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1.
J Infect Dis ; 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1886452

ABSTRACT

BACKGROUND: 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 two mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a pre-specified, randomly-selected per-protocol immunogenicity population (n = 272 placebo; n = 1,185 mRNA-1273). Serum binding (bAb) and neutralizing (nAb) antibodies 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 = 1,197) and -positive (n = 260) status, age and sex. RESULTS: SARS-CoV-2-negative vaccinees had bAb geometric mean (GM) AU/ml levels of 35,753 at day 29 that increased to 316,448 at day 57 and nAb ID50 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 (1,479) higher than in SARS-CoV-2-negative vaccinees, respectively, and were comparable to levels after two injections in uninfected participants. Findings were generally consistent by age and sex. CONCLUSION: 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.ClinicalTrials.gov: NCT04470427.

2.
N Engl J Med ; 386(21): 2011-2023, 2022 05 26.
Article in English | MEDLINE | ID: covidwho-1839612

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).


Subject(s)
2019-nCoV Vaccine mRNA-1273 , COVID-19 , 2019-nCoV Vaccine mRNA-1273/adverse effects , 2019-nCoV Vaccine mRNA-1273/immunology , 2019-nCoV Vaccine mRNA-1273/therapeutic use , Adolescent , Adult , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/complications , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/therapeutic use , Child , Double-Blind Method , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , Vaccine Efficacy , Young Adult
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334439

ABSTRACT

Waning immunity after two SARS-CoV-2 mRNA vaccinations and the emergence of variants precipitated the need for a third dose of vaccine. We evaluated early safety and immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary series in the Phase 1 trial approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA-1273.351 that encodes Beta variant spike protein, and bivalent vaccine of 25 mcg each of mRNA-1273 and mRNA-1273.351. A third dose of mRNA vaccine appeared safe with acceptable reactogenicity. Vaccination induced rapid increases in binding and neutralizing antibody titers to D614G, Beta, and Delta variants that were similar or greater than peak responses after the second dose. Spike-specific CD4+ and CD8+ T cells increased to similar levels as after the second dose. A third mRNA vaccination was well tolerated and generated robust humoral and T cell responses. ClinicalTrials.gov numbers NCT04283461 (mRNA-1273 Phase 1) and NCT04785144 (mRNA-1273.351 Phase 1)

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334405

ABSTRACT

Waning immunity after two SARS-CoV-2 mRNA vaccinations and the emergence of variants precipitated the need for booster doses. We evaluated safety and serological and cellular immunogenicity through 6 months after a third mRNA vaccination in adults who received the mRNA-1273 primary series in the Phase 1 trial approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA-1273.351 that encodes Beta variant spike protein, and bivalent vaccine of 25 mcg each of mRNA-1273 and mRNA-1273.351. A third dose of mRNA vaccine appeared safe with acceptable reactogenicity. Vaccination induced rapid increases in binding and neutralizing antibody titers to D614G, Beta, Delta and Omicron variants that persisted through 6 months post-boost, particularly after administration of Beta-containing vaccines. Spike-specific CD4 + and CD8 + T cells increased to levels similar to those following the second dose. Boost vaccination induced broad and durable humoral and T cell responses. ClinicalTrials.gov numbers NCT04283461 (mRNA-1273 Phase 1) and NCT04785144 (mRNA-1273.351 Phase 1)

5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329786

ABSTRACT

Background: There is a need for automated, high throughput assays to quantify immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study assessed the combined utility of the Roche assays, Elecsys® Anti-SARS-CoV-2 S (ACOV2S) and Elecsys Anti-SARS-CoV-2 (ACOV2N) using samples from the 2019-nCoV vaccine (mRNA-1273, Spikevax™) phase 2 trial ( NCT04405076 ). Methods: Samples from 593 healthy participants in two age cohorts (18-54 years and ≥55 years), who received two injections with either placebo (n=198) or mRNA-1273 at a dose of either 50 ≥g (n=197) or 100 ≥g (n=198), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results were used to assess the humoral response to vaccination in different clinical trial subgroups and were compared to a live virus microneutralization assay. Sample panels from patients with evidence of previous or concomitant infection (as identified using ACOV2N) or with an inconsistent antibody response pattern were analyzed separately. Results: Receptor-binding domain (RBD)-specific antibodies were readily detectable by ACOV2S for the vast majority of participants (174/189 [50 ≥g dose group] and 178/192 [100 ≥g]) at the first time point of assessment, with non-converters predominantly older in age. Complete seroconversion for all participants was observed at the subsequent timepoint (Day 29) and before administration of the second dose of vaccine. Two weeks after the first vaccine dose (Day 15), geometric mean concentration (GMC) of antibody levels were 1.37-fold higher in the 100 ≥g compared with the 50 ≥g dose group;this difference reduced to 1.09-fold two weeks after the second dose (Day 43). In both the 50 ≥g and 100 ≥g dose groups, a more pronounced response was observed in the younger versus the older age group on Day 15 (2.49-fold and 3.94-fold higher GMC, respectively) and Day 43 (1.35-fold and 1.50-fold higher GMC). Few subjects had a previous or concomitant natural SARS-CoV-2-infection (n=8). Vaccination of pre-infected individuals boosted the immune response to very high ACOV2S results compared to infection-naïve vaccine recipients. ACOV2S measurements were strongly correlated with those from the live microneutralization assay (Pearson's r=0.779;p<0.0001) and good qualitative agreement was achieved (100% positive and 91.8% negative percentage agreement;90.0% positive and 100% negative predictive value). Conclusion: The results from this study confirmed that ACOV2S is a highly valuable assay for the tracking of vaccine-related immune responses. Combined application with ACOV2N enables serologic monitoring for breakthrough infection or stratification of previous natively-infected individuals. The adaptive measuring range and high resolution of ACOV2S allows for the early identification of seroconversion as well as for resolution of very high titers and detection of longitudinal differences between age and dose groups. Additionally, good correlation of ACOV2S with live virus microneutralization indicates the utility of ACOV2S as a reliable estimate of neutralization capacity in routine diagnostic settings.

6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329741

ABSTRACT

Importance: Due to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed. Objectives: Evaluate safety and immunogenicity of 100-μg of mRNA-1273 booster dose in adults. Design: Open-label, Phase 2/3 study. Setting: Multicenter study at 8 sites in the U.S. Participants: The mRNA-1273 100-μg booster was administered to adults who previously received a two dose primary series of 100-μg mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. Intervention: Lipid nanoparticle containing 100-μg of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1). Main Outcomes and Measures: Solicited 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. Results: The 100-μg 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-μg 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-μg 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-μg booster of mRNA-1273. Conclusions and Relevance: The 100-μg mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2 and reactogenicity was higher with the 100-μg booster dose compared to authorized booster dose level in adults (50-μg). mRNA-1273 100-μg booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065

7.
Nat Med ; 28(5): 1042-1049, 2022 05.
Article in English | MEDLINE | ID: covidwho-1730305

ABSTRACT

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.


Subject(s)
COVID-19 , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , Adult , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Immunity , Immunogenicity, Vaccine
8.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327227

ABSTRACT

ABSTRACT 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 µg) mRNA-1273 primary vaccination series and after a 50-µg 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.

9.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327223

ABSTRACT

During the SARS-CoV-2 pandemic, multiple variants with differing amounts of escape from pre-existing immunity have emerged, causing concerns about continued protection. Here, we use antigenic cartography to quantify and visualize the antigenic relationships among 16 SARS-CoV-2 variants titrated against serum samples taken post-vaccination and post-infection with seven different variants. We find major antigenic differences caused by substitutions at positions 417, 452, 484, and possibly 501. B.1.1.529 (Omicron) showed the highest escape from all sera tested. Visualization of serological responses as antibody landscapes shows how reactivity clusters in different regions of antigenic space. We find changes in immunodominance of different spike regions depending on the variant an individual was exposed to, with implications for variant risk assessment and vaccine strain selection.

10.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327106

ABSTRACT

Background: The 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. Methods Neutralizing 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 Background The 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. Methods Neutralizing 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-<12 years) in the KidCOVE trial administered two doses of 50 μg 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). Results At 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-<12 years), 4 weeks post-second dose of 50 μg 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. Conclusions A 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.

11.
Nat Med ; 28(4): 823-830, 2022 04.
Article in English | MEDLINE | ID: covidwho-1684093

ABSTRACT

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) log10 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.


Subject(s)
COVID-19 , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , COVID-19/epidemiology , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , United States
12.
Front Immunol ; 12: 798117, 2021.
Article in English | MEDLINE | ID: covidwho-1674335

ABSTRACT

Background: The ability to quantify an immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential. This study assessed the clinical utility of the quantitative Roche Elecsys® Anti-SARS-CoV-2 S assay (ACOV2S) using samples from the 2019-nCoV vaccine (mRNA-1273) phase 1 trial (NCT04283461). Methods: Samples from 30 healthy participants, aged 18-55 years, who received two injections with mRNA-1273 at a dose of 25 µg (n=15) or 100 µg (n=15), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results (shown in U/mL - equivalent to BAU/mL per the first WHO international standard) were compared with results from ELISAs specific to antibodies against the Spike protein (S-2P) and the receptor binding domain (RBD) as well as neutralization tests including nanoluciferase (nLUC80), live-virus (PRNT80), and a pseudovirus neutralizing antibody assay (PsVNA50). Results: RBD-specific antibodies were already detectable by ACOV2S at the first time point of assessment (d15 after first vaccination), with seroconversion before in all but two participants (25 µg dose group); all had seroconverted by Day 29. Across all post-baseline visits, geometric mean concentration of antibody levels was 3.27-7.48-fold higher in the 100 µg compared with the 25 µg dose group. ACOV2S measurements were highly correlated with those from RBD ELISA (Pearson's r=0.938; p<0.0001) and S-2P ELISA (r=0.918; p<0.0001). For both ELISAs, heterogeneous baseline results and smaller increases in antibody levels following the second vs first vaccination compared with ACOV2S were observed. ACOV2S showed absence of any baseline noise indicating high specificity detecting vaccine-induced antibody response. Moderate-strong correlations were observed between ACOV2S and neutralization tests (nLUC80 r=0.933; PsVNA50, r=0.771; PRNT80, r=0.672; all p ≤ 0.0001). Conclusion: The Elecsys Anti-SARS-CoV-2 S assay (ACOV2S) can be regarded as a highly valuable method to assess and quantify the presence of RBD-directed antibodies against SARS-CoV-2 following vaccination and may indicate the presence of neutralizing antibodies. As a fully automated and standardized method, ACOV2S could qualify as the method of choice for consistent quantification of vaccine-induced humoral response.


Subject(s)
/immunology , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay/methods , SARS-CoV-2/physiology , Adolescent , Adult , Aged , Automation , COVID-19/immunology , Female , Humans , Immunity, Humoral , Immunogenicity, Vaccine , Male , Middle Aged , Neutralization Tests , Reference Standards , Young Adult
14.
Science ; 375(6576): 43-50, 2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1649486

ABSTRACT

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Clinical Trials, Phase III as Topic , Female , Humans , Immunogenicity, Vaccine , Male , Middle Aged , Randomized Controlled Trials as Topic , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology , Young Adult
15.
Sci Rep ; 11(1): 23921, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585804

ABSTRACT

Vaccine-induced neutralizing antibodies (nAbs) are key biomarkers considered to be associated with vaccine efficacy. In United States government-sponsored phase 3 efficacy trials of COVID-19 vaccines, nAbs are measured by two different validated pseudovirus-based SARS-CoV-2 neutralization assays, with each trial using one of the two assays. Here we describe and compare the nAb titers obtained in the two assays. We observe that one assay consistently yielded higher nAb titers than the other when both assays were performed on the World Health Organization's anti-SARS-CoV-2 immunoglobulin International Standard, COVID-19 convalescent sera, and mRNA-1273 vaccinee sera. To overcome the challenge this difference in readout poses in comparing/combining data from the two assays, we evaluate three calibration approaches and show that readouts from the two assays can be calibrated to a common scale. These results may aid decision-making based on data from these assays for the evaluation and licensure of new or adapted COVID-19 vaccines.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19/immunology , Neutralization Tests/standards , SARS-CoV-2/immunology , /immunology , Antibodies, Viral/blood , COVID-19/blood , Clinical Decision-Making , Clinical Trials as Topic , Diagnostic Tests, Routine , Humans , Neutralization Tests/methods , World Health Organization
18.
J Virol ; 95(23): e0131321, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1434895

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to growing concerns over increased transmissibility and the ability of some variants to partially escape immunity. Sera from participants immunized on a prime-boost schedule with the mRNA-1273 COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants, including variants of concern (VOCs) and variants of interest (VOIs), compared to neutralization of the wild-type SARS-CoV-2 virus (designated D614G). Results showed minimal, statistically nonsignificant effects on neutralization titers against the B.1.1.7 (Alpha) variant (1.2-fold reduction compared with D614G); other VOCs, such as B.1.351 (Beta, including B.1.351-v1, B.1.351-v2, and B.1.351-v3), P.1 (Gamma), and B.1.617.2 (Delta), showed significantly decreased neutralization titers ranging from 2.1-fold to 8.4-fold reductions compared with D614G, although all remained susceptible to mRNA-1273-elicited serum neutralization. IMPORTANCE In light of multiple variants of SARS-CoV-2 that have been documented globally during the COVID-19 pandemic, it remains important to continually assess the ability of currently available vaccines to confer protection against newly emerging variants. Data presented herein indicate that immunization with the mRNA-1273 COVID-19 vaccine produces neutralizing antibodies against key emerging variants tested, including variants of concern and variants of interest. While the serum neutralization elicited by mRNA-1273 against most variants tested was reduced compared with that against the wild-type virus, the level of neutralization is still expected to be protective. Such data are crucial to inform ongoing and future vaccination strategies to combat COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Pandemics/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Antibodies, Viral/immunology , Female , Humans , Male , Mutation , Neutralization Tests , Vaccination
19.
N Engl J Med ; 385(19): 1774-1785, 2021 Nov 04.
Article in English | MEDLINE | ID: covidwho-1434206

ABSTRACT

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Adolescent , Adult , Aged , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Follow-Up Studies , Humans , Immunization, Secondary , Incidence , Intention to Treat Analysis , Male , Middle Aged , Patient Acuity , Single-Blind Method , Treatment Outcome , Young Adult
20.
Nat Med ; 27(11): 2025-2031, 2021 11.
Article in English | MEDLINE | ID: covidwho-1412033

ABSTRACT

The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19 Vaccines/adverse effects , Female , Healthy Volunteers , Humans , Immunization, Secondary/adverse effects , Male , Middle Aged , Preliminary Data , RNA, Messenger/adverse effects , RNA, Messenger/genetics , RNA, Messenger/immunology , SARS-CoV-2/genetics , Treatment Outcome , United States , Vaccination/adverse effects
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