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Clinical Trial
. 2024 May 15;78(5):1194-1203.
doi: 10.1093/cid/ciad718.

A Bivalent Omicron-BA.4/BA.5-Adapted BNT162b2 Booster in ≥12-Year-Olds

Lisa Usdan  1 , Sohil Patel  2 , Hector Rodriguez  3 , Xia Xu  4 , Dung-Yang Lee  4 , Daniel Finn  5 , Hayley Wyper  2 , Francine S Lowry  4 , Federico J Mensa  6 , Claire Lu  7 , David Cooper  7 , Kenneth Koury  7 , Annaliesa S Anderson  7 , Özlem Türeci  6 , Uğur Şahin  6 , Kena A Swanson  7 , William C Gruber  7 , Nicholas Kitchin  2 ; C4591044 Study Group
Collaborators, Affiliations
Clinical Trial

A Bivalent Omicron-BA.4/BA.5-Adapted BNT162b2 Booster in ≥12-Year-Olds

Lisa Usdan et al. Clin Infect Dis. .

Abstract

Background: Protection against contemporary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires sequence-adapted vaccines.

Methods: In this ongoing phase 2/3 trial, 12-17-year-olds (n = 108), 18-55-year-olds (n = 313), and >55-year-olds (n = 306) who previously received 3 original BNT162b2 30-µg doses, received a fourth dose (second booster) of 30-µg bivalent original/Omicron-BA.4/BA.5-adapted BNT162b2 (BNT162b2-Omi.BA.4/BA.5). For comparisons with original BNT162b2, participants were selected from another phase 3 trial. Immunologic superiority 1 month after vaccination, with respect to 50% neutralizing titers (lower bound [LB] of 2-sided 95% confidence interval [CI] for geometric mean ratio [GMR], >1), and noninferiority with respect to seroresponse rates (LB of 2-sided 95% CI for rate difference, greater than -5%), for Omicron BA.4/BA.5 were assessed in >55-year-olds versus original BNT162b2 as a second booster. Noninferiority with respect to neutralizing titer level (LB of 2-sided 95% CI for GMR, > 0.67) and seroresponse rate (LB of 2-sided 95% CI for rate difference, greater than -10%) of Omicron BA.4/BA.5 immune response for BNT162b2-Omi.BA.4/BA.5 in 18-55 versus >55-year-olds was assessed.

Results: One month after vaccination in >55-year-olds, the model-adjusted GMR of Omicron BA.4/BA.5 neutralizing titers for the BNT162b2-Omi.BA.4/BA.5 versus BNT162b2 groups (2.91 [95% CI, 2.45-3.44]) demonstrated the superiority of BNT162b2-Omi.BA.4/BA.5. Adjusted difference in the percentages of >55-year-olds with seroresponse (26.77% [95% CI, 19.59-33.95]) showed noninferiority of BNT162b2-Omi.BA.4/BA.5 to BNT162b2. Noninferiority of BNT162b2-Omi.BA.4/BA.5 in 18-55-year-olds compared with >55-year-olds was met for model-adjusted GMR and seroresponse. Geometric mean titers in 12-17-year-olds increased from baseline to 1 month after vaccination. The BNT162b2-Omi.BA.4/BA.5 safety profile was similar to the profiles for booster doses of bivalent Omicron BA.1-modified BNT162b2 and original BNT162b2 reported in previous studies.

Conclusions: Based on immunogenicity and safety data up to 1 month after vaccination in participants who previously received 3 original BNT162b2 doses, a BNT162b2-Omi.BA.4/BA.5 30-µg booster has a favorable benefit-risk profile.

Clinical trials registration: NCT05472038.

Keywords: BNT162b2 vaccine; Omicron variant; SARS-CoV-2; booster; immunogenicity.

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Conflict of interest statement

Potential conflicts of interest . L. U. reports consulting fees made to institution from Pfizer Survey and a role as Memphis Medical Society President. S. P., X. X., D. Y. L., H. W., F. S. L., C. L., D. C., K. K., A. S. A., K. A. S., W. C. G., and N. K. are employees of Pfizer and may hold stock or stock options. H. R. reports consulting fees from Moderna for Vaccine advisory meeting. D. F. received funding from Pfizer for conducting research trials. F. J. M., Ö. T., and U. Ş. are employees of BioNTech and may hold stock or stock options. Ö. T. reports grants or contracts for joint development from Pfizer, is a coauthor on various issued or pending patents related to RNA technology and coronavirus disease 2019 (COVID-19) vaccines from BioNTech, and is a cofounder and chief executive officer of BioNTech. U. Ş. reports grants or contracts for joint development from Pfizer, is a coauthor on various issued or pending patents related to RNA technology and COVID-19 vaccines from BioNTech, and is a cofounder and chief executive officer of BioNTech. 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

Figure 1.
Figure 1.
Randomization and vaccine administration. *Includes participants from the first cohort (cohort 2; defined in Supplementary Table 1). †Includes participants from the first and second cohorts (cohorts 2 and 3 combined; defined in Supplementary Table 1). Figure shows all participant dispositions in the 2 cohorts as of the database cutoff date of 12 October 2022 (first cohort [cohort 2]) and 31 October 2022 (second cohort [cohort 3]). At data cutoff, some participants had not reached the subsequent postvaccination visit. Of the enrolled population of 940 participants, 1 who did not receive the vaccine and 1 who did not sign the informed consent document are not included in the safety and immunogenicity analysis populations. Abbreviation: bivalent BNT162b2, Omicron BA.4/BA.5-adapted BNT162b2 vaccine.
Figure 2.
Figure 2.
Model-adjusted geometric mean ratios (GMRs) and unadjusted geometric mean titers (GMTs) (A) and adjusted differences in percentages of participants with seroresponses (B) 1 month after the second booster for Omicron BA.4/BA.5-adapted BNT162b2 vaccine (bivalent BNT162b2-Omi.BA.4/BA.5) and original BNT162b2. Data are for the evaluable immunogenicity population and include participants with or without evidence of previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Comparisons with original BNT162b2 use participants from another ongoing trial (study C4591031 [NCT04955626]; see Supplementary Table 3 for demographic characteristics of this population). Shown in A are model-adjusted GMRs (95% confidence intervals [CIs]) for the vaccine or age group comparison (graph) and associated unadjusted GMTs (table). Assay results below the lower limit of quantitation (LLOQ) were set to 0.5 × LLOQ, and a separate model was fit for each comparison. Shown in B are the adjusted differences in percentages (95% CIs) of participants with Omicron BA.4/BA.5 seroresponses between vaccine or age groups. Dotted lines represent superiority or noninferiority criteria for each comparison. For the comparison between bivalent BNT162b2-Omi.BA.4/BA.5 and original BNT162b2 vaccine in terms of BA.4/BA.5 titers, superiority based on GMR was declared if the lower bound of the 2-sided 95% CI was >1, and noninferiority based on seroresponse was declared if the lower bound of the 2-sided 95% CI for the difference in seroresponse percentage was greater than −5% (dotted line). For the comparison of bivalent BNT162b2-Omi.BA.4/BA.5 in participants 18–55 versus >55 years of age, noninferiority based on the GMR was declared if the lower bound of the 2-sided 95% CI for the GMR was greater than 0.67, and noninferiority based on seroresponse was declared if the lower bound of the 2-sided 95% CI for the difference in percentages of participants with seroresponse was greater than −10%. For the comparison between bivalent BNT162b2-Omi.BA.4/BA.5 and original BNT162b2 in terms of ancestral strain titers, noninferiority based on GMR was declared if the lower bound of the 2-sided 95% CI was >0.67 and the GMR point estimate was ≥0.8.
Figure 3.
Figure 3.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4/BA.5 neutralization assay results by baseline SARS-CoV-2 status for bivalent BNT162b2-Omi.BA.4/BA.5 (A) and bivalent BNT162b2-Omi.BA.1 (B). Shown are the geometric mean titers (GMTs) and associated 95% confidence intervals (CIs) of SARS-CoV-2 Omicron BA.4/BA.5 neutralizing antibodies before and 1 month after vaccination. Values above the bars are GMTs; values above the brackets, geometric mean fold rises (GMFRs). Data are for the evaluable immunogenicity population. Data for participants receiving bivalent BNT162b2.Omi-BA.1 are from another ongoing trial (study C4591031 [NCT04955626]). Assay results below the lower limit of quantitation (LLOQ) were set to 0.5 × LLOQ. Data in A included only participants from the first cohort (cohort 2). Details regarding how the group in B was selected are provided in the Supplementary Materials. Abbreviations: bivalent BNT162b2-Omi.BA.1 and bivalent BA.1, Omicron BA.1-adapted BNT162b2 vaccine; bivalent BNT162b2-Omi.BA.4/BA.5 and bivalent BA.4/BA.5, Omicron BA.4/BA.5-adapted BNT162b2 vaccine; NT50, 50% neutralizing titer.
Figure 4.
Figure 4.
Local reactions (A) and systemic events (B) reported within 7 days of vaccination. Data are for the safety population. Error bars represent 95% confidence intervals (CIs), and numbers above the error bars indicate the percentage of participants in each group reporting the specified event. 12–17 y, 30 µg includes 12–17-year-olds who received bivalent BNT162b2-Omi.BA.4/BA.5 30 µg (n = 107); 18–55 y, 30 µg, 18–55-year-olds who received bivalent BNT162b2-Omi.BA.4/BA.5 30 µg (n = 309–310); 18–55 y, 60 µg, 18–55-year-olds who received bivalent BNT162b2-Omi.BA.4/BA.5 60 µg (n = 110); >55 y, 30 µg, >55-year-olds who received bivalent BNT162b2-Omi.BA.4/BA.5 30 µg (n = 300–301); and >55 y, 60 µg, >55-year-olds who received bivalent BNT162b2-Omi.BA.4/BA.5 60 µg (n = 101–102).
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