A Bivalent Omicron-Containing Booster Vaccine against Covid-19

Abstract

Background: The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known.

Methods: In this ongoing, phase 2-3 study, we compared the 50-μg bivalent vaccine mRNA-1273.214 (25 μg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-μg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-μg) primary series and first booster (50-μg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose.

Results: Interim results are presented. Sequential groups of participants received 50 μg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-μg mRNA-1273.214 and 50-μg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster.

Conclusions: The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065.).

Figure 1. Study Profile.

Eligible participants who received a previous two-injection primary series of 100-μg mRNA-1273 and a 50-μg mRNA-1273 booster dose either in the Coronavirus Efficacy (COVE) trial or under the U.S. emergency use authorization (EUA) were enrolled to receive a second booster dose of 50-μg mRNA-1273 (administered between February 18 and March 8, 2022) or mRNA-1273.214 (administered between March 8 and March 23, 2022). A total of 379 participants received a second booster dose of 50-μg mRNA-1273; 1 participant had previously received the primary series but not a first booster dose, and another participant had a major protocol deviation. These 2 participants were excluded from all analysis sets. A total of 437 participants received a second booster dose of mRNA-1273.214; 3 participants had discontinued the study before they received the second booster and were excluded from all analysis sets. The data-cutoff date was April 27, 2022.

Figure 2. Solicited Local and Systemic Adverse Reactions, According to Grade.

Shown are the percentages of participants in whom solicited local or systemic adverse reactions occurred within 7 days after the booster dose in the solicited safety set (351 participants in the mRNA-1273 group and 437 participants in the mRNA-1273.214 group). For some systemic adverse reactions, data were available for 350 participants in the mRNA-1273 group.

Figure 3. Observed Neutralizing Antibody Titers against Ancestral SARS-CoV-2 (D614G) and Omicron after 50 μg of mRNA-1273.214 or mRNA-1273 Administered as a Second Booster Dose.

Pseudovirus neutralizing antibody geometric mean titers are provided for all participants regardless of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection before the booster (per-protocol immunogenicity set) and for those with or without previous SARS-CoV-2 infection before the booster. Data are from participants with nonmissing data at the time point. Nine participants in the mRNA-1273 group had missing data on prebooster SARS-CoV-2 status. Antibody values that were reported as below the lower limit of quantification (18.5 for ancestral SARS-CoV-2 [D614G] and 19.9 for omicron) were replaced by 0.5 times the lower limit of qualification. Values greater than the upper limit of quantification (45,118 for ancestral SARS-CoV-2 [D614G] and 15,502.7 for omicron) were replaced by the upper limit of qualification if actual values were not available. The 95% confidence intervals (indicated by 𝙸 bars) were calculated on the basis of the t-distribution of the log-transformed values for geometric mean titer, then back-transformed to the original scale for presentation. Data for observed neutralizing antibody geometric mean titers according to previous SARS-CoV-2 infection are provided in Table S7.