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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., (© 2023. Moderna, Inc.)

The mRNA-1273 vaccine for coronavirus disease 2019 (COVID-19) demonstrated 93.2% efficacy in reduction of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the blinded portion of the Phase 3 Coronavirus Efficacy (COVE) trial. While mRNA-1273 demonstrated high efficacy in prevention of COVID-19, including severe disease, its effect on the viral dynamics of SARS-CoV-2 infections is not understood. Here, in exploratory analyses, we assessed the impact of mRNA-1273 vaccination in the ongoing COVE trial (number NCT04470427) on SARS-CoV-2 copy number and shedding, burden of disease and infection, and viral variants. Viral variants were sequenced in all COVID-19 and adjudicated COVID-19 cases (n = 832), from July 2020 in the blinded part A of the study to May 2021 of the open-label part B of the study, in which participants in the placebo arm started to receive the mRNA-1273 vaccine after US Food and Drug Administration emergency use authorization of mRNA-1273 in December 2020. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval) by 100-fold on the day of diagnosis compared with placebo (4.1 (3.4-4.8) versus 6.2 (6.0-6.4) log 10 copies per ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 days for placebo. Vaccination also substantially reduced the burden of disease and infection scores. Vaccine efficacies (95% confidence interval) against SARS-CoV-2 variants circulating in the United States during the trial assessed in this post hoc analysis were 82.4% (40.4-94.8%) for variants Epsilon and Gamma and 81.2% (36.1-94.5%) for Epsilon. The detection of other, non-SARS-CoV-2, respiratory viruses during the trial was similar between groups. While additional study is needed, these data show that in SARS-CoV-2-infected individuals, vaccination reduced both the viral copy number and duration of detectable viral RNA, which may be markers for the risk of virus transmission., (© 2022. The Author(s).)

Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg -1 , or two weekly doses at 0.3 mg kg -1 . At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml -1 ) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg -1 (mean t 1/2 approximately 69 d). A second 0.3 mg kg -1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted., (© 2021. The Author(s).)