections in humans.


Subject(s)
Influenza A Virus, H7N9 Subtype , Influenza, Human/genetics , Influenza, Human/virology , Myxovirus Resistance Proteins/genetics , Agricultural Workers' Diseases/genetics , Agricultural Workers' Diseases/virology , Animals , Cell Line , Genetic Predisposition to Disease , Genetic Variation , Heterozygote , Humans , Influenza A Virus, H7N9 Subtype/physiology , Influenza A virus/physiology , Mutation, Missense , Myxovirus Resistance Proteins/chemistry , Myxovirus Resistance Proteins/metabolism , Poultry , Viral Zoonoses , Whole Genome Sequencing
13.
Nature ; 597(7875): 268-273, 2021 09.
Article in English | MEDLINE | ID: covidwho-1328849

ABSTRACT

SARS-CoV-2 spike mRNA vaccines1-3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4-6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Vaccination , Vaccines, Synthetic/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Cells, Cultured , Epitopes, T-Lymphocyte/immunology , Humans , Immunization, Secondary , Immunologic Memory/immunology , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Time Factors
14.
Nat Med ; 27(1): 78-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065910

ABSTRACT

Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/blood , Case-Control Studies , Convalescence , Coronavirus Nucleocapsid Proteins/chemistry , Cross Reactions , Cross-Sectional Studies , Epitopes, T-Lymphocyte , Flow Cytometry , HLA-B Antigens/immunology , Humans , Immunologic Memory , Longitudinal Studies , Phosphoproteins/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry
15.
JAMA Pediatr ; 175(6): 586-593, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1044436

ABSTRACT

Importance: School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. Objective: To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. Design, Setting, and Participants: This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. Exposures: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. Results: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). Conclusions and Relevance: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.


Subject(s)
Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Adult , Age Distribution , Age Factors , Aged , COVID-19/blood , COVID-19 Serological Testing , Child , Child, Preschool , Cross-Sectional Studies , Germany/epidemiology , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Parents , Prevalence , Seroepidemiologic Studies
16.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-5070

ABSTRACT

Background: School and day-care closures were enforced as measures to confine the COVID-19 pandemic based on the assumption that young children may play a key role in SARS-CoV-2 spreading. However, infection prevalence in children under 10 years of age is not very well analysed. Methods: The COVID-19 BaWü study is a large-scale multicentre cross-sectional investigation of children aged 1–10 years and one of their parents, both not diagnosed with COVID-19 before, in southwest Germany. We tested for SARS-CoV-2 RNA from nasopharyngeal swabs by RT-PCR and for SARS-CoV-2 specific IgG antibodies in serum by ELISA and immunofluorescence. Discordant results were clarified by ECLIA, a second ELISA or an in-house Luminex-based assay. We used mixed effects logistic regression to estimate the seroprevalence and to analyse the association between SARS-CoV-2 seropositivity and covariates. Findings: Between April 22nd and May 15th, 2020, we enrolled 4964 subjects, 2482 children and 2482 corresponding parents. 0•04% tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1•8%;95% CI, 1•2–2•4%) and 3-fold lower in children (0•6%;95% CI, 0•3–1•0%). We observed virus-neutralizing activity for 66 of 70 IgG-positive sera (94•3%). Interpretation: The spread of SARS-CoV-2 infection during a period of lock-down in southwest Germany was particularly low in children aged 1–10 years. Accordingly, it is unlikely that children have boosted the pandemic. This largest reported SARS-CoV-2 prevalence study focussing on children is instructive for how ad hoc mass testing provides the basis for rational political decision making in a pandemic setting. Funding: Grant from the Federal State of Baden-Württemberg, Germany Declaration of Interests: All authors state no conflict of interest. Ethics Approval Statement: The study protocol was approved by the independent Ethics committees of each centre. The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all parents/guardians, with assent from children when appropriate for their age.

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