The anti-SARS-CoV-2 immunoglobulin G levels and neutralising capacities against alpha and delta virus variants of concern achieved after initial immunisation with vector vaccine followed by mRNA vaccine boost are comparable to those after double immunisation with mRNA vaccines

  1. Ruben Rose
  2. Franziska Neumann
  3. Olaf Grobe
  4. Thomas Lorentz
  5. Helmut Fickenscher
  6. Andi Krumbholz

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Abstract

Background

The humoral immune response after primary immunisation with a SARS-CoV-2 vector vaccine (AstraZeneca AZD1222, ChAdOx1 nCoV-19, Vaxzevria) followed by an mRNA vaccine boost (Pfizer/BioNTech, BNT162b2; Moderna, m-1273) was examined and compared with the antibody response after homologous vaccination schemes (AZD1222/AZD1222 or BNT162b2/BNT162b2).

Methods

Sera from 59 vaccinees were tested for anti-SARS-CoV-2 immunoglobulin G (IgG) and virus-neutralising antibodies (VNA) with four IgG assays, a surrogate neutralisation test (sVNT), and a Vero cell-based neutralisation test (cVNT) using the B.1.1.7 variant of concern (VOC; alpha) as antigen. Investigation was done before and after heterologous (n=31 and 42) or homologous booster vaccination (AZD1222/AZD1222, n=8/9; BNT162b2/BNT162b2, n=8/8). After the second immunisation, 26 age and gender matched sera (AZD1222/mRNA, n=9; AZD1222/AZD1222, n=9; BNT162b2/BNT162b2, n=8) were also tested for VNA against VOC B.1.617.2 (delta) in the cVNT. The strength of IgG binding to separate SARS-CoV-2 antigens was measured by avidity.

Results

After the first vaccination, prevalence of IgG directed against (trimeric) SARS-CoV-2 spike (S)-protein and its receptor-binding domain (RBD) varied from 55-95 % (AZD1222) to 100% (BNT162b2), depending on the vaccine used and the SARS-CoV-2 antigen used. The booster vaccination resulted in 100 percent seroconversion and appearance of highly avid IgG as well as VNA against VOC B.1.1.7. The results of the anti-SARS-CoV-2 IgG tests showed an excellent correlation to the VNA titres against this VOC. The agreement of cVNT and sVNT results was good. However, the sVNT seems to overestimate non and weak B.1.1.7-neutralising titres. The mean anti-SARS-CoV-2 IgG and B.1.1.7-neutralising titres were significantly higher after heterologous vaccination compared to the homologous AZD1222 scheme. If VOC B.1.617.2 was used as antigen, significantly lower mean VNAs were measured in the cVNT, and three (33.3%) vector vaccine recipients had a VNA titre <1:10.

Conclusions

The heterologous SARS-CoV-2 vaccination leads to a strong antibody response with anti-SARS-CoV-2 IgG and VNA titres at a level comparable to that of a homologous BNT162b2 vaccination scheme. Irrespectively of the chosen immunisation regime, highly avid IgG antibodies can be detected just two weeks after the second vaccine dose indicating the development of a robust humoral immunity. The observed reduction in the VNA titre against VOC B.1.617.2 is remarkable and may be attributed to a partial immune escape of the delta variant.

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  1. Version published to 10.1101/2021.07.09.21260251v2 on medRxiv
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    SciScore for 10.1101/2021.07.09.21260251: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Forty-seven female and twelve male vaccinees with a median age of 31 years (age span 18 – 61 years) were recruited for this study and gave their informed consent.
    IRB: The ethics committee of the medical faculty of the Christian-Albrechts-Universität zu Kiel (Kiel, Germany) approved the study design (D467/20, 16.04.2020, amendment 02.02.2021).
    Sex as a biological variableForty-seven female and twelve male vaccinees with a median age of 31 years (age span 18 – 61 years) were recruited for this study and gave their informed consent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The results of the three IgG assays were given in Binding Antibody Units (BAU) per milliliter (BAU / ml), using the manufacturer’s conversion factors, which were based on measurements of the WHO International Standard Anti-SARS-CoV-2 Immunoglobulin (NIBSC code 20-136) [22].
    Anti-SARS-CoV-2
    suggested: None
    Recombinant DNA
    SentencesResources
    The anti-S and anti-RBD IgG response after heterologous immunisation with a SARS-CoV-2 vector vaccine as prime and an mRNA vaccine as boost was compared to that after homologous vaccination with vector or mRNA vaccines.
    SARS-CoV-2
    suggested: RRID:Addgene_164583)
    Software and Algorithms
    SentencesResources
    Anti-SARS-CoV-2 specific IgG immunoassays: The sera were tested with the SERION ELISA agile SARS-COV-2 IgG assay (S-protein as antigen; Institut Virion\Serion GmbH, Würzburg, Germany) and the Abbott SARS-CoV-2 IgG II Quant assay (RBD as antigen; Abbott, Wiesbaden, Germany) as described previously [20].
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Data evaluation and statistical calculations: Data were statistically analysed by help of the GraphPad Prism version 9.1.2 software (GraphPad Software, San Diego, CA, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    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:
    Important limitations of our report are (i) the heterogeneity of the study groups, (ii) the small group size of individuals who received a homologous vaccination scheme, (iii) the subjects, who are predominantly in younger to middle adulthood, (iv) the lack of information on the durability of the detected antibodies, and (v) the missing consideration of cellular and innate immunity after immunisation. Therefore, among other things, no statements can be made from our data about the need for further booster vaccinations. In addition, no better protection against SARS-CoV-2 infections can be derived from the level of the antibody titre per se. In summary, the combination of a first vaccination with a vector vaccine followed by a second administration of an mRNA vaccine leads to a strong humoral immune response, comparable to that achieved after two vaccinations with an mRNA vaccine. Regardless of the vaccination schedule, all individuals develop highly avid anti-SARS-CoV-2 IgGs and VNA shortly after the second vaccination.

    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.

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  3. Version published to 10.1101/2021.07.09.21260251v1 on medRxiv