Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination

  1. Rahul K. Suryawanshi
  2. Irene P. Chen
  3. Tongcui Ma
  4. Abdullah M. Syed
  5. Noah Brazer
  6. Prachi Saldhi
  7. Camille R. Simoneau
  8. Alison Ciling
  9. Mir M. Khalid
  10. Bharath Sreekumar
  11. Pei-Yi Chen
  12. G. Renuka Kumar
  13. Mauricio Montano
  14. Ronne Gascon
  15. Chia-Lin Tsou
  16. Miguel A. Garcia-Knight
  17. Alicia Sotomayor-Gonzalez
  18. Venice Servellita
  19. Amelia Gliwa
  20. Jenny Nguyen
  21. Ines Silva
  22. Bilal Milbes
  23. Noah Kojima
  24. Victoria Hess
  25. Maria Shacreaw
  26. Lauren Lopez
  27. Matthew Brobeck
  28. Fred Turner
  29. Frank W. Soveg
  30. Ashley F. George
  31. Xiaohui Fang
  32. Mazharul Maishan
  33. Michael Matthay
  34. Mary Kate Morris
  35. Debra Wadford
  36. Carl Hanson
  37. Warner C. Greene
  38. Raul Andino
  39. Lee Spraggon
  40. Nadia R. Roan
  41. Charles Y. Chiu
  42. Jennifer A. Doudna
  43. Melanie Ott

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Abstract

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals 1,2 . The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

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  1. Version published to 10.1038/s41586-022-04865-0
  2. Version published to 10.1101/2022.01.13.22269243v3 on medRxiv
  3. Version published to 10.1101/2022.01.13.22269243v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2022.01.13.22269243: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIACUC: K18-hACE2 mouse infection model: All protocols concerning animal use were approved (AN169239-01A) by the Institutional Animal Care and Use committees at the University of California, San Francisco and Gladstone Institutes and conducted in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animal (Council, 2011).
    Consent: Remnant samples were aliquoted and biobanked and retrospective medical chart review for relevant demographic and clinical metadata were performed under a waiver of consent and according to “no subject contact” protocols approved by the UCSF Institutional Review Board (protocol number 10-01116).
    IRB: Remnant samples were aliquoted and biobanked and retrospective medical chart review for relevant demographic and clinical metadata were performed under a waiver of consent and according to “no subject contact” protocols approved by the UCSF Institutional Review Board (protocol number 10-01116).
    Field Sample Permit: Plasma samples were also collected through the UMPIRE (UCSF EMPloyee and community member Immune REsponse) study (protocol number 20-33083), a longitudinal COVID-19 research study focused on collection of prospective whole blood and plasma samples from enrolled subjects to evaluating the immune response to vaccination, with and without boosting, and/or vaccine breakthrough infection.
    Sex as a biological variableBriefly, the study involved intranasal infection of 6-8-week-old female K18-hACE2 mice with B.1.617.2 and B.1.1.529, while WA1 served as a control strain of SARS-CoV-2.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    A549 cells expressing ACE2 (A549-ACE2) and Vero cells expressing TMPRSS (Vero-TMPRSS2) were a gift from O. Schwartz and S.P.J. Whelan, respectively.
    A549
    suggested: None
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    A549-ACE2 and Vero-TMPRSS2 cells were cultured in DMEM supplemented with 10% FBS and blasticidin (20ug/ml) (Sigma) at 37°C and 5% CO2.
    Vero-TMPRSS2
    suggested: JCRB Cat# JCRB1818, RRID:CVCL_YQ48)
    Vero stably co-expressing human ACE2 and TMPRSS2 cells (gifted from A. Creanga and B. Graham at NIH) were maintained at 37°C and 5% CO2 in Dulbecco’s Modified Eagle medium (DMEM; Gibco) supplemented with 10% fetal calf serum, 100ug/mL penicillin and streptomycin (Gibco) and 10μg/mL of puromycin (Gibco).
    TMPRSS2
    suggested: None
    293T cells stably co-expressing ACE2 and TMPRSS2 were generated through sequential transduction of 293T cells with TMPRSS2-encoding (generated using Addgene plasmid #170390, a gift from Nir Hacohen and ACE2-encoding (generated using Addgene plasmid #154981, a gift from Sonja Best) lentiviruses and selection with hygromycin (250 µg/mL) and blasticidin (10 µg/mL) for 10 days, respectively.
    293T
    suggested: None
    A 100 uL of freshly trypsinized Vero-hACE2-TMPRSS2 cells, resuspended in infection media (made as above but with 2x penicillin/streptomycin, 5ug/mL amphotericin B [Bioworld] and no puromycin) were added to the nasal sample dilutions at 2.5×105 cells/mL concentration.
    Vero-hACE2-TMPRSS2
    suggested: None
    Cellular infection studies: A549-ACE2 cells were seeded into 12-well plates.
    A549-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    For data analysis, CyTOF datasets were normalized to EQ calibration and manually gated using the FlowJO software (BD Biosciences)
    FlowJO
    suggested: (FlowJo, RRID:SCR_008520)
    tSNE visualizations of the datasets were performed in Cytobank, with default settings.
    Cytobank
    suggested: (Cytobank, RRID:SCR_014043)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT05171803RecruitingInvestigating Immune Escape by SARS-CoV-2 Variants

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/5880034.

    In this preprint study, Suryawanshi et al., have made significant advances in assessing various immunity responses to COVID-19 strains. They review three COVID-19 variant infections in mice and track the inflammatory and innate immunity response to the strains. The mice sera were then crossed with the other COVID-19 variants to assess their neutralization efficacies. The Delta strain had the broadest neutralization against the other strains, including Omicron. When transitioned to human sera of vaccinated or previously infected individuals, the overarching result was that sera from vaccinated individuals who had an Omicron breakthrough infection had the highest level of protection from all other variants despite the Omicron infection producing negligible immunity in non-vaccinated exposed sera. This led the authors to conclude that Omicron infection in vaccinated individuals boosted immune response to infection against other variants. 

     

    I would firstly like to commend the authors for their astutely relevant work on this study. I found this preprint important not only for furthering multivalent vaccine development for broad COVID-19 protection but also because there's currently controversy with acquiring an Omicron infection as reason for vaccine hesitancy amongst the general public. Furthermore, this preprint may have contradicting evidence to a claim made in a recent publication that states the Delta variant does not elicit cross-variant neutralization for Omicron.

     

    One minor concern would be that the authors do not seem confident the strain the convalescent sera were exposed to was in fact Delta. It therefore makes me question whether or not the inability to confirm the antibodies that the convalescent sera contain would have an effect on the results. 

     

    I highly look forward to reading subsequent versions of this paper.

  6. Version published to 10.1101/2022.01.13.22269243v1 on medRxiv