Neutralization heterogeneity of circulating SARS-CoV-2 variants to sera elicited by a vaccinee or convalescent
Abstract
COVID-19, which was first reported in December 2019 in China, has caused a global outbreak. Five variants of concern (VOCs) have been identified in different countries since the global pandemic, namely, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.529). Although multiple vaccines have been found to be effective, some of the amino acid changes may increase the infectivity of virus and decrease the sensitivity to antibodies. Here we characterize the VOCs and discuss their sensitivity to antibodies elicited by convalescent and vaccinee sera. In conclusion, several variants display a reduction in the susceptibility to neutralization antibodies generated by natural infection or vaccination, which threatens the containment of the epidemic.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5(4), 536–544 (2020).
- 2. A new coronavirus associated with human respiratory disease in China. Nature 579(7798), 265–269 (2020).
- 3. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798), 270–273 (2020).
- 4. . Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus. Virus Res. 194, 90–99 (2014).
- 5. . Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 9(8), e1003565 (2013).
- 6. . Why are RNA virus mutation rates so damn high? PLoS Biol. 16(8), e3000003 (2018).
- 7. . Quasispecies theory and the behavior of RNA viruses. PLoS Pathog. 6(7), e1001005 (2010).
- 8. . Maximum daily temperature, precipitation, ultraviolet light, and rates of transmission of severe acute respiratory syndrome coronavirus 2 in the United States. Clin. Infect. Dis. 71(9), 2482–2487 (2020).
- 9. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Virological (2020). 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
- 10. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv
doi: https://doi.org/10.1101/2020.12.21.20248640 (2020) (Epub ahead of print). - 11. Genomic characterisation of an emergent SARS-CoV-2 lineage in manaus: preliminary findings. Virological (2021). https://virological.org/t/genomic-characterisation-of-an-emergent-SARS-CoV-2-lineage-in-manaus-preliminary-findings/586
- 12. World Health Organization. Tracking SARS-CoV-2 variants (2021). https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ • Information of new SARS-CoV-2 variants could be traced from the WHO website.
- 13. . The Architecture of SARS-CoV-2 Transcriptome. Cell 181(4), 914–921 (2020).
- 14. Molecular Architecture of the SARS-CoV-2 Virus. Cell 183(3), 730–738 (2020).
- 15. . Coronaviridae. In Fields Virology (5th Edition). Knipe DMHowley PM (Eds). Lippincott Williams & Wilkins, PA, USA, 1306–1335 (2007).
- 16. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181(4), 894–904 (2020).
- 17. . Potential for developing a SARS-CoV receptor-binding domain (RBD) recombinant protein as a heterologous human vaccine against coronavirus infectious disease (COVID)-19. Hum. Vaccin. Immunother. 16(6), 1239–1242 (2020).
- 18. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368(6491), 630–633 (2020).
- 19. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 369(6504), 650–655 (2020). •• It described the neutralization activity of 4A8 and pointed that antibodies-targeting N-terminal domain (NTD) may also important to the preventation or therapeutic of SARS-CoV-2.
- 20. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593(7857), 130–135 (2021). • It reported the reduced susceptibility of Alpha and Beta to antibodies against the receptor-binding domain and N-terminal domain. In addition, it pointed out that Beta may be more worrisome when compared with Alpha.
- 21. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2. Cell 184(15), 3936–3948 (2021).
- 22. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc. Natl Acad. Sci. USA 111(19), 2018–2026 (2014).
- 23. Broadening of neutralization activity to directly block a dominant antibody-driven SARS-coronavirus evolution pathway. PLoS Pathog. 4(11), e1000197 (2008).
- 24. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 3(7), e237 (2006).
- 25. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell 182(4), 812–827 (2020). •• It reported the emergence of D614G variant and pointed that it increased the transmissibility of SARS-CoV-2.
- 26. A unique clade of SARS-CoV-2 viruses is associated with lower viral loads in patient upper airways. medRxiv
doi: 10.1101/2020.05.19.20107144 (2020) (Epub ahead of print). - 27. Comparing viral load and clinical outcomes in Washington State across D 614G mutation in Spike protein of SARS-CoV-2 (2020). https://github.com/blab/ncov-wa-d614g/blob/39f87ba09a8e9ad1789052039f8602a445364b9e/README.md
- 28. SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat. Commun. 11(1), 6013 (2020).
- 29. The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types. Elife 10, e65365 (2021).
- 30. SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nat. Commun. 12(1), 848 (2021).
- 31. Neutralization of viruses with European, South African, and United States SARS-CoV-2 variant spike proteins by convalescent sera and BNT162b2 mRNA vaccine-elicited antibodies. bioRxiv
doi: 10.1101/2021.02.05.430003 (2021). - 32. . Emergence of a Highly Fit SARS-CoV-2 Variant. N. Engl. J. Med. 383(27), 2684–2686 (2020).
- 33. Susceptibility of circulating SARS-CoV-2 variants to neutralization. N. Engl. J. Med. 384(24), 2354–2356 (2021).
- 34. Public Health England. Investigation of novel SARS-CoV-2 variant. variant of concern 202012/01: technical briefing. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/959360/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3.pdf
- 35. Estimated transmissibility and severity of novel SARS-CoV-2 variant of concern 202012/01 in England. medRxiv
doi: https://doi.org/10.1101/2020.12.24.20248822 (2021) (Epub ahead of print). - 36. . SARS-CoV-2 B.1.1.7 and B.1.351 spike variants bind human ACE2 with increased affinity. bioRxiv
doi: 10.1101/2021.02.22.432359 (2021) (Epub ahead of print). - 37. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 369(6511), 1603–1607 (2020).
- 38. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell 182(5), 1295–1310 (2020).
- 39. . A multibasic cleavage site in the spike protein of SARS-CoV-2 Is essential for infection of human lung cells. Mol. Cell 78(4), 779–784 (2020).
- 40. . The furin cleavage site of SARS-CoV-2 spike protein is a key determinant for transmission due to enhanced replication in airway cells. bioRxiv
doi: https://doi.org/10.1101/2020.09.30.318311 (2020) (Epub ahead of print). - 41. Neutralising antibodies in spike mediated SARS-CoV-2 adaptation. medRxiv
doi: https://doi.org/10.1101/2020.12.05.20241927 (2020) (Epub ahead of print). - 42. . Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 372, n579 (2021).
- 43. . Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature 593(7858), 270–274 (2021). • It is the first article which reported the Alpha variant causes increasing mortality.
- 44. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581(7807), 215–220 (2020).
- 45. . Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc. Natl Acad. Sci. USA 117(25), 13967–13974 (2020).
- 46. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. Centre for Mathematical Modelling of Infectious Diseases (2021). https://cmmid.github.io/topics/covid19/sa-novel-variant.html
- 47. Phylogenetic relationship of SARS-CoV-2 sequences from Amazonas with emerging Brazilian variants harboring mutations E484K and N501Y in spike protein. Virological (2021). https://virological.org/t/phylogenetic-relationship-of-SARS-CoV-2-sequences-from-amazonas-with-emerging-brazilian-variants-harboring-mutations-e484k-and-n501y-in-the-spike-protein/585
- 48. Circulating SARS-CoV-2 variants B.1.1.7, 501Y.V2, and P.1 have gained ability to utilize rat and mouse Ace2 and altered in vitro sensitivity to neutralizing antibodies and ACE2-Ig. bioRxiv
doi: https://doi.org/10.1101/2021.01.27.428353 (2021) (Epub ahead of print). - 49. . Mutations Strengthened SARS-CoV-2 Infectivity. J. Mol. Biol. 432(19), 5212–5226 (2020).
- 50. Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-CoV-2 variants. bioRxiv
doi: https://doi.org/10.1101/2021.02.22.432189 (2021) (Epub ahead of print). - 51. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe 29(3), 463–476 (2021).
- 52. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 182(5), 1284–1294 (2020).
- 53. Viral infection and transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant. medRxiv
doi: https://doi.org/10.1101/2021.07.07.21260122 (2021) (Epub ahead of print). - 54. The Delta variant of SARS-CoV-2 maintains high sensitivity to interferons in human lung cells. bioRxiv
doi: https://doi.org/10.1101/2021.11.16.468777 (2021) (Epub ahead of print). - 55. Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose. Lancet 399(10325), 625–6263 (2022).
- 56. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384(5), 403–416 (2021).
- 57. Safety and Efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 383(27), 2603–2615 (2020).
- 58. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 369(6499), 77–81 (2020).
- 59. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell 182(3), 713–721 (2020).
- 60. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect. Dis. 21(1), 39–51 (2021).
- 61. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397(10275), 671–681 (2021). •• It reported the effectiveness of heterologous prime-boost COVID-19 vaccines.
- 62. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397(10269), 99–111 (2021).
- 63. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nat. Commun. 11(1), 4081 (2020).
- 64. The establishment of reference sequence for SARS-CoV-2 and variation analysis. J. Med. Virol. 92(6), 667–674 (2020).
- 65. Neutralization heterogeneity of United Kingdom and South-African SARS-CoV-2 variants in BNT162b2-vaccinated or convalescent COVID-19 healthcare workers. bioRxiv
doi: https://doi.org/10.1101/2021.03.05.434089 (2021) (Epub ahead of print). - 66. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies. Nat. Med. 27(5), 917–924 (2021).
- 67. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines. Cell Host Microbe 29(4), 529–539 (2021).
- 68. Infection and mRNA-1273 vaccine antibodies neutralize SARS-CoV-2 UK variant. medRxiv
doi: https://doi.org/10.1101/2021.02.02.21250799 (2021) (Epub ahead of print). - 69. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine–elicited human sera. Science 371(6534), 1152–1153 (2021).
- 70. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv
doi: https://doi.org/10.1101/2021.01.25.427948 (2021) (Epub ahead of print). - 71. . Novavax covid vaccine protects people against variants. Nature 590(7844), 17 (2021).
- 72. Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant. bioRxiv
doi: https://doi.org/10.1101/2021.02.20.432046 (2021) (Epub ahead of print). - 73. . E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: binding free energy calculation studies. bioRxiv
doi: https://doi.org/10.1101/2021.02.17.431566 (2021) (Epub ahead of print). - 74. Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization. bioRxiv
doi: https://doi.org/10.1101/2021.03.01.433466 (2021) (Epub ahead of print). - 75. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 29(3), 477–488 (2021).
- 76. Efficacy and safety of a COVID-19 inactivated vaccine in healthcare professionals in Brazil: the PROFISCOV study. http://dx.doi.org/10.2139/ssrn.3822780 (2021).
- 77. . Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review. Clin. Microbiol. Infect. 28(2), 202–221 (2021).
- 78. Effectiveness of COVID-19 vaccines against the B.1.617.2 (Delta) variant. N. Engl. J. Med. 385(7), 585–594 (2021). • Found that both BNT162b2 and ChAdOx1vaccines were less effective against the delta variant than against the B.1.1.7 (Alpha) variant.
- 79. Comparison of neutralizing antibody titers elicited by mRNA and adenoviral vector vaccine against SARS-CoV-2 variants. bioRxiv
doi: https://doi.org/10.1101/2021.07.19.452771 (2021) (Epub ahead of print). - 80. Infection and vaccine-induced neutralizing-antibody responses to the SARS-CoV-2 B.1.617 variants. N. Engl. J. Med. 385(7), 664–666 (2021). •• It reported that the circulating Delta variant was less susceptible to the serum from convalescent and two mRNA vaccinees.
- 81. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell 184(16), 4220–4236 (2021).
- 82. . Effectiveness of BNT162b2 vaccine against omicron variant in South Africa. N. Engl. J. Med. 386(5), 494–496 (2021).
- 83. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. bioRxiv
doi: https://doi.org/10.1101/2021.12.12.472269 (2021) (Epub ahead of print). - 84. Booster of mRNA-1273 strengthens SARS-CoV-2 omicron neutralization. medRxiv
doi: https://doi.org/10.1101/2021.12.15.21267805 (2021) (Epub ahead of print). - 85. Waning immune humoral response to BNT162b2 COVID-19 vaccine over 6 months. N. Engl. J. Med. 385(24), e84 (2021).
- 86. Heterologous SARS-CoV-2 booster vaccinations – preliminary report. medRxiv
doi: https://doi.org/10.1101/2021.10.10.21264827 (2021) (Epub ahead of print). - 87. The effects of heterologous immunization with prime-boost COVID-19 vaccination against SARS-CoV-2. Vaccines (Basel) 9(10), 1163 (2021).
- 88. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 184(9), 2372–2383 (2021).
- 89. Efficacy of the ChAdOx1 nCoV-19 COVID-19 vaccine against the B.1.351 variant. N. Engl. J. Med. 384(20), 1885–1898 (2021).
- 90. 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. Lancet 397(10282), 1351–1362 (2021).
- 91. . Vaccine efficacy in mutant SARS-CoV-2 variants. Int. J. Cell. Biol. Physiol. 4(1–2), 1–12 (2021).