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As SARS-CoV-2 variants continue to emerge globally, a major challenge for COVID-19 vaccination is the generation of a durable antibody response with cross-neutralizing activity against both current and newly emerging viral variants. Cross-neutralizing activity against major variants of concern (B.1.1.7, P.1 and B.1.351) has been observed following vaccination, albeit at a reduced potency, but whether vaccines based on the Spike glycoprotein of these viral variants will produce a superior cross-neutralizing antibody response has not been fully investigated. Here, we used sera from individuals infected in wave 1 in the UK to study the long-term cross-neutralization up to 10 months post onset of symptoms (POS), as well as sera from individuals infected with the B.1.1.7 variant to compare cross-neutralizing activity profiles. We show that neutralizing antibodies with cross-neutralizing activity can be detected from wave 1 up to 10 months POS. Although neutralization of B.1.1.7 and B.1.351 is lower, the difference in neutralization potency decreases at later timepoints suggesting continued antibody maturation and improved tolerance to Spike mutations. Interestingly, we found that B.1.1.7 infection also generates a cross-neutralizing antibody response, which, although still less potent against B.1.351, can neutralize parental wave 1 virus to a similar degree as B.1.1.7. selleckchem These findings have implications for the optimization of vaccines that protect against newly emerging viral variants.SARS-CoV-2 mutations with antigenic effects pose a risk to immunity developed through vaccination and natural infection. While vaccine updates for current variants of concern (VOCs) are underway, it is likewise important to prepare for further antigenic mutations as the virus navigates the heterogeneous global landscape of host immunity. Toward this end, a wealth of data and tools exist that can augment existing genetic surveillance of VOC evolution. In this study, we integrate published datasets describing genetic, structural, and functional constraints on mutation along with computational analyses of antibody-spike co-crystal structures to identify a set of potential antigenic drift sites (PADS) within the receptor binding domain (RBD) and N-terminal domain (NTD) of SARS-CoV-2 spike protein. Further, we project the PADS set into a continuous epitope-paratope space to facilitate interpretation of the degree to which newly observed mutations might be antigenically synergistic with existing VOC mutations, and this representation suggests that functionally convergent and synergistic antigenic mutations are accruing across VOC NTDs. The PADS set and synergy visualization serve as a reference as new mutations are detected on VOCs, enable proactive investigation of potentially synergistic mutations, and offer guidance to antibody and vaccine design efforts.Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http//toppcell.cchmc.org/COVID-19). As examples, we develop three hypotheses (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) novel platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus within 20 years that gave rise to a life-threatening disease and the first to reach pandemic spread. To make therapeutic headway against current and future coronaviruses, the biology of coronavirus RNA during infection must be precisely understood. Here, we present a robust and generalizable framework combining high-throughput confocal and super-resolution microscopy imaging to study coronavirus infection at the nanoscale. Employing the model human coronavirus HCoV-229E, we specifically labeled coronavirus genomic RNA (gRNA) and double-stranded RNA (dsRNA) via multicolor RNA-immunoFISH and visualized their localization patterns within the cell. The exquisite resolution of our approach uncovers a striking spatial organization of gRNA and dsRNA into three distinct structures and enables quantitative characterization of the status of the infection after antiviral drug treatment. Our approach provides a comprehensive framework that supports investigations of coronavirus fundamental biology and therapeutic effects.The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development of bottom-up coarse-grained (CG) models validated with cryo-electron tomography (cryo-ET) data, and the use of CG molecular dynamics simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.