Review Article

Exploring COVID-19: Relating the spike protein to infectivity, pathogenicity and Immunogenicity

Vinod Nikhra*

Published: 27 January, 2021 | Volume 5 - Issue 1 | Pages: 001-010

Introduction: SARS-CoV-2 life cycle: The disease which reportedly began in Chinese city Wuhan in November-December 2019 manifesting as severe respiratory illness, soon spread to various parts of the world, and was named COVID-19, and declared a pandemic by WHO. The life cycle of SARS-CoV-2 begins with membrane fusion mediated by Spike (S) protein binding to the ACE2 receptors. Following viral entry and release of genome into the host cell cytoplasm there occurs replication and transcription to generate viral structural and non-structural proteins. Finally, VLPs are produced and the mature virions are released from the host cell.

Immunogenicity of the spike protein: The S protein is considered the main antigenic component among structural proteins of SARS-CoV-2 and responsible for inducing the host immune response. The neutralising antibodies (nAbs) targeting the S protein are produced and may confer a protective immunity against the viral infection. Further, the role of the S protein in infectivity also makes it an important tool for diagnostic antigen-based testing and vaccine development. The S-specific antibodies, memory B and circulating TFH cells are consistently elicited following SARS-CoV-2 infection, and COVID-19 vaccine shots in clinical trials.

The emerging SARS-CoV-2 variants: The early genomic variations in SARS-CoV-2 have gone almost unnoticed having lacked an impact on disease transmission or its clinical course. Some of the recently discovered mutations, however, have impact on transmissibility, infectivity, or immune response. One such mutation is the D614G variant, which has increased in prevalence to currently become the dominant variant world-over. Another, relatively new variant, named VUI-202012/01 or B.1.1.7 has acquired 17 genomic alterations and carries the risk of enhanced infectivity. Further, its potential impact on vaccine efficacy is a worrisome issue.

Conclusion: THE UNMET CHALLENGES: COVID-19 as a disease and SARS-CoV-2 as its causative organism, continue to remain an enigma. While we continue to explore the agent factors, disease transmission dynamics, pathogenesis and clinical spectrum of the disease, and therapeutic modalities, the grievous nature of the disease has led to emergency authorizations for COVID-19 vaccines in various countries. Further, the virus may continue to persist and afflict for years to come, as future course of the disease is linked to certain unknown factors like effects of seasonality on virus transmission and unpredictable nature of immune response to the disease.

Read Full Article HTML DOI: 10.29328/journal.ijcv.1001029 Cite this Article Read Full Article PDF


ACE2 receptors; COVID-19; Neutralising antibodies; Receptor binding domain; SARS-CoV-2; SNVs; Spike protein; SARS-CoV-2 mutants; D614G; B.1.1.7; VUI-202012/01


  1. Nikhra V. COVID-19 pandemic, recurrent outbreaks, and prospects for assimilation of hCoV-19 into the human genome. Int J Clin Virol. 2020; 4: 111-115. https://www.heighpubs.org/hjcv/ijcv-aid1025.php
  2. Pillay TS. Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein. J Clin Pathol. 2020, 73:7, 366-369. PubMed: https://pubmed.ncbi.nlm.nih.gov/32376714/
  3. Lu R, Zhao X, Li J, Niu P, Yang B, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395: 565–574. PubMed: https://pubmed.ncbi.nlm.nih.gov/32007145/
  4. Ou X, Liu Y, Lei X, Li P, Mi D, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020; 11: 1620. PubMed: https://pubmed.ncbi.nlm.nih.gov/32221306/
  5. Daly JL, Simonetti B, Klein K, Chen K, Williamson MK, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science. 2020; 370: 6518; 861-865. PubMed: https://pubmed.ncbi.nlm.nih.gov/33082294/
  6. Walls AC, Park YJ, Tortorici MA, et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 181: 281–292. PubMed: https://pubmed.ncbi.nlm.nih.gov/32155444/
  7. Huang Y, Yang C, Xu XF, Wall A, McGuire AT, et al. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020; 41: 1141–1149. PubMed:
  8. Wang Y, Liu M, Gao J. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. PNAS. 2020; 117: 13967-13974. PubMed: https://pubmed.ncbi.nlm.nih.gov/32503918/
  9. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, et al. Cryo-Em structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367: 1260-1263. PubMed: https://pubmed.ncbi.nlm.nih.gov/32075877/
  10. Hussain M, Jabeen N, Raza F, Shabbir S, Baig AA, et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J Med Virol. 2020; 92: 1580-1586. PubMed: https://pubmed.ncbi.nlm.nih.gov/32249956/
  11. Yan R, Zhang Y, Li Y, Xia L, Guo Y, et al. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020; 367: 6485: 1444-1448. PubMed: https://pubmed.ncbi.nlm.nih.gov/32132184/
  12. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, et al. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020; 176: 104742. PubMed: https://pubmed.ncbi.nlm.nih.gov/32057769/
  13. Nguyen HL, Lan PD, Thai NQ, Nissley DA, O'Brien EP, et al. Does SARS-CoV-2 Bind to Human ACE2 More Strongly Than Does SARS-CoV? J Phys Chem B. 2020; 124: 7336–7347. PubMed: https://pubmed.ncbi.nlm.nih.gov/32790406/
  14. Hurtley SM. Another host factor for SARS-CoV-2. Science. 2020; 370: 805-807.
  15. Huang Y, Yang C, Xu XF, Xu W, Liu SW, et al. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacologica Sinica. 2020; 41: 1141-1149. PubMed: https://pubmed.ncbi.nlm.nih.gov/32747721/
  16. Yuan M, Wu NC, Zhu X, Lee CD, So RTY, et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020; 368: 630-633. PubMed: https://pubmed.ncbi.nlm.nih.gov/32245784/
  17. Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science. 2020; 369: 806-811. PubMed: https://pubmed.ncbi.nlm.nih.gov/32434945/
  18. Kelly PN. Prototype DNA vaccines for SARS-CoV-2. Science. 2020; 369: 783-785.
  19. Schütz D, Ruiz-Blancob YB, Münch J, Kirchhoff F, Sanchez-Garcia E, et al. Peptide and peptide-based inhibitors of SARS-CoV-2 entry. Adv Drug Deliv Rev. 2020; 167: 47-65. PubMed: https://pubmed.ncbi.nlm.nih.gov/33189768/
  20. Gao Q, Bao L, Mao H, Wang L, Xu K, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020; 369: 77-81. PubMed: https://pubmed.ncbi.nlm.nih.gov/32376603/
  21. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis. 2020; 221: 1762–1769. PubMed: https://pubmed.ncbi.nlm.nih.gov/32227123/
  22. Ni L, Ye F, Cheng ML, Feng Y, Deng YQ, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 2020; 52: 971–977. PubMed: https://pubmed.ncbi.nlm.nih.gov/32413330/
  23. Duan L, Zheng Q, Zhang H, Niu Y, Lou Y, et al. The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens. Front Immunol. 2020; 11:576622. PubMed: https://pubmed.ncbi.nlm.nih.gov/33117378/
  24. Shang J, Wan Y, Luo C, Ye G, Geng Q, et al. Cell entry mechanisms of SARS-CoV-2. PNAS. 2020; 117: 11727-11734. PubMed: https://pubmed.ncbi.nlm.nih.gov/32376634/
  25. Shah VK, Firmal P, Alam A, Ganguly D, Chattopadhyay S. Overview of Immune Response During SARS-CoV-2 Infection: Lessons from the Past. Front Immunol. 2020; PubMed: https://pubmed.ncbi.nlm.nih.gov/32849654/
  26. Juno JA, Tan HX, Lee WS, Reynaldi A, Kelly HG, et al. Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. Nat Med. 2020; 26: 1428–1434. PubMed: https://pubmed.ncbi.nlm.nih.gov/32661393/
  27. Zhao J, Yuan Q, Wang H, Liu W, Liao X, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020; 71: 2027-2034. PubMed: https://pubmed.ncbi.nlm.nih.gov/32221519/
  28. Zhang J, Wu Q, Qu X, Wang Q, Wu J, et al. Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in COVID-19-convalescent individuals. Nat Microbiol. 2020; 6: 51-58. PubMed: https://pubmed.ncbi.nlm.nih.gov/33199863/
  29. Chen G, Wu D, Guo W, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130: 2620–2629. PubMed: https://pubmed.ncbi.nlm.nih.gov/32217835/
  30. Chen X, Li R, Pan Z, Qian C, Yang Y, et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cell Mol Immunol. 2020; 17: 647–649. PubMed: https://pubmed.ncbi.nlm.nih.gov/32313207/
  31. Lumley SF, O’Donnell D, Stoesser NE, et al. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. N Engl J Med. 2020; NEJMoa2034545. PubMed: https://pubmed.ncbi.nlm.nih.gov/33369366/
  32. Klompus S, Leviatan S, Vogl T, et al. Cross-reactive antibody responses against SARS-CoV-2 and seasonal common cold coronaviruses. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. 2020.
  33. Ng KW, Faulkner N, Cornish GH, Rosa A, Harvey R, et al. Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans. Science. 2020; 370: 1339-1343. PubMed: https://pubmed.ncbi.nlm.nih.gov/33159009/
  34. Demers-Mathieu V, Do DM, Mathijssen GB, Sela DA, Seppo A, et al. Difference in levels of SARS-CoV-2 S1 and S2 subunits- and nucleocapsid protein-reactive SIgM/IgM, IgG and SIgA/IgA antibodies in human milk. J Perinatol. 2020; 1-10. PubMed: https://pubmed.ncbi.nlm.nih.gov/32873904/
  35. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020; 181: 281-292. PubMed: https://pubmed.ncbi.nlm.nih.gov/32155444/
  36. Wen J, Cheng Y, Ling R, Dai Y, Huang B, et al. Antibody-dependent enhancement of coronavirus. Int J Infecti Dis. 2020; 100: 483-489. PubMed: https://pubmed.ncbi.nlm.nih.gov/32920233/
  37. Zang J, Gu C, Zhou B, Zhang C, Yang Y, et al. Immunization with the receptor-binding domain of SARS-CoV-2 elicits antibodies cross-neutralizing SARS-CoV-2 and SARS-CoV without antibody-dependent enhancement. Cell Discov. 2020: 6: 61. PubMed: https://pubmed.ncbi.nlm.nih.gov/32901211/
  38. Nikhra V. Stages in COVID-19 vaccine development: The Nemesis, the Hubris, and the Elpis. Int J Clin Virol. 2020; 4: 126-135. https://www.heighpubs.org/hjcv/ijcv-aid1028.php
  39. Flanagan KL, Best E, Crawford NW, Giles M, Koirala A, et al. Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines. Front Immunol. 2020; 11:579250. PubMed: https://pubmed.ncbi.nlm.nih.gov/33123165/
  40. Cai Y, Zhang J, Xiao T, Peng H, Sterling SM, et al. Distinct conformational states of SARS-CoV-2 spike protein. Science. 2020; 369: 1586-1592. PubMed: https://pubmed.ncbi.nlm.nih.gov/32694201/
  41. Duan L, Zheng Q, Zhang H, Niu Y, Lou Y, et al. The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens. Front Immunol. 2020; 11:576622. PubMed: https://pubmed.ncbi.nlm.nih.gov/33117378/
  42. Naqvi AAT, Fatima K, Mohammad T, Fatima U, Singh IK, et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim Biophys Acta Mol Basis Dis. 2020; 1866: 165878. PubMed: https://pubmed.ncbi.nlm.nih.gov/32544429/
  43. Robson F, Khan KS, Le TK, Paris C, Demirbag S, et al. Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting. Mol Cell. 2020; 79: 710-727. PubMed: https://pubmed.ncbi.nlm.nih.gov/32853546/
  44. Andrés C, Garcia-Cehic D, Gregori J, Piñana M, Rodriguez-Frias F, et al. Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients. Emerg Microbes Infect. 2020; 9: 1900-1911. PubMed: https://pubmed.ncbi.nlm.nih.gov/32752979/
  45. Kemp SA, Datir RP, Collier DA, Ferreira IATM, Carabelli A, et al. Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion ΔH69/ΔV70. bioRxiv preprint. 2020.
  46. Wang F, Huang S, Gao R. Zhou Y, Lai C, et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 2020; 6: 83. PubMed: https://pubmed.ncbi.nlm.nih.gov/33298875/
  47. Yang HC, Chen CV, Wang JH, Liao HC, Yang CT, et al. Analysis of genomic distributions of SARS-CoV-2 reveals a dominant strain type with strong allelic associations. PNAS. 2020: 117: 30679-30686. PubMed: https://pubmed.ncbi.nlm.nih.gov/33184173/
  48. Baric RS. Emergence of a Highly Fit SARS-CoV-2 Variant. N Engl J Med. 2020; 383: 2684-2686. PubMed: https://pubmed.ncbi.nlm.nih.gov/33326716/
  49. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, et al. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 Virus. Cell. 2020; 182: 812-827. PubMed: https://pubmed.ncbi.nlm.nih.gov/32697968/
  50. Zhang L, Jackson CB, Mou H, Ojha A, Rangarajan ES, et al. The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. bioRxiv preprint. 2020. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310631/
  51. Zhang L, Jackson CB, Mou H, Ojha A, Rangarajan ES,et al. The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. Preprint. bioRxiv. 2020. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310631/
  52. Plante JA, Liu Y, Liu J, Liu J, Xia H, et al. Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility. Nature. 2020; rs.3.rs-70482. PubMed: https://pubmed.ncbi.nlm.nih.gov/32935091/
  53. Hou YJ, Chiba S, Halfmann P, Ehre C, Kuroda M, et al. SARS-CoV-2 D614G Variant Exhibits Enhanced Replication ex vivo and Earlier Transmission in vivo. Preprint. bioRxiv. 2020; 2020. 09.28.317685. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536872/
  54. Emerging SARS-CoV-2 Variants In UK Like The B.1.1.7 Strain And The 501.V2 Strain In South Africa And Elsewhere Will Change Course Of COVID-19 Badly. 2020. https://www.biogenetech.co.th/wp-content/uploads/2020/12/2-Emerging.pdf
  55. Chand M, Hopkins S, Dabrera G. Investigation of novel SARS-COV-2 variant: Variant of Concern 202012/01 (Report). Public Health England. 2020.
  56. Washington N, White S, Barrett KS. for the Helix Research Team. Is the new SARS-CoV-2 UK variant (B.1.1.7) already in the US? Maybe. CDC on B.1.1.7 mutant. 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-emerging-variant.html
  57. European CDC on B.1.1.7 mutant: https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf
  58. Report Rambaut A, Loman N, Pybus O, et al. on behalf of COVID-19 Genomics Consortium UK (CoG-UK)9. Report – Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563.
  59. Nigeria identifies new variant of COVID-19 in samples collected in August: Report. Devdiscourse News Desk. 2020. https://www.devdiscourse.com/news-source/Devdiscourse%20News%20Desk
  60. Pereira F. Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene. Infect Genet Evol. 2020; 85: 104525. PubMed: https://pubmed.ncbi.nlm.nih.gov/32890763/
  61. Mercatelli D, Giorgi FM. Geographic and Genomic Distribution of SARS-CoV-2 Mutations. Front Microbiol. 2020. PubMed: https://pubmed.ncbi.nlm.nih.gov/32793182/
  62. Zhang L, Jackson CB, Mou H, Ojha A, Peng H, et al. SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat Commun. 2020; 11: 6013. PubMed: https://pubmed.ncbi.nlm.nih.gov/33243994/
  63. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell. 2020; 182: 812-827. PubMed: https://pubmed.ncbi.nlm.nih.gov/32697968/
  64. Poland GA, Ovsyannikova IG, Kennedy RBl. SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates. Lancet. 2020; 396: 1595-1606. PubMed: https://pubmed.ncbi.nlm.nih.gov/33065034/
  65. Florindo HF, Kleiner R, Vaskovich-Koubi D, Acúrcio RC, Carreira B, et al. Immune-mediated approaches against COVID-19. Nat Nanotechnol. 2020; 15: 630–645. PubMed: https://pubmed.ncbi.nlm.nih.gov/32661375/
  66. Tillett RL, Sevinsky JR, Hartley PD, Kerwin H, Crawford N, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. The Lancet Infeft Dis. 2020; 21: 52-58. PubMed: https://pubmed.ncbi.nlm.nih.gov/33058797/
  67. Max Planck Institute for the Science of Human History. COVID-19 is here to stay for the foreseeable future: Future of field-based sciences in the time of coronavirus. ScienceDaily. 2020. www.sciencedaily.com/releases/2020/09/200914112206.htm


Figure 1

Figure 1

Figure 1

Figure 2

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More