Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity against prevalent SARS-CoV-2 variants

Rüdiger Groß, Michelle Zanoni, Alina Seidel, Carina Conzelmann, Andrea Gilg, Daniela Krnavek, Sümeyye Erdemci-Evin, Benjamin Mayer, Markus Hoffmann, Stefan Pöhlmann, Weimin Liu, Beatrice H Hahn, Alexandra Beil, Joris Kroschel, Bernd Jahrsdörfer, Hubert Schrezenmeier, Frank Kirchhoff, Jan Münch, Janis A Müller, Rüdiger Groß, Michelle Zanoni, Alina Seidel, Carina Conzelmann, Andrea Gilg, Daniela Krnavek, Sümeyye Erdemci-Evin, Benjamin Mayer, Markus Hoffmann, Stefan Pöhlmann, Weimin Liu, Beatrice H Hahn, Alexandra Beil, Joris Kroschel, Bernd Jahrsdörfer, Hubert Schrezenmeier, Frank Kirchhoff, Jan Münch, Janis A Müller

Abstract

Background: Heterologous COVID-19 vaccination regimens combining vector- and mRNA-based vaccines are already administered, but data on solicited adverse reactions, immunological responses and elicited protection are limited.

Methods: To evaluate the reactogenicity and humoral as well as cellular immune responses towards most prevalent SARS-CoV-2 variants after a heterologous ChAdOx1 nCoV-19 BNT162b2 prime-boost vaccination, we analysed a cohort of 26 clinic employees aged 25-46 (median 30.5) years who received a ChAdOx1 nCoV-19 prime followed by a BNT162b2 boost after an 8-week interval. Serological data were compared to a cohort which received homologous BNT162b2 vaccination with a 3-week interval (14 individuals aged 25-65, median 42).

Findings: Self-reported solicited symptoms after ChAdOx1 nCoV-19 prime were in line with previous reports and more severe than after the BNT162b2 boost. Antibody titres increased significantly over time resulting in strong neutralization titres two weeks after the BNT162b2 boost and subsequently slightly decreased over the course of 17 weeks. At the latest time point measured, all analysed sera retained neutralizing activity against the currently dominant Delta (B.1.617.2) variant. Two weeks post boost, neutralizing activity against the Alpha (B.1.1.7) and immune-evading Beta (B.1.351) variant was ∼4-fold higher than in individuals receiving homologous BNT162b2 vaccination. No difference was observed in neutralization of Kappa (B.1.617.1). In addition, heterologous vaccination induced CD4+ and CD8+ T cells reactive to SARS-CoV-2 spike peptides of all analysed variants; Wuhan-Hu-1, Alpha, Beta, Gamma (P.1), and Delta.

Interpretation: In conclusion, heterologous ChAdOx1 nCoV-19 / BNT162b2 prime-boost vaccination is not associated with serious adverse events and induces potent humoral and cellular immune responses. The Alpha, Beta, Delta, and Kappa variants of spike are potently neutralized by sera from all participants and reactive T cells recognize spike peptides of all tested variants. These results suggest that this heterologous vaccination regimen is at least as immunogenic and protective as homologous vaccinations and also offers protection against current variants of concern.

Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme, the German Research Foundation, the BMBF, the Robert Koch Institute (RKI), the Baden-Württemberg Stiftung, the county of Lower Saxony, the Ministry for Science, Research and the Arts of Baden-Württemberg, Germany, and the National Institutes of Health.

Keywords: B.1.617.2; COVID-19; Delta; heterologous vaccination; immunity.

Conflict of interest statement

Declaration of interest The authors have nothing to disclose.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Solicited adverse reactions following ChAdOx1 nCoV-19 prime and BNT162b2 boost vaccination. Percentages of n=26 participants with individual symptoms following prime (a) or boost (b) vaccination. Severity is graded on a scale of 1-2 (for some symptoms) or 1-3 (for most), as adapted from the Common Terminology Criteria for Adverse Events (US Department of Health and Human Services, Version 4.03). (c) Cumulative solicited adverse reaction (cSAR) scores of all participants following prime and boost vaccination. For calculation of cSAR scores, symptom gradings are summed and an additional score point is added for symptoms lasting more than 24 h. Paired two-tailed t-test compares prime and boost vaccination. (d,e) Analysis of cSAR scores by participant sex (Mann-Whitney-U test). (f) Spearman correlation of cSAR scores following prime and boost vaccination. The SARS-CoV-2 convalescent individual (triangle) was excluded in all statistical analyses.; ns not significant; ** p

Figure 2

Humoral response. Quantification of anti-SARS-CoV-2…

Figure 2

Humoral response. Quantification of anti-SARS-CoV-2 S1 spike domain (a) IgG and (b) IgA…

Figure 2
Humoral response. Quantification of anti-SARS-CoV-2 S1 spike domain (a) IgG and (b) IgA titres. (c) Quantification of anti-SARS-CoV-2 spike IgG and IgM responses as units per ml (U/ml) by immunoassay. (d) SARS-CoV-2 surrogate virus ACE2 neutralization test. (e) VSV-based Alpha SARS-CoV-2 spike pseudovirus neutralization assay. (f) VSV-based Alpha, Beta, and Kappa SARS-CoV-2 spike pseudovirus neutralization assay from sera obtained 14-19 days post boost. (g) VSV-based Delta SARS-CoV-2 spike pseudovirus neutralization assay from sera obtained 38-48 and 93-116 days post boost. Titres expressed as serum dilution resulting in 50% pseudovirus neutralization (PVNT50) were obtained from triplicate infections. Triangle indicates SARS-CoV-2 convalescent individual, who was excluded from all statistical analyses. Grey symbols indicate datapoints pre-vaccination, red datapoints indicate datapoints after prime and light-blue after boost vaccination. Dark-blue indicates samples of participants with homologous BNT162b2 prime-boost regimen. Dashed horizontal lines indicate upper and lower limit of detection/cut-off, respectively. Dashed vertical lines indicate prime and boost vaccination. Samples were obtained from n=26 participants. Longitudinal antibody measurements were analysed by means of a mixed linear regression model. Mann-Whitney-U test compares ChAdOx1 nCoV-19 and BNT162b2 titres and variants *** p

Figure 3

SARS-CoV-2 spike-specific CD4 + and…

Figure 3

SARS-CoV-2 spike-specific CD4 + and CD8 + T cell responses. PBMCs from day…

Figure 3
SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses. PBMCs from day -2/0 pre-vaccination (pre) and day 6-11 or 16-19 post boost (64-65 or 72-73 post prime) of n = 21 study participants were stimulated with (a) SARS-CoV-2 Wuhan-Hu-1 (Wu) spike peptide-pool and cytokine production determined by flow cytometry. Cytokine+ T cells were background-corrected for unstimulated cells. Values lower than median plus one standard deviation of pre-vaccination (0.04% for CD4, 0.01% for CD8) were considered negative. (b) PBMCs from day 0-2 pre and day 6-11 post boost (day 64-65 post prime) were stimulated with SARS-CoV-2 spike peptide pools derived from Alpha, Beta, or Gamma, or of epitopes of different infectious agents (CEFX) and compared with Wuhan-Hu-1 from (a). (c) PBMCs from day 14-19 post boost (72-73 post prime) were stimulated with a SARS-CoV-2 Delta spike peptide-pool or control (DMSO) (control) and cytokine production determined by flow cytometry. Triangle symbol indicates SARS-CoV-2 convalescent individual, where cytokine release was already high in absence of stimulation. Longitudinal T cell responses were analysed by means of a mixed linear regression model. Mann-Whitney-U test compares cytokine-positive cells at 6-11 days post boost (64-65 days after prime) upon stimulation with different SARS-CoV-2 spike variants. Unpaired t-test compares T cell responses upon control versus Delta spike-peptide treatment. *** p < 0.0001, ** p < 0.01, * p < 0.05, ns = not significant.
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References
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Figure 2
Figure 2
Humoral response. Quantification of anti-SARS-CoV-2 S1 spike domain (a) IgG and (b) IgA titres. (c) Quantification of anti-SARS-CoV-2 spike IgG and IgM responses as units per ml (U/ml) by immunoassay. (d) SARS-CoV-2 surrogate virus ACE2 neutralization test. (e) VSV-based Alpha SARS-CoV-2 spike pseudovirus neutralization assay. (f) VSV-based Alpha, Beta, and Kappa SARS-CoV-2 spike pseudovirus neutralization assay from sera obtained 14-19 days post boost. (g) VSV-based Delta SARS-CoV-2 spike pseudovirus neutralization assay from sera obtained 38-48 and 93-116 days post boost. Titres expressed as serum dilution resulting in 50% pseudovirus neutralization (PVNT50) were obtained from triplicate infections. Triangle indicates SARS-CoV-2 convalescent individual, who was excluded from all statistical analyses. Grey symbols indicate datapoints pre-vaccination, red datapoints indicate datapoints after prime and light-blue after boost vaccination. Dark-blue indicates samples of participants with homologous BNT162b2 prime-boost regimen. Dashed horizontal lines indicate upper and lower limit of detection/cut-off, respectively. Dashed vertical lines indicate prime and boost vaccination. Samples were obtained from n=26 participants. Longitudinal antibody measurements were analysed by means of a mixed linear regression model. Mann-Whitney-U test compares ChAdOx1 nCoV-19 and BNT162b2 titres and variants *** p

Figure 3

SARS-CoV-2 spike-specific CD4 + and…

Figure 3

SARS-CoV-2 spike-specific CD4 + and CD8 + T cell responses. PBMCs from day…

Figure 3
SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses. PBMCs from day -2/0 pre-vaccination (pre) and day 6-11 or 16-19 post boost (64-65 or 72-73 post prime) of n = 21 study participants were stimulated with (a) SARS-CoV-2 Wuhan-Hu-1 (Wu) spike peptide-pool and cytokine production determined by flow cytometry. Cytokine+ T cells were background-corrected for unstimulated cells. Values lower than median plus one standard deviation of pre-vaccination (0.04% for CD4, 0.01% for CD8) were considered negative. (b) PBMCs from day 0-2 pre and day 6-11 post boost (day 64-65 post prime) were stimulated with SARS-CoV-2 spike peptide pools derived from Alpha, Beta, or Gamma, or of epitopes of different infectious agents (CEFX) and compared with Wuhan-Hu-1 from (a). (c) PBMCs from day 14-19 post boost (72-73 post prime) were stimulated with a SARS-CoV-2 Delta spike peptide-pool or control (DMSO) (control) and cytokine production determined by flow cytometry. Triangle symbol indicates SARS-CoV-2 convalescent individual, where cytokine release was already high in absence of stimulation. Longitudinal T cell responses were analysed by means of a mixed linear regression model. Mann-Whitney-U test compares cytokine-positive cells at 6-11 days post boost (64-65 days after prime) upon stimulation with different SARS-CoV-2 spike variants. Unpaired t-test compares T cell responses upon control versus Delta spike-peptide treatment. *** p < 0.0001, ** p < 0.01, * p < 0.05, ns = not significant.
Figure 3
Figure 3
SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses. PBMCs from day -2/0 pre-vaccination (pre) and day 6-11 or 16-19 post boost (64-65 or 72-73 post prime) of n = 21 study participants were stimulated with (a) SARS-CoV-2 Wuhan-Hu-1 (Wu) spike peptide-pool and cytokine production determined by flow cytometry. Cytokine+ T cells were background-corrected for unstimulated cells. Values lower than median plus one standard deviation of pre-vaccination (0.04% for CD4, 0.01% for CD8) were considered negative. (b) PBMCs from day 0-2 pre and day 6-11 post boost (day 64-65 post prime) were stimulated with SARS-CoV-2 spike peptide pools derived from Alpha, Beta, or Gamma, or of epitopes of different infectious agents (CEFX) and compared with Wuhan-Hu-1 from (a). (c) PBMCs from day 14-19 post boost (72-73 post prime) were stimulated with a SARS-CoV-2 Delta spike peptide-pool or control (DMSO) (control) and cytokine production determined by flow cytometry. Triangle symbol indicates SARS-CoV-2 convalescent individual, where cytokine release was already high in absence of stimulation. Longitudinal T cell responses were analysed by means of a mixed linear regression model. Mann-Whitney-U test compares cytokine-positive cells at 6-11 days post boost (64-65 days after prime) upon stimulation with different SARS-CoV-2 spike variants. Unpaired t-test compares T cell responses upon control versus Delta spike-peptide treatment. *** p < 0.0001, ** p < 0.01, * p < 0.05, ns = not significant.

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