Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review

  1. Julie Perry
  2. Selma Osman
  3. James Wright
  4. Melissa Richard-Greenblatt
  5. Sarah A. Buchan
  6. Manish Sadarangani
  7. Shelly Bolotin

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Abstract

A correlate of protection (CoP) is an immunological marker associated with protection against infection. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined.

Objectives

Our objective was to review the evidence for a humoral correlate of protection for SARS-CoV-2, including variants of concern.

Methods

We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment.

Results

Twenty-five studies were included in our systematic review. Two studies examined the correlation of antibody levels to VE, and reported values from 48.5% to 94.2%. Similarly, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, suggesting that both humoral immunity and other immune components contribute to protection. However, individual level data suggest infection can still occur in the presence of high levels of antibodies. Two studies estimated a quantitative CoP: for Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. No studies have yet reported an Omicron-specific CoP.

Conclusions

Our review suggests that a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.

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  1. Version published to 10.1371/journal.pone.0266852
  2. ScreenIT

    SciScore for 10.1101/2022.01.21.22269667: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Studies passed title and abstract screening if their abstracts discussed re-infection with SARS-CoV-2 or breakthrough infection following vaccination with COVID-19 vaccine; mentioned antibody measures specific to SARS-CoV-2; or mentioned a correlate or threshold of protection against SARS-CoV-2.
    SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    Data Sources and Searches: We searched the OVID MEDLINE database for peer-reviewed articles published from database inception to December 31, 2021, and the EMBASE, Global Health, Biosis Previews and Scopus databases from inception to January 4, 2022.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    We extracted data from figures using WebPlotDigitizer (18).
    WebPlotDigitizer
    suggested: (WebPlotDigitizer, RRID:SCR_013996)

    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:
    There were several limitations to the available literature for this systematic review. Many studies did not meet our inclusion criteria and pre-set definitions, which were designed to minimize bias. Our review included many different study types, including several case-reports, which generally provide a lower level of evidence and are particularly prone to bias (61, 62). There was heterogeneity in the targets that were measured, including neutralizing antibodies or antibody isotypes directed against spike (whole Spike, S1, receptor binding domain) or nucleocapsid protein. The included studies used different laboratory assays, which were generally not comparable. The WHO IS was seldom used, likely because it was not made available until late 2020. The diversity of laboratory assays and results precluded a meta-analysis of our data. To overcome the lack of calibration between laboratory assays, some studies normalized results against convalescent sera. However, since the humoral immune response to natural infection varies by age and disease severity (63), this method is not ideal for calibrating results. Most studies did not report which SARS-CoV-2 lineage was associated with the breakthrough or re-infection, with only a few studies reporting antibody levels preceding infection with a VOC. With the emergence of Omicron (B.1.1.529), the lack of Omicron-specific serological data prior to re-infection or breakthrough is unfortunate. Evidence based on in vitro neutralization assays...

    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 10.1101/2022.01.21.22269667v1 on medRxiv