Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study

  1. Marit J. van Gils
  2. Ayesha Lavell
  3. Karlijn van der Straten
  4. Brent Appelman
  5. Ilja Bontjer
  6. Meliawati Poniman
  7. Judith A. Burger
  8. Melissa Oomen
  9. Joey H. Bouhuijs
  10. Lonneke A. van Vught
  11. Marleen A. Slim
  12. Michiel Schinkel
  13. Elke Wynberg
  14. Hugo D. G. van Willigen
  15. Marloes Grobben
  16. Khadija Tejjani
  17. Jacqueline van Rijswijk
  18. Jonne L. Snitselaar
  19. Tom G. Caniels
  20. Amsterdam UMC COVID-19 S3/HCW study group
  21. Alexander P. J. Vlaar
  22. Maria Prins
  23. Menno D. de Jong
  24. Godelieve J. de Bree
  25. Jonne J. Sikkens
  26. Marije K. Bomers
  27. Rogier W. Sanders

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Abstract

Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.

Methods and findings

In a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231–556] and 214 [95% CI 153–299], respectively; p<0.05), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 18 [95% CI 11–30] and 14 [95% CI 8–25] IU/ml, respectively; p<0.001). VOCs neutralization was reduced in all vaccine groups, with the greatest reduction in neutralization GMT observed against the Omicron variant (fold change 0.03 [95% CI 0.02–0.04], p<0.001). The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. We used linear regression and linear mixed model analysis. All results were adjusted for possible confounding of age and sex. Study limitations include the lack of cellular immunity data.

Conclusions

Overall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination.

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  1. Version published to 10.1371/journal.pmed.1003991
  2. Version published to 10.1101/2021.09.27.21264163v3 on medRxiv
  3. Version published to 10.1101/2021.09.27.21264163v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.09.27.21264163: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The S3 study, the COSCA study and the RECoVERED study were approved by the medical ethical review board of the Amsterdam University Medical Centers (
    Consent: All participants provided written informed consent.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    All S constructs were verified by Sanger sequencing and subsequently produced in HEK293F cells (ThermoFisher) and purified as previously described22.
    HEK293F
    suggested: None
    Pseudoviruses were produced by co-transfecting the SARS-CoV-2-S expression plasmid with the pHIV-1NL43 ΔEnv-NanoLuc reporter virus plasmid in HEK293T cells (ATCC, CRL-11268), as previously described48.
    HEK293T
    suggested: ATCC Cat# CRL-11268, RRID:CVCL_1926)
    Shortly, HEK293T/ACE2 cells, kindly provided by Dr. Paul Bieniasz48, were seeded at a density of 20,000 cells/well in a 96-well plate coated with 50 μg/mL poly-L-lysine one day prior to the start of the neutralization assay.
    HEK293T/ACE2
    suggested: None
    Recombinant DNA
    SentencesResources
    They were ordered as gBlock gene fragments (Integrated DNA Technologies) and cloned in a pPPI4 expression vector containing a hexahistidine (his) tag with Gibson Assembly (ThermoFisher)22.
    pPPI4
    suggested: None
    Pseudovirus construction: The WT, D614G, Alpha, Alpha E484K, Beta and Gamma pseudovirus S constructs were ordered as gBlock gene fragments (Integrated DNA Technologies) and cloned using SacI and ApaI in the pCR3 SARS-CoV-2-SΔ19 expression plasmid48 using Gibson Assembly (ThermoFisher)c
    pCR3
    suggested: None
    Pseudoviruses were produced by co-transfecting the SARS-CoV-2-S expression plasmid with the pHIV-1NL43 ΔEnv-NanoLuc reporter virus plasmid in HEK293T cells (ATCC, CRL-11268), as previously described48.
    pHIV-1NL43 ΔEnv-NanoLuc
    suggested: None
    Software and Algorithms
    SentencesResources
    The inhibitory concentration (IC50) and neutralization titers (ID50) were determined as the NAb concentration and serum dilution at which infectivity was inhibited by 50%, respectively, using a non-linear regression curve fit (GraphPad Prism software version 8.3).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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 are several limitations of our study. First, our study includes substantially more female than male participants, reflecting the gender distribution among HCW at our institute. Second, the age distribution in the four groups is not identical. In particular, the AZD1222 group is, on average, considerably older as a consequence of restrictive use of the AZD1222 vaccine in individuals aged 60-64 years in the Netherlands. As immune responses tend to become weaker with higher age, this is a relevant factor when considering the weaker responses in the AZD1222 group. Finally, the samples we tested were taken at the expected peak of immunity. It will be relevant to study the durability of the neutralizing antibody responses after vaccination with each of these vaccines. Some studies suggest that immunity induced by adenovirus vaccines might be more durable than immunity from mRNA vaccines8,45. We have only analyzed known VOCs and VOIs and cannot predict how our results apply to future variants. One consideration is that current VOCs were probably selected based on increased fitness and/or transmissibility, while future variants may very well be selected based on escape from immunity when more and more people are vaccinated or have experienced COVD-19. Such escape variants may be more resistant to neutralizing antibodies induced by current vaccines than the VOCs and VOIs studied here and may render vaccines even less effective at preventing infection. However, while circulating ...

    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.

    About SciScore

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  5. Version published to 10.1101/2021.09.27.21264163v1 on medRxiv