Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Nanomaterial delivery systems for mRNA vaccines. Kowalczyk, A. et al. Xia, S. et al. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Dis. Call the COVID-19 Hotline at. J. Science https://doi.org/10.1126/science.abj9106 (2021). Prof. Robert Howarth, ecology and evolutionary biology, has advanced climate understanding throughout his career, conducting groundbreaking research and speaking with world leaders. 384, 20922101 (2021). Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Most of the allergens are proteins, which are not contained in these chemically defined vaccines (section mRNA vaccines). They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. In addition, approaches to cope with the problem of the lability of the viral S protein cause variation across all current vaccines. What is coronavirus? COVID-19 explained | CNN The first category consists of mRNA and adenoviral vector vaccines (herein referred to as genetic vaccines, sections: Genetic vaccinesgeneral, mRNA vaccines, Adenovirus-vector vaccines), both of which do not contain the spike protein but provide genetic information for its biosynthesis in body cells of the vaccinee. AZD1222-induced neutralising antibody activity against SARS-CoV-2 Delta VOC. The Concept of the Crown and Its Potential Role in the Downfall of Features, Evaluation, and Treatment of Coronavirus (COVID-19) Alum is the most frequently used adjuvant in human vaccines and is used in the Sinopharm and Sinovac vaccines137,138. The impact of COVID-19 on healthcare-associated infections. Bottermann, M. & James, L. C. Intracellular antiviral immunity. Unique genomic features of fatal coronaviruses https://doi.org/10.1038/s41591-021-01413-7 (2021). Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate. Science 369, 77 (2020). The most striking difference is that COVID-19 can cause a loss of sense and smell. Here, we briefly discuss existing data and describe distinguishing features that can contribute to differences among vaccine responses independent of the structure and presentation of the S immunogen. ACS Central Sci. Results from a phase 1 clinical trial with the Curevac vaccine had indeed already shown relatively low titers of neutralizing antibodies induced by the dose used in the phase 3 clinical trial56,59. Google Scholar. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. Irrespective of these categories, all vaccines have to cope with the intrinsic problem of conformational instability of the spike protein, whether it is synthesized in the vaccinee after genetic vaccination or in cell culture systems for production of conventional vaccines. However, we would like to emphasize that there is an enormous pipeline of further developments (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines), including subunit vaccines that contain only parts of the S protein, in some instances combined with components of other viral proteins. Krause, P., Fleming, T. R., Longini, I., Henao-Restrepo, A. M. & Peto, R. COVID-19 vaccine trials should seek worthwhile efficacy. Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. The pathway to this mRNA however is substantially more complex than with mRNA vaccines because it takes a detour of the adenoviral DNA through the nucleus (where it remains extrachromosomal) and requires a number of additional cellular processes, including RNA transcription and processing (Fig. The European Union teams up with WHO to boost COVID-19 vaccination coverage in Africa. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. Planas, D. et al. Adv. Prof. Robert Howarth's Climate Research, Outreach Makes Waves Therefore, isolation of the final product includes detergent solubilization of the cells and several steps of purification101. Corresponding scientific investigations into the mechanisms of vaccine-induced anaphylactic reactions are ongoing125. Cleared for takeoff. McMahan, K. et al. Information on cellular impurities are so far restricted to ChAdOx1 and comparative analyses of all adenovector vaccines are not yet available. distinguishing feature of COVID-19 compared with other infective pneumonias and its association with disease severity Meera Mehta ,1 Hakim Ghani ,1 Felix Chua,2,3 Adrian Draper,4 Sam Calmonson,1 Meghna Prabhakar,1 Rijul Shah,1 Alessio Navarra,1 Tejal Vaghela,1 Andrew Barlow,1 Rama Vancheeswaran1 Thess, A. et al. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. The mmWave technology is just one technology that 5G networks can use. Pinto, D. et al. Quantitative recovery of adenoviral vector particles involves lysis of the cells by detergents (Fig. The vaccine thus presents the correctly folded immunogen in essentially pure form and in combination with a potent adjuvant. In both instances, the virus is grown in Vero cells and inactivated by beta-propiolactone (BPL), which is used as an inactivating agent for other viral vaccines, including rabies vaccines85. Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine. Such effects have been specifically shown for the ionizable lipid component in LNPs124. It usually spreads between people who are in close contact. Nature 594, 483 (2021). Google Scholar. and K.S. 21, 181192 (2021). The impact of coronavirus disease 2019 (COVID-19) on healthcare-associated infections in 2020: a summary of data reported to the National Healthcare Safety Network. Zhang, Y. et al. The domains were colored according to reference.20. Schmidt, T. et al. A severe complication of COVID-19 is viral pneumonia. . 1a), the S protein is synthesized from one of the viral subgenomic mRNAs and co-translationally transported into the lumen of the endoplasmic reticulum (ER) by the use of a signal sequence at its N-terminus, comprising residues 1 to 13 of its total 1273 amino acids14. Cell 184, 23162331.e2315 (2021). Irrespective of pre-existing immunity, all adenovirus vector vaccines are prone to induce immune responses against the vector particles129. Cagigi, A. In this article, we review the relevance of structural modifications of S in different vaccines and the different modes of antigen expression after vaccination with genetic adenovirus-vector and mRNA vaccines. In one study they collected 15 false and 15 true headlines about Covid-19. Two pertinent references do not indicate specific steps of purification after inactivation and removal of cell debris88,89, but one figure in a publication by Wang et al.90 suggests a step of chromatography, albeit without providing details of this process and the purity of the vaccine. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Coronavirus disease (COVID-19) / Feature stories; COVID feature stories. The uniting feature of current genetic COVID-19 vaccines is the provision of mRNAs for the whole, membrane-anchored spike protein (Figs. a Schematic of the process using the authentic viral signal peptide only (as in the vaccines of BionTech-Pfizer, Moderna, Janssen-Johnson&Johnson and Gamaleya Institute). Article Antiviral Res 176, 104742104742 (2020). Abu-Raddad, L. J., Chemaitelly, H. & Butt, A. Coronavirus symptoms tend to begin in certain order: Fever first, then In Plotkins Vaccines 7th edn (eds Orenstein, W. A., Offit, P. A. As outlined in the preceding sections, substantial differences appear to exist among current vaccines that can affect the conformation of S and its presentation to the immune system. Another BPL-inactivated whole-virus vaccine in development (by the European company Valneva) makes use of Alum in combination with CpG to induce preferentially a desired Th1 response138, and a similar effect has been attributed to the Matrix-MTM adjuvant used in the Novavax subunit vaccine99,101,102. Sadoff, J. et al. Zost, S. J. et al. Science. Liu, L. et al. High rates of seropositivity against adenovirus 5 (the pioneer of adenovirus vector development) have been reported in the population126,127, and a number of studies have shown that pre-existing vector immunity can impair the response to the vaccine antigen128,129,130. They are known to infect the neurological, respiratory, enteric, and hepatic systems. Front. They can also spread it to others. Constituents in the Oxford-AstraZeneca vaccine were recently analyzed in the context of a search for potential causes of venous sinus thrombosis as a rare post-vaccinal complication121. Each spike is about 20 nm long and is composed of a trimer of the S protein. Chen, N. et al. Although the constructs for all four adenovirus-vector vaccines contain the full-length spike protein, there are some differences in construct design with respect to mutations for stabilizing S as well as to the signal peptide at the N-terminus of S that require attention. 13, 43 (2021). Th1 skewed immune response of whole virion inactivated SARS CoV 2 vaccine and its safety evaluation. Lancet 396, 887897 (2020). In addition, background expression of remaining adenoviral genes has been demonstrated in this as well as in other studies with human adenovirus-based vectors72,76. Kremsner, P. et al. Coronaviruses are a large family of viruses, but only seven of its members infect humans. Google Scholar. Structure 28, 12181224.e1214 (2020). However, the authors discuss evidence of shedding of the cleaved S1 portion78, which has also been observed in model studies with unmodified S proteins compared to mutationally stabilized proteins18 (Fig. What defines an efficacious COVID-19 vaccine? Immunol. Liu, C. et al. Trends Biochem. Nat. J. Virol. Science 369, 1586 (2020). Tumban, E. Lead SARS-CoV-2 candidate vaccines: expectations from phase III Trials and recommendations post-vaccine approval. 8, 654866 (2021). . Similar to mRNA vaccines, adenovirus vector vaccines are intended to result in the production of native S proteins from a specific mRNA in cells of the vaccinee (Figs. Slider with three articles shown per slide. The unifying feature of all current adenovirus-vaccine vectors is the replacement of one of the early adenoviral genes (E1) for the full-length SARS-Cov-2 S gene in the adenoviral DNA (Fig. In predynastic Egypt, Atum was a solar deity associated with the sun god Ra . J. Med.383, 26032615 (2020). Distinguishing viral pneumonia from bacterial pneumonia is difficult in the community. Potently neutralizing and protective human antibodies against SARS-CoV-2. Science Translational Medicine. Duan, L. et al. Coutard, B. et al. However, the absence of interactions with other viral components for particle assembly may modulate glycosylation patterns and stability of the S trimers. Immunol. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. A comprehensive review of the global efforts on COVID-19 vaccine development. Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity. Immunity 54, 12761289.e1276 (2021). Cell Host Microbe 28, 586601.e586 (2020). SARS-CoV-2 Variant Classifications and Definitions 5a) may be especially critical for obtaining natively folded S, because there is a cysteine immediately downstream of the cleavage site (amino acid 2) that has to form an S-S bond with the cysteine at position 136. Although corresponding data do not yet exist in the public domain for the other adenoviral vector vaccines, the problem of cellular impurities may be similar, because they all depend on the lysis of production cells for releasing the engineered vector particles (section Adenovirus-vector vaccines). Other components of cellular immunity, such as CD8 T cells, also contribute to immune responses after SARS-CoV-2 infection or vaccination, although their role in COVID-19 infections and protection from disease is still incompletely resolved12,13. A team of researchers from the National Library of Medicine (NLM), part of the National Institutes of Health, identified genomic features of SARS-CoV-2, the virus that causes COVID-19, and other high-fatality coronaviruses that distinguish them from other members of the coronavirus family. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines. So far, no data are available that would allow a direct comparison of the various vaccines and their effectiveness against the different VOCs. Science 372, 525 (2021). 26, 14221427 (2020). RNA sensors of the innate immune system and their detection of pathogens. 1; Black students are more likely than White students to receive harsher consequences . Distinguishing feature definition and meaning - Collins Dictionary 80). 384, 18851898 (2021). Piccoli, L. et al. The World Health Organization (WHO) has increased the assessment of the risk of spread and the risk of impact of COVID-19 to very high at a global level . Nature 586, 567571 (2020). b Schematic of a lipidnanoparticle (LNP) used for delivery of mRNA vaccines. Sometimes coronaviruses that infect animals can evolve and make people sick and become a new human coronavirus. Hasan, T., Beardsley, J., Marais, B. J., Nguyen, T. A. "As a council member, I'm disappointed and appalled that no one else would think that there was anything wrong with this report," said Jones, a Democrat who represents District 2. & Stiasny, K. Profiles of current COVID-19 vaccines. Independent of such antigenic effects, the fundamentally different mechanisms of action and ways of production are likely to introduce additional variation to the characteristics of immune responses and possible adverse reactions. Article ERendoplasmic reticulum; ERGICendoplasmic reticulum Golgi intermediate compartment; TGNTrans Golgi Network; RNPRibonucleoprotein; Viral proteins: Sspike, Mmembrane; Eenvelope; Nnucleoprotein. Science 369, 650 (2020). Lancet 397, 16461657 (2021). Key features of the vaccines discussed in this review are summarized in Table1. You are using a browser version with limited support for CSS. Science 369, 643 (2020). Buschmann, M. D. et al. Animal experiments have shown that adenovirus-vector DNA can remain detectable for months after inoculation in transcriptionally active form82 in contrast to rapidly degraded RNA55,83. Section navigation Coronavirus disease (COVID-19) Feature stories Situation reports; Media resources. Both vaccines use aluminum hydroxide as an adjuvant. One of the constituents discussed as being causally linked to anaphylaxis is polyethylene glycol (PEG), which is used in the formulation of LNPs that protect the RNA and facilitate its transfer into cells (section mRNA vaccines). Coronaviruses | Microbiology Society Pardi, N. et al. What is the coronavirus? - Science Coronavirus variants: Facts about omicron, delta and other COVID-19 5). Preprint at https://www.researchsquare.com/article/rs-558954/v1 (2021). RSV vs. COVID-19 Coronavirus: Symptoms and Their Differences - WebMD CAS Severe acute respiratory syndrome, also known as SARS, is the other coronavirus that can cause more severe symptoms. Google Scholar. Share information from trusted sources. 5b), based on a previous study with Middle East respiratory syndrome coronavirus (MERS-CoV79 (Fig. An infection often resolves quickly and can appear similar to food poisoning. Cai, Y. et al. 22, 539540 (2021). Nelson, J. et al. Choe, H. & Farzan, M. How SARS-CoV-2 first adapted in humans. Science 370, 950 (2020). Details of manufacturing processes may differ between the companies, and subtle product-specific variations of RNA sequences were recently confirmed by comparative analyses of RNA extracted from original vials of the two vaccines (https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273/blob/main/Assemblies%20of%20putative%20SARS-CoV2-spike-encoding%20mRNA%20sequences%20for%20vaccines%20BNT-162b2%20and%20mRNA-1273.docx.pdf). Vaidyanathan, S. et al. Cell 184, 18211835.e1816 (2021). ACS Central Sci. PDF Retrospective case control study to evaluate hypocalcaemia as a Prevention of infection with the Beta, Gamma and Delta variants might be lower, although evidence indicates substantial protection from severe disease after two vaccinations110,112,113. ACS Central Sci. After completion of translation, the protein remains attached to the ER membrane through a C-terminal membrane anchor, trimerizes and moves to the ER-Golgi intermediate compartment (ERGIC) where virus assembly occurs by budding into the ERGIC lumen (Fig. The RNA in this vaccine is also codon-optimized and contains modifications to improve its performance, butdifferent from the BioNTech-Pfizer and Moderna mRNA vaccines described aboveit does not contain the m1 nucleoside modifications57,58. Cureus | Coronavirus (COVID-19): A Review of Clinical Features Comparison of Clinical Features of COVID-19 vs Seasonal - JAMA Dis. Andreano, E. et al. The components used for LNP formulation include phospholipids, cholesterol, special cationic (ionizable) lipids and polyethylene glycol (PEGylated) lipids that are mixed in a sophisticated and critical production step (parts of which are not documented in the published literature) to yield the final vaccine53. Vogel, A. In most people, common cold symptoms usually peak within the first two to three days of infection, while the effects of Covid appear two to 14 days after exposure. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. and K.S. Recently, data from a phase 3 clinical trial became available, showing a relatively low efficacy of 47% at preventing disease (https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/), well below the efficacies reported for the BionTech-Pfizer and Moderna vaccines46,47 and below the requirement of at least 50% efficacy proposed by WHO (https://www.who.int/publications/m/item/considerations-for-the-assessment-of-covid-19-vaccines-for-listing-by-who). Adjuvants for coronavirus vaccines. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Only the Janssen vaccine contains S-stabilizing mutations (Table1), comprising not only the two prolines in S2 but also the S1/S2 furin cleavage site, which is mutated from 682-RRAS-685 to SRAG19,62. Google Scholar. The loss of the E1 gene abolishes replication competence of the vector. Kelso, J. M. Anaphylactic reactions to novel mRNA SARS-CoV-2/COVID-19 vaccines. Correspondence to 1b) (as in mRNA and adenovirus vector vaccines as well as for production of recombinant subunit vaccines), the pathway of biosynthesis is very similar. and K.S. Coronavirus is mostly spread through the air, when people are in close contact with each other. Vaccines 11, 695719 (2012). Preprint at https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). Details of these processes, affecting the purity and quality of the final vaccines (containing at least 51010 particles per dose), are not accessible in the published literature (see section Contaminations from cell substrates). Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the common cold are examples of coronaviruses that cause illness in humans. 5b). Many uncertainties remain in our understanding of the spread of Covid-19 and its management. Correct processing of the signal peptide by signal peptidase to generate the final N-terminus of S (Fig. Nature 584, 443449 (2020). Lancet Infect. 2c, d). SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Watanabe, Y. et al. Therefore, it is urgent to know the epidemic . Rogers, T. F. et al. Vaccines 12, 379393 (2013). Nat. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018215766. Lancet Respiratory Med. Nat. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Club-shaped glycoprotein spikes in the envelope give the viruses a crownlike, or coronal, appearance. Collectively, these data showed that the most potently neutralizing antibodies were specific for the RBD27,28,29,30,31,32,33,34, but several strongly neutralizing antibodies also recognized the NTD27,34,35,36,37, and some were dependent on the quaternary assembly of the trimer27,38. Current COVID-19 vaccines present the spike protein in very different ways to the immune system, and two main categories have to be discerned. JAMA 324, 951960 (2020). SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Distinguishing features of current COVID-19 vaccines: knowns and Virus particles are transported through the TGN and released from the cells probably via lysosomes. LithiumBank Resources distinguishing itself with industry-leading Manish Sadarangani, Arnaud Marchant & Tobias R. Kollmann, Samir Andrade Mendona, Reka Lorincz, David T. Curiel, Nikolaos C. Kyriakidis, Andrs Lpez-Corts, Esteban Ortiz Prado, Guido Forni, Alberto Mantovani & on behalf of the COVID-19 Commission of Accademia Nazionale dei Lincei, Rome, Milja Belik, Pinja Jalkanen, Ilkka Julkunen, Aileen Ebenig, Mona V. Lange & Michael D. Mhlebach, Neeltje van Doremalen, Jonathan E. Schulz, Vincent J. Munster, Chih-Jung Chen, Lan-Yan Yang, Kuan-Ying A. Huang, Simon P. Graham, Rebecca K. McLean, Teresa Lambe, npj Vaccines Science 367, 1260 (2020). Coughlan, L. Factors which contribute to the immunogenicity of non-replicating adenoviral vectored vaccines. Literature data indicate that production of the Sinovac vaccine includes several steps of virus purification, leading to a product that contains primarily the viral proteins and consists of essentially pure viral particles86,87. Coronavirus | Definition, Features, & Examples | Britannica Cell cultures are also used for production of the inactivated whole-virus vaccines (Vero cells) of Sinopharm88, Sinovac86 and Bharat97 as well as for the Novavax subunit vaccine (insect Sf9 cells)99,101 (sections Inactivated vaccines and Subunit vaccines and Table1). N. Engl. 21, e26e35 (2021). Introduction of two prolines and removal of the polybasic cleavage site lead to higher efficacy of a recombinant spike-based SARS-CoV-2 vaccine in the mouse model. Frontiers | Features of Cytokine Storm Identified by Distinguishing In the following sections, we will discuss these basic differences, and provide information on variations and modifications that can affect the structural integrity of the spike in genetic and conventional vaccines. Linares-Fernndez, S., Lacroix, C., Exposito, J.-Y. N. Engl. These vaccines are now used worldwide for mass immunization programs, and data on vaccine efficacies justify the hope that vaccination can indeed be the main instrument for preventing serious disease and death, and more generally for combating the pandemic1,2,3,4. Expert Rev. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory. Immunol. Med. Four types cause minor illnesses like the common cold, while other coronaviruses . npj Vaccines 5, 91 (2020). Eye Opener: Alex Murdaugh faces possible life sentence for murder of wife and son Guilty on all counts, disgraced South Carolina attorney Alex Murdaugh now faces possible life in prison for the . On one hand, it can stimulate genes that fight off infection or help cells survive damage, but on the other hand, it may provide extra targets that help the virus infect more cells. You may also have heard about "low band" frequencies and "sub-6GHz," both of which are also part of the standard . Dev. We also address the grey matter of additional variables, such as ill-defined downstream production processes and purity of vaccines as well as differences in triggering sensors of innate immunity. The development of COVID-19 vaccines was extremely fast and successful, with several manufacturers having obtained market authorization for their products within the first year from the identification of the virus (SARS-CoV-2). Nat. Lancet https://doi.org/10.1016/s0140-6736(21)01462-8 (2021). A. It has been confirmed that the recent outbreak and epidemic of coronavirus disease 2019 (COVID-19) was caused by a new coronavirus that has been named SARS-CoV-2. The two protease cleavage sites are indicated by arrows. Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. After vaccination with mRNA vaccines, rare events of anaphylactic shock above the average incidence in the population have been reported, largely in individuals with a history of allergy123,124. coronavirus, any virus belonging to the family Coronaviridae. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. N. Engl. The different classes of currently available COVID-19 vaccines exhibit fundamental differences with respect to their modes of action and the ways by which the spike antigen is presented to the immune system. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Janssen-Johnson&Johnson and Gamaleya-Institute use the authentic SARS-CoV-2 S protein signal sequence19,67, whereas CanSino replaced it with that of human tissue plasminogen activator (tPA) (Fig. Some people infected with the coronavirus have mild COVID-19 illness, and others have no symptoms at all. The coronavirus disease 2019 (COVID-19) pandemic is currently spreading worldwide and contributing to widespread mortality. van Doremalen, N. et al. npj Vaccines 2, 29 (2017). and JavaScript. A., Whittaker, G. R. & Daniel, S. Coronavirus membrane fusion mechanism offers a potential target for antiviral development. 4b)70. Liang, Z. et al. The effect of dissociation of soluble S1 from the trimer complex on the quality of immune responses is incompletely understood, but some data suggest it may contribute to a higher proportion of non-neutralizing relative to neutralizing antibodies19,81. Vaccine 35, 37803788 (2017).
Report Abandoned Vehicle Stockton, Ca,
Articles T
*
Be the first to comment.