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    Quantatitive Analysis of Conserved Sites on the SARS-CoV-2 Receptor-Binding Domain to Promote Development of Universal SARS-Like Coronavirus Vaccines

    Authors: Siling Wang; Dinghui Wu; Hualong Xiong; Juan Wang; Zimin Tang; Zihao Chen; Yizhen Wang; Yali Zhang; Dong Ying; Xue Lin; Chang Liu; Shaoqi Guo; Weikun Tian; Yajie Lin; Xiaoping Zhang; Quan Yuan; Hai Yu; Tianying Zhang; Zizheng Zheng; Ningshao Xia

    doi:10.1101/2021.04.10.439161 Date: 2021-04-11 Source: bioRxiv

    Although vaccines have been successfully developed and approved against SARS-CoV-2, it is still valuable to perform studies on conserved antigenic sites for preventing possible pandemic-risk of other SARS-like coronavirus in the future and prevalent SARS-CoV-2 variants. By antibodies obtained from convalescent COVID-19 MESHD individuals, receptor binding domain ( RBD MESHD) were identified as immunodominant neutralizing domain that efficiently elicits neutralizing antibody response with on-going affinity mature. Moreover, we succeeded to define a quantitative antigenic map of neutralizing sites within SARS-CoV-2 RBD, and found that sites S2, S3 and S4 (new-found site) are conserved sites and determined as subimmunodominant sites, putatively due to their less accessibility than SARS-CoV-2 unique sites. P10-6G3, P07-4D10 and P05-6H7, respectively targeting S2, S3 and S4, are relatively rare antibodies that also potently neutralizes SARS-CoV MESHD, and the last mAbs performing neutralization without blocking S protein PROTEIN binding to receptor. Further, we have tried to design some RBDs to improve the immunogenicity of conserved sites. Our studies, focusing on conserved antigenic sites of SARS-CoV-2 and SARS-CoV MESHD, provide insights for promoting development of universal SARS-like coronavirus vaccines therefore enhancing our pandemic preparedness.

    E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 HGNC but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

    Authors: Wei Bu Wang; Yu Liang; Yu Qin Jin; Jing Zhang; Ji Guo Su; Qi Ming Li

    doi:10.1101/2021.02.17.431566 Date: 2021-02-17 Source: bioRxiv

    The pandemic of the COVID-19 MESHD disease caused by SARS-CoV-2 has led to more than 100 million infections and over 2 million deaths worldwide. The progress in the developments of effective vaccines and neutralizing antibody therapeutics brings hopes to eliminate the threat of COVID-19 MESHD. However, SARS-CoV-2 continues to mutate, and several new variants have been emerged. Among the various naturally-occurring mutations, the E484K mutation shared by both the 501Y.V2 and 501Y.V3 variants attracted serious concerns, which may potentially enhance the receptor binding affinity and reduce the immune response. In the present study, the molecular mechanism behind the impacts of E484K mutation on the binding affinity of the receptor-binding domain (RBD) with the receptor human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) was investigated by using the molecular dynamics ( MD MESHD) simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method. Our results indicate that the E484K mutation results in more favorable electrostatic interactions compensating the burial of the charged and polar groups upon the binding of RBD with hACE2 HGNC, which significantly improves the RBD- hACE2 HGNC binding affinity. Besides that, the E484K mutation also causes the conformational rearrangements of the loop region containing the mutant residue, which leads to more tight binding interface of RBD with hACE2 HGNC and formation of some new hydrogen bonds. The more tight binding interface and the new hydrogen bonds formation also contribute to the improved binding affinity of RBD to the receptor hACE2 HGNC. In addition, six neutralizing antibodies and nanobodies complexed with RBD MESHD were selected to explore the effects of E484K mutation on the recognition of these antibodies to RBD. The simulation results show that the E484K mutation significantly reduces the binding affinities to RBD for most of the studied neutralizing antibodies, and the decrease in the binding affinities is mainly owing to the unfavorable electrostatic interactions caused by the mutation. Our studies revealed that the E484K mutation may improve the binding affinity between RBD and the receptor hACE2 HGNC, implying more transmissibility of the E484K-containing variants, and weaken the binding affinities between RBD and the studied neutralizing antibodies, indicating reduced effectiveness of these antibodies. Our results provide valuable information for the effective vaccine development and antibody drugs design.

    Chronic COVID-19 Syndrome MESHD and Chronic Fatigue Syndrome MESHD ( ME/CFS MESHD) following the first pandemic wave in Germany: a first analysis of a prospective observational study

    Authors: Claudia Kedor; Helma Freitag; Lil-Antonia Meyer-Arndt; Kirsten Wittke; thomas Zoller; Fridolin Steinbeis; Milan Haffke; Rudolf Gordon; Bettina Heidecker; Hans Dieter Volk; Carsten Skurk; Friedemann Paul; Judith Bellmann-Strobl; Carmen Scheibenbogen

    doi:10.1101/2021.02.06.21249256 Date: 2021-02-08 Source: medRxiv

    Objective: Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 MESHD infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome MESHD (CCS). Methods: Setting: Charite Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charite University hospital. Participants: 42 patients who presented with persistent moderate to severe fatigue MESHD six months following a mostly mild SARS-CoV-2 infection MESHD at the Charite Fatigue Center from July to November 2020. Main outcome measures: The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome MESHD ( ME/CFS MESHD). Relevant neurological and cardiopulmonary morbidity was excluded. Results: The median age was 36.5, range 22-62, 29 patients were female and 13 male. At six months post acute COVID-19 MESHD all patients had fatigue MESHD (Chalder Fatigue Score median 25 of 33, range 14-32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms MESHD (n=40), headache MESHD (n=38), and muscle pain MESHD (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15-90) of 100 (healthy) and Short Form 36 (SF36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome MESHD ( ME/CFS MESHD). These patients reported more fatigue MESHD in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p= 0.003), and hypersensitivity MESHD to noise (p=0.029), light (p=0.0143) and temperature (0.024) compared to patients not meeting ME/CFS MESHD criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin ( MBL HGNC MBL MESHD) deficiency was observed frequently (22% of all patients) and elevated IL-8 HGNC levels were found in 43% of patients. Conclusions: Chronic COVID-19 MESHD Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS MESHD in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

    Single-dose immunization with a chimpanzee adenovirus-based vaccine induces sustained and protective immunity against SARS-CoV-2 infection MESHD

    Authors: Linqi Zhang; Mingxi Li; Jingao Guo; Shuaiyao Lu; Runhong Zhou; Hongyang Shi; Xuangling Shi; Lin Cheng; Qingtai Liang; Hongqi Liu; Pui Wang; Nan Wang; Yifeng Wang; Lili Fu; Man Xing; Bin Ju; Li Liu; Siu-Ying Lau; Wenxu Jia; Xin Tong; Lin Yuan; Yong Guo; Hai Qi; Qi Zhang; Zhen Huang; Honglin Chen; Zheng Zhang; Zhiwei Chen; Xiaozhong Peng; Dongming Zhou; Ruoke Wang

    doi:10.21203/rs.3.rs-155550/v1 Date: 2021-01-26 Source: ResearchSquare

    The development of an effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 ( COVID-19 MESHD), is a global priority. Here, we present three chimpanzee adenovirus vaccines that express either the full-length spike (ChAdTS-S), or receptor-binding domain (RBD) with two different signal sequences ( ChAdTS-RBD and ChAdTS-RBDs MESHD). Single-dose intranasal or intramuscular immunization induced robust and sustained neutralizing antibody responses in BALB/c mice, with ChAdTS-S being superior to ChAdTS-RBD and ChAdTS-RBDs MESHD. Intranasal immunization appeared to induce a predominately Th2-based response whereas intramuscular administration resulted in a predominately Th1 response. The neutralizing activity against several circulating SARS-CoV-2 variants remained unaffected for mice serum but reduced for rhesus macaque serum. Importantly, immunization with ChAdTS-S via either route induced protective immunity against high-dose challenge with live SARS-CoV-2 in rhesus macaques. Vaccinated macaques demonstrated dramatic decreases in viral RNA in the lungs and nasal swabs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in a golden Syrian hamster model of SARS-CoV-2 infection MESHD. Taken together, these results confirm that ChAdTS-S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.

    mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

    Authors: Zijun Wang; Fabian Schmidt; Yiska Weisblum; Frauke Muecksch; Christopher O Barnes; Shlomo Finkin; Dennis Schaefer-Babajew; Melissa Cipolla; Christian Gaebler; Jenna A Lieberman; Zhi Yang; Morgan E Abernathy; Kathryn E Huey-Tubman; Arlene Hurley; Martina Turroja; Kamille A West; Kristie Gordon; Katrina G Millard; Victor Ramos; Justin Da Silva; Jianliang Xu; Robert A Colbert; Roshni Patel; Juan P Dizon; Irina Shimeliovich; Anna Gazumyan; Marina Caskey; Pamela J Bjorkman; Rafael Casellas; Theodora Hatziioannou; Paul D Bieniasz; Michel C Nussenzweig

    doi:10.1101/2021.01.15.426911 Date: 2021-01-19 Source: bioRxiv

    To date severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 ( COVID-19 MESHD) including two novel mRNA-based vaccines. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti- SARS-CoV-2 spike PROTEIN protein (S PROTEIN), receptor binding domain (RBD) binding titers. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes epitopes MESHD in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus MESHD (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

    Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

    Authors: Micah Rapp; Yicheng Guo; Eswar Reddy Reddem; Lihong Liu; Pengfei Wang; Jian Yu; Gabriele Cerutti; Jude Bimela; Fabiana Bahna; Seetha Mannepalli; Baoshan Zhang; Peter D. Kwong; David D. Ho; Lawrence Shapiro; Zizhang Sheng; Luis Martinez-Sobrido; Muhammad Munir; Gwo-Yu Chuang; David D Ho; Zizhang Sheng; Peter D Kwong; Lawrence Shapiro; Tiannan Guo

    doi:10.1101/2021.01.11.426218 Date: 2021-01-11 Source: bioRxiv

    Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike PROTEIN in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD up and down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycan N343 on a neighboring RBD - a quaternary interaction accommodated by an increase in RBD separation of up to 12 angstrom. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component MESHD specifying recognition of RBD MESHD and CDRH3 component specifying quaternary interactions.

    Multi-organ complement deposition in COVID-19 MESHD patients

    Authors: Paolo Macor; Paolo Durigutto; Alessandro Mangogna; Rossana Bussani; Stefano D'Errico; Martina Zanon; Nicola Pozzi; Pier Luigi Meroni; Francesco Tedesco

    doi:10.1101/2021.01.07.21249116 Date: 2021-01-08 Source: medRxiv

    Background: Increased levels of circulating complement activation products have been reported in COVID-19 MESHD patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear. Methods: We performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 MESHD patients who died of acute respiratory failure MESHD. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein PROTEIN of SARS-CoV-2. Findings: Lung deposits of C1q HGNC, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar MESHD cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein PROTEIN is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 MESHD lungs and are consistent with activation of the alternative pathway, whereas MBL MESHD MBL HGNC and MASP-2 HGNC were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits MESHD were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver. Interpretation. Complement deposits MESHD in different organs of deceased COVID-19 MESHD patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.

    Recurrent independent emergence and transmission of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN amino acid H69/V70 deletions

    Authors: Ravindra Gupta; Steven Kemp; William Harvey; Spyros Lytras; Alessandro Carabelli; David Robertson

    doi:10.21203/rs.3.rs-136937/v1 Date: 2020-12-28 Source: ResearchSquare

    SARS-CoV-2 Spike PROTEIN amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, 𝚫H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the 𝚫H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (𝚫H69/V70 and 𝚫144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infe ction. Gi MESHDven our recent evidence that 𝚫H69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitne ss appe MESHDars to be independent to the RBD changes. Enhanced surveillance for the 𝚫H69/V70 deletion with and without RBD mu tat MESHDions should be considered as a priority. Permissive mutations such as 𝚫H69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral f itness. MESHD

    Recurrent emergence and transmission of a SARS-CoV-2 Spike PROTEIN deletion ΔH69/V70

    Authors: Steven Kemp; Rawlings Datir; Dami Collier; Isabella Ferreira; Alessandro Carabelii; William Harvey; David L Robertson; Ravindra K Gupta; Saori Suzuki; Tomokazu Tamura; Alexander H. Tavares; Mohsan Saeed; Alex S. Holehouse; Alexander Ploss; Ilya Levental; Florian Douam; Robert F. Padera; Bruce D. Levy; Clifford P. Brangwynne

    doi:10.1101/2020.12.14.422555 Date: 2020-12-14 Source: bioRxiv

    SARS-CoV-2 Spike PROTEIN amino acid replacements occur relatively frequently in the receptor binding domain (RBD) and some have a consequences for immune recognition. Here we report recurrent emergence and significant onward transmission of a six nucleotide deletion in the Spike gene, which results in the loss of two amino acids: {Delta}H69/V70. Of particular note this deletion often follows the receptor binding motif amino acid replacements N501Y, N439K and Y453F. In addition, we report a sub-lineage of over 350 sequences bearing seven spike mutations across the RBD (N501Y, A570D), S1 ({Delta}H69/V70) and S2 (P681H, T716I, S982A and D1118H) in England. These mutations have possibly arisen as a result of the virus evolving from immune selection pressure in infected individuals. Enhanced surveillance for the {Delta}H69/V70 deletion with and without RBD MESHD mutations should be considered as a priority.

    Improved production of SARS-CoV-2 spike PROTEIN receptor-binding domain (RBD) for serology assays

    Authors: Jennifer Mehalko; Matthew Drew; Kelly Snead; John-Paul Denson; Vanessa Wall; Troy Taylor; Kaitlyn Sadtler; Simon Messing; William Gillette; Dominic Esposito; Giovanna Fusco; Marika Comegna; Angelo Boccia; Maurizio Viscardi; Giorgia Borriello; Sergio Brandi; Bianca Maria Pierri; Claudia Tiberio; Luigi Atripaldi; Giovanni Paolella; Giuseppe Castaldo; Stefano Pascarella; Martina Bianchi; Rosa Della Monica; Lorenzo Chiariotti; Kyong Seop Yun; Jae Ho Cheong; Hong Yeoul Kim; Massimo Zollo; Katie Jeffery; David W Eyre; Talat Mokhtari-Azad; Reza Najafipour; Reza Malekzadeh; Kimia Kahrizi; Seyed Mohammad Jazayeri; Hossein Najmabadi

    doi:10.1101/2020.11.18.388868 Date: 2020-11-18 Source: bioRxiv

    The receptor-binding domain (RBD) of the SARS-CoV-2 spike PROTEIN protein is a commonly used antigen for serology assays critical to determining the extent of SARS-CoV-2 exposure in the population. Different versions of the RBD protein have been developed and utilized in assays, with higher sensitivity attributed to particular forms of the protein. To improve the yield of these high-sensitivity forms of RBD and support the increased demand for this antigen in serology assays, we investigated several protein expression variables including DNA elements such as promoters and signal peptides, cell culture expression parameters, and purification processes. Through this investigation, we developed a simplified and robust purification strategy that consistently resulted in high levels of the high-sensitivity form of RBD MESHD and demonstrated that a carboxyterminal tag is responsible for the increased sensitivity in the ELISA. These improved reagents and processes produce high-quality proteins which are functional in serology assays and can be used to investigate seropositivity to SARS-CoV-2 infection MESHD. Highlights: O_LIImproved yields of SARS-CoV-2 spike PROTEIN RBD through modification of DNA constructs and purification parameters C_LIO_LITwo versions of RBD show different sensitivity in serology assays C_LIO_LIYields of greater than 50 mg/l obtained under optimal conditions C_LIO_LIMagnetic bead purification technology improves throughput of protein production C_LI

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