van Doremalen, N. et al. 384, 20922101 (2021). Vaccines (Basel) 9, 65 (2021). Rochman, N. D. et al. Krause, P., Fleming, T. R., Longini, I., Henao-Restrepo, A. M. & Peto, R. COVID-19 vaccine trials should seek worthwhile efficacy. As of mid-March 2022, omicron is the dominant coronavirus variant in the world . JAMA 325, 15621565 (2021). Med. 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. In some cases, they could co-exist, increasing the chance of a more unfortunate outcome. IUBMB Life 69, 297304 (2017). N. Engl. Lancet Infect. What is a coronavirus? Like many other viruses, SARS-CoV-2 is an RNA virus. Science Translational Medicine. Tatsis, N. et al. Wang, H. et al. Center for Virology, Medical University of Vienna, Vienna, Austria, You can also search for this author in Front. MASHANTUCKET, Conn.When the Covid-19 pandemic shuttered Foxwoods Resort Casino in Connecticut for three months in 2020, its owners, the Mashantucket Pequot Tribal Nation, had to reckon with . RBDreceptor binding domain; NTDN-terminal domain; FPfusion peptide. McMahan, K. et al. 7, 512533 (2021). 17, 13331339 (2009). Extremely potent human monoclonal antibodies from COVID-19 convalescent patients. 11, 589833 (2020). Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the common cold are examples of coronaviruses that cause illness in humans. Excessive innate responses can not only result in strong reactogenicity of vaccination but also restrict antigen translation from the vaccine RNA, thus impairing adaptive immune responses. Fausther-Bovendo, H. & Kobinger, G. P. Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, whats important? 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 . J. The variant gambit: COVID-19s next move. Increasing evidence indicates that neutralizing antibodies are indeed a reliable correlate of protection5,6,7,8,9. Vaccines (Basel) 9, 61 (2021). 4a) and the additional deletion of E319,61,62,64,65,69. The extended N-terminal leader sequence results in two consecutive signal peptides separated by an intervening stretch of tPA propeptide (Fig. The study, published in Frontiers in Public Health, finds that a distinguishing feature of COVID-19 is the order in which symptoms first appear. Dis. Correspondence to 21, 195197 (2021). Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Med. 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. BMJ 373, n969 (2021). Liu, C. et al. 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. Development of an inactivated vaccine candidate for SARS-CoV-2. N. Engl. The S protein is in turn composed of an S1 and S2 subunit. Persistence of antigen expression may be a distinctive feature of adenovirus vector vaccines, and has been proposed to contribute to induction of sustained immune responses and long-lasting immunity (reviewed in41). Sometimes coronaviruses that infect animals can evolve and make people sick and become a new human coronavirus. Ella, R. et al. J. Med. Amanat, F. et al. Because of its essential functions during viral entry (receptor binding and membrane fusion), the S protein is the major target of antibodies that can potently neutralize the virus. b Schematic of a lipidnanoparticle (LNP) used for delivery of mRNA vaccines. It is unclear, at present, which influences anti-vector responses will have on necessary COVID-19 booster vaccinations in the future. Lancet 397, 99111 (2021). 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. In a note to clients, the analysts wrote that the hydrogeological study indicates Park Place hosts a combined 76.3 cubic kilometres of lithium-bearing brine, meaning . Adv. Front. Pharm. "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. Manipulations of the authentic viral signal sequence may cause inhomogeneities of the N-terminus and impair native folding of S19 (see also section Adenovirus-vector vaccines and Fig. BMJ 373, n958 (2021). a Trimeric pre-fusion spike with all RBDs in down position. Encapsulating the RNA genome is the viral envelope (teal . 48, 6572 (2021). Distinguishing viral pneumonia from bacterial pneumonia is difficult in the community. & Yan, J. SARS-CoV-2 virus: vaccines in development. COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. The risk of immediate serious infection is thought to be very low. Lancet 397, 13511362 (2021). A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Immunol 11, 1673 (2020). Nature 590, 630634 (2021). Importantly, the human neutralizing antibody response in SARS-CoV-2 infection appears to be dominated by RBD-specific antibodies, whichon averagewere shown to contribute 90% of the total neutralizing activity of human post-infection sera39. In principle, all current vaccines are affected similarly by VOCs, because they are all based on original wild-type strains from the early phase of the pandemic (see Table1) and therefore their S protein sequences differ from those of VOCs to the same degrees. In one study they collected 15 false and 15 true headlines about Covid-19. 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/). FEMA helps the public distinguish between rumors and facts regarding the response to the Coronavirus (COVID-19) pandemic. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. The total amount of protein per dose was found to be 35 to 40g, most of which can be assumed to be cellular protein, because the protein of 51010 adenovirus particles per dose would account for only about 8g (for calculation see122). Google Scholar. Lancet 396, 479488 (2020). 2ac)20,21. The most striking difference is that COVID-19 can cause a loss of sense and smell. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action, https://doi.org/10.1038/s41541-021-00369-6. A plethora of viral mutants arose and spread since the emergence of SARS-CoV-2104,105. Nature 584, 443449 (2020). When S is synthesized as an isolated protein (Fig. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. 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). Gilbert, S. C., Hill, A. V. & Morris, S. J. Compositions and Methods for Inducing an Immune Response. & Fox, G. J. Amanat, F. et al. Cell 181, 281292.e286 (2020). Although in vitro model studies with one of the current adenovirus vector vaccines (ChAdOx1 nCoV-19; Table1) have shown that S-coding transcripts dominate the transcription patterns, rare aberrant splicing or polyadenylation site usage were observed72. 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. 9, e42e43 (2021). 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. This adjuvant results in polarization towards a Th2 response, which has been regarded as unfavorable in the case of coronavirus and other viral infections and vaccinations118,139,140. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. 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. c Expression of spike in cells of vaccinated individuals. & Lor, K. Immune responses induced by mRNA vaccination in mice, monkeys and humans. 4c). N. Engl. The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: implications for the design of spike-based vaccine immunogens. 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. 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N. Engl. ACS Central Sci. Jagannathan, P. & Wang, T. T. Immunity after SARS-CoV-2 infections. Rev. Immunol. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Therefore, for production of the engineered particles as a vaccine, immortalized helper cell lines are used that contain the E1 gene in their chromosomal DNA and provide the missing function, allowing the biosynthesis of structural proteins, replication of modified genomic DNA, and finally assembly of replication-incompetent virus particles in the cells (Fig. Fan, X., Cao, D., Kong, L. & Zhang, X. Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein. Piccoli, L. et al. Ther. 80). 2c)20,21. Suryadevara, N. et al. 1, 131138 (2021). Extensive modifications by N- and O-glycosylation occur in the compartments encountered by S during its intracellular transport18. Hasanpourghadi, M., Novikov, M. & Ertl, H. C. J. COVID-19 vaccines based on adenovirus vectors. 2d)24,25,26. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. Preprint at https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). ; Approval of final manuscript: F.X.H. Hasan, T., Beardsley, J., Marais, B. J., Nguyen, T. A. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. The past few decades have seen endemic outbreaks in the form of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute . The implementation of mass-vaccination against SARS-CoV-2: a systematic review of existing strategies and guidelines. PubMed SPsignal peptide; SRPsignal recognition particle; tPAtissue plasminogen activator; ERendoplasmic reticulum; C-terC terminus; N-terN terminus. npj Vaccines 5, 91 (2020). Th1 skewed immune response of whole virion inactivated SARS CoV 2 vaccine and its safety evaluation. Chi, X. et al. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. Development of chimpanzee adenoviruses as vaccine vectors: challenges and successes emerging from clinical trials. Our major focus is on variations of the constructs for S biosynthesis in genetic vaccines and on possible conformational differences of S in conventional vaccines. Release of newly produced vector particles through cell lysis. Top. Nat. 137, https://doi.org/10.1080/08820139.2021.1904977 (2021). Both the Pfizer and Moderna vaccines work by giving the body instructions for how to make a harmless protein that is a distinguishing feature of the actual virus so that when or if the vaccinated person gets exposed to the virus, their body already knows what to do to fight it off. Liu, L. et al. These data can serve as an indirect measure for the structural integrity of S in the vaccines and the quality of B cell immune responses. It has been speculated that pre-existing PEG antibodies might be involved in these allergic events124. A distinguishing feature of SARSCoV2 is its incorporation of a polybasic site cleaved by furin, which appears to be an important element enhancing its virulence. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. The amount of impurities depends on the purification steps applied in the manufacturing process. Heinz, F.X., Stiasny, K. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action. Google Scholar. The energy gained by the formation of this hairpin-like structure, in which the fusion peptide is juxtaposed to the C-terminal membrane anchor, is the driving force for viral membrane fusion during entry22. Article Science 369, 956 (2020). Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. Internet Explorer). coronavirus, any virus belonging to the family Coronaviridae. Dicks, M. D. J. et al. 888-535-6136. https://doi.org/10.1038/s41591-021-01413-7 (2021). Wiener Klinische Wochenschrift 133, 271283 (2021). Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. They are known to infect the neurological, respiratory, enteric, and hepatic systems. Vaccine 34, 38823893 (2016). Natl Acad. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. 384, 21872201 (2021). SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Sadoff, J. et al. JAMA 325, 12411243 (2021). This classification was based on the following: Detection of cases attributed to Omicron in multiple countries, including among those without travel history. In the course of cellular SARS-CoV-2 infection (Fig. Virus Res. Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines. With this kind of vaccines, the specific design of genetic sequences for the correct formation and presentation of properly folded spike proteins to B cells are in the foreground of interest. Thiagarajan, K. Covid-19: India is at centre of global vaccine manufacturing, but opacity threatens public trust. Eichinger, K. M. et al. 17, 261279 (2018). Prefusion RSV F immunization elicits Th2-mediated lung pathology in mice when formulated with a Th2 (but not a Th1/Th2-balanced) adjuvant despite complete viral protection. Hum. It is therefore a major goal of all COVID-19 vaccines to present the spike and its RBD in a most native conformation for inducing a high proportion of potently neutralizing antibodies after vaccination. Coronaviruses have enveloped virions (virus particles) that measure approximately 120 nm (1 nm = 10 9 metre) in diameter. 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. Xu, C. et al. Our modern-day corona conceptualization of club-shaped spikes on the coronavirus surface comes from traditional representations of crowns as radiate headbands, worn as symbols of sovereign power, to liken that power to that of the sun. Brun, J. et al. Teijaro, J. R. & Farber, D. L. COVID-19 vaccines: modes of immune activation and future challenges. Email COVID19@michigan.gov. In Plotkins Vaccines 7th edn (eds Orenstein, W. A., Offit, P. A. 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. Robbiani, D. F. et al. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. In the CanSino vaccine, the signal peptide of S is replaced by that of human tPA (https://patents.google.com/patent/CN111218459B/en). Ma, J. et al. N. Engl. To obtain SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. 21, 3951 (2021). Release 333, 511520 (2021). Evidence for antibody as a protective correlate for COVID-19 vaccines. Nat. Understanding of COVID-19 is evolving. Vaccine 29, 52035209 (2011). Lancet https://doi.org/10.1016/s0140-6736(21)01462-8 (2021). Article 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. Gao, Q. et al. Lancet 397, 18191819 (2021). Wearing a mask over your mouth and nose helps to stop your water . Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. 13, eabi9915. Tumban, E. Lead SARS-CoV-2 candidate vaccines: expectations from phase III Trials and recommendations post-vaccine approval. 5b). International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Key features of the vaccines discussed in this review are summarized in Table1. The trigger comprises binding of RBD to ACE2 and a further proteolytic cleavage by cellular proteases (in addition to the furin cleavage between S1 and S2) at the so-called S2 site, resulting in the removal of a small sequence element and the exposure of the fusion peptide at the N-terminus of S2 (Fig. Tang, T., Bidon, M., Jaimes, J. The impact of COVID-19 on healthcare-associated infections. Cell 183, 10241042.e1021 (2020). 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. 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. Preprint at https://www.medrxiv.org/content/10.1101/2021.05.07.21256809v1 (2021). ISSN 2059-0105 (online). Haas, E. J. et al. We thank Leonhard Heinz for critically reading the manuscript. volume6, Articlenumber:104 (2021) PubMed & Stiasny, K. Profiles of current COVID-19 vaccines. Cai, Y. et al. Thank you for visiting nature.com. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. In addition, approaches to cope with the problem of the lability of the viral S protein cause variation across all current vaccines. Therefore, it is urgent to know the epidemic . and K.S. Ther.Nucleic Acids 12, 530542 (2018). Khoury, D. S. et al. et al. 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. 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.