Bivalent Omicron BA.1–Adapted BNT162b2 Booster in Adults Older than 55 Years

Abstract

Background The 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. Methods In 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 [NT 50 ] 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. Results A 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 NT 50 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 NT 50 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%). Conclusions The 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 .)

mRNA Vaccines against SARS-CoV-2: Advantages and Caveats

“…Pfizer–BioNTech and Moderna brought to the market two bivalent vaccines—Comirnaty and Spikevax—containing mRNAs encoding the spike protein of the original variant together with BA.4-5 Omicron variants [ 114 , 115 ]. Booster doses with these vaccines seem to offer increased protection against new Omicron subvariants, generating higher titers of Omicron-specific neutralizing antibodies than monovalent vaccines [ 115 , 116 ]. Nevertheless, long-term follow-up studies should be carried out to obtain more solid and robust data on the impact on the protection and spreading of the virus in the human population.…”

Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine

“…Participants were older than 55 years of age and had received three 30-μg doses of BNT162b2 vaccine and either a fourth monovalent booster dose of BNT162b2 vaccine (30 μg) approximately 6.6 months after the third dose (in the C4591031 clinical trial 5 ) or the bivalent vaccine (15 μg of messenger RNA [mRNA] directed against the ancestral strain of SARS-CoV-2 and 15 μg of mRNA directed against BA.4–BA.5) approximately 11 months after the third dose (in the C4591044 clinical trial; ClinicalTrials.gov number, NCT05472038 ). The protocols are available with the full text of this letter at NEJM.org.…”

Immunogenicity of the BA.1 and BA.4/BA.5 SARS-CoV-2 Bivalent Boosts: Preliminary Results from the COVAIL Randomized Clinical Trial

“…However, there was increasing neutralization escape with contemporary, late 2022, Omicron subvariants (BQ.1.1 and XBB.1) that was similar between the two bivalent vaccines even though BA.1 and BA.4/5 spike sequences are known to have different mutations in the receptor binding domain. 3 Though modest serologic advantages to Omicron BA.1 and BA.4/5 have been previously reported with bivalent compared to wildtype vaccines, 4 our findings highlight ongoing concern that the breadth of antibody response from current updated vaccines are still not optimized for the pace of virus evolution; though more precise immune correlates of protection for emerging variants are still needed. Additionally, while early vaccine effectiveness (VE) data with bivalent vaccines has emerged, 5 continuous surveillance is crucial to assess for potential VE waning.…”