Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants

Abstract

Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines 1,2 . Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.

References 39

1. 1.

   Carreno, J. M. et al. Activity of convalescent and vaccine serum against a B. 1.1. 529 variant SARS-CoV-2 isolate. Nature10.1038/s41586-022-04399-5 (2021).

   Not in our library10.1038/s41586-022-04399-5

2. 2.
   Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies · 2021

   No notice
3. 3.
   SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion · 2021

   No notice
4. 4.

   Wang G-L, et al. Susceptibility of circulating SARS-CoV-2 variants to neutralization. N. Engl. J. Med. 2021;384:2354-2356.

   Not in our library10.1056/nejmc2103022

5. 5.

   Altmann DM, Boyton RJ, Beale R. Immunity to SARS-CoV-2 variants of concern. Science. 2021;371:1103-1104.

   Not in our library10.1126/science.abg7404

6. 6.

   Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: a new chapter in the COVID-19 pandemic. Lancet. 2021;398:2126-2128.

   Not in our library10.1016/s0140-6736(21)02758-6

7. 7.

   Wang, K. et al. A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2. Preprint at 10.1101/2021.09.02.21261735 (2021).

   Not in our library10.1093/procel/pwae033

8. 8.
   Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study · 2021

   No notice
9. 9.

   Yuan M, et al. Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants. Science. 2021;373:818-823.

   Not in our library10.1126/science.abh1139

10. 10.
    Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant · 2021

    No notice
11. 11.
    Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation · 2021

    No notice
12. 12.

    Mbaeyi S, et al. The Advisory Committee on Immunization Practices’ interim recommendations for additional primary and booster doses of COVID-19 vaccines—United States, 2021. Morb. Mortal. Wkly Rep. 2021;70:1545.

    Not in our library10.15585/mmwr.mm7044e2

13. 13.

    Garcia-Beltran WF, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022;185:457-466.e4.

    Not in our library10.1016/j.cell.2021.12.033

14. 14.
    Development of an inactivated vaccine candidate for SARS-CoV-2 · 2020

    No notice
15. 15.

    SAGE. Interim statement on booster doses for COVID-19 vaccination. WHOhttps://www.who.int/news/item/04-10-2021-interim-statement-on-booster-doses-for-covid-19-vaccination (2021).

    Not in our library

16. 16.

    Wang Z, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature. 2021;592:616-622.

    Not in our library10.1038/s41586-021-03324-6

17. 17.
    Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody · 2020

    No notice
18. 18.

    Yao H, et al. Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection. Cell Res. 2021;31:25-36.

    Not in our library10.1038/s41422-020-00444-y

19. 19.

    Barnes CO, et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature. 2020;588:682-687.

    Not in our library10.1038/s41586-020-2852-1

20. 20.
    The antigenic anatomy of SARS-CoV-2 receptor binding domain · 2021

    No notice
21. 21.

    Tong P, et al. Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike. Cell. 2021;184:4969-4980.e4915.

    Not in our library10.1016/j.cell.2021.07.025

22. 22.
    Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants · 2021

    No notice
23. 23.

    Park Y-J, et al. Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science. 2022;375:449-454.

    Not in our library10.1126/science.abm8143

24. 24.

    Cameroni, E. et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature10.1038/s41586-021-04386-2 (2021).

    Not in our library10.1038/s41586-021-04386-2

25. 25.

    Kathryn, W. et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Preprint at 10.1101/2021.04.30.442182 (2022).

    Not in our library10.1016/j.celrep.2022.110812

26. 26.

    Zhu L, et al. Double lock of a potent human therapeutic monoclonal antibody against SARS-CoV-2. Natl Sci. Rev. 2021;8:nwaa297.

    Not in our library10.1093/nsr/nwaa297

27. 27.
    Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail · 2020

    No notice
28. 28.

    Chen Q, et al. Transient acquisition of cross-species infectivity during the evolution of SARS-CoV-2. Natl Sci. Rev. 2021;8:nwab167.

    Not in our library10.1093/nsr/nwab167

29. 29.

    Bao L, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020;583:830-833.

    Not in our library10.1038/s41586-020-2312-y

30. 30.

    Wilhelm, A. et al. Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies. Preprint at 10.1101/2021.12.07.21267432 (2021).

    Not in our library

31. 31.
    Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection · 2021

    No notice
32. 32.

    Gardner, B. J. & Kilpatrick, A. M. Estimates of reduced vaccine effectiveness against hospitalization, infection, transmission and symptomatic disease of a new SARS-CoV-2 variant, Omicron (B. 1.1. 529), using neutralizing antibody titers. Preprint at 10.1101/2021.12.10.21267594 (2021).

    Not in our library

33. 33.

    Biswas A, Chakrabarti AK, Dutta S. Current challenges: from the path of “original antigenic sin” towards the development of universal flu vaccines: Flu vaccine efficacy encounters significant hurdles from pre-existing immunity of the host suggesting assessment of host immunity before vaccination. Int. Rev. Immunol. 2020;39:21-36.

    Not in our library10.1080/08830185.2019.1685990

34. 34.

    Cui, Z. et al. Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant. Preprint at 10.1101/2021.12.29.474402 (2021).

    Not in our library

35. 35.

    Zhou Y, et al. Enhancement versus neutralization by SARS-CoV-2 antibodies from a convalescent donor associates with distinct epitopes on the RBD. Cell Rep. 2021;34:108699.

    Not in our library10.1016/j.celrep.2021.108699

36. 36.

    Wang N, et al. Structure-based development of human antibody cocktails against SARS-CoV-2. Cell Res. 2021;31:101-103.

    Not in our library10.1038/s41422-020-00446-w

37. 37.
    New tools for automated high-resolution cryo-EM structure determination in RELION-3 · 2018

    No notice
38. 38.

    Punjani A, Rubinstein JL, Fleet DJ, Brubaker M. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods. 2017;14:290-296.

    Not in our library10.1038/nmeth.4169

39. 39.

    Sun Y, et al. Structure-based development of three-and four-antibody cocktails against SARS-CoV-2 via multiple mechanisms. Cell Res. 2021;31:597-600.

    Not in our library10.1038/s41422-021-00497-7

Cited by papers we hold 5

• COVID-19 vaccine update: vaccine effectiveness, SARS-CoV-2 variants, boosters, adverse effects, and immune correlates of protection · 2022
  No notice
• Immunosenescence, aging and successful aging · 2022
  No notice
• Modeling transmission of SARS-CoV-2 Omicron in China · 2022
  No notice
• Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape · 2022
  No notice
• Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution · 2022
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.