Hodgson, S. H. et al. After amplification in bacterial cells, the plasmid DNA is linearized and impurities are removed before in vitro transcription into RNA. Another mRNA vaccine, manufactured by the company CureVac (current name CVnCoV; Table1) is in an advanced stage of development56. Coronaviruses are a family of viruses that contain RNA (instead of DNA, like people have). Cell 184, 39363948.e3910 (2021). 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. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Internet Explorer). 10, 28752884 (2014). Zhang, J. et al. Article High-resolution structural analysis revealed that the purified protein is stably locked in the preferred pre-fusion conformation, in part as free trimers and in part as multitrimer complexes103. To help spearhead significant victories . For meaningful conclusions, studies on these topics will require head-to-head comparisons of vaccines, and corresponding publications are expected to expand rapidly in the near future. Preprint at https://www.researchsquare.com/article/rs-558954/v1 (2021). A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. In vitro transcription is followed by several steps of mRNA purification, including the removal of dsRNA, which could lead to an excessive innate immune response and concomitant reactogenicity48,50. Google Scholar. . Robbiani, D. F. et al. classical inactivated whole-virus and innovative subunit vaccines, which contain S in different forms and combinations with adjuvants (Sections: Protein-based vaccinesgeneral, Inactivated vaccines, Subunit vaccines). The precise mechanisms of how the RNA is taken up by different cells after vaccination and escapes from LNPs and intracellular vesicles is incompletely resolved53,55. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines. Cite this article. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Vaccine 39, 21902200 (2021). Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate. Zhao, P. et al. Immunol. Corbett, K. S. et al. 3a; see section Vaccine-specific differences of innate responses)51,52. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China . J. Lancet 396, 887897 (2020). These are the products (in alphabetical order) of CanSino Biological Inc./Beijing Institute of Biotechnology, Janssen-Johnson&Johnson, Oxford-AstraZeneca and The Gamaleya Institute Moscow (Table1). The uniting feature of current genetic COVID-19 vaccines is the provision of mRNAs for the whole, membrane-anchored spike protein (Figs. There is an urgent need to clarify the pathogenic mechanism underlying the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Capone, S. et al. Given the same antigenic difference of all vaccines relative to VOCs, the most important parameter determining cross-protection may be the quantity of neutralizing antibodies and relevant cellular immune reactivity at the time of infection. This complex artificial sequence element may lead to some inhomogeneity in proteolytic processing and impairment of correct formation of the S N-terminus during biosynthesis, as recently shown in comparative model studies with similar constructs19. In this review, we discuss the biosynthesis and relevant structural features of the viral spike as a basis for understanding differences of its presentation in current COVID-19 vaccines. 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. Wrapp, D. et al. It consists of the trimeric full-length spike that is produced as a recombinant protein in insect Sf9 (Spodoptera frugiperda) cells using a baculovirus expression system and contains mutations to stabilize S2 (K986P and V987P) as well as to delete the furin cleavage site (682-RRAS-685 changed to QQAQ)99 (Table1 and Fig. 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). 21, 195197 (2021). In one study they collected 15 false and 15 true headlines about Covid-19. There are open questions concerning the structure of S in the inactivated vaccines. 1,2 However, coronavirus disease 2019 (COVID-19) has also demonstrated distinct clinical characteristics, such as anosmia and hypogeusia. 65, 1420 (2020). Details of purification procedures of the Bharat vaccine and the degree of cellular contaminants in the Sinopharm vaccine (which is less purified than that of Sinovac according to ref. Preprint at https://www.medrxiv.org/content/10.1101/2021.05.07.21256809v1 (2021). & Stiasny, K. Profiles of current COVID-19 vaccines. Science 369, 643 (2020). Sci. 9, e42e43 (2021). Development of an inactivated vaccine candidate for SARS-CoV-2. 3,4 Although the . C. R. Biol. This quantitative aspect is important for future analyses of the impact of waning immunity on protection and decisions about optimal timings of booster immunizations. In the BionTech-Pfizer and Moderna vaccines this problem was taken into account by modifications of the RNA sequence and the inclusion of m1 (section mRNA vaccines), which is not contained in CureVacs mRNA vaccine56. Lutz, J. et al. Kids face the same risk of catching it as adults, although the disease is usually milder in children. Structure 28, 12181224.e1214 (2020). Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. Lancet https://doi.org/10.1016/s0140-6736(21)01462-8 (2021). Nat. Mol. Structural impact on SARS-CoV-2 spike protein by D614G substitution. Amanat, F. et al. Irrespective of pre-existing immunity, all adenovirus vector vaccines are prone to induce immune responses against the vector particles129. & Nauwynck, H. J. Inactivated virus vaccines from chemistry to prophylaxis: merits, risks and challenges. Ther. 17, 13331339 (2009). Science 372, 466 (2021). Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. 384, 20922101 (2021). Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. 3b)53,54. Nature https://doi.org/10.1038/s41586-021-03777-9 (2021). 2c, d). SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID 1-3.Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions 1-3; however, the basic biological mechanisms responsible . Specifically developed and improved ionizable lipids are used in the Moderna and Biontech-Pfizer vaccines (designated Lipid H, SM-102 and ALC-0315, respectively), which together with the molar ratios of the lipid components in LNPs play a critical role for RNA delivery54. JAMA 325, 12411243 (2021). Nature 595, 344345 (2021). COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. 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. The relevance of these differences for protection are not yet clear. Xia, S. et al. Drug Discov. Preprint at https://www.biorxiv.org/content/10.1101/2021.04.14.439844v1 (2021). Nat. Biosci. Xia, S. et al. Electron microscopical pictures of the viral spikes in the Sinovac vaccine have been interpreted differently, either as displaying the pre-fusion structure86 or the post-fusion structure25,92. In fact, . 1, 2) in tissues after intramuscular application. PubMed Central Coronavirus (COVID-19) is an enveloped RNA virus that is diversely found in humans and wildlife. Blumenthal, K. G. et al. 2d)19. It is believed (but not systematically studied and formally shown) that muscle cells, fibroblasts, endothelial cells, and/or immune cells such as dendritic cells contribute to the expression of S after intramuscular vaccination40,41,42. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. 8, 14301435 (2011). SARS-CoV-2 vaccine ChAdOx1 nCoV-19 infection of human cell lines reveals low levels of viral backbone gene transcription alongside very high levels of SARS-CoV-2 S glycoprotein gene transcription. Hopefully, more details will become available in the near future. Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. Some of these mutants are considered Variants of Concern (VOCs) because of their highly efficient transmission, the concomitant replacement of previously circulating strains, and the presence of mutations in the spike protein that can lead to immune escape (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Watanabe, Y. et al. Alum is the most frequently used adjuvant in human vaccines and is used in the Sinopharm and Sinovac vaccines137,138. 81, 65946604 (2007). Kustin, T. et al. Information on cellular impurities are so far restricted to ChAdOx1 and comparative analyses of all adenovector vaccines are not yet available. 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). The virus spreads through respiratory droplets released when someone breathes, coughs, sneezes, talks or sings. The coronavirus at the root of COVID-19 is the newest known member of this family. We have reviewed the most apparent and significant differences among the vaccines as far as they can be recognized from published literature, which unfortunately is still incomplete. Pollard, A. J. Hum. 118, e2104241118 (2021). Science 369, 956 (2020). The domains were colored according to reference.20. Xu, C. et al. ; Writing: F.X.H. Fan, X., Cao, D., Kong, L. & Zhang, X. Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein. Mol. McMahan, K. et al. Nature 590, 630634 (2021). Typically, patients will experience fever, cough, muscle pain and then nausea, and/or vomiting, and diarrhea. These subunits remain associated in the trimer through noncovalent interactions, and the virus is probably secreted via exocytic lysosomes with disrupted lysosomal functions17. Adv. In parallel to genetic vaccines, more conventional approaches of vaccine development were pursued with similar intensity and led to the authorization of inactivated whole-virus vaccines and a subunit vaccine that is in a stage of pre-authorization (Table1). Currently, four adenovirus-vector vaccines are in widespread use. . Liu, C. et al. Thess, A. et al. Curr. There is indirect evidence that virus strains having emerged later in the pandemic (e.g. Although all current vaccines for which phase 3 efficacy data are available rely on the whole viral spike protein as an antigen, its presentation to the immune system is strikingly different not only between genetic vaccines and protein-based vaccines, but also between vaccines within these categories. a Schematic of replication-incompetent adenoviral vector particle and its DNA. Barouch, D. H. et al. 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. Latin America is the world's new coronavirus epicenter, but Uruguay - a small South American nation of 3.5 million people - has so far avoided the devastation raging across the rest of the . Comparative analyses of antibody and T cell responses and their fine specificities will allow indirect but important conclusions to be drawn. https://doi.org/10.1007/82_2020_217 (2020). Krause, P., Fleming, T. R., Longini, I., Henao-Restrepo, A. M. & Peto, R. COVID-19 vaccine trials should seek worthwhile efficacy. Earle, K. A. et al. Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients. COVID-19 and the flu have many symptoms in common, including: Fever Cough Shortness of breath or difficulty breathing Tiredness Sore throat Runny or stuffy nose Muscle aches Headache Nausea or vomiting, but this is more common in children than in adults The signs and symptoms of both diseases can range from no symptoms to mild or severe symptoms. Nat. The CDC lists these as the most common symptoms of COVID-19: Fever or chills Cough Shortness of breath or difficulty breathing Fatigue Muscle or body aches Headache New loss of taste or smell. Immunol. While these efforts resulted in successful classification systems, the design of a portable and cost-effective COVID-19 diagnosis system has not been addressed yet. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Mol. Hasan, T., Beardsley, J., Marais, B. J., Nguyen, T. A. The variant gambit: COVID-19s next move. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 437442 (2020). Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Coronavirus Rumor Control. PubMed The findings of the MIT team suggest that interferon's potential role in fighting Covid-19 may be complex. Delrue, I., Verzele, D., Madder, A. These considerations of vector immunity also prompted the development of non-human adenovirus vectors such as ChAdOx1 derived from chimpanzee adenovirus Y2564, now used in the Oxford-AstraZeneca vaccine77. Collectively, this kind of adverse event is designated vaccine-induced immune thrombotic thrombocytopenia (VITT). 100, 309354 (2018). JAMA 324, 951960 (2020). Front. A total of six species have been identified to cause disease in humans. However, the situation of COVID-19 outbreak is getting worse in other countries over the last few days, such as Italy, America and Spain . 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. Virus-receptor interactions of glycosylated SARS-CoV-2 spike and human ACE2 receptor. The company formulates the S trimer as a nanoparticle in polysorbate 80 (PS80) detergent and uses a special proprietary saponin-based adjuvant (Matrix-M) that comprises 40nm particles composed of Quillaja saponins, cholesterol and phospholipids102,103. You may also have heard about "low band" frequencies and "sub-6GHz," both of which are also part of the standard . In conclusion, since the emergence of COVID-19 pneumonia and due to its similar radiological patterns, we believe that a SARS-CoV-2 RT-PCR should be systematically realized in case of respiratory . Dev. J. Med. What is a coronavirus? N. Engl. It is part of the unknowns of current COVID-19 adenovirus vector vaccines, how the patterns of background-vector DNA and protein expression look like after vaccination and whether immune reactions to such proteins are induced. Mol. J. Med.383, 26032615 (2020). Virus particles are transported through the TGN and released from the cells probably via lysosomes. Four types cause minor illnesses like the common cold, while other coronaviruses . 2). For reducing potential negative effects of pre-existing immunity, alternative adenoviruses were developed as vectors, one of them adenovirus 26, which has lower rates of seropositivity in the population127 and is now used in the Janssen-Johnson&Johnson vaccine19,62 as well as in the first shot of the Gamaleya-Institute vaccine67,68. To reach this conclusion, the USC researchers studied the rates of symptom incidence in two . The diseases caused by these viruses also share similar clinical presentations, including fever and respiratory symptoms that range from mild forms, such as cough, to severe lung infections. Adenovirus-vector and mRNA vaccines promote substantially different innate responses that will certainly influence the nature of adaptive immune responses43. Vaccine 34, 38823893 (2016). 80). & Ertl, H. C. New insights on adenovirus as vaccine vectors. Lancet 397, 13511362 (2021). Several studies have been conducted to decide whether the chest X-ray and computed tomography (CT) scans of patients indicate COVID-19. 21, e26e35 (2021). Another inactivated whole-virus vaccine using similar technology is produced by the Indian company Bharat and has received emergency use authorization in India even before completion of phase III clinical trials91 (Table1). A severe complication of COVID-19 is viral pneumonia. 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 FEMA helps the public distinguish between rumors and facts regarding the response to the Coronavirus (COVID-19) pandemic. Different from SARS-CoV and MERS-CoV in genetics and epidemiology, SARS-CoV-2 is a novel -coronavirus [ 6, 7 ]. For delivery, the RNA vaccines are formulated as complexes with specific lipids in the form of lipid nanoparticles (LNP), which not only provide protection from RNA degradation in tissues but also facilitate cellular uptake and release into the cytoplasm for RNA translation (Fig. Vaccines (Basel) 9, 61 (2021). Cell 184, 42204236.e13 (2021). 46, 429430 (2021). At 10.9 inches, the 4th-generation iPad Air boasts a larger screen than the iPad . Burki, T. K. Challenges in the rollout of COVID-19 vaccines worldwide. Distinct conformational states of SARS-CoV-2 spike protein. 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.
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