• Patricia Winokur, Juleen Gayed, David Fitz-Patrick, Stephen J Thomas, Oyeniyi Diya, Stephen Lockhart, Xia Xu, Ying Zhang, Vishva Bangad, Howard I Schwartz, Douglas Denham, Jose F Cardona, Lisa Usdan, John Ginis, Federico J Mensa, Jing Zou, Xuping Xie, Pei-Yong Shi, Claire Lu, Sandra Buitrago, Ingrid L Scully, David Cooper, Kenneth Koury, Kathrin U Jansen, Özlem Türeci, Uğur Şahin, Kena A Swanson, William C Gruber, Nicholas Kitchin, and C4591031 Clinical Trial Group.
• From the Division of Infectious Diseases, Carver College of Medicine, University of Iowa, Iowa City (P.W.); Vaccine Research and Development, Pfizer, Hurley, United Kingdom (J. Gayed, O.D., S.L., N.K.); East-West Medical Research Institute, Honolulu (D.F.-P.); the State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine Research and Development, Pfizer, Pearl River (Y.Z., C.L., S.B., I.L.S., D.C., K.K., K.U.J., K.A.S., W.C.G.) - both in New York; Vaccine Research and Development, Pfizer, Collegeville, PA (X. Xu, V.B., J. Ginis); CenExel RCA, Hollywood (H.I.S.), and Indago Research and Health Center, Hialeah (J.F.C.) - both in Florida; Clinical Trials of Texas, San Antonio (D.D.), and the University of Texas Medical Branch, Galveston (J.Z., X. Xie, P.-Y.S.) - both in Texas; CNS Healthcare, Memphis, TN (L.U.); and BioNTech, Mainz, Germany (F.J.M., Ö.T., U.Ş.).
• N. Engl. J. Med. 2023 Jan 19; 388 (3): 214227214-227.

BackgroundThe emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019.MethodsIn an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-μg doses of the BNT162b2 vaccine were randomly assigned to receive 30 μg or 60 μg of BNT162b2, 30 μg or 60 μg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 μg (15 μg of BNT162b2 + 15 μg of monovalent BA.1) or 60 μg (30 μg of BNT162b2 + 30 μg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 μg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants.ResultsA total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 μg and 60 μg) and monovalent BA.1 (60 μg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 μg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 μg) were also noninferior to BNT162b2 (30 μg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-μg bivalent BA.1 than with 30-μg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 μg). Adverse events were more common in the 30-μg monovalent-BA.1 (8.5%) and 60-μg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%).ConclusionsThe candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 μg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).Copyright © 2023 Massachusetts Medical Society.

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