Age-related seroprevalence trajectories of seasonal coronaviruses in children (preprint)

Four seasonal coronaviruses, including HCoV-NL63 and HCoV-229E, HCoV-OC43 and HCoV-HKU1 cause approximately 15–30% of common colds in adults. However, the frequency and timing of early infection with four seasonal coronaviruses in the infant are still not well studied. Here, we evaluated the serological response to four seasonal coronaviruses in 1886 children under 18-year-old to construct the viral infection rates. The antibody levels were also determined from the plasma samples of 485 pairs postpartum women and their newborn babies. This passive immunity waned at one year after birth and the resurgence of the IgGs were found thereafter with the increase of the age. Taken together, our results show the age-related seroprevalence trajectories of seasonal coronaviruses in children and provide useful information for deciding vaccine strategy for coronaviruses in the future.

Extended Shedding and Enhanced Fitness of the SARS-CoV-2 Variant of Concern B.1.1.7 in Human Organoid Systems (preprint)

A new phase of the COVID-19 pandemic has started as SARS-CoV-2 variants are emerging globally, raising concerns for increased transmissibility. Early 2021 the B.1.1.7 (or Alpha) variant, became the dominant variant globally and epidemiological data suggests this variant spreads faster than its ancestors. However, this does not prove that a variant is intrinsically phenotypically different, let alone more transmissible or fit. Therefore, rapid phenotyping of SARS-CoV-2 variants of concern is urgently needed. We found that airway, intestinal and alveolar organoids infected with the B.1.1.7 variant produced higher levels of infectious virus late in infection compared to its 614G-containing ancestor. The B.1.1.7 variant also had a clear fitness advantage in human airway organoids. In alveolar organoids, the B.1.1.7 variant induced lower levels of innate immunity. These findings suggest that the B.1.1.7 variant is phenotypically different from its ancestor and may explain why this clade has spread rapidly across the globe.Funding Information: This work was supported by Netherlands Organization for Health Research and Development (10150062010008; B.L.H.), PPP allowance (LSHM19136; B.L.H.). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874735. Declaration of Interests: H.C. is inventor on patents held by the Royal Netherlands Academy of Arts and Sciences that cover organoid technology. H.C.’s full disclosure is given at https://www.uu.nl/staff/JCClevers. All other authors have nothing to declare. Ethics Approval Statement: The Medical Ethical Committee of the Erasmus MC Rotterdam granted permission for this study (METC 2012-512). The study was approved by the UMC Utrecht (Utrecht, The Netherlands) ethical committee and was in accordance with the Declaration of Helsinki and according to Dutch law. This study is compliant with all relevant ethical regulations regarding research involving human participants.

Unlocking capacities of viral genomics for the COVID-19 pandemic response (preprint)

More than any other infectious disease epidemic, the COVID-19 pandemic has been characterized by the generation of large volumes of viral genomic data at an incredible pace due to recent advances in high-throughput sequencing technologies, the rapid global spread of SARS-CoV-2, and its persistent threat to public health. However, distinguishing the most epidemiologically relevant information encoded in these vast amounts of data requires substantial effort across the research and public health communities. Studies of SARS-CoV-2 genomes have been critical in tracking the spread of variants and understanding its epidemic dynamics, and may prove crucial for controlling future epidemics and alleviating significant public health burdens. Together, genomic data and bioinformatics methods enable broad-scale investigations of the spread of SARS-CoV-2 at the local, national, and global scales and allow researchers the ability to efficiently track the emergence of novel variants, reconstruct epidemic dynamics, and provide important insights into drug and vaccine development and disease control. Here, we discuss the tremendous opportunities that genomics offers to unlock the effective use of SARS-CoV-2 genomic data for efficient public health surveillance and guiding timely responses to COVID-19.

Dynamics of B-Cell Repertoires and Emergence of Cross-Reactive Responses in COVID-19 Patients with Different Disease Severity (preprint)

COVID-19 patients show varying severity of the disease ranging from asymptomatic to requiring intensive care. Although a number of SARS-CoV-2 specific monoclonal antibodies have been identified, we still lack an understanding of the overall landscape of B-cell receptor (BCR) repertoires in COVID-19 patients. Here, we used high-throughput sequencing of bulk and plasma B-cells collected over multiple time points during infection to characterize signatures of B-cell response to SARS-CoV-2 in 19 patients. Using principled statistical approaches, we determined differential features of BCRs associated with different disease severity. We identified 38 significantly expanded clonal lineages shared among patients as candidates for specific responses to SARS-CoV-2. Using single-cell sequencing, we verified reactivity of BCRs shared among individuals to SARS-CoV-2 epitopes. Moreover, we identified natural emergence of a BCR with cross-reactivity to SARS-CoV-1 and SARS-CoV-2 in a number of patients. Our results provide important insights for development of rational therapies and vaccines against COVID-19. Funding: This work was supported by DFG grant (SFB1310) on Predictability in Evolution (A.N., Z.M., J.O., G.I.), the Max Planck Society through MPRG funding (A.N., Z.M., J.O., G.I.), Department of Physics at the University of Washington (A.N., Z.M.), Royalty Research Fund at the University of Washington (A.N., Z.M.), NIH NIAID F31AI150163 (WSD), Calmette and Yersin scholarship from the Pasteur International Network Association (H.L.), Bill and Melinda Gates Foundation OPP1170236 (I.A.W.), a startup fund at the University of Illinois at Urbana-Champaign (N.C.W.), US National Institutes of Health (contract no. HHSN272201400006C) (J.S.M.P), National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Joint Research Scheme(N_HKU737/18) (C.K.P.M. and J.S.M.P) and the Research Grants Council of the Hong Kong Special Administrative Region, China (Project no. T11-712/19-N) (J.S.M.P). Conflict of Interest: The authors declare no competing interests.Ethical Approval: The study was approved by the institutional review board of the Hong Kong West Cluster of the Hospital Authority of Hong Kong (approval number: UW20-169).

A Sars-Cov-2 Neutralizing Antibody Protects from Lung Pathology in a Covid-19 Hamster Model (preprint)

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC 50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.