Immunogenicity analysis
infection, SARS-CoV-2 infection
INFECTION, SARS-COV-2 INFECTION
The primary immunogenicity objectives were evaluated using a prespecified hierarchical approach which compared 50 µg mRNA-1273.222 to 50 µg mRNA-1273 (active control arm in part F, Cohort 2) as second booster doses (Supplementary Fig. 50 µg mRNA-1273.222, as a second booster dose, against Omicron BA.4/5 is noninferior to the second booster dose of (50 µg) mRNA-1273 against Omicron BA.4/5 based on the GMT ratio of mRNA-1273.222 against Omicron BA.4/5 at Day 29 compared to mRNA-1273 against Omicron BA.4/5 at Day 29 with a noninferiority margin of 1.5.50 μg mRNA-1273.222, as a second booster dose, against Omicron BA.4/5 is noninferior to the second booster dose of (50 μg) mRNA-1273 against Omicron BA.4/5 based on the difference in SRR at Day 29 with a noninferiority margin, ifthe lower bound of the 95% CI of the SRR difference (50 μg mRNA-1273.222 against Omicron BA.4/5 at Day 29 - 50 μg mRNA-1273 against Omicron BA.4/5 at Day 29) is >-5%, then the noninferiority of mRNA-1273.222 against Omicron BA. 4/5 compared to that of mRNA-1273 is demonstrated based on a noninferiority margin of 5%.the lower bound of the 95% CI of the seroresponse difference (50 μg mRNA-1273.222 against Omicron BA.4/5 at day 29 - 50 μg mRNA-1273 against Omicron BA.4/5 at day 29) is >-10% but  ≤-5%, then noninferiority of mRNA-1273.222 against Omicron BA. 4/5 compared to that of mRNA-1273 is demonstrated based on a noninferiority margin of 10%.50 μg mRNA-1273.222, as a second booster dose, against the ancestral SARS-CoV-2 D614G is noninferior to the second booster dose of (50 μg) mRNA-1273 against the ancestral SARS-CoV-2 D614G based on the GMT ratio of mRNA-1273.222 against the ancestral SARS-CoV-2 D614G at day 29 compared to mRNA-1273 against the ancestral SARS-CoV-2 D614G at day 29 with a noninferiority margin of 1.5.50 μg mRNA-1273.222, as a second booster dose, against the ancestral SARS-CoV-2 D614G is noninferior to the second booster dose of (50 μg) mRNA-1273 against ancestral SARS-CoV-2 D614G based on the difference in SRR at day 29 with a noninferiority margin of 10%.50 μg mRNA-1273.222, as a second booster dose, against the Omicron BA.4/BA.5 is superior to the second booster dose of (50 μg) mRNA-1273 against Omicron BA.4/BA.5 day 29.The primary immunogenicity objectives were assessed in the per-protocol immunogenicity-SARS-CoV-2-negative set with a target enrollment of approximately 500 participants for 50 μg mRNA-1273.222. Assuming 40% of participants were excluded from the per-protocol immunogenicity-SARS-CoV-2-negative set (due to a SARS-CoV-2 infection prebooster), with approximately 300 participants in the 50 μg mRNA-1273.222 and 260 participants in the 50 μg mRNA-1273 (Part F, Cohort 2–50 μg mRNA-1273) arms in the per-protocol immunogenicity-SARS-CoV-2-negative set, there is approximately 60% power to demonstrate the primary immunogenicity objectives with an alpha of 0.05 (two-sided) at day 29. The assumptions were that the true GMR (mRNA-1273.222 second booster versus mRNA-1273 second booster) against Omicron BA.4/5 is 1.5, GMR (mRNA-1273.222 second booster versus mRNA-1273 second booster) against ancestral SARS-CoV-2 D614G is 1, the standard deviation of the log-transformed titer is 1.5 and the noninferiority margin for GMR is 1.5. The true SRR against Omicron BA.4/5 after mRNA-1273.222 as a second booster dose is 95% (same assumption for 50 μg mRNA-1273), and noninferiority margin for SRR difference against Omicron BA.4/5 is 5%. The true SRR against ancestral SARS-CoV-2 D614G after mRNA-1273.222 as a second booster dose is 95% (same assumption for 50 μg mRNA-1273), and the noninferiority margin for SRR difference against ancestral SARS-CoV-2 D614G is 10%.For the primary immunogenicity objective, an interim analysis was planned at day 29 with a two-sided alpha (0.05) allocated for immunogenicity hypothesis testing. The primary immunogenicity objective was considered met for noninferiority when the lower bound of the 95 CI of the GMR was >0.667 and the SRR difference is >-10%. Superiority was considered met when the lower bound of the 95 CI of GMR is >1. These noninferiority and superiority criteria were chosen based on FDA guidelinesObserved GMTs (95% CI) using Seroresponse is defined as ≥4 × lower limit of quantification (LLOQ) for those with baseline <LLOQ; ≥fourfold rise for those baseline ≥LLOQ. Seroresponse was derived based on prevaccination (preinjection 1 of the primary series) and prebooster baselines Seroresponse, based on change (fold-rise) from preinjection 1 of the primary series, was considered the primary approach for seroresponse. For participants without preinjection 1 antibody titer information, seroresponse was defined as ≥4× LLOQ for those with negative SARS-CoV-2 status at preinjection 1 of the primary series, and antibody titers were imputed as <LLOQ at preinjection 1 of primary series. For participants who were without SARS-CoV-2 status information at preinjection 1 of the primary series, their prebooster SARS-CoV-2 status was used to impute their SARS-CoV-2 status at preinjection 1.The SRR of each arm against ancestral SARS-CoV-2 (D614G) and variants, defined as the percentage of participants achieving seroresponse against ancestral SARS-CoV-2 (D614G) and variants, respectively, are provided for each arm with the 95% CI calculated using the Clopper–Pearson method. The differences of SRR between mRNA-1273.222 and mRNA-1273 were calculated with 95% CI based on the stratified Miettinen–Nurminen method adjusting for age groups.An analysis of the primary immunogenicity endpoints was also performed in the per-protocol set for immunogenicity (participants with and without evidence of prior SARS-CoV-2 infection prebooster), using an ANCOVA model, with antibody titers at day 29 post booster as the dependent variable and the vaccine group variable as the fixed effect, adjusting for age groups (<65, ≥65 years), prebooster SARS-CoV-2 infection status and prebooster titers. The seroresponse difference between the mRNA-1273.222 and mRNA-1273 groups was calculated with 95% CI based on stratified Miettinen–Nurminen method adjusted for the prebooster SARS-CoV-2 infection status and age group. A preplanned subgroup analysis of participants with prior evidence of SARS-CoV-2 infection prebooster was performed using an ANCOVA model to assess nAb differences between the mRNA-1273.222 and mRNA-1273 groups based on GMRs with 95% CIs. Lastly, a sensitivity analysis was performed excluding the participants with evidence of SARS-CoV-2 infection after the booster dose. Evidence of prior SARS-CoV-2 infection was defined as a negative binding antibody test against SARS-CoV-2 nucleocapsid and a negative RT–PCR at booster day 1 and participants who had evidence of SARS-CoV-2 infection defined as a positive binding antibody test against SARS-CoV-2 nucleocapsid or positive RT–PCR at booster day 1.Immunogenicity analyses included assessment of the observed bAb GM levels against SARS-CoV-2 variants and bAb comparisons between mRNA-1273.222 and mRNA-1273 based on ANCOVA-estimated antibody levels and GMRs (95% CIs). A posthoc analysis of immunogenicity against Omicron BQ.1.1 and XBB.1 variants that emerged during the study was additionally explored in random samples of recipients (Pseudovirus neutralizing antibodies against BQ.1.1, XBB.1 and XBB.1.5 were assessed in subsets of recipients (Additionally, the effect of time intervals between the first booster dose of mRNA-1273 and second booster doses of mRNA-1273 and mRNA-1273.222 on neutralizing antibody responses against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 (D614G) post boost were explored in participants without previous infection grouped by quartiles of dosing intervals within each booster vaccine group, and GMT and GMFR at day 29 were summarized.