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Randomized Controlled Trial
. 2022 Sep 12;13(1):5362.
doi: 10.1038/s41467-022-33036-y.

Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial

Daniel Mrak #  1 , Daniela Sieghart #  1 , Elisabeth Simader  1 , Selma Tobudic  2 , Helga Radner  1 , Peter Mandl  1 , Lisa Göschl  1 , Maximilian Koblischke  3 , Nikolaus Hommer  4 , Angelika Wagner  5 , Margareta Mayer  3 , Lorenz Schubert  2 , Lukas Hartl  6 , Karin Kozbial  6 , Philipp Hofer  7 , Felix Kartnig  1 , Thomas Hummel  1 , Andreas Kerschbaumer  1 , Thomas Deimel  1 , Antonia Puchner  1 , Venugopal Gudipati  8 , Renate Thalhammer  9 , Petra Munda  6 , Keziban Uyanik-Ünal  10 , Andreas Zuckermann  10 , Gottfried Novacek  6 , Thomas Reiberger  6 , Erika Garner-Spitzer  5 , Roman Reindl-Schwaighofer  11 , Renate Kain  7 , Stefan Winkler  2 , Josef S Smolen  1 , Karin Stiasny  3 , Gottfried F Fischer  12 , Thomas Perkmann  9 , Helmuth Haslacher  9 , Markus Zeitlinger  4 , Ursula Wiedermann  5 , Judith H Aberle  3 , Daniel Aletaha  1 , Leonhard X Heinz #  13 , Michael Bonelli #  14
Affiliations
Randomized Controlled Trial

Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial

Daniel Mrak et al. Nat Commun. .

Abstract

Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.

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Conflict of interest statement

P.M. reports speaker fees from AbbVie, Janssen, and Novartis and research grants from AbbVie, BMS, Novartis, Janssen, MSD, and UCB. M.B. reports about personal fees from Eli Lilly, D.A. received grants and consulting fees from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, and Sandoz, J.S. reports about grants, consulting, and personal fees from AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, and UCB, M.Z. received grants and consulting fees from Nabriva, AntibioTxApS, Shionogi, NovoNordisk, Merck, Infectopharm, and Pfizer, H.H. received grants from Glock Health, BlueSky Immunotherapies, and Neutrolis. G.N. served as a speaker/consultant/advisory board member for AbbVie, MSD, Takeda, Janssen, Sandoz, Pfizer, Astro Pharma, Falk Pharma GmbH, Ferring, Gilead, Galapagos, and Vifor. E.S. reports support for meeting attendances from Pfizer and Bristol Myers Squibb. D.M. received support for meeting attendances from Pfizer. T.R. received grant support from Abbvie, Boehringer-Ingelheim, Gilead, Gore, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, and Siemens; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Abbvie, Boehringer-Ingelheim, Gilead, and Roche. A.K. reports about speaker and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, and Pfizer. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Screening, randomization, and follow-up of patients.
Patients randomized to an additional mRNA vaccine dose received the same compound as with their primary vaccination. Patients were blinded to the type of vaccine used until week 4.
Fig. 2
Fig. 2. Antibody seroconversion 4 weeks after vector vs. mRNA booster vaccination.
Antibodies to the receptor-binding domain (RBD) of the viral spike (S) protein were determined using an anti-SARS-CoV-2 immunoassay 4 weeks after vaccination. a Anti-RBD antibody levels in patients with (n = 44) and without (n = 2) peripheral B-cells, as indicated by the color of the circles. Dashed line indicates the threshold for seroconversion (0.8 BAU/ml). b Seroconversion rate was calculated based on the presence of anti-RBD antibodies in patients stratified by booster vaccination with vector or mRNA vaccine. c Anti-RBD antibody levels in patients 4 weeks after booster vaccination were correlated with levels of detectable peripheral CD19+ B-cells, with the color of the circles indicating status of seroconversion. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. SARS-CoV-2-specific T-cell responses.
a Representative ex vivo IFN-γ ELISpot result from peripheral blood mononuclear cells (PBMCs) stimulated or not (neg, n = 4) with phytohemagglutinin (PHA, n = 1) or spike subunit S1 and S2 peptide pools (S1, S2, n = 2 for each) shown for one healthy control (HC) and one patient before and after booster vaccination. Bar graphs show mean spot-forming cells (SFCs) per 106 PBMCs. Dots represent individual replicates. b Composite ELISpot results from prepandemic controls (n = 5), vaccinated HC (n = 10), and patients before (pre, n = 41) and 1 week after (post, n = 46) third vaccination with vector and mRNA vaccine. Circles show sum of total responses from S1 and S2 peptide pools. Vertical lines indicate the mean. Paired Wilcoxon test was used to compare samples before and after booster vaccination. Mann–Whitney-U test was utilized to compare cellular vaccine responses. All tests were two-sided and no correction for multiple testing was performed. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Predictors of vaccination response.
a Pairwise correlation plot of antibodies to the receptor-binding domain (RBD) of the viral spike (S) protein after third vaccination and leukocyte subsets in patients. Correlation coefficients are displayed as Kendall’s τ. Source data are provided as a Source Data file. b Odds ratios (OR) of logistic regression assessing seroconversion after third vaccination (n = 46). OR were calculated using a multivariate logistic regression model. OR for peripheral CD4+, CD8+, and CD19+ cells are presented per 100 cells/μL. Numbers indicate OR, bars represent the 95% confidence interval. **p = 0.002, *p = 0.034.
Fig. 5
Fig. 5. Safety.
Local and systemic reactogenicity evaluated daily during the first 7 days after vaccination.
See this image and copyright information in PMC

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