Humoral Immunity to SARS-CoV-2 and Inferred Protection from Infection in a French Longitudinal Community Cohort

  1. Tom Woudenberg
  2. Laurie Pinaud
  3. Laura Garcia
  4. Laura Tondeur
  5. Stéphane Pelleau
  6. Alix De Thoisy
  7. Françoise Donnadieu
  8. Marija Backovic
  9. Mikaël Attia
  10. Nathanael Hozé
  11. Cécile Duru
  12. Aymar Davy Koffi
  13. Sandrine Castelain
  14. Marie-Noelle Ungeheuer
  15. Sandrine Fernandes Pellerin
  16. Delphine Planas
  17. Timothée Bruel
  18. Simon Cauchemez
  19. Olivier Schwartz
  20. Arnaud Fontanet
  21. Michael White

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Abstract

Population-level immunity to SARS-CoV-2 is growing through vaccination as well as ongoing circulation. Given waning immunity and emergence of new variants, it is important to dynamically determine the risk of re-infection in the population. For estimating immune protection, neutralization titers are most informative, but these assays are difficult to conduct at a population level. Measurement of antibody levels can be implemented at high throughput, but has not been robustly validated as a correlate of protection. Here, we have developed a method that predicts neutralization and protection based on variant-specific antibody measurements to SARS-CoV-2 antigens. This approach allowed us to estimate population-immunity in a longitudinal cohort from France followed for up to 2 years. Participants with a single vaccination or immunity caused by infection only are especially vulnerable to COVID-19 or hospitalization due to SARS-CoV-2. While the median reduced risk to COVID-19 in participants with 3 vaccinations was 96%, the median reduced risk among participants with infection-acquired immunity only was 42%. The results presented here are consistent with data from vaccine-effectiveness studies indicating robustness of our approach. Our multiplex serological assay can be readily optimized and employed to study any new variant and provides a framework for development of an assay that would include protection estimates.

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    SciScore for 10.1101/2022.05.23.22275460: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: Ethics: Collection of samples from the Orleans cohort had been approved by the Comité de Protection des Personnes Ile de France IV (NCT04750720).
    IRB: Collection of samples from the Strasbourg cohort was approved by Institutional Review Board of Strasbourg University Hospital (NCT04441684).
    Consent: Informed consent was obtained from all participants, and parents provided informed consent for any children under the age of 18 years.
    Sex as a biological variablenot detected.
    RandomizationThe antigen associated with the lowest sum of residual sum of squares among the four different variant-specific random forest regression models was kept in the model.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationContamination: Cells tested negative for mycoplasma.

    Table 2: Resources

    Antibodies
    SentencesResources
    Samples: Viral neutralization studies: To correlate antibody measurements with neutralization titers, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired immunity to SARS-CoV-2.
    SARS-CoV-2
    suggested: None
    R-PE) conjugated goat or donkey anti-human IgG antibody was used as detector antibody at 1/120 dilution and goat anti-human IgA at 1/200.
    anti-human IgG
    suggested: None
    anti-human IgA
    suggested: None
    This assay allowed simultaneous detection of antibodies to 30 antigens, including stabilized trimeric Spike ectodomain (16), RBD, Membrane protein (M), Membrane Envelope protein (E), Nucleocapsid protein (NP), and a Membrane-Envelope fusion protein (ME).
    RBD , Membrane protein ( M) , Membrane Envelope protein ( E) , Nucleocapsid protein ( NP) ,
    suggested: None
    In addition to the measurement of the presence of antibodies to antigens, we also measured the strength of antibody (Ab) binding with an avidity assay (Garcia et al, submitted to Viruses, 2022).
    antigens
    suggested: None
    After these 5 minutes and washing, 100μL of secondary antibodies conjugated to R-phycoerythrin (Jackson Immunoresearch) for detection of specific IgG, diluted at 1/100 was added for 15 minutes.
    R-phycoerythrin
    suggested: None
    Briefly, Nucleocapsid-specific IgG antibodies were assessed using an ELISA-based assays on sera incubated in antigen-coated wells.
    Nucleocapsid-specific IgG
    suggested: None
    The Anti-Fc IgG VHH (Fc1) was derived from an antibody from immunized alpaca and expressed as a tandem with an optimized catalytic domain nanoKAZ from Oplophorous gracilirostris luciferase.
    Anti-Fc IgG
    suggested: None

    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:
    A limitation of our study was that we assessed levels of immunity from serum only. There is clearly also a role for mucosal immunity in protecting against SARS-CoV-2 infection, especially in the case of infection-acquired immunity. For the last three session in our study we collected nasopharyngeal samples, which we plan to incorporate in future research. Our analysis is dependent on the suitability of neutralizing titers as a correlate of protection against symptomatic COVID-19, based on meta-analyses of vaccine studies (7, 8). This assumption is supported by an analysis of data from phase 3 trials of Moderna’s mRNA-1273 vaccine, which indicated that 68% of vaccine efficacy can be explained by neutralizing titers (31). This leaves up to 32% variation that may be explained by other effects such as cellular immunity or host factors. An additional limitation is that the evidence base for neutralizing titers as a correlate of protection is built on studies of infection with the Ancestral variant. However, antibody levels have been observed to be associated with reduced infection with other variants, most notably Delta (32). Although neutralizing titers have frequently been shown to be associated with protection against severe COVID-19 (7-9), there is a weaker evidence base for their use as a correlate of protection. A final, important limitation is that there is uncertainty in the statistical relationships utilized in this analysis. When considering the inferred protection from ...

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

    IdentifierStatusTitle
    NCT04750720RecruitingStudy of the Kinetics of COVID-19 Antibodies for 24 Months i…
    NCT04441684CompletedSeroprevalence of SARS-CoV-2 in Strasbourg University Hospit…
    NCT04644159RecruitingLongitudinal Follow-up of a Population Cohort in a French Ci…
    NCT04325646RecruitingSero-epidemiological Study of the SARS-CoV-2 Virus Responsib…

    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

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  2. Version published to 10.1101/2022.05.23.22275460v1 on medRxiv