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. 2023 Nov 30;77(11):1511-1520.
doi: 10.1093/cid/ciad402.

Omicron Variant-Specific Serological Imprinting Following BA.1 or BA.4/5 Bivalent Vaccination and Previous SARS-CoV-2 Infection: A Cohort Study

Eva A M Baerends  1   2 , Joanne Reekie  3 , Signe R Andreasen  1   2 , Nina B Stærke  1   2 , Dorthe Raben  3 , Henrik Nielsen  4   5 , Kristine T Petersen  4 , Isik S Johansen  6   7 , Susan O Lindvig  6   7 , Lone W Madsen  6   7 , Lothar Wiese  8 , Mette B Iversen  8 , Thomas Benfield  9   10 , Kasper K Iversen  10   11 , Fredrikke D Larsen  1   2 , Sidsel D Andersen  1   2 , Anna K Juhl  1   2 , Lisa L Dietz  1   2 , Astrid K Hvidt  1   2 , Sisse R Ostrowski  12   13 , Tyra G Krause  14 , Lars Østergaard  1   2 , Ole S Søgaard  1   2 , Jens Lundgren  3   10   15 , Martin Tolstrup  1   2
Affiliations

Omicron Variant-Specific Serological Imprinting Following BA.1 or BA.4/5 Bivalent Vaccination and Previous SARS-CoV-2 Infection: A Cohort Study

Eva A M Baerends et al. Clin Infect Dis. .

Abstract

Background: Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outpaces monovalent vaccine cross-protection to new viral variants. Consequently, bivalent coronavirus disease 2019 (COVID-19) vaccines including Omicron antigens were developed. The contrasting immunogenicity of the bivalent vaccines and the impact of prior antigenic exposure on new immune imprinting remains to be clarified.

Methods: In the large prospective ENFORCE cohort, we quantified spike-specific antibodies to 5 Omicron variants (BA.1 to BA.5) before and after BA.1 or BA.4/5 bivalent booster vaccination to compare Omicron variant-specific antibody inductions. We evaluated the impact of previous infection and characterized the dominant antibody responses.

Results: Prior to the bivalent fourth vaccine, all participants (N = 1697) had high levels of Omicron-specific antibodies. Antibody levels were significantly higher in individuals with a previous polymerase chain reaction positive (PCR+) infection, particularly for BA.2-specific antibodies (geometric mean ratio [GMR] 6.79, 95% confidence interval [CI] 6.05-7.62). Antibody levels were further significantly boosted in all individuals by receiving either of the bivalent vaccines, but greater fold inductions to all Omicron variants were observed in individuals with no prior infection. The BA.1 bivalent vaccine generated a dominant response toward BA.1 (adjusted GMR 1.31, 95% CI 1.09-1.57) and BA.3 (1.32, 1.09-1.59) antigens in individuals with no prior infection, whereas the BA.4/5 bivalent vaccine generated a dominant response toward BA.2 (0.87, 0.76-0.98), BA.4 (0.85, 0.75-0.97), and BA.5 (0.87, 0.76-0.99) antigens in individuals with a prior infection.

Conclusions: Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen. Importantly, both bivalent vaccines induce high levels of Omicron variant-specific antibodies, suggesting broad cross-protection of Omicron variants.

Keywords: COVID-19; antibodies; bivalent vaccines; booster vaccination; immunogenicity.

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Conflict of interest statement

Potential conflicts of interest. N. B. S. declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic, and AstraZeneca. H. N. declares to have been on advisory boards for GSK and MSD and reports grants or contracts from Novo Nordisk Foundation (payment to institution, RCT of brain abscess treatment strategy). T. B. declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. M. T. declares to be on a Data Safety Monitoring Board for ImmunoCore. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Antibody levels in serum to wild-type spike and 5 Omicron spike variants BA.1 to BA.5 prior to the fourth vaccine dose. A, Panel shows the antibody levels in participants triple-vaccinated with no prior infection (Dark red box [+], n = 627) and participants triple-vaccinated with a previous PCR+ infection (Dark blue box [O], n = 1070). Data show the geometric mean with 95% confidence intervals. B, Panel displays the geometric mean ratio with 95% confidence intervals between previous PCR+ infected and non-infected. Abbreviations: CI, confidence interval; PCR, polymerase chain reaction.
Figure 2.
Figure 2.
Antibody levels in serum to wild-type spike and 5 Omicron spike variants BA.1 to BA.5 prior to and after the bivalent fourth vaccine dose. A, Panel shows participants vaccinated with the BA.1 bivalent vaccine with no prior infection (n = 280) before (dark red box [O]) and after (light red box [+]) bivalent vaccination, and participants vaccinated with the BA.1 bivalent vaccine with a previous PCR+ infection (n = 392) before (dark blue box [X]) and after (light blue box [Δ]) bivalent vaccination. B, Panel shows participants vaccinated with the BA.4/5 bivalent vaccine with no prior infection (n = 347) before (dark red box [O]) and after (light red box [+]) bivalent vaccination, and participants vaccinated with the BA.4/5 bivalent vaccine with a previous PCR+ infection (n = 678) before (dark blue box [X]) and after (light blue box [Δ]) bivalent vaccination. Data show the geometric mean with 95% confidence intervals. C, Panel shows the geometric mean ratio (before/after bivalent fourth vaccine dose) with 95% confidence intervals for each of the 4 groups to the 6 antigens. Abbreviations: CI, confidence interval; PCR, polymerase chain reaction.
Figure 3.
Figure 3.
Forest plot of the univariable and multivariable linear regression displaying antibody responses to the bivalent fourth vaccine dose (BA.1 vs BA.4/5) by prior infection status. Data show the adjusted geometric mean ratio with 95% confidence intervals.
Figure 4.
Figure 4.
Proportion of participants with dominant responses to the 5 Omicron antigens BA.1 to BA.5. A, Panel shows the dominant induced responses in participants with no prior infection following bivalent BA.1 and BA.4/5 vaccination. B, Panel shows the dominant induced responses in participants with a previous PCR+ infection following bivalent BA.1 and bivalent BA.4/5 vaccination. C, Panel shows pie charts with the proportion of participants with dominant serological responses before and after the bivalent fourth vaccine dose. Abbreviation: PCR, polymerase chain reaction.
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