At Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant

  1. Nagendrakumar B. Singanallur
  2. Petrus Jansen van Vuren
  3. Alexander J. McAuley
  4. Matthew P. Bruce
  5. Michael J. Kuiper
  6. Stella M. Gwini
  7. Shane Riddell
  8. Sarah Goldie
  9. Trevor W. Drew
  10. Kim R. Blasdell
  11. Mary Tachedjian
  12. Shruthi Mangalaganesh
  13. Simran Chahal
  14. Leon Caly
  15. Julian D. Druce
  16. Jennifer A. Juno
  17. Stephen J. Kent
  18. Adam K. Wheatley
  19. Seshadri S. Vasan

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Abstract

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT 50 ) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.

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  1. Version published to 10.3389/fimmu.2022.883612
  2. Version published to 10.1101/2022.02.20.22271237v3 on medRxiv
  3. Version published to 10.1101/2022.02.20.22271237v2 on medRxiv
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    SciScore for 10.1101/2022.02.20.22271237: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study protocols were approved by institutional ethics committees of the Peter Doherty Institute, Melbourne Australia [University of Melbourne Central Human Research Ethics Committee (2021-21198-15398-3)] and the CSIRO (CSIRO Human Research Ethics Committee ID 2021_123_RR).
    IACUC: Biosafety protocols for handling the human samples and the infectious agents were approved by the Institutional Biosafety Committee of ACDP, Geelong before infectious work commenced.
    Sex as a biological variableHuman Plasma Samples: Blood samples in EDTA blood collection tubes (BD Biosciences, Australia) were collected from healthy volunteers, aged between 25-70 (both female and male), who received COVID-19 vaccine manufactured by either AstraZeneca (Vaxzevria/AZD1222; University of Oxford-AstraZeneca, Oxford/Cambridge, UK), Pfizer (Comirnaty/BNT162b2; BioNTech-Pfizer, Brooklyn, New York, USA), or Moderna (Spikevax/mRNA-1273; Moderna Inc, Cambridge, MA, USA) (Table 1).
    RandomizationSubject identification number was added as a random variable while day post vaccination/booster (as a factor) and vaccine, sex and age groups and the interactions were considered as explanatory variables.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Briefly, VeroE6 cells were grown in 150 cm2 flasks in Dulbecco’s Modified Eagle Medium (DMEM) containing 10% heat-inactivated fetal bovine serum (FBS)
    VeroE6
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Software and Algorithms
    SentencesResources
    2mM GlutaMAX supplement, 100U/mL penicillin, and 100 μg/mL streptomycin (all components from ThermoFisher Scientific; Scoresby, VIC, Australia) until >80% confluent.
    ThermoFisher Scientific
    suggested: None
    Denatured libraries were sequenced on an Illumina MiniSeq using a 300-cycle Mid-Output Reagent kit as per the manufacturer’s protocol.
    MiniSeq
    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:
    Because of the aforementioned limitations, calculation of such fold changes for AstraZeneca and Moderna were not possible. However, it is worthwhile to compare their neutralisation titres two weeks post-second dose relative to the Pfizer vaccine samples. Across all three variants, we did not find any significant difference between Pfizer and Moderna vaccines by 2nd week post second dose of the vaccines (Supplementary Table S1). ANOVA and Linear Mixed Models (lm and lmer) analyses were used to investigate the interactions of age, sex, vaccine, and day post vaccination/booster with neutralising antibody titres to the three different virus variants (Supplementary Text S1). One-way and two-way ANOVA analyses showed that, for all vaccines (Pfizer, Moderna and AstraZeneca), day post vaccination/booster and virus variant were the main contributors to differences in neutralising antibody responses, while age and sex did not have significant effects. Based on ANOVA analysis there was no significant difference in neutralising titres based on age or sex for any of the vaccines (Supplementary Tables S2 & S3; Figure 2A-C). However, based on Linear Mixed Models (lm) analysis, younger individuals tended to have higher neutralising antibody titres (Supplementary Tables S4 & S5; Figure 3A-C). The titres were dependent on the vaccine, day post-vaccination and variant (p<0.001) and to an extent the age where antibody titres in young showed statistically significant difference when compared to t...

    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.
    • Thank you for including a protocol registration statement.

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

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  5. Version published to 10.1101/2022.02.20.22271237v1 on medRxiv