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Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections.

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination. 514 monoclonal antibodies (mAbs) were generated from antigen-specific memory B cells. Antibodies isolated at 5 to 12 months following vaccination displayed greater potency and breadth, relative to those identified at 1.4 months. Notably, 15 out of 338 (∼4.4%) antibodies isolated at 1.4∼6 months after the primary vaccination showed extraordinary neutralization potency against SARS-CoV-2 omicron BA.1, despite the absence of BA.1 neutralization in serum. Two of them, 25F9 and 20A7, neutralized authentic clade Ia sarbecoviruses (SARS-CoV, WIV-1, SHC014) and clade Ib sarbecoviruses (SARS-CoV-2 D614G, SARS-CoV-2 BA.1, Pangolin-GD) with half-maximal inhibition concentrations of (0.85 ng/ml, 3 ng/ml, 6 ng/ml, 6 ng/ml, 42 ng/ml, 6 ng/ml) and (13 ng/ml, 2 ng/ml, 18 ng/ml, 9 ng/ml, 6 ng/ml, 345 ng/ml), respectively. Furthermore, 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants of concern and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1 and XBB variants. X-ray crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved RBD sites. In vivo prophylactic protection of 25F9, 20A7 and 27A12 was confirmed in aged Balb/c mice. Notably, administration of 25F9 provided complete protection against SARS-CoV-2, SARS-CoV-2 BA.1, SARS-CoV, and SHC014 challenge, underscoring that these mAbs are promising pan-sarbecovirus therapeutic antibodies.One Sentence SummaryExtremely potent pan-sarbecovirus neutralizing antibodies

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S)protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad invivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.

Additional file 4.. Details of ���Polymod��� and ���Comix��� contact matrices.

Additional file 3.. Alternative model assumptions for norovirus.

Additional file 2. Description of the model fitting procedure.

Additional file 2. These figure is analogous to Figure 4 for additional z-score threshold z.

Additional file 1: Full description of the mathematical model for norovirus. Table S1. Parameters within the mathematical model for norovirus and sources of values used.

Background: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets. Results: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality. Conclusions: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses.

Additional file 4. This figure is analogous to Figure 4 for additional z-score threshold z.

Additional file 3. These figure is analogous to Figure 4 for additional z-score threshold z.

Coronaviridae Study Group of the International Committee on Taxonomy of Viruses* The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS- CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks. pon U a viral outbreak, it is important to rapidly establish whether the outbreak is caused by a new or a previously known virus (Box 1), as this helps decide which approaches and actions are most appropriate to detect the causative agent, con- trol its transmission and limit potential consequences of the epi- demic. The assessment of virus novelty also has implications for virus naming and, on a different timescale, helps to define research priorities in virology and public health. For many human virus infections such as influenza virus 1 or norovirus 2 infections, well-established and internationally approved methods, standards and procedures are in place to identify and name the causative agents of these infections and report this infor- mation promptly to public health authorities and the general public. In outbreaks involving newly emerged viruses, the situation may be different, and appropriate procedures to deal with these viruses need to be established or refined with high priority. Here, we present an assessment of the genetic relatedness of the newly identified human coronavirus 3, provisionally named 2019- nCoV, to known coronaviruses, and detail the basis for (re)naming this virus severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), which will be used hereafter. Given the public interest in nam- ing newly emerging viruses and the diseases caused by these viruses in humans, we will give a brief introduction to virus discovery and classification — specifically the virus species concept — and the roles of different bodies, such as the World Health Organization (WHO) and the International Committee on Taxonomy of Viruses (ICTV), in this process. We hope this will help readers to better understand the scientific approach we have taken to arrive at this name, and we will also discuss implications of this analysis and naming decision. Classifying and naming viruses and virus species Defining the novelty of viruses is one of the topics that virus classification deals with. The classification of RNA viruses needs to consider their inherent genetic variability, which often results in two or more viruses with non-identical but similar genome sequences being regarded as variants of the same virus. This immediately poses the question of how much difference to an existing group is large enough to recognize the candidate virus as a member of a new, distinct group. This question is answered in best practice by evaluating the degree of relatedness of the candidate virus to previously identified viruses infecting the same host or established monophy- letic groups of viruses, often known as genotypes or clades, which may or may not include viruses of different hosts. This is formally addressed in the framework of the official classification of virus taxonomy and is overseen and coordinated by the ICTV 4. Viruses are clustered in taxa in a hierarchical scheme of ranks in which the spe- cies represents the lowest and most populous rank containing the least diverged groups (taxa) of viruses (Box 2). The ICTV maintains a Study Group for each virus family. The Study Groups are respon- sible for assigning viruses to virus species and taxa of higher ranks, such as subgenera, genera and subfamilies. In this context they play an important role in advancing the virus species concept and highlighting its significance 5. Virus nomenclature is a formal system of names used to label viruses and taxa. The fact that there are names for nearly all viruses within a species is due to the historical perception of viruses as causative agents of specific diseases in specific hosts, and to the way we usually catalogue and classify newly discovered viruses, which increasingly includes viruses that have not been linked to any known disease in their respective hosts (Box 1). The WHO, an agency of the United Nations, coordinates international public health activities aimed at combating, containing and mitigating the consequences of communicable diseases—including major virus epidemics—and is responsible for naming disease(s) caused by newly emerging human viruses. In doing so, the WHO often takes the traditional approach of linking names of specific diseases to viruses (Box 1) and *A list of authors and their affiliations appears at the end of the paper. assessing virus novelty by an apparent failure to detect the causative agent using established diagnostic assays. Apart from disease, geography and the organism from which a given virus was isolated also dominate the nomenclature, occasionally engraving connections that may be accidental (rather than typical) or even stigmatizing, which should be avoided. Establishing a universal nomenclature for viruses was one of the major tasks of the ICTV when it was founded more than 50 years ago 4. When the species rank was established in the taxonomy of viruses 6, ICTV’s responsibility for naming viruses was shifted to naming and establishing species. ICTV Study Groups may also be involved in virus naming on a case-by-case basis as an extension of their official remit, as well as using the special expertise of their members. As virus species names are often very similar to the name of the founding member of the respective species, they are frequently confused in the literature with names of individual viruses in this species. The species name is italicized, starts with a capital letter and should not be spelled in an abbreviated form 7; hence the species name Severe acute respiratory syndrome-related coronavirus. In contrast, this convention does not apply to virus names, hence severe acute respiratory syndrome coronavirus, or SARS-CoV, as it is widely known., Published as part of Gorbalenya, Alexander E., Baker, Susan C., Baric, Ralph S., de Groot, Raoul J., Drosten, Christian, Gulyaeva, Anastasia A., Haagmans, Bart L., Lauber, Chris, Leontovich, Andrey M., Neuman, Benjamin W., Penzar, Dmitry, Perlman, Stanley, Poon, Leo L. M., Samborskiy, Dmitry V., Sidorov, Igor A., Sola, Isabel & Ziebuhr, John, 2020, The species Severe acute respiratory syndromerelated coronavirus: classifying 2019 - nCoV and naming it SARS-CoV- 2, pp. 536-544 in Nature Microbiology 5 on pages 536-537, DOI: 10.1038/s41564-020-0695-z, http://zenodo.org/record/3725837, {"references":["1. Krammer, F. et al. Influenza. Nat. Rev. Dis. Primers 4, 3 (2018).","2. Zheng, D. P. et al. Norovirus classification and proposed strain nomenclature. Virology 346, 312 - 323 (2006).","3. Wu, A. et al. Genome composition and divergence of the novel","5. Gorbalenya, A. E., Lauber, C. & Siddell, S. Taxonomy of Viruses, in Reference Module in Biomedical Sciences (Elsevier, 2019) https: // doi. org / 10.1016 / B 978 - 0 - 12 - 801238 - 3.99237 - 7.","49. ICD- 11 (World Health Organization, 2018).","4. Adams, M. J. et al. 50 years of the International Committee on Taxonomy of Viruses: progress and prospects. Arch. Virol. 162, 1441 - 1446 (2017).","6. Van Regenmortel, M. H., Maniloff, J. & Calisher, C. The concept of virus species. Arch. Virol. 120, 313 - 314 (1991).","7. ICTV Code. The International Code of Virus Classification and Nomenclature https: // talk. ictvonline. org / information / w / ictv-information / 383 / ictv-code (2018)."]}

Background The emergence of severe acute respiratory syndrome (SARS) in 2002 and 2003 affected global health and caused major economic disruption. Adequate animal models are required to study the underlying pathogenesis of SARS-associated coronavirus (SARS-CoV) infection and to develop effective vaccines and therapeutics. We report the first findings of measurable clinical disease in nonhuman primates (NHPs) infected with SARS-CoV. Methods and Findings In order to characterize clinically relevant parameters of SARS-CoV infection in NHPs, we infected cynomolgus macaques with SARS-CoV in three groups: Group I was infected in the nares and bronchus, group II in the nares and conjunctiva, and group III intravenously. Nonhuman primates in groups I and II developed mild to moderate symptomatic illness. All NHPs demonstrated evidence of viral replication and developed neutralizing antibodies. Chest radiographs from several animals in groups I and II revealed unifocal or multifocal pneumonia that peaked between days 8 and 10 postinfection. Clinical laboratory tests were not significantly changed. Overall, inoculation by a mucosal route produced more prominent disease than did intravenous inoculation. Half of the group I animals were infected with a recombinant infectious clone SARS-CoV derived from the SARS-CoV Urbani strain. This infectious clone produced disease indistinguishable from wild-type Urbani strain. Conclusions SARS-CoV infection of cynomolgus macaques did not reproduce the severe illness seen in the majority of adult human cases of SARS; however, our results suggest similarities to the milder syndrome of SARS-CoV infection characteristically seen in young children., Jason Paragas and colleagues report the first findings of measurable clinical disease in nonhuman primates infected with the virus that causes SARS, SARS-CoV.

Additional file 6. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S1) for z-score theshold z.

Additional file 8. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S3) for z-score theshold z.

Additional file 5: Figure S1. Comparison of simulations and cases reported to SGSS between July 2019 to June 2021.

Additional file 7. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S2) for z-score theshold z.

Additional file 5. This figure shows the p-values for the GSEA enrichment scores (shown in Figure 4) for z-score theshold z.

Immune homeostasis is the state that the immune system maintains in the absence of insult. Perturbation of immune homeostasis can impact autoimmunity/allergy and adversely affect infectious responses. To date, much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. Since the lungs are a major site of environmental exposure and infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at homeostasis. We found that all 54 immune cell phenotypes measured showed strong genetic variation in cell type abundances. We identified 28 quantitative trait loci associated with variation in 24 immune cell populations or the relationship between cell populations. Further, we identified significant associations between 20 of these loci and responses to either influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease in the same strains of mice. Notably, a locus mapped for variation in Ly6C+ monocyte abundance was associated with SARS-CoV weight loss, as well as titer at days 2 and 4 post-infection. This locus is also associated with influenza-induced disease, as measured by weight loss post-infection. Our analysis highlights the strong genetic control of immune homeostasis, and the key role that immune homeostasis plays in contributing to downstream infectious responses. In particular, our analysis suggests that the abundance of a variety of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

Additional file 8. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S3) for z-score theshold z.

Additional file 7. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S2) for z-score theshold z.

Additional file 6. This figure shows the p-values for the GSEA enrichment scores (shown in Figure S1) for z-score theshold z.

Additional file 5: Figure S1. Comparison of simulations and cases reported to SGSS between July 2019 to June 2021.

Additional file 5. This figure shows the p-values for the GSEA enrichment scores (shown in Figure 4) for z-score theshold z.

Additional file 6: Figure S2. Investigating the impact of reduced contact patterns from July 2021 compared to pre-pandemic.

Additional file 6: Figure S2. Investigating the impact of reduced contact patterns from July 2021 compared to pre-pandemic.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced following infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants potentially impacting transmission, virulence, and resistance to convalescent and vaccine-induced immunity. The SAVE program serves as a critical data-generating component of the United States Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines, and therapeutics and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity, and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models, and pivotal findings facilitated by this collaborative approach and identify future challenges. This program serves as a template for the response against rapidly evolving pandemic pathogens by monitoring viral evolution in the human population to identify variants that could erode the effectiveness of countermeasures.