Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim results

Abstract

This ongoing, open-label, phase 2/3 trial compared the safety and immunogenicity of the Omicron BA.4/BA.5-containing bivalent mRNA-1273.222 vaccine with the ancestral Wuhan-Hu-1 mRNA-1273 as booster doses. Two groups of adults who previously received mRNA-1273 as primary vaccination series and booster doses were enrolled in a sequential, nonrandomized manner and received single-second boosters of mRNA-1273 (n = 376) or bivalent mRNA-1273.222 (n = 511). Primary objectives were safety and the noninferiority or superiority of neutralizing antibody (nAb) responses against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 with the D614G mutation (ancestral SARS-CoV-2 (D614G)), 28 days post boost. Superiority and noninferiority were based on prespecified success criteria (lower bounds of 95% CI > 1 and < 0.677, respectively) of the mRNA-1273.222:mRNA-1273 geometric mean ratios. Bivalent Omicron BA.4/BA.5-containing mRNA-1273.222 elicited superior nAb responses against BA.4/BA.5 versus mRNA-1273 and noninferior responses against ancestral SARS-CoV-2 (D614G) at day 29 post boost in participants without detectable prior SARS-CoV-2 infection. Day 29 seroresponses against Omicron BA.4/BA.5 were higher for mRNA-1273.222 than for mRNA-1273 and similar against ancestral SARS-CoV-2 (D614G), both meeting noninferiority criterion. The safety profile of mRNA-1273.222 was similar to that previously reported for mRNA-1273 with no new safety concerns identified. Continued monitoring of neutralization and real-world vaccine effectiveness are needed as additional divergent-virus variants emerge. ClinicalTrials.gov registration: NCT04927065.

Fig. 1. Enrollment and analysis populations in the trial.

a, Trial profile. Eligible participants were sequentially enrolled as two cohorts to receive single-second booster doses of 50 µg mRNA-1273 (enrolled during 18 February–8 March 2022) or 50 µg mRNA-1273.222 (enrolled during 10–23 August 2022). ^a379 participants were enrolled and received mRNA-1273; two participants had previously received the primary series but not a first booster dose and another participant had a major protocol deviation, and three were excluded from all analysis sets. Data cutoff dates were 23 September 2022 for mRNA-1273.222 at the day 29 interim analysis and 6 July 2022 for the within-study noncontemporaneous mRNA-1273 at the day 91 interim analysis. b, Analysis populations. The full analysis set consisted of all participants who received study vaccine. The safety set consisted of all participants who received study vaccine and was used for all safety analyses except for solicited adverse reactions which were assessed in the solicited safety set. HIV, human immunodeficiency virus. ^aThe per-protocol set for immunogenicity consisted of all participants in the full analysis set who received the planned dose of study vaccination and had antibody data available at prebooster and day 29 and no major protocol deviations. ^bSeven participants in the mRNA-1273.222 and eight participants in the mRNA-1273 arm of the per-protocol immunogenicity set had missing prebooster SARS-CoV-2 information. ^cPrior SARS-CoV-2 infection based on positive RT–PCR and/or serology test at prebooster baseline. ^dThe per-protocol immunogenicity negative set (PPIS-negative) consists of participants in the per-protocol set for immunogenicity (PPIS) who have no serologic or virologic evidence of SARS-CoV-2 infection at prebooster baseline, that is, who are SARS-CoV-2 infection negative, based on both negative RT–PCR tests for SARS-CoV-2 and negative SARS-CoV-2 nucleocapsid antibody test, and is the primary analysis set for immunogenicity. A total of 379 participants received a second booster dose of 50 μg mRNA-1273; two participants had previously received the primary series but not a first booster dose, and another participant had a major protocol deviation. These three participants were excluded from all analysis sets. Source data

Fig. 2. Solicited local and systemic adverse reactions.

Percentages of participants who had solicited local or systemic adverse reactions within 7 days by grade after the 50 µg mRNA-1273.222 second booster dose (left) and mRNA-1273 historical group (right) at day 91 (ref. ) in the solicited safety sets.

Fig. 3. nAb titers after 50 µg of mRNA-1273.222 and mRNA-1273 administered as second booster doses.

a,b, Observed nAb titers against Omicron BA.4/BA.5 (a) and ancestral SARS-CoV-2 (D614G) (b) after 50 µg of mRNA-1273.222 and mRNA-1273 administered as second booster doses. Pseudovirus nAb GMTs are provided for all participants regardless of SARS-CoV-2 infection prebooster status, and those with and without previous SARS-CoV-2 infection prebooster. Data are from participants with nonmissing data at the timepoint. Seven participants in mRNA-1273.222 and eight participants in the mRNA-1273 group were missing prebooster SARS-CoV-2 status in the per protocol immunogenicity set. Antibody values reported as below the LLOQ (18.5 (1.3 in log₁₀ scale) for ancestral SARS-CoV-2 (D614G) and 36.7 (1.6 in log₁₀ scale) for Omicron BA.4/BA.5) were replaced by 0.5 × LLOQ. Values greater than the upper limit of quantification (ULOQ 45,118 (4.7 in log₁₀ scale) for ancestral SARS-CoV-2 (D614G); 13,705 (4.1 in log₁₀ scale) for Omicron BA.4/BA.5) were replaced by the ULOQ if actual values were not available. 95% CIs were calculated based on the t-distribution of the log-transformed values for GM value, then back-transformed to the original scale for presentation. Data for observed nAb GMTs by prior SARS-CoV-2 infection are provided in Supplementary Table 7.

Fig. 4. nAb titers against Omicron variants after 50 µg of mRNA-1273.222 administered as a second booster dose by prior SARS-CoV-2 infection status at prebooster.

Prebooster and day 29 nAb titers (log₁₀) against Omicron BA.4/BA.5, BQ.1.1, XBB.1 and XBB.1.5 variants in randomly selected subsets of participants in the mRNA-1273.222 booster group with (n = 20) and without (n = 40) prior SARS-CoV-2 infection. Prebooster and day 29 geometric mean titers and geometric mean fold-rises from baseline (X) are displayed above the corresponding data points. Antibody values reported as below the LLOQ (18.5 (1.3 in log₁₀ scale) for ancestral SARS-CoV-2 (D614G) and 36.7 (1.6 in log₁₀ scale) for Omicron BA.4/BA.5) were replaced by 0.5 × LLOQ. Values greater than the ULOQ (45,118 (4.7 in log₁₀ scale) for ancestral SARS-CoV-2 (D614G); 13,705 (4.1 in log₁₀ scale) for Omicron BA.4/BA.5) were replaced by the ULOQ if actual values were not available. The limit of detection (LOD) of the pseudovirus nAb assay for BQ.1.1, XBB.1 and XBB.1.5 was 10; antibody values reported as below the LOD are replaced by 0.5 × LOD. Boxes and horizontal bars denote IQR and median endpoint titers; whisker endpoints are the maximum and minimum values below or above the median ±1.5 times the IQR.

Extended Data Fig. 1. Distribution of Observed Neutralizing Antibody Titers.

Distribution of neutralizing antibody titers (ID50 log₁₀) in the pseudovirus assay against Omicron BA.4/BA.5 (Panel A) and ancestral SARS-CoV-2 (D614G) (Panel B) are shown for serum samples collected before the second booster dose of 50-µg of mRNA-1273.222 or 50-µg of mRNA-1273 (prebooster), and at 28 days after the second booster dose (day 29) in those with and without prior SARS-CoV-2 infection. The circles are values from individual serum samples. Pseudovirus neutralizing antibody assay lower limits of quantification (LLOQ) are 18.5 (1.3 log₁₀) for ancestral SARS-CoV-2 [D614G] and 36.7 (1.6 log₁₀) for Omicron BA.4/BA.5; upper limits of quantification (ULOQ) are 45,118 (4.7 log₁₀) for ancestral SARS-CoV-2 [D614G] and 13,705 (4.1 log₁₀) for Omicron BA.4/BA.5. Boxes and horizontal bars denote interquartile (IQR) ranges and median endpoint titers; whisker endpoints are the maximum and minimum values below or above the median ±1.5 times the IQR. Refer to Table 2 for the observed geometric mean titers and geometric mean fold-rises, and the estimated neutralizing antibody geometric mean titers and geometric mean ratios (ANCOVA model-based) following the second booster doses of 50-µg mRNA-1273 or 50-µg of mRNA-1273.214.

Extended Data Fig. 2. Observed Neutralizing Antibody Response by Age Groups.

Observed neutralizing antibody titers (GM titer log10) in the pseudovirus assay against Omicron BA.4/BA.5 (a) and ancestral SARS-CoV-2 (D614G) (b) are shown for serum samples collected before the second booster dose of 50-µg of mRNA-1273.222 or 50-µg of mRNA-1273 (prebooster) (day 0), and at 28 days (day 29) after the second booster dose in all participants and those ≥18 to <65 or ≥65 years of age in the per-protocol immunogenicity set without evidence of prebooster SARS-CoV-2 infection. N=Number of participants with nonmissing data at the timepoint; CI=Confidence interval; GMT=geometric mean titer; LLOQ=lower limit of quantification; ULOQ=upper limit of quantification; PPIS=Per-protocol immunogenicity set. Antibody values assessed by pseudovirus neutralizing antibody assay reported as below the LLOQ (18.5 [1.3 in log10 scale] for ancestral SARS-CoV-2 (D614G) and 36.7 [1.6 in log10 scale] for Omicron BA.4/BA.5) are replaced by 0.5 × LLOQ. Values greater than ULOQ (45,118 [4.7 in log10 scale] for ancestral SARS-CoV-2 (D614G) and 13,705 [4.1 in log10 scale] for Omicron BA.4/BA.5) are replaced by the ULOQ if actual values are not available. Includes participants in the per-protocol immunogenicity set without evidence of prebooster SARS-CoV-2 infection (PPIS-negative). 95% CIs were calculated based on the t-distribution of the log-transformed values for GM value, then back-transformed to the original scale for presentation.

Extended Data Fig. 3. Neutralizing Antibody Titers and Geometric Fold-Rises by Time Intervals.

Neutralizing antibody titers against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 (a) and geometric fold-rises from baseline levels (b) were assessed in participants without previous infection grouped by quartiles of dosing intervals between the first booster dose of mRNA-1273 and second booster doses of mRNA-1273 and mRNA-1273.222 post boost within each booster vaccine group at day 29. 95% CIs were calculated based on the t-distribution of the log-transformed values for GM value, then back-transformed to the original scale for presentation. Quartiles 1, 2, 3 and 4 represent quartiles indicated s in panel a for mRNA-1273 and mRNA-1273.222.