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Updated immunization strategies are needed to address multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here we report interim results from an ongoing, open-label phase 2/3 trial evaluating the safety and immunogenicity of the bivalent Coronavirus Disease 2019 (COVID-19) vaccine candidate mRNA-1273.211, which contains equal mRNA amounts encoding the ancestral SARS-CoV-2 and Beta variant spike proteins, as 50-µg (n = 300) and 100-µg (n = 595) first booster doses administered approximately 8.7–9.7 months after the mRNA-1273 primary vaccine series (NCT04927065). The primary objectives were to evaluate the safety and reactogenicity of mRNA-1273.211 and to demonstrate non-inferior antibody responses compared to the mRNA-1273 100-µg primary series. Additionally, a pre-specified immunogenicity objective was to demonstrate superior antibody responses compared to the previously authorized mRNA-1273 50-µg booster. The mRNA-1273.211 booster doses (50-µg or 100-µg) 28 days after immunization elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and Beta variant than those elicited 28 days after the second mRNA‑1273 dose of the primary series (NCT04470427). Antibody responses 28 days and 180 days after the 50-µg mRNA-1273.211 booster dose were also higher than those after a 50-µg mRNA-1273 booster dose (NCT04405076) against the ancestral SARS-CoV-2 and Beta, Omicron BA.1 and Delta variants, and all pre-specified immunogenicity objectives were met. The safety and reactogenicity profile of the bivalent mRNA-1273.211 booster (50-µg) was similar to the booster dose of mRNA-1273 (50-µg). Immunization with the primary series does not set a ceiling to the neutralizing antibody response, and a booster dose of the bivalent vaccine elicits a robust response with titers that are likely to be protective against COVID-19. These results indicate that bivalent booster vaccines can induce potent, durable and broad antibody responses against multiple variants, providing a new tool in response to emerging variants.

Background Messenger RNA (mRNA)–1273 vaccine demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial. The humoral immunogenicity results are now reported. Methods Participants received 2 mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a prespecified, randomly selected per-protocol immunogenicity population (n = 272 placebo; n = 1185 mRNA-1273). Serum binding antibodies (bAbs) and neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2–negative (n = 1197) and SARS-CoV-2–positive (n = 260) status, age, and sex. Results SARS-CoV-2–negative vaccinees had bAb geometric mean AU/mL levels of 35 753 at day 29 that increased to 316 448 at day 57 and nAb inhibitory dilution 50% titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2–positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410 049) and 27-fold (1479) higher than in SARS-CoV-2–negative vaccinees, respectively, and were comparable to levels after 2 injections in uninfected participants. Findings were generally consistent by age and sex. Conclusions mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2 status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously infected support a booster-type effect. Clinical Trials Registration. NCT04470427.

BackgroundOmicron-containing bivalent boosters are available worldwide. Results of a large, randomized, active-controlled study are presented.MethodsThis phase 3, randomized, observer-blind, active-controlled trial in the United Kingdom evaluated the immunogenicity and safety of 50-µg doses of omicron-BA.1-monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50-µg mRNA-1273 administered as boosters in individuals ≥16 years. Participants had previously received 2 doses of any authorized/approved Covid-19 vaccine with or without an mRNA vaccine booster. Safety and immunogenicity were primary objectives; immunogenicity was assessed in all participants, with analysis conducted based on prior infection status. Incidence of Covid-19 post-boost was a secondary (mRNA-1273.214) or exploratory (mRNA-1273.529) objective.ResultsIn part 1 of the study, 719 participants received mRNA-1273.529 (n=362) or mRNA-1273 (n=357); in part 2, 2813 received mRNA-1273.214 (n=1418) or mRNA-1273 (n=1395). Median durations (months [interquartile range]) between the most recent Covid-19 vaccine and study boosters were similar in the mRNA-1273.529 (4.0 [3.6-4.7]) and mRNA-1273 (4.1 [3.5-4.7]) (part 1), and mRNA-1273.214 (5.5 [4.8-6.2] and mRNA-1273 (5.4 [4.8-6.2]) groups (part 2).Both mRNA-1273.529 and mRNA-1273.214 elicited superior neutralizing antibody responses against omicron BA.1 with geometric mean ratios (99% CIs) of 1.68 (1.45-1.95) and 1.53 (1.41-1.67) compared to mRNA-1273 at day 29 post-boost. Although the study was not powered to assess relative vaccine efficacy, the incidence rates/1000 person years (95% CI) of Covid-19 trended lower with mRNA-1273.529 (670.5 [528.3-839.3]) than mRNA-1273 (769.3 [615.4-950.1]) and mRNA-1273.214 (633.0 [538.1-739.7]) than mRNA-1273 (711.6 [607.5-828.5]).Sequence analysis in part 2 showed that this was driven by lower incidence of Covid-19 in the mRNA-1273.214 cohort with BA.2 and BA.4 sublineages but not BA.5 sublineages. All study boosters were well-tolerated.ConclusionThe bivalent omicron BA.1-containing booster elicited superior neutralizing antibody responses against omicron BA.1 with acceptable safety results consistent with the BA.1 monovalent vaccine. Incidence rates for Covid-19 were numerically lower in participants who received mRNA-1273.214 compared to the original booster vaccine mRNA-1273, driven by the BA.2 and BA.4 sublineages.

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-μg mRNA-1273.222 (25-μg each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-μg mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-μg) primary series and first booster (50-μg) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost.ResultsParticipants received 50-μg 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.govIdentifier:NCT04927065)

Background Vaccination strategies that provide enhanced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are needed. We evaluated the safety and immunogenicity of a bivalent omicron containing vaccine, mRNA-1273.214 (50 µg), administered as a second booster dose in adult participants. Methods In this ongoing phase 2/3 trial, 50 µg of the bivalent vaccine mRNA-1273.214 (25 µg each ancestral Wuhan-Hu-1 and omicron BA.1 spike mRNAs) or 50 µg of the authorized mRNA-1273 were administered as second boosters in adults who previously received a 2 dose (100 µg) primary series and a first booster (50 µg) dose of mRNA-1273 (≥ 3 months prior). Primary objectives were safety and reactogenicity and immunogenicity 28 days post-booster dose. Results In participants with no prior SARS-CoV-2 infection who received booster doses of mRNA-1273.214 (n=334) or mRNA-1273 (n=260), neutralizing antibody (nAb) geometric mean titers (GMTs [95% confidence interval (CI)]) against omicron BA.1 were 2372.4 (2070.6−2718.2) and 1473.5 (1270.8−1708.4), respectively. The model-based GMT ratio (GMR [97.5% CI]) of mRNA-1273.214 compared to mRNA-1273 was 1.75 (1.49−2.04), meeting the pre-specified superiority criterion against omicron BA.1. The pre-specified criterion for non-inferiority against the ancestral SARS-CoV-2 strain was also met. Additionally, mRNA-1273.214 elicited higher GMTs (727.4 [632.8−836.1]) than mRNA-1273 (492.1 [431.1−561.9]) against omicron subvariants BA.4/BA.5 [GMR (95% CI) 1.69 [1.51−1.90])]. Binding antibody responses against alpha, beta, gamma, delta, and omicron were numerically higher in the mRNA-1273.214 group compared to mRNA-1273. mRNA-1273.214 GMTs were consistently higher across age (18-< 65 and ≥ 65 years) and pre-booster SARS-CoV-2 infection subgroups (Figure). Safety and reactogenicity were similar for both vaccine groups. Conclusion The bivalent omicron containing mRNA-1273.214 elicited superior nAb responses against omicron 28 days post-immunization compared to mRNA-1273 regardless of age and prior SARS-CoV-2 infection; no new safety concerns were identified. Disclosures Spyros Chalkias, MD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Stephen R. Walsh, MD, Janssen Vaccines: Grant/Research Support|Moderna, Inc.: Grant/Research Support|NIAID/NIH: Grant/Research Support|Sanofi Pasteur: Grant/Research Support Nichole McGhee, B.S., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Joanne Tomassini, Ph.D., Moderna, Inc.: Advisor/Consultant Xing Chen, Sc.D., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Ying Chang, M.S., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Andrea Sutherland, M.D., MPH, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds David Montefiori, Ph.D., Moderna, Inc.: Grant/Research Support Bethany Girard, Ph.D., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Darin Edwards, Ph.D., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Jing Feng, M.S., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Honghong Zhou, Ph.D., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Lindsey R. Baden, MD, Moderna, Inc.: Grant/Research Support|NIAID: Grant/Research Support Jacqueline Miller, MD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Rituparna Das, M.D., Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds.

We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study 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. Here we present day 91 post-booster results. Participants were sequentially enrolled to receive 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. In participants with no pre-booster severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-neutralizing antibody titers that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar between boosters 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 induced improved antibody persistence compared to mRNA-1273.

The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown.Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo.On the basis of safety and immunogenicity results in part 1 of the trial, the 25-μg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-μg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-μg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant.Two 25-μg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

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-μg bivalent vaccine mRNA-1273.214 (25-μg each ancestral Wuhan-Hu-1 and omicron B.1.1.529 spike SARS-CoV-2 mRNAs) was compared to the authorized 50-μg mRNA-1273 booster in adults who previously received 2-dose primary series of 100-μg mRNA-1273 and a first booster dose of 50-μg mRNA-1273 at least 3 months prior. Primary objectives were safety and reactogenicity, and immunogenicity of 50-μg mRNA-1273.214 compared with 50-μg mRNA-1273. Immunogenicity data 28 days after the booster dose are presented.ResultsFour hundred thirty-seven and 377 participants received 50-μg 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-μg 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-μg was well-tolerated and elicited a superior neutralizing antibody response against omicron, compared to mRNA-1273 50-μg, 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.

Immunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons.To evaluate antinucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection.Nested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427).99 sites in the United States, July 2020 through March 2021.Participants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase.2 mRNA-1273 or placebo injections 28 days apart.Nasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay.Among 812 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% [95% CI, 27% to 54%]) versus 605 of 648 placebo recipients (93% [CI, 92% to 95%]). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 [CI, 1.59 to 2.28]).The scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial.Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing.National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

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 trial’s 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 testingTrial RegistrationClinicalTrials.govNCT04470427Key PointsQuestionDoes 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.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have caused multiple waves of infection globally. This phase 2/3 study evaluated the safety and immunogenicity of the bivalent vaccine candidate mRNA-1273.211 (equal mRNA amounts of ancestral SARS-CoV-2 and Beta variant spike proteins) as 50-µg (n=300) and 100-µg (n=595) first booster doses approximately 8.8-9.8 months after the mRNA-1273 primary series. The mRNA-1273.211 booster (50 and 100-µg) elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and the Beta variant than that after the second mRNA‑1273 dose. Antibody responses after the 50-µg mRNA-1273.211 booster dose were also higher than that after a 50-µg mRNA-1273 booster dose for the ancestral SARS-CoV-2, Beta, Omicron and Delta variants (28 days after the booster dose) and for the ancestral SARS-CoV-2, Beta and Omicron (180 days after the booster dose), and the immunogenicity objectives were met. The safety and reactogenicity profile of the mRNA-1273.211 booster (50-µg) was comparable to mRNA-1273 (50-µg). These results indicate that bivalent booster vaccines can induce potent and durable antibody responses providing a new tool in response to emerging variants. Trial registration: https://www.clinicaltrials.gov NCT04927065

The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in a pseudovirus assay in two different laboratories. Omicron was 49-84-fold less sensitive to neutralization than D614G and 5.3-6.2-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 µg mRNA-1273. A 50 µg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.

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 µg mRNA-1273 and from children (6-ResultsAt 4 weeks following a second dose of mRNA-1273 (100 µg), 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 µg), and compared with adults, were 1.5- and 3.8-fold higher for D614G and the Omicron variant, respectively. In children (6-ConclusionsA two-dose regimen of 100 µg mRNA-1273 in adolescents and of 50 µg 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.

Following 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.Covid-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.There 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.Incidence 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.

Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6–8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 (NCT04405076). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.

Rising breakthrough infections of coronavirus-2 (SARS-CoV-2) in previously immunized individuals has raised concerns for a booster to combat suspected waning immunity and new variants. Participants immunized 6-8 months earlier with a primary series of two doses of 50 or 100 µg of mRNA-1273 were administered a booster injection of 50 µg of mRNA-1273. Neutralizing antibody levels against wild-type virus and the Delta variant at one month after the booster were 1.7-fold and 2.1-fold higher, respectively, than those 28 days post primary series second injection indicating an immune memory response. The reactogenicity after the booster dose was similar to that after the second dose in the primary series of two doses of mRNA-1273 (50 or 100 µg) with no serious adverse events reported in the one-month follow-up period. These results demonstrate that a booster injection of mRNA-1273 in previously immunized individuals stimulated an immune response greater than the primary vaccination series.

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.

Background The incidence of coronavirus disease 2019 (Covid-19) among adolescents between 12 and 17 years of age was approximately 900 per 100,000 population from April 1 through June 11, 2021. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in adolescents are unknown. Methods In this ongoing phase 2–3, placebo-controlled trial, we randomly assigned healthy adolescents (12 to 17 years of age) in a 2:1 ratio to receive two injections of the mRNA-1273 vaccine (100 μg in each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of mRNA-1273 in adolescents and the noninferiority of the immune response in adolescents as compared with that in young adults (18 to 25 years of age) in a phase 3 trial. Secondary objectives included the efficacy of mRNA-1273 in preventing Covid-19 or asymptomatic severe acute respiratory syndrome coronavirus 2 infection. Results A total of 3732 participants were randomly assigned to receive mRNA-1273 (2489 participants) or placebo (1243 participants). In the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted. The geometric mean titer ratio of pseudovirus neutralizing antibody titers in adolescents relative to young adults was 1.08 (95% confidence interval [CI], 0.94 to 1.24), and the absolute difference in serologic response was 0.2 percentage points (95% CI, −1.8 to 2.4), which met the noninferiority criterion. No cases of Covid-19 with an onset of 14 days after the second injection were reported in the mRNA-1273 group, and four cases occurred in the placebo group. Conclusions The mRNA-1273 vaccine had an acceptable safety profile in adolescents. The immune response was similar to that in young adults, and the vaccine was efficacious in preventing Covid-19. (Funded by Moderna and the Biomedical Advanced Research and Development Authority; Teen COVE ClinicalTrials.gov number, NCT04649151.)