Interim report of the reactogenicity and immunogenicity of SARS-CoV-2 XBB-containing vaccines.

BACKGROUND: Monovalent Omicron XBB.1.5-containing vaccines were approved for Coronavirus disease 2019 (COVID-19) 2023-2024 immunizations. METHODS: This ongoing, open-label, phase 2/3 study evaluated mRNA-1273.815-monovalent (50-µg Omicron XBB.1.5-spike mRNA) and mRNA-1273.231-bivalent (25-µg each Omicron XBB.1.5- and BA.4/BA.5-spike mRNAs))vaccines, administered as 5th doses to adults who previously received a primary series, a 3rd dose of an original mRNA COVID-19 vaccine, and a 4th dose of an Omicron BA.4/BA.5 bivalent vaccine. Interim safety and immunogenicity results 29 days post-vaccination are reported. RESULTS: Participants (randomized 1:1) received 50-µg mRNA-1273.815(n=50) or mRNA-1273.231(n=51); median (interquartile range) months from the prior BA.4/BA.5-bivalent dose were 8.2 (8.1-8.3) and 8.3 (8.1-8.4), respectively. Neutralizing antibody (nAb) increased from pre-booster levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants tested. Day 29 nAb fold-increases from pre-booster levels were numerically higher against XBB.1.5, XBB.1.16, EG.5.1, BA.2.86, and JN.1 than BA.4/BA.5, BQ.1.1 and D614G. The monovalent vaccine also cross-neutralized FL.1.5.1, EG.5.1, BA.2.86, HK.3.1, HV.1 and JN.1 variants in a participant (n=20) subset, 15 days post-vaccination. Reactogenicity was similar to previously reported mRNA-1273 original and bivalent vaccines. CONCLUSIONS: XBB.1.5-containing mRNA-1273 vaccines elicit robust, diverse nAb responses against more recent SARS-CoV-2 variants including JN.1, supporting the XBB.1.5-spike sequence selection for the 2023-2024 COVID-19 vaccine update.

Three-month antibody persistence of a bivalent Omicron-containing booster vaccine against COVID-19.

We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study (NCT04927065) comparing the Omicron-BA.1-containing bivalent vaccine mRNA-1273.214 (50-µg) to the 50-µg mRNA-1273 booster in adults who previously received the mRNA-1273 primary series (100-µg) and mRNA-1273 first booster (50-µg) dose. Primary endpoints were safety, non-inferiority of the neutralizing antibody (nAb) and seroresponse against Omicron BA.1, superiority of the nAb response against Omicron-BA.1, and non-inferiority of the nAb response against ancestral SARS-CoV-2 for second boosters of mRNA-1273.214 versus mRNA-1273 at days 29 and 91. The key secondary endpoint was the seroresponse difference of mRNA-1273.214 versus mRNA-1273 against ancestral SARS-CoV-2 at days 29 and day 91. Participants were sequentially enrolled and dosed with 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. Here we present day 91 post-booster results. In participants with no pre-booster, severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-nAb titers (95% confidence interval [CI]) that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar to those of mRNA-1273 against ancestral SARS-CoV-2 at day 91. mRNA-1273.214 also induced higher binding antibody responses against Omicron BA.1 and alpha, gamma and delta variants than mRNA-1273. Safety profiles were similar for both vaccines. The Omicron-BA.1 bivalent vaccine improved antibody responses compared to mRNA-1273 through 90 days post-booster.

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

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.

A Bivalent Omicron-Containing Booster Vaccine against Covid-19.

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.).