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BackgroundInformation on the safety and immunogenicity of the omicron BA.4/BA.5-containing bivalent booster mRNA-1273.222 are needed. MethodsIn this ongoing, phase 2/3 trial, 50-g mRNA-1273.222 (25-g each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-g mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-g) primary series and first booster (50-g) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost. ResultsParticipants received 50-g of mRNA-1273 (n=376) or mRNA-1273.222 (n=511) as second booster doses. Omicron BA.4/BA.5 and ancestral SARS-CoV-2 D614G neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after mRNA-1273.222 (2324.6 [1921.2-2812.7] and 7322.4 [6386.2-8395.7]) were significantly higher than mRNA-1273 (488.5 [427.4-558.4] and 5651.4 (5055.7-6317.3) respectively, at day 29 post-boost in participants with no prior SARS-CoV-2-infection. A randomly selected subgroup (N=60) of participants in the mRNA-1273.222 group also exhibited cross-neutralization against the emerging omicron variants BQ.1.1 and XBB.1. No new safety concerns were identified with mRNA-1273.222. Vaccine effectiveness was not assessed in this study; in an exploratory analysis 1.6% (8/511) of mRNA-1273.222 recipients had Covid-19 post-boost. ConclusionThe bivalent omicron BA.4/BA.5-containing vaccine mRNA-1273.222 elicited superior neutralizing antibody responses against BA.4/BA.5 compared to mRNA-1273, with no safety concerns identified. (Supported by Moderna; ClinicalTrials.gov Identifier: NCT04927065)
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BackgroundUpdated vaccination strategies against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern are needed. Interim results of the safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster candidate are presented. MethodsIn this ongoing, phase 2/3 trial, the 50-g bivalent vaccine mRNA-1273.214 (25-g each ancestral Wuhan-Hu-1 and omicron B.1.1.529 spike SARS-CoV-2 mRNAs) was compared to the authorized 50-g mRNA-1273 booster in adults who previously received 2-dose primary series of 100-g mRNA-1273 and a first booster dose of 50-g mRNA-1273 at least 3 months prior. Primary objectives were safety and reactogenicity, and immunogenicity of 50-g mRNA-1273.214 compared with 50-g mRNA-1273. Immunogenicity data 28 days after the booster dose are presented. ResultsFour hundred thirty-seven and 377 participants received 50-g of mRNA-1273.214, or mRNA-1273, respectively. Median time between first and second booster doses of mRNA-1273.214 and mRNA-1273 were similar (136 and 134 days, respectively). In participants with no prior SARS-CoV-2 infection, observed omicron neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after the mRNA-1273.214 and mRNA-1273 booster doses, were 2372.4 (2070.6-2718.2) and 1473.5 (1270.8-1708.4) respectively and the model-based GMT ratio (97.5% confidence interval) was 1.75 (1.49-2.04). All pre-specified non-inferiority (ancestral SARS-CoV-2 with D614G mutation [D614G] GMT ratio; ancestral SARS-CoV-2 [D614G] and omicron seroresponse rates difference) and superiority primary objectives (omicron GMT ratio) for mRNA-1273.214 compared to mRNA-1273 were met. Additionally, mRNA-1273.214 50-g induced a potent neutralizing antibody response against omicron subvariants BA.4/BA.5 and higher binding antibody responses against alpha, beta, gamma, delta and omicron variants. Safety and reactogenicity profiles were similar and well-tolerated for both vaccines groups. ConclusionThe bivalent vaccine mRNA-1273.214 50-g was well-tolerated and elicited a superior neutralizing antibody response against omicron, compared to mRNA-1273 50-g, and a non-inferior neutralizing antibody response against the ancestral SARS-CoV-2 (D614G), 28 days after immunization, creating a new tool as we respond to emerging SARS-CoV-2 variants.
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ImportanceThe performance of immunoassays for determining past SARS-CoV-2 infection, which were developed in unvaccinated individuals, has not been assessed in vaccinated individuals. ObjectiveTo evaluate anti-nucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 vaccine efficacy trial participants after SARS-CoV-2 infection during the trials blinded phase. DesignNested analysis in a Phase 3 randomized, placebo-controlled vaccine efficacy trial. Nasopharyngeal swabs for SARS-CoV-2 PCR testing were taken from all participants on Day 1 and Day 29 (vaccination days), and during symptom-prompted illness visits. Serum samples from Days 1, 29, 57, and the Participant Decision Visit (PDV, when participants were informed of treatment assignment, median day 149) were tested for anti-N Abs. SettingMulticenter, randomized, double-blind, placebo-controlled trial at 99 sites in the US. ParticipantsTrial participants were [≥] 18 years old with no known history of SARS-CoV-2 infection and at appreciable risk of SARS-CoV-2 infection and/or high risk of severe Covid-19. Nested sub-study consists of participants with SARS-CoV-2 infection during the blinded phase of the trial. InterventionTwo mRNA-1273 (Moderna) or Placebo injections, 28 days apart. Main Outcome and MeasureDetection of serum anti-N Abs by the Elecsys (Roche) immunoassay in samples taken at the PDV from participants with SARS-CoV-2 infection during the blinded phase. The hypothesis tested was that mRNA-1273 recipients have different anti-N Ab seroconversion and/or seroreversion profiles after SARS-CoV-2 infection, compared to placebo recipients. The hypothesis was formed during data collection; all main analyses were pre-specified before being conducted. ResultsWe analyzed data from 1,789 participants (1,298 placebo recipients and 491 vaccine recipients) with SARS-CoV-2 infection during the blinded phase (through March 2021). Among participants with PCR-confirmed Covid-19 illness, seroconversion to anti-N Abs at a median follow up of 53 days post diagnosis occurred in 21/52 (40%) of the mRNA-1273 vaccine recipients vs. 605/648 (93%) of the placebo recipients (p < 0.001). Higher SARS-CoV-2 viral copies at diagnosis was associated with a higher likelihood of anti-N Ab seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). Conclusions and RelevanceAs a marker of recent infection, anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected. Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing Trial RegistrationClinicalTrials.gov NCT04470427 Key PointsO_ST_ABSQuestionC_ST_ABSDoes prior mRNA-1273 vaccination influence anti-nucleocapsid antibody seroconversion and/or seroreversion after SARS-CoV-2 infection? FindingsAmong participants in the mRNA-1273 vaccine efficacy trial with PCR-confirmed Covid-19, anti-nucleocapsid antibody seroconversion at the time of study unblinding (median 53 days post diagnosis and 149 days post enrollment) occurred in 40% of the mRNA-1273 vaccine recipients vs. 93% of the placebo recipients, a significant difference. Higher SARS-CoV-2 viral copy number upon diagnosis was associated with a greater chance of anti-nucleocapsid antibody seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). All infections analyzed occurred prior to the circulation of delta and omicron viral variants. MeaningConclusions about the prevalence and incidence of SARS-CoV-2 infection in vaccinated persons based on anti-nucleocapsid antibody assays need to be weighed in the context of these results.
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ImportanceDue to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed. ObjectivesEvaluate safety and immunogenicity of 100-{micro}g of mRNA-1273 booster dose in adults. DesignOpen-label, Phase 2/3 study. SettingMulticenter study at 8 sites in the U.S. ParticipantsThe mRNA-1273 100-{micro}g booster was administered to adults who previously received a two dose primary series of 100-{micro}g mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. InterventionLipid nanoparticle containing 100-{micro}g of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1). Main Outcomes and MeasuresSolicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated. ResultsThe 100-{micro}g booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-{micro}g mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-{micro}g booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-{micro}g booster of mRNA-1273. Conclusions and RelevanceThe 100-{micro}g mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-{micro}g booster dose compared to the authorized booster dose level in adults (50-{micro}g). mRNA-1273 100-{micro}g booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065 Key PointsQuestion: What is the safety and immunogenicity of a booster dose of 100 {micro}g of mRNA-1273 in adults who previously received the primary series of mRNA-1273? Findings: In this open-label, Phase 2/3 study, the 100 {micro}g booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 {micro}g booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 {micro}g booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants. Meaning: mRNA-1273 100 {micro}g booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.
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The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant has led to growing concerns of increased transmissibility and escape of both natural and vaccine-induced immunity. In this analysis, sera from adult participants in a phase 2 clinical study (NCT04405076) were tested for neutralizing activity against B.1.1.529 after a 2-dose (100 {micro}g) mRNA-1273 primary vaccination series and after a 50-{micro}g mRNA-1273 booster dose. Results from this preliminary analysis show that 1 month after completing the primary series, mRNA-1273-elicited serum neutralization of B.1.1.529 was below the lower limit of quantification; however, neutralization was observed at 2 weeks after the mRNA-1273 booster dose, although at a reduced level relative to wild-type SARS-CoV-2 (D614G) and lower than that observed against D614G at 1 month after the primary series.
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BackgroundThe highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant is a global concern. This study assessed the neutralization activity of two-dose regimens of mRNA-1273 vaccination against Omicron in adults, adolescents and children. MethodsNeutralizing activity against the Omicron variant was evaluated in serum samples from adults ([≥]18 years) in the phase 3, Coronavirus Efficacy (COVE) and from adolescents (12-17 years) in the TeenCOVE trials following a two-dose regimen of 100 {micro}g mRNA-1273 and from children (6-<12 years) in the KidCOVE trial administered two doses of 50 {micro}g mRNA-1273. Neutralizing antibody geometric mean ID50 titers (GMT) were measured using a lentivirus-based pseudovirus neutralizing assay at day 1 and 4 weeks (day 57) following the second mRNA-1273 dose, compared with wild-type (D614G). ResultsAt 4 weeks following a second dose of mRNA-1273 (100 {micro}g), the GMT was reduced 28.8-fold compared with D614G in adults ([≥]18 years). In adolescents (12-17 years), the GMT was 11.8-fold lower than D614G, 4 weeks after a second dose of mRNA-1273 (100 {micro}g), and compared with adults, were 1.5- and 3.8-fold higher for D614G and the Omicron variant, respectively. In children (6-<12 years), 4 weeks post-second dose of 50 {micro}g mRNA-1273, Omicron GMTs were reduced 22.1-fold versus D614G and were 2.0-fold higher for D614G and 2.5-fold higher for Omicron compared with adults. ConclusionsA two-dose regimen of 100 {micro}g mRNA-1273 in adolescents and of 50 {micro}g in children elicited neutralization responses against the Omicron variant that were reduced compared with the wild-type D614G, and numerically higher than those in adults.
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This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, which has not been assessed in this study.
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BackgroundFollowing emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase, with a focus on July-August 2021, when delta-variants surged in the US. MethodsCovid-19 cases were identified in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to-treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed. ResultsThere were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group [36.4% (95% CI 17.1%-51.5%) reduction]. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) [46.0% (95% CI -52.4%-83.2%) reduction]. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group. ConclusionIncidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.
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BackgroundIn the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection. MethodsThrough case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors. ResultsDay 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.42 (0.27, 0.65; p<0.001); 0.35 (0.20, 0.61; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%). ConclusionsBinding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19. Trial registration numberCOVE ClinicalTrials.gov number, NCT04470427
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BackgroundSeveral candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known. MethodsFollowing vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease. ResultsPost-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods. ConclusionsWe advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.
