A Bivalent Omicron-Containing Booster Vaccine against Covid-19
Study Population
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.
Between February 18 and March 8, 2022 (part F, cohort 2), and between March 8 and March 23, 2022 (part G), 819 participants were enrolled who had previously received the primary series of 100-μg mRNA-1273 and a first booster dose of 50-μg mRNA-1273, at least 3 months before enrollment (Figure 1). Of these, 197 of the COVE participants (44.8%) and 243 of the U.S. EUA participants (55.2%) were assigned to receive second booster doses of 50-μg mRNA-1273.214 (440 participants), and 264 participants (69.7%) and 115 participants (30.3%), respectively, were assigned to receive 50-μg mRNA-1273 (379 participants). A total of 437 participants (53.7%) in the 50-μg mRNA-1273.214 group and 377 participants (46.3%) in the 50-μg mRNA-1273 group received second boosters. Two participants (0.5%) withdrew consent and discontinued the study after receiving mRNA-1273.214.
Demographic and Clinical Characteristics of the Participants (Safety Set).
The demographic and clinical characteristics of the participants were similar in the two groups (Table 1). The mean ages were 57.3 in the 50-μg mRNA-1273.214 group and 57.5 in the 50-μg mRNA-1273 group, and 59.0% and 50.7% of the participants, respectively, were female. Most participants were White (87.2% in the mRNA-1273.214 group and 85.4% in the mRNA-1273 group), and 10.5% and 9.8%, respectively, were Hispanic or Latinx. Black participants were underrepresented. The percentages of participants with evidence of previous SARS-CoV-2 infection were 22.0% in the mRNA-1273.214 group and 26.8% in the mRNA-1273 group. The median time between the second dose of mRNA-1273 in the primary series and the first booster of mRNA-1273 was similar in the two groups (245 days [interquartile range, 224 to 275] in the mRNA-1273.214 group and 242 days [interquartile range, 225 to 260] in the mRNA-1273 group), as was the median time between the first booster dose of mRNA-1273 and the second booster dose (136 days [interquartile range, 118 to 150] and 134 days [interquartile range, 118 to 150], respectively).
Safety
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.
The median durations of follow-up were 43 days (interquartile range, 41 to 45) for the mRNA-1273.214 booster and 57 days (interquartile range, 56 to 62) for the mRNA-1273 booster. Occurrences of solicited adverse reactions within 7 days after the second booster dose were similar for mRNA-1273.214 and mRNA-1273 (Figure 2 and Table S3). The most frequent local adverse reaction after administration of both second boosters was injection-site pain, and the most frequent systemic reactions were fatigue, headache, myalgia, and arthralgia in both groups. The majority of solicited adverse reactions were mild to moderate (grades 1 and 2) for both boosters. Incidences of grade 3 events were similar in the two groups, and the most common such events were fatigue and myalgia. No grade 4 events occurred in either group.
Unsolicited adverse events regardless of the relationship to vaccination at least 28 days after the second booster doses occurred in 18.5% of the participants in the mRNA-1273.214 group and in 20.7% of those in the mRNA-1273 group (Table S4). The overall incidences of adverse events that were considered by the investigator to be related to study vaccination were 5.7% and 5.8% in the respective groups. Serious adverse events were observed in two participants in the mRNA-1273.214 group (prostate cancer and traumatic fracture) and in one participant in the mRNA-1273 group (spinal osteoarthritis); none were considered to be related to study vaccination. Medically attended adverse events occurred in 9.8% of mRNA-1273.214 participants and in 13.8% of mRNA-1273 participants. Medically attended adverse events that were considered to be related to study vaccination occurred in two participants (0.5%) in the mRNA-1273.214 group (grade 2 fatigue and grade 1 dermatitis) and in two participants (0.5%) in the mRNA-1273 group (hypertension and urticaria, both grade 1). No fatal events or adverse events leading to study discontinuation were observed. At the data-cutoff date, no deaths and no events of myocarditis or pericarditis occurred, and one additional serious adverse event (grade 3 nephrolithiasis), considered to be unrelated to study vaccination, was reported in the mRNA-1273.214 group.
Immunogenicity
Primary Immunogenicity Analysis of Ancestral SARS-CoV-2 (D614G) and Omicron after 50 μg of mRNA-1273.214 or mRNA-1273 as a Second Booster Dose in Participants with No Previous SARS-CoV-2 Infection.
In the primary analysis set of participants without evidence of previous SARS-CoV-2 infection, the observed geometric mean titers of neutralizing antibodies against ancestral SARS-CoV-2 (D614G) were 5977.3 (95% confidence interval [CI], 5321.9 to 6713.3) and 5649.3 (95% CI, 5056.8 to 6311.2) and against omicron were 2372.4 (95% CI, 2070.6 to 2718.2) and 1473.5 (95% CI, 1270.8 to 1708.4) 28 days after the mRNA-1273.214 and mRNA-1273 boosters, respectively (Table 2). Estimated geometric mean titers after adjustment for age groups and prebooster titers were 6422.3 (95% CI, 5990.1 to 6885.7) and 5286.6 (95% CI, 4887.1 to 5718.9) against ancestral SARS-CoV-2 (D614G) 28 days after the mRNA-1273.214 and mRNA-1273 boosters, respectively, with a geometric mean titer ratio of 1.22 (97.5% CI, 1.08 to 1.37), which met the prespecified criterion for noninferiority. Estimated geometric mean titers against omicron were 2479.9 (95% CI, 2264.5 to 2715.8) and 1421.2 (95% CI, 1283.0 to 1574.4) 28 days after the mRNA-1273.214 and mRNA-1273 booster doses, respectively, with a geometric mean titer ratio of 1.75 (97.5% CI, 1.49 to 2.04), which met the prespecified superiority criterion.
The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9 to 100) for mRNA-1273.214 and 100% (95% CI, 98.6 to 100) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. The percentages of participants with a seroresponse against omicron were 100% (95% CI, 98.9 to 100) for mRNA-1273.214 and 99.2% (95% CI, 97.2 to 99.9) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 1.5 percentage points (97.5% CI, −1.1 to 4.0), which met the noninferiority criterion. Therefore, the criteria for all primary and key secondary immunogenicity end points were met according to the prespecified testing sequence. The criteria for all immunogenicity end points were also met in the study participants overall, regardless of SARS-CoV-2 infection before the booster (Table S5).
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.
In participants with previous SARS-CoV-2 infection, geometric mean titers were higher after the mRNA-1273.214 booster than after the mRNA-1273 booster against both ancestral SARS-CoV-2 (D614G) and omicron, with geometric mean titer ratios of 1.27 (95% CI, 1.07 to 1.51) and 1.90 (95% CI, 1.50 to 2.40), respectively (Figure 3 and Tables S6 and S7). For both boosters, the percentage of participants with a seroresponse was 100% for ancestral SARS-CoV-2 (D614G) and omicron, and the difference was 0.
In participants without evidence of previous SARS-CoV-2 infection, the observed geometric mean titer of neutralizing antibodies against omicron BA.4/5 subvariants at 28 days after the mRNA-1273.214 booster (727.4 [95% CI, 632.8 to 836.1]) was higher than that after the mRNA-1273 booster (492.1 [95% CI, 431.1 to 561.9]), and the model-based geometric mean titer ratio was 1.69 (95% CI, 1.51 to 1.90) (Fig. S3 and Table S8). Similarly, geometric mean titers against the subvariants were higher after the mRNA-1273.214 booster than after the mRNA-1273 booster in participants with previous SARS-CoV-2 infection (2337.4 [95% CI, 1825.5 to 2992.9] vs. 1270.8 [95% CI, 987.3 to 1635.8]) and also in all participants regardless of previous SARS-CoV-2 infection (940.6 [95% CI, 826.3 to 1070.6] vs. 645.4 [95% CI, 570.1 to 730.6]), with corresponding geometric mean titer ratios of 1.60 (95% CI, 1.34 to 1.91) and 1.68 (1.52 to 1.84), both having lower boundaries of the confidence interval greater than 1.
In participants without evidence of previous SARS-CoV-2 infection, geometric mean levels of spike-binding antibody were higher (nominal alpha level, 0.05) after the mRNA-1273.214 booster than after the mRNA-1273 booster, and geometric mean titer ratios ranged from 1.11 (95% CI, 1.03 to 1.19) to 1.24 (95% CI, 1.14 to 1.35) across the ancestral SARS-CoV-2 (D614G) and omicron (BA.1), alpha, beta, gamma, and delta variants (Fig. S4 and Table S9). Similar geometric mean titer ratios were seen in all participants regardless of previous SARS-CoV-2 infection (Table S10). Observed geometric mean levels of spike-binding antibody are summarized in Table S11.
Incidence of SARS-CoV-2 Infection
Among all participants, starting 14 days after the booster and regardless of prebooster SARS-CoV-2 infection status, SARS-CoV-2 infection occurred in 11 participants (2.5%) in the mRNA-1273.214 group and in 9 participants (2.4%) in the mRNA-1273 group. Asymptomatic infection occurred in 6 participants (1.4%) in the mRNA-1273.214 group and in 7 participants (1.9%) in the mRNA-1273 group; Covid-19 according to the COVE trial definition occurred in 4 participants (0.9%) and in 2 participants (0.5%), respectively, and Covid-19 according to the Centers for Disease Control and Prevention (CDC) definition occurred in 5 participants (1.1%) and in 2 participants (0.5%), respectively.
In participants with no previous SARS-CoV-2 infection, infections occurred in 11 of 339 participants (3.2%) in the mRNA-1273.214 group and in 5 of 266 participants (1.9%) in the mRNA-1273 group after the booster (Table S12). Asymptomatic infection occurred in 6 participants (1.8%) in the mRNA-1273.214 group and in 4 participants (1.5%) in the mRNA-1273 group; Covid-19 according to the COVE trial definition occurred in 4 participants (1.2%) and in 1 participant (0.4%), respectively, and Covid-19 according to the CDC definition occurred in 5 participants (1.5%) and in 1 participant (0.4%), respectively.
There were three SARS-CoV-2 reinfections in the mRNA-1273 group. No emergency department visits or hospitalizations due to Covid-19 were seen.
