Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination

  1. Jinyi Tang
  2. Cong Zeng
  3. Thomas M. Cox
  4. Chaofan Li
  5. Young Min Son
  6. In Su Cheon
  7. Yue Wu
  8. Supriya Behl
  9. Justin J. Taylor
  10. Rana Chakaraborty
  11. Aaron J. Johnson
  12. Dante N. Shiavo
  13. James P. Utz
  14. Janani S. Reisenauer
  15. David E. Midthun
  16. John J. Mullon
  17. Eric S. Edell
  18. Mohamad G. Alameh
  19. Larry Borish
  20. William G. Teague
  21. Mark H. Kaplan
  22. Drew Weissman
  23. Ryan Kern
  24. Haitao Hu
  25. Robert Vassallo
  26. Shan-Lu Liu
  27. Jie Sun

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Abstract

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

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  1. Version published to 10.1126/sciimmunol.add4853
  2. ScreenIT

    SciScore for 10.1101/2022.01.26.22269659: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study cohorts: BAL or blood samples were collected from unvaccinated donors, vaccinated individuals, or SARS-CoV-2 infected individuals at Mayo Clinic under protocols approved by Mayo Clinic Institutional Review Boards (protocol ID 19-012187).
    Consent: Informed consent for the use of BAL, blood and their derivatives for research was obtained from all enrolled individuals.
    Sex as a biological variable8- to 10-week-old female mice were vaccinated with two doses of 1 μg mRNA-S with a 21-day interval.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Binding antibody response against SARS-CoV-2: General ELISA method has been previously described (13).
    SARS-CoV-2
    suggested: None
    Secondary antibodies including anti-human IgG (Sigma-Aldrich,
    anti-human IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The viruses were incubated with plasma or BAL for 1 hour at 37°C, followed by infection of 2×104 pre-seeded HEK293T-ACE2 cells on a 96-well polystyrene tissue culture plate.
    HEK293T-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    Neutralizing titer 50% (NT50) for each sample was determined by non-linear regression with least squares fit in GraphPad Prism 5 (GraphPad Software).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Cell population data were acquired on a multi-spectral flow cytometer Cytek Aurora (Cytek Biosciences) or Attune NxT (Thermo Fisher Science) and analyzed using FlowJo Software (10.8.1
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)

    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: We detected the following sentences addressing limitations in the study:
    Our study has several limitations. Due to the highly invasive nature of the BAL procedure, we were not able to recruit a large cohort of study participants. Furthermore, the study procedure made it challenging to time recruitment or perform a longitudinal analysis; rather it enabled a snapshot of vaccination or infection-induced mucosal immunity. Additionally, most of the participants were older and may not be representative of the entire vaccinated population, although this age group is considered as the primary targeting population for vaccination as they are at highest risk of infection associated with mortality and complications. These limitations need to be addressed by future studies. Nevertheless, we provide key evidence detailing mucosal humoral and cellular immunity following vaccination in the respiratory tract. Our study highlights the importance of focusing on vaccine-induced mucosal immunity (37) and argues for the necessity of a mucosal booster strategy in addition to the current approach of intramuscular COVID-19 vaccines.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

  3. Version published to 10.1101/2022.01.26.22269659v1 on medRxiv