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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine T he n e w e n g l a n d j o u r n a l of m e d i cin e Original Article Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine L.R. Baden, H.M. El Sahly, B. Essink, K. Kotloff, S. Frey, R. Novak, D. Diemert, S.A. Spector, N. Rouphael, C.B. Creech, J. McGettigan, S. Khetan, N. Segall, J. Solis, A. Brosz, C. Fierro, H. Schwartz, K. Neuzil, L. Corey, P. Gilbert, H. Janes, D. Follmann, M. Marovich, J. Mascola, L. Polakowski, J. Ledgerwood, B.S. Graham, H. Bennett, R. Pajon, C. Knightly, B. Leav, W. Deng, H. Zhou, S. Han, M. Ivarsson, J. Miller, and T. Zaks, for the COVE Study Group* A B S T R AC T BACKGROUND Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect The authors’ full names, academic de- grees, and affiliations are listed in the persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid Appendix. Address reprint requests to nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabi- Dr. El Sahly at the Departments of Molec- lized full-length spike protein of the severe acute respiratory syndrome corona- ular Virology and Microbiology and Medi- cine, 1 Baylor Plaza, BCM-MS280, Houston, virus 2 (SARS-CoV-2), the virus that causes Covid-19. TX 77030, or at hana . elsahly@ bcm . edu; or to Dr. Baden at the Division of Infec- METHODS tious Diseases, Brigham and Women’s This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted Hospital, 15 Francis St., PBB-A4, Boston, at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infec- MA 02115, or at lbaden@bwh.harvard.edu. tion or its complications were randomly assigned in a 1:1 ratio to receive two intra- *A complete list of members of the COVE muscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The pri - Study Group is provided in the Supple- mentary Appendix, available at NEJM.org. mary 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 Drs. Baden and El Sahly contributed equal- ly to this article. SARS-CoV-2. This article was published on December 30, RESULTS 2020, at NEJM.org. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to DOI: 10.1056/NEJMoa2035389 receive either vaccine or placebo (15,210 participants in each group). More than Copyright © 2020 Massachusetts Medical Society. 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 ill- ness was confirmed in 185 participants in the placebo group (56.5 per 1000 person- years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA- 1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 partici- pants, with one fatality; all 30 were in the placebo group. Moderate, transient re- actogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.) n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e he emergence in December 2019 of a in medically stable condition at 99 U.S. sites. novel coronavirus, the severe acute respi- Participants received the first trial injection be- Tratory syndrome coronavirus 2 (SARS- tween July 27 and October 23, 2020. The trial is CoV-2), has had devastating consequences glob- being conducted in accordance with the Inter- ally. Control measures such as the use of masks, national Council for Harmonisation of Techni- A Quick Take physical distancing, testing of exposed or symp- cal Requirements for Pharmaceuticals for Hu- is available at tomatic persons, contact tracing, and isolation man Use, Good Clinical Practice guidelines, NEJM.org have helped limit the transmission where they have and applicable government regulations. The cen- been rigorously applied; however, these actions tral institutional review board approved the have been variably implemented and have proved protocol and the consent forms. All partici- insufficient in impeding the spread of coronavi- pants provided written informed consent be- rus disease 2019 (Covid-19), the disease caused by fore enrollment. Safety is reviewed by a protocol SARS-CoV-2. Vaccines are needed to reduce the safety review team weekly and by an indepen- morbidity and mortality associated with Covid-19, dent data and safety monitoring board on a and multiple vaccine platforms have been involved continual basis. The trial Investigational New 1-9 in the rapid development of vaccine candidates. Drug sponsor, Moderna, was responsible for The mRNA vaccine platform has advantages the overall trial design (with input from the as a pandemic-response strategy, given its f lexi- Biomedical Advanced Research and Develop- bility and efficiency in immunogen design and ment Authority, the NIAID, the Covid-19 Pre- manufacturing. Earlier work had suggested that vention Network, and the trial cochairs), site the spike protein of the coronavirus responsible selection and monitoring, and data analysis. for the 2002 SARS outbreak was a suitable target Investigators are responsible for data collection. for protective immunity. Numerous vaccine can- A medical writer funded by Moderna assisted didates in various stages of development are now in drafting the manuscript for submission. The 11-13 being evaluated. Shortly after the SARS-CoV-2 authors vouch for the accuracy and complete- genetic sequence was determined in January ness of the data and for the fidelity of the trial 2020, mRNA-1273, a lipid-nanoparticle (LNP)– to the protocol. The trial is ongoing, and the encapsulated mRNA vaccine expressing the pre- investigators remain unaware of participant- fusion-stabilized spike glycoprotein, was developed level data. Designated team members within by Moderna and the Vaccine Research Center at Moderna have unblinded access to the data, to the National Institute of Allergy and Infectious facilitate interface with the regulatory agencies Diseases (NIAID), within the National Institutes and the data and safety monitoring board; all of Health (NIH). The mRNA-1273 vaccine dem- other trial staff and participants remain un- onstrated protection in animal-challenge experi- aware of the treatment assignments. ments and encouraging safety and immunoge- 1,4 Participants, Randomization, and Data nicity in early-stage human testing. The efficacy Blinding and safety of another mRNA vaccine, BNT162b2, was recently demonstrated. Eligible participants were persons 18 years of age The Coronavirus Efficacy (COVE) phase 3 trial or older with no known history of SARS-CoV-2 was launched in late July 2020 to assess the infection and with locations or circumstances safety and efficacy of the mRNA-1273 vaccine in that put them at an appreciable risk of SARS- preventing SARS-CoV-2 infection. An independent CoV-2 infection, a high risk of severe Covid-19, data and safety monitoring board determined or both. Inclusion and exclusion criteria are pro- that the vaccine met the prespecified efficacy vided in the protocol (available with the full text criteria at the first interim analysis. We report the of this article at NEJM.org). To enhance the di- primary analysis results of this ongoing pivotal versity of the trial population in accordance with phase 3 trial. Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from M e th o ds racial and ethnic minorities in the trial, in addi- Trial Oversight tion to the persons at risk for SARS-CoV-2 infec- This phase 3 randomized, stratified, observer- tion in the local population. The upper limit for blinded, placebo-controlled trial enrolled adults stratification of enrolled participants considered n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Safety Assessments to be “at risk for severe illness” at screening was increased from 40% to 50%. Safety assessments included monitoring of solic- Participants were randomly assigned in a 1:1 ited local and systemic adverse events for 7 days ratio, through the use of a centralized interactive after each injection; unsolicited adverse reac- response technology system, to receive vaccine or tions for 28 days after each injection; adverse placebo. Assignment was stratified, on the basis events leading to discontinuation from a dose, of age and Covid-19 complications risk criteria, from participation in the trial, or both; and into the following risk groups: persons 65 years medically attended adverse events and serious of age or older, persons younger than 65 years of adverse events from day 1 through day 759. Ad- age who were at heightened risk (at risk) for se- verse event grading criteria and toxicity tables vere Covid-19, and persons younger than 65 years are described in the protocol. Cases of Covid-19 of age without heightened risk (not at risk). Par- and severe Covid-19 were continuously moni- ticipants younger than 65 years of age were cate- tored by the data and safety monitoring board gorized as having risk for severe Covid-19 if they from randomization onward. had at least one of the following risk factors, Efficacy Assessments based on the Centers for Disease Control and Pre- vention (CDC) criteria available at the time of trial The primary end point was the efficacy of the design: chronic lung disease (e.g., emphysema, mRNA-1273 vaccine in preventing a first occur- chronic bronchitis, idiopathic pulmonary fibro- rence of symptomatic Covid-19 with onset at sis, cystic fibrosis, or moderate-to-severe asthma); least 14 days after the second injection in the cardiac disease (e.g., heart failure, congenital per-protocol population, among participants who coronary artery disease, cardiomyopathies, or pul- were seronegative at baseline. End points were monary hypertension); severe obesity (body mass judged by an independent adjudication committee index [the weight in kilograms divided by the that was unaware of group assignment. Covid-19 square of the height in meters] ≥40); diabetes cases were defined as occurring in participants (type 1, type 2, or gestational); liver disease; or in- who had at least two of the following symptoms: fection with the human immunodeficiency virus. fever (temperature ≥38°C), chills, myalgia, head- Vaccine dose preparation and administration ache, sore throat, or new olfactory or taste dis- were performed by pharmacists and vaccine ad- order, or as occurring in those who had at least ministrators who were aware of treatment as- one respiratory sign or symptom (including cough, signments but had no other role in the conduct shortness of breath, or clinical or radiographic of the trial. Once the injection was completed, evidence of pneumonia) and at least one naso- only trial staff who were unaware of treatment pharyngeal swab, nasal swab, or saliva sample assignments performed assessments and inter- (or respiratory sample, if the participant was acted with the participants. Access to the ran- hospitalized) that was positive for SARS-CoV-2 domization code was strictly controlled at the by reverse-transcriptase–polymerase-chain-reac- pharmacy. The data and safety monitoring board tion (RT-PCR) test. Participants were assessed for reviewed efficacy data at the group level and the presence of SARS-CoV-2–binding antibodies unblinded safety data at the participant level. specific to the SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) Trial Vaccine and had a nasopharyngeal swab for SARS-CoV-2 The mRNA-1273 vaccine, provided as a sterile RT-PCR testing (Viracor, Eurofins Clinical Di- liquid at a concentration of 0.2 mg per milliliter, agnostics) before each injection. SARS-CoV-2– was administered by injection into the deltoid infected volunteers were followed daily, to assess muscle according to a two-dose regimen. Injec- symptom severity, for 14 days or until symptoms tions were given 28 days apart, in the same arm, resolved, whichever was longer. A nasopharyn- in a volume of 0.5 ml containing 100 μg of geal swab for RT-PCR testing and a blood sam- mRNA-1273 or saline placebo. Vaccine mRNA- ple for identifying serologic evidence of SARS- 1273 was stored at 2° to 8°C (35.6° to 46.4°F) at CoV-2 infection were collected from participants clinical sites before preparation and vaccination. with symptoms of Covid-19. No dilution was required. Doses could be held in The consistency of vaccine efficacy at the pri- syringes for up to 8 hours at room temperature mary end point was evaluated across various before administration. subgroups, including age groups (18 to <65 years n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e of age and ≥65 years), age and health risk for mate, based on a total of 95 adjudicated cases severe disease (18 to <65 years and not at risk; (63% of the target total), was 94.5%, with a 18 to <65 years and at risk; and ≥65 years), sex one-sided P value of less than 0.001 to reject the (female or male), race and ethnic group, and risk null hypothesis that vaccine efficacy would be for severe Covid-19 illness. If the number of 30% or less. The data and safety monitoring participants in a subgroup was too small, it was board recommendation to the oversight group combined with other subgroups for the sub- and the trial sponsor was that the efficacy find- group analyses. ings should be shared with the participants and A secondary end point was the efficacy of the community (full details are available in the mRNA-1273 in the prevention of severe Covid-19 protocol and statistical analysis plan). as defined by one of the following criteria: respi- Vaccine efficacy was assessed in the full analy- ratory rate of 30 or more breaths per minute; sis population (randomized participants who re- heart rate at or exceeding 125 beats per minute; ceived at least one dose of mRNA-1273 or pla- oxygen saturation at 93% or less while the par- cebo), the modif ied intention-to-treat population ticipant was breathing ambient air at sea level or (participants in the full analysis population who a ratio of the partial pressure of oxygen to the had no immunologic or virologic evidence of fraction of inspired oxygen below 300 mm Hg; Covid-19 on day 1, before the first dose), and the respiratory failure; acute respiratory distress syn- per-protocol population (participants in the mod- drome; evidence of shock (systolic blood pressure ified intention-to-treat population who received <90 mm Hg, diastolic blood pressure <60 mm Hg, two doses, with no major protocol deviations). or a need for vasopressors); clinically significant The primary efficacy end point in the interim acute renal, hepatic, or neurologic dysfunction; and primary analyses was assessed in the per- admission to an intensive care unit; or death. protocol population. Participants were evaluated Additional secondary end points included the in the treatment groups to which they were as- efficacy of the vaccine at preventing Covid-19 signed. Vaccine efficacy was defined as the per- after a single dose or at preventing Covid-19 ac- centage reduction in the hazard ratio for the cording to a secondary (CDC), less restrictive primary end point (mRNA-1273 vs. placebo). A case definition: having any symptom of Covid-19 stratified Cox proportional hazards model was and a positive SARS-CoV-2 test by RT-PCR (see used to assess the vaccine efficacy of mRNA-1273 Table S1 in the Supplementary Appendix, avail- as compared with placebo in terms of the per- able at NEJM.org). centage hazard reduction. (Details regarding the analysis of vaccine efficacy are provided in the Statistical Analysis Methods section of the Supplementary Appendix.) For analysis of the primary end point, the trial Safety was assessed in all participants in the was designed for the null hypothesis that the solicited safety population (i.e., those who re- efficacy of the mRNA-1273 vaccine is 30% or ceived at least one injection and reported a solic- less. A total of 151 cases of Covid-19 would pro- ited adverse event). Descriptive summary data vide 90% power to detect a 60% reduction in the (numbers and percentages) for participants with hazard rate (i.e., 60% vaccine efficacy), with two any solicited adverse events, unsolicited adverse planned interim analyses at approximately 35% events, unsolicited severe adverse events, serious and 70% of the target total number of cases adverse events, medically attended adverse (151) and with a one-sided O’Brien–Fleming events, and adverse events leading to discontinu- boundary for efficacy and an overall one-sided ation of the injections or withdrawal from the error rate of 0.025. The efficacy of the mRNA- trial are provided by group. Two-sided 95% exact 1273 vaccine could be demonstrated at either the confidence intervals (Clopper–Pearson method) interim or the primary analysis, performed when are provided for the percentages of participants the target total number of cases had been ob- with solicited adverse events. Unsolicited adverse served. The Lan–DeMets alpha-spending func- events are presented according to the Medical tion was used for calculating efficacy boundar- Dictionary for Regulatory Activities (MedDRA), ver- ies at each analysis. At the first interim analysis sion 23.0, preferred terms and system organ on November 15, 2020, vaccine eff icacy had been class categories. demonstrated in accordance with the prespeci- To meet the regulatory agencies’ requirement of fied statistical criteria. The vaccine efficacy esti- a median follow-up duration of at least 2 months n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine 30,420 Participants underwent randomization (1:1) 15,210 Were assigned to receive 15,210 Were assigned to receive two doses of mRNA-1273, placebo 100 μg each 15,185 Were included in the 15,181 Received at least one 15,170 Received at least one 15,166 Were included in the safety analysis dose and were included dose and were included safety analysis in the full analysis set in the full analysis set 29 Did not receive any 40 Did not receive any injection injection 14,550 Were included in the 14,598 Were included in the modified intention-to- modified intention-to- treat population treat population 631 Were SARS-CoV-2–positive 572 Were SARS-CoV-2–positive at baseline or had missing at baseline or had missing data and were excluded data and were excluded 416 Were excluded from per-protocol analysis 525 Were excluded from per-protocol analysis 6 Received an incorrect mRNA injection 7 Received incorrect injection 168 Discontinued without receiving dose 2 231 Discontinued without receiving dose 2 93 Received dose 2 outside dose 2 window 109 Received dose 2 outside dose 2 window 138 Did not receive dose 2, or were out 154 Did not receive dose 2, or were out of window for per-protocol analysis of window for per-protocol analysis 11 Had other major deviations from protocol 24 Had other major deviations from protocol 14,134 Were included in the 14,073 Were included in the per-protocol analysis per-protocol analysis Figure 1. Randomization and Analysis Populations. The data cutoff for the primary analysis occurred on November 25, 2020. The full analysis population consisted of participants who un- derwent randomization and received at least one dose of mRNA-1273 or placebo; the modified intention-to-treat population comprised participants in the full analysis population who had no immunologic or virologic evidence of Covid-19 on day 1, before the first dose; and the per-protocol analysis population included participants in the modified intention-to-treat population who received two doses, with no major protocol deviations. The safety population included all participants who received at least one injection. Among partici- pants who received an incorrect injection, three participants in the mRNA-1273 group received at least one dose of placebo and no dose of mRNA-1273 and were included in the placebo safety population, and three received one dose of placebo and one dose of mRNA-1273 and were included in the mRNA-1273 safety population; in the placebo group all seven received mRNA-1273 and were included in the mRNA-1273 safety population. Participants who received dose 2 outside the window for the per-protocol analysis are those who did not receive the second dose between 7 days before and 14 days after day 29. after completion of the two-dose regimen, a sec- sented in this report. Subsequent analyses are ond analysis was performed, with an efficacy considered supplementary. data cutoff date of November 21, 2020. This second analysis is considered the primary analy- R e s u l t s sis of efficacy, with a total of 196 adjudicated Trial Population Covid-19 cases in the per-protocol population, which exceeds the target total number of cases Between July 27, 2020, and October 23, 2020, a (151) specified in the protocol. This was an in- total of 30,420 participants underwent random- crease from the 95 cases observed at the first ization, and the 15,210 participants in each interim analysis data cutoff on November 11, group were assigned to receive two doses of ei- 2020. Results from the primary analysis are pre- ther placebo or mRNA-1273 (100 μg) (Fig. 1). n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Table 1. Demographic and Clinical Characteristics at Baseline.* Placebo mRNA-1273 Total Characteristics (N=15,170) (N=15,181) (N=30,351) Sex — no. of participants (%) Male 8,062 (53.1) 7,923 (52.2) 15,985 (52.7) Female 7,108 (46.9) 7,258 (47.8) 14,366 (47.3) Mean age (range) — yr 51.3 (18–95) 51.4 (18–95) 51.4 (18–95) Age category and risk for severe Covid-19 — no. of participants (%)† 18 to <65 yr, not at risk 8,886 (58.6) 8,888 (58.5) 17,774 (58.6) 18 to <65 yr, at risk 2,535 (16.7) 2,530 (16.7) 5,065 (16.7) ≥65 yr 3,749 (24.7) 3,763 (24.8) 7,512 (24.8) Hispanic or Latino ethnicity — no. of participants (%)‡ Hispanic or Latino 3,114 (20.5) 3,121 (20.6) 6,235 (20.5) Not Hispanic or Latino 11,917 (78.6) 11,918 (78.5) 23,835 (78.5) Not reported and unknown 139 (0.9) 142 (0.9) 281 (0.9) Race or ethnic group — no. of participants (%)‡ White 11,995 (79.1) 12,029 (79.2) 24,024 (79.2) Black or African American 1,527 (10.1) 1,563 (10.3) 3,090 (10.2) Asian 731 (4.8) 651 (4.3) 1,382 (4.6) American Indian or Alaska Native 121 (0.8) 112 (0.7) 233 (0.8) Native Hawaiian or Other Pacific Islander 32 (0.2) 35 (0.2) 67 (0.2) Multiracial 321 (2.1) 315 (2.1) 636 (2.1) Other 316 (2.1) 321 (2.1) 637 (2.1) Not reported and unknown 127 (0.8) 155 (1.0) 282 (0.9) Baseline SARS-CoV-2 status — no. of participants (%)§ Negative 14,598 (96.2) 14,550 (95.8) 29,148 (96.0) Positive 337 (2.2) 343 (2.3) 680 (2.2) Missing data 235 (1.5) 288 (1.9) 523 (1.7) Baseline RT-PCR test — no. of participants (%) Negative 14,923 (98.4) 14,917 (98.3) 29,840 (98.3) Positive 95 (0.6) 87 (0.6) 182 (0.6) Missing data 152 (1.0) 177 (1.2) 329 (1.1) Baseline bAb anti–SARS-CoV-2 assay — no. of participants (%) Negative 14,726 (97.1) 14,690 (96.8) 29,416 (96.9) Positive 303 (2.0) 305 (2.0) 608 (2.0) Missing data 141 (0.9) 186 (1.2) 327 (1.1) Risk factor for severe Covid-19 — no. of participants (%) Chronic lung disease 744 (4.9) 710 (4.7) 1,454 (4.8) Significant cardiac disease 744 (4.9) 752 (5.0) 1,496 (4.9) Severe obesity 1,021 (6.7) 1,025 (6.8) 2,046 (6.7) Diabetes 1,440 (9.5) 1,435 (9.5) 2,875 (9.5) Liver disease 96 (0.6) 100 (0.7) 196 (0.6) Human immunodeficiency virus infection 87 (0.6) 92 (0.6) 179 (0.6) n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Table 1. (Continued.) Placebo mRNA-1273 Total Characteristics (N=15,170) (N=15,181) (N=30,351) Body-mass index¶ No. of participants 15,007 14,985 29,992 Mean ±SD 29.3±6.7 29.3±6.9 29.3±6.8 * Internet-based randomization was used to assign participants to treatment groups on the basis of information entered by the investigator regarding the participant’s age and coexisting conditions. Percentages are based on the full analysis population; baseline demographics and characteristics for the per-protocol population are provided in the Supplementary Appendix. Percentages may not total 100 because of rounding. The abbreviation bAb denotes binding antibody concentration, and RT-PCR reverse-transcriptase polymerase chain reaction. † Risk was based on a stratification factor from the Internet-based interactive response system used for randomization; participa nts who were younger than 65 years of age were categorized as at risk for severe Covid-19 illness if they had at least one of the risk factors specified in the trial protocol at screening. ‡ Race or ethnic group was reported by the participant. Participants could be included in more than one category. § Baseline SARS-CoV-2 status was positive if there was immunologic or virologic evidence of previous illness with Covid-19, as defined by a positive RT-PCR test or a positive bAb against SARS-CoV-2 nucleocapsid assay result that was above the limit of detection or by a lower limit of quantification at day 1. Baseline SARS-CoV-2 status was negative if there was a negative RT-PCR test and negative bAb against SARS-CoV-2 assay result at day 1. ¶ The body-mass index is the weight in kilograms divided by the square of the height in meters. More than 96% of participants received the sec- proportions were generally representative of U.S. ond dose (Fig. S1). Common reasons for not re- demographics, including 10.2% Black or African ceiving the second dose were withdrawal of American and 20.5% Hispanic or Latino. Evi- consent (153 participants) and the detection of dence of SARS-CoV-2 infection at baseline was SARS-CoV-2 by PCR before the administration present in 2.3% of participants in the mRNA- of the second dose on day 29 (114 participants: 1273 group and in 2.2% in the placebo group, as 69 in the placebo group and 45 in the mRNA- detected by serologic assay or RT-PCR testing. 1273 group). The primary efficacy and safety Safety analyses were performed in the per-protocol and safety populations, respectively. Of the partici- Solicited adverse events at the injection site oc- pants who received a first injection, 14,073 of curred more frequently in the mRNA-1273 group those in the placebo group and 14,134 in the than in the placebo group after both the first mRNA-1273 group were included in the primary dose (84.2%, vs. 19.8%) and the second dose efficacy analysis; 525 participants in the placebo (88.6%, vs. 18.8%) (Fig. 2 and Tables S3 and S4). group and 416 in the mRNA-1273 group were In the mRNA-1273 group, injection-site events excluded from the per-protocol population, in- were mainly grade 1 or 2 in severity and lasted cluding those who had not received a second a mean of 2.6 and 3.2 days after the first and dose by the day 29 data cutoff (Fig. 1). As of second doses, respectively (Table S5). The most November 25, 2020, the participants had a me- common injection-site event was pain after in- dian follow-up duration of 64 days (range, 0 to jection (86.0%). Delayed injection-site reactions 97) after the second dose, with 61% of partici- (those with onset on or after day 8) were noted pants having more than 56 days of follow-up. in 244 participants (0.8%) after the first dose Baseline demographic characteristics were and in 68 participants (0.2%) after the second balanced between the placebo group and the dose. Reactions were characterized by erythema, mRNA-1273 vaccine group (Table 1 and Table S2). induration, and tenderness, and they resolved The mean age of the participants was 51.4 years, over the following 4 to 5 days. Solicited sys- 47.3% of the participants were female, 24.8% temic adverse events occurred more often in the were 65 years of age or older, and 16.7% were mRNA-1273 group than in the placebo group younger than 65 years of age and had predispos- after both the first dose (54.9%, vs. 42.2%) and ing medical conditions that put them at risk for the second dose (79.4%, vs. 36.5%). The severity severe Covid-19. The majority of participants of the solicited systemic events increased after were White (79.2%), and the racial and ethnic the second dose in the mRNA-1273 group, with n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Grade 1 Grade 2 Grade 3 A Local Events Any Adverse Event Pain Erythema Swelling Lymphadenopathy B Systemic Events Any Adverse Fever Headache Fatigue Myalgia Arthralgia Nausea Chills Event or Vomiting Figure 2. Solicited Local and Systemic Adverse Events. Shown is the percentage of participants who had a solicited local or systemic adverse event within 7 days after injection 1 or injection 2 of either the placebo or the mRNA-1273 vaccine. an increase in proportions of grade 2 events tively (Table S5). Both solicited injection-site and (from 16.5% after the first dose to 38.1% after systemic adverse events were more common the second dose) and grade 3 events (from 2.9% among younger participants (18 to <65 years of to 15.8%). Solicited systemic adverse events in the age) than among older participants (≥65 years mRNA-1273 group lasted a mean of 2.6 days and of age). Solicited adverse events were less com- 3.1 days after the first and second doses, respec- mon in participants who were positive for SARS- n engl j med nejm.org Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 Placebo, dose 1 mRNA-1273, dose 1 Placebo, dose 2 mRNA-1273, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 1 Placebo, dose 2 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 1 mRNA-1273, dose 2 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Percentage of Participants Percentage of Participants Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine CoV-2 infection at baseline than in those who incidence of these adverse events according to were negative at baseline (Tables S6 and S7). vaccine group was not affected by age. The frequency of unsolicited adverse events, Efficacy unsolicited severe adverse events, and serious adverse events reported during the 28 days after After day 1 and through November 25, 2020, a injection was generally similar among partici- total of 269 Covid-19 cases were identified, with pants in the two groups (Tables S8 through S11). an incidence of 79.8 cases per 1000 person-years Three deaths occurred in the placebo group (one (95% confidence interval [CI], 70.5 to 89.9) from intraabdominal perforation, one from car- among participants in the placebo group with diopulmonary arrest, and one from severe sys- no evidence of previous SARS-CoV-2 infection. temic inflammatory syndrome in a participant For the primary analysis, 196 cases of Covid-19 with chronic lymphocytic leukemia and diffuse were diagnosed: 11 cases in the vaccine group bullous rash) and two in the vaccine group (one (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0) from cardiopulmonary arrest and one by sui- and 185 cases in the placebo group (56.5 per cide). The frequency of grade 3 adverse events in 1000 person-years; 95% CI, 48.7 to 65.3), indi- the placebo group (1.3%) was similar to that in cating 94.1% efficacy of the mRNA-1273 vaccine the vaccine group (1.5%), as were the frequencies (95% CI, 89.3 to 96.8%; P<0.001) for the preven- of medically attended adverse events (9.7% vs. tion of symptomatic SARS-CoV-2 infection as 9.0%) and serious adverse events (0.6% in both compared with placebo (Fig. 3A). Findings were groups). Hypersensitivity reactions were report- similar across key secondary analyses (Table ed in 1.5% and 1.1% of participants in the vac- S16), including assessment starting 14 days after cine and placebo groups, respectively (Table S12). dose 1 (225 cases with placebo, vs. 11 with Bell’s palsy occurred in the vaccine group (3 par- mRNA-1273, indicating a vaccine efficacy of ticipants [<0.1%]) and the placebo group (1 partici- 95.2% [95% CI, 91.2 to 97.4]), and assessment pant [<0.1%]) during the observation period of including participants who were SARS-CoV-2 the trial (more than 28 days after injection). seropositive at baseline in the per-protocol anal- Overall, 0.5% of participants in the placebo ysis (187 cases with placebo, vs. 12 with mRNA- group and 0.3% in the mRNA-1273 group had 1273; one volunteer assigned to receive mRNA- adverse events that resulted in their not receiving 1273 was inadvertently given placebo], indicating the second dose, and less than 0.1% of partici- a vaccine efficacy of 93.6% [95% CI, 88.6 to pants in both groups discontinued participation 96.5]). Between days 1 and 42, seven cases of in the trial because of adverse events after any Covid-19 were identified in the mRNA-1273 dose (Table S8). No evidence of vaccine-associated group, as compared with 65 cases in the placebo enhanced respiratory disease was noted, and group (Fig. 3B). fewer cases of severe Covid-19 or any Covid-19 A key secondary end point evaluated the effi- were observed among participants who received cacy of mRNA-1273 at preventing severe Covid- mRNA-1273 than among those who received 19. Thirty participants in the trial had severe placebo (Tables S13 and S14). Adverse events Covid-19; all 30 were in the placebo group (indi- that were deemed by the trial team to be related cating vaccine efficacy of 100% [95% CI, could to the vaccine or placebo were reported among not be estimated to 1.0]), and one death among 4.5% of participants in the placebo group and these participants was attributed to Covid-19 8.2% in the mRNA-1273 group. The most com- (Table S16). The vaccine efficacy to prevent mon treatment-related adverse events (those re- Covid-19 was consistent across subgroups strati- ported in at least 1% of participants) in the pla- fied by demographic and baseline characteristics cebo group and the mRNA-1273 group were (Fig. 4): age groups (18 to <65 years of age and fatigue (1.2% and 1.5%) and headache (0.9% and ≥65 years), presence of risk for severe Covid-19, 1.4%). In the overall population, the incidence of sex, and race and ethnic group (non-Hispanic treatment-related severe adverse events was White and communities of color). Among par- higher in the mRNA-1273 group (71 participants ticipants who were positive for SARS-CoV-2, by [0.5%]) than in the placebo group (28 partici- serologic or virologic testing, at baseline (337 in pants [0.2%]) (Tables S8 and S15). The relative the placebo group and 343 in the mRNA-1273 n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e A Per-Protocol Analysis Vaccine Efficacy Incidence Rate (95% CI) (95% CI) 3.5 % per 1000 person-yr 3.0 Placebo 56.5 (48.7–65.3) mRNA-1273 94.1 (89.3–96.8) 3.3 (1.7–6.0) Placebo 2.5 2.0 1.5 1.0 0.5 mRNA-1273 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days since Randomization No. at Risk Placebo 14,073 14,073 14,073 14,072 13,416 12,992 12,361 11,147 9474 6563 3971 1172 0 mRNA-1273 14,134 14,134 14,134 14,133 13,483 13,073 12,508 11,315 9684 6721 4094 1209 0 B Modified Intention-to-Treat Analysis Vaccine Efficacy Incidence Rate 3.5 (95% CI) (95% CI) Placebo % per 1000 person-yr 3.0 Placebo 79.8 (70.5–89.9) mRNA-1273 93.0 (88.9–95.6) 5.6 (3.4–8.8) 2.5 2.0 1.5 1.0 0.5 mRNA-1273 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days since Randomization No. at Risk Placebo 14,598 14,590 14,567 14,515 13,806 12,352 12,694 11,450 9736 6729 4067 1200 0 mRNA-1273 14,550 14,543 14,532 14,504 13,825 13,398 12,791 11,573 9911 6871 4179 1238 0 Placebo mRNA-1273 Covid-19 Onset (N= 14,598) (N= 14,550) Randomization to 14 days after dose 1 11 14 Days after dose 1 to dose 2 35 2 Dose 2 to 14 days after dose 2 19 Starting 14 days after dose 2 204 12 269 19 Total (any time after randomization) n engl j med nejm.org Cumulative Event Rate (%) Cumulative Event Rate (%) Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine the placebo group, which suggests that mRNA- Figure 3 (facing page). Vaccine Eff icacy of mRNA-1273 1273 is likely to have an effect on preventing to Prevent Covid-19. severe illness, which is the major cause of health Shown is the cumulative incidence of Covid-19 events in the primary analysis based on adjudicated assess- care utilization, complications, and death. The ment starting 14 days after the second vaccination in finding of fewer occurrences of symptomatic the per-protocol population (Panel A) and after ran- SARS-CoV-2 infection after a single dose of domization in the modified intention-to-treat popula- mRNA-1273 is encouraging; however, the trial tion (Panel B) (see the Supplementary Appendix). The was not designed to evaluate the efficacy of a dotted line in Panel A indicates day 42 (14 days after vaccination 2), when the per-protocol follow-up began, single dose, and additional evaluation is war- and arrows in both panels indicate days 1 and 29, when ranted. injections were administered. Tick marks indicate cen- The magnitude of mRNA-1273 vaccine effi- sored data. Vaccine efficacy was defined as 1 minus the cacy at preventing symptomatic SARS-CoV-2 in- hazard ratio (mRNA vs. placebo), and the 95% confi- fection is higher than the efficacy observed for dence interval was estimated with the use of a stratified Cox proportional hazards model, with Efron’s method vaccines for respiratory viruses, such as the in- of tie handling and with treatment group as a covariate, activated inf luenza vaccine against symptomatic, with adjustment for stratification factor. Incidence was virologically confirmed disease in adults, for defined as the number of events divided by number of which studies have shown a pooled efficacy of participants at risk and was adjusted by person-years. 59%. This high apparent efficacy of mRNA- Symptomatic Covid-19 case accrual for placebo and vac- cine in the modified intention-to-treat population is dis- 1273 is based on short-term data, and waning of played (does not include asymptomatic cases of SARS- efficacy over time has been demonstrated with CoV-2 detected at the day 29 by nasopharyngeal swab). other vaccines. Also, the efficacy of the vaccine was tested in a setting of national recommenda- group), one case of Covid-19 was diagnosed by tions for masking and social distancing, which RT-PCR testing in a placebo recipient and no may have translated into lower levels of infec- cases were diagnosed in mRNA-1273 recipients tious inoculum. The eff icacy of mRNA-1273 is in (Table S17). Among participants who were nega- line with that of the recently reported BNT162b2 tive for SARS-CoV-2 at baseline (by RT-PCR or mRNA vaccine. The COVE trial is ongoing, and antibody testing), in addition to symptomatic longitudinal follow-up will allow an assessment Covid-19 cases 39 (0.3%) in the placebo group of efficacy changes over time and under evolving and 15 (0.1%) in the mRNA-1273 group had epidemiologic conditions. nasopharyngeal swabs that were positive for Overall, the safety of the mRNA-1273 vaccine SARS-CoV-2 by RT-PCR at the second dose visit regimen and platform is reassuring; no unex- (surveillance swab) but had no evidence of pected patterns of concern were identified. The Covid-19 symptoms (Table S18). reactogenicity associated with immunization with mRNA-1273 in this trial is similar to that 1,4 in the phase 1 data reported previously. Over- D i s c u s s ion all, the local reactions to vaccination were mild; The COVE trial provides evidence of short-term however, moderate-to-severe systemic side ef- efficacy of the mRNA-1273 vaccine in preventing fects, such as fatigue, myalgia, arthralgia, and symptomatic SARS-CoV-2 infection in a diverse headache, were noted in about 50% of partici- adult trial population. Of note, the trial was pants in the mRNA-1273 group after the second designed for an infection attack rate of 0.75%, dose. These side effects were transient, starting which would have necessitated a follow-up peri- about 15 hours after vaccination and resolving in od of 6 months after the two vaccine doses to most participants by day 2, without sequelae. accrue 151 cases in 30,000 participants. The The degree of reactogenicity after one dose of pandemic trajectory accelerated in many U.S. mRNA-1273 was less than that observed for the regions in the late summer and fall of 2020, re- recently approved recombinant adjuvanted zoster sulting in rapid accrual of 196 cases after a vaccine and after the second mRNA-1273 dose 21,22 median follow-up of 2 months. It is important to was similar to that of the zoster vaccine. note that all the severe Covid-19 cases were in Delayed injection-site reactions, with an onset n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Placebo mRNA-1273 Subgroup (N=14,073) (N=14,134) Vaccine Efficacy (95% CI) no. of events/total no. All patients 185/14,073 11/14,134 94.1 (89.3–96.8) Age ≥18 to <65 yr 156/10,521 7/10,551 95.6 (90.6–97.9) ≥65 yr 29/3552 4/3583 86.4 (61.4–95.2) Age, risk for severe Covid-19 18 to <65 yr, not at risk 121/8403 5/8396 95.9 (90.0–98.3) 94.4 (76.9–98.7) 18 to <65 yr, at risk 35/2118 2/2155 86.4 (61.4–95.2) ≥65 yr 29/3552 4/3583 Sex Male 87/7462 4/7366 95.4 (87.4–98.3) 93.1 (85.2–96.8) Female 98/6611 7/6768 At risk for severe Covid-19 90.9 (74.7–96.7) Yes 43/3167 4/3206 No 142/10,906 7/10,928 95.1 (89.6–97.7) Race and ethnic group 93.2 (87.1–96.4) White 144/8916 10/9023 Communities of color 41/5132 1/5088 97.5 (82.2–99.7) 0 25 50 75 100 Figure 4. Vaccine Eff icacy of mRNA-1273 to Prevent Covid-19 in Subgroups. The efficacy of the RNA-1273 vaccine in preventing Covid-19 in various subgroups in the per-protocol population was based on adjudicated assessments starting 14 days after the second injection. Vaccine efficacy, defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo), and 95% confidence intervals were estimated with the use of a stratified Cox proportional hazards model, with Efron’s method of tie handling and with the treatment group as a covariate, adjusting for stratification factor if applicable. Race and ethnic group categories shown are White (non- Hispanic) and communities of color (all others, including those whose race and ethnicity were both reported as un- known, were not reported, or were both missing at screening). Data for communities of color were pooled owing to limited numbers of participants in each racial or ethnic group, to ensure that the subpopulations would be large enough for meaningful analyses. 8 days or more after injection, were uncommon. immune response and eosinophilic pulmonary The overall incidence of unsolicited adverse infiltration on histopathological examination. events reported up to 28 days after vaccination Of note, preclinical testing of mRNA-1273 and and of serious adverse events reported through- other SARS-CoV-2 vaccines in advanced clinical out the entire trial was similar for mRNA-1273 evaluation has shown a Th1-skewed vaccine re- 15,26-28 and placebo. A risk of acute hypersensitivity is sponse and no pathologic lung infiltrates. sometimes observed with vaccines; however, no Whether mRNA-1273 vaccination results in en- such risk was evident in the COVE trial, although hanced disease on exposure to the virus in the the ability to detect rare events is limited, given long term is unknown. the trial sample size. The anecdotal finding of a Key limitations of the data are the short dura- slight excess of Bell’s palsy in this trial and in tion of safety and efficacy follow-up. The trial is the BNT162b2 vaccine trial arouses concern that ongoing, and a follow-up duration of 2 years is it may be more than a chance event, and the planned, with possible changes to the trial de- possibility bears close monitoring. sign to allow participant retention and ongoing The mRNA-1273 vaccine did not show evi- data collection. Another limitation is the lack of dence in the short term of enhanced respiratory an identified correlate of protection, a critical disease after infection, a concern that emerged tool for future bridging studies. As of the data from animal models used in evaluating some cutoff, 11 cases of Covid-19 had occurred in the SARS and Middle East respiratory syndrome mRNA-1273 group, a finding that limits our 23-25 (MERS) vaccine constructs. A hallmark of ability to detect a correlate of protection. As enhanced respiratory disease is a Th2-skewed cases accrue and immunity wanes, it may be- n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Supported by the Office of the Assistant Secretary for Pre- come possible to determine such a correlate. In paredness and Response, Biomedical Advanced Research and addition, although our trial showed that mRNA- Development Authority (contract 75A50120C00034) and by the 1273 reduces the incidence of symptomatic National Institute of Allergy and Infectious Diseases (NIAID). The NIAID provides grant funding to the HIV Vaccine Trials SARS-CoV-2 infection, the data were not suffi- Network (HVTN) Leadership and Operations Center (UM1 cient to assess asymptomatic infection, although AI 68614HVTN), the Statistics and Data Management Center our results from a preliminary exploratory anal- (UM1 AI 68635), the HVTN Laboratory Center (UM1 AI 68618), the HIV Prevention Trials Network Leadership and Operations ysis suggest that some degree of prevention may Center (UM1 AI 68619), the AIDS Clinical Trials Group Leader- be afforded after the first dose. Evaluation of the ship and Operations Center (UM1 AI 68636), and the Infectious incidence of asymptomatic or subclinical infec- Diseases Clinical Research Consortium leadership group 5 (UM1 AI148684-03). tion and viral shedding after infection are under Disclosure forms provided by the authors are available with way, to assess whether vaccination affects infec- the full text of this article at NEJM.org. tiousness. The relatively smaller numbers of A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. cases that occurred in older adults and in par- We thank the participants in the trial and the members of the ticipants from ethnic or racial minorities and mRNA-1273 trial team (listed in the Supplementary Appendix) the small number of previously infected persons for their dedication and the contributions to the trial, and the members of the data and safety monitoring board (Richard J. who received the vaccine limit efficacy evalua- Whitley [chair], University of Alabama School of Medicine; Abdel tions in these groups. Longer-term data from Babiker, MRC Clinical Trials Unit at University College, London; the ongoing trial may allow a more careful Lisa A. Cooper, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; Susan S. Ellenberg, University evaluation of the vaccine efficacy in these of Pennsylvania; Alan Fix, Vaccine Development Global Program groups. Pregnant women and children were ex- Center for Vaccine Innovation and Access PATH; Marie Griffin, cluded from this trial, and additional evaluation Vanderbilt University Medical Center; Steven Joffe, Perelman School of Medicine, University of Pennsylvania; Jorge Kalil, Heart of the vaccine in these groups is planned. Institute, Hospital das Clínicas da Faculdade de Medicina da Uni- Within 1 year after the emergence of this versidade de São Paulo; Myron M. Levine, University of Maryland School of Medicine; Malegapuru W. Makgoba, University of Kwa- novel infection that caused a pandemic, a patho- Zulu-Natal; Anastasios A. Tsiatis, North Carolina State University; gen was determined, vaccine targets were identi- Renee H. Moore, Emory University); and Sally Hunsberger [Execu- fied, vaccine constructs were created, manufac- tive Secretary], NIAID) for their hard work, support, and guidance of the trial; and the adjudication committee (Richard J. Hamill turing to scale was developed, phase 1 through [chair], Baylor College of Medicine; Lewis Lipsitz, Harvard Medi- phase 3 testing was conducted, and data have cal School; Eric S. Rosenberg, Massachusetts General Hospital; been reported. This process demonstrates what and Anthony Faugno, Tufts Medical Center) for their critical and timely review of the trial data. We also acknowledge the contri- is possible in the context of motivated collabora- bution from the mRNA-1273 Product Coordination Team from tion among key sectors of society, including aca- the Biomedical Advanced Research and Development Authority demia, government, industry, regulators, and the (BARDA) (Robert Bruno, Richard Gorman, Holli Hamilton, Gary Horwith, Chuong Huynh, Nutan Mytle, Corrina Pavetto, Xiaomi larger community. Lessons learned from this Tong, and John Treanor), and Joanne E. Tomassini (JET Scien- endeavor should allow us to better prepare for tific), for assistance in writing the manuscript for submission, the next pandemic pathogen. and Frank J. Dutko, for editorial support (funded by Moderna). Appendix The authors’ full names and academic degrees are as follows: Lindsey R. Baden, M.D., Hana M. El Sahly, M.D., Brandon Essink, M.D., Karen Kotloff, M.D., Sharon Frey, M.D., Rick Novak, M.D., David Diemert, M.D., Stephen A. Spector, M.D., Nadine Rouphael, M.D., C. Buddy Creech, M.D., John McGettigan, M.D., Shishir Khetan, M.D., Nathan Segall, M.D., Joel Solis, M.D., Adam Brosz, M.D., Car- los Fierro, M.D., Howard Schwartz, M.D., Kathleen Neuzil, M.D., Larry Corey, M.D., Peter Gilbert, Ph.D., Holly Janes, Ph.D., Dean Follmann, Ph.D., Mary Marovich, M.D., John Mascola, M.D., Laura Polakowski, M.D., Julie Ledgerwood, D.O., Barney S. Graham, M.D., Hamilton Bennett, M.S., Rolando Pajon, Ph.D., Conor Knightly, M.P.H., Brett Leav, M.D., Weiping Deng, Ph.D., Honghong Zhou, Ph.D., Shu Han, Ph.D., Melanie Ivarsson, Ph.D., Jacqueline Miller, M.D., and Tal Zaks, M.D. The authors’ affiliations are as follows: Brigham and Women’s Hospital (L.R.B.), Boston, and Moderna, Cambridge (H.B., R.P., C.K., B.L., W.D., H.Z., S.H., M.I., J. 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Publisher
Pubmed Central
Copyright
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
ISSN
0028-4793
eISSN
1533-4406
DOI
10.1056/NEJMoa2035389
Publisher site
See Article on Publisher Site

Abstract

T he n e w e n g l a n d j o u r n a l of m e d i cin e Original Article Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine L.R. Baden, H.M. El Sahly, B. Essink, K. Kotloff, S. Frey, R. Novak, D. Diemert, S.A. Spector, N. Rouphael, C.B. Creech, J. McGettigan, S. Khetan, N. Segall, J. Solis, A. Brosz, C. Fierro, H. Schwartz, K. Neuzil, L. Corey, P. Gilbert, H. Janes, D. Follmann, M. Marovich, J. Mascola, L. Polakowski, J. Ledgerwood, B.S. Graham, H. Bennett, R. Pajon, C. Knightly, B. Leav, W. Deng, H. Zhou, S. Han, M. Ivarsson, J. Miller, and T. Zaks, for the COVE Study Group* A B S T R AC T BACKGROUND Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect The authors’ full names, academic de- grees, and affiliations are listed in the persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid Appendix. Address reprint requests to nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabi- Dr. El Sahly at the Departments of Molec- lized full-length spike protein of the severe acute respiratory syndrome corona- ular Virology and Microbiology and Medi- cine, 1 Baylor Plaza, BCM-MS280, Houston, virus 2 (SARS-CoV-2), the virus that causes Covid-19. TX 77030, or at hana . elsahly@ bcm . edu; or to Dr. Baden at the Division of Infec- METHODS tious Diseases, Brigham and Women’s This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted Hospital, 15 Francis St., PBB-A4, Boston, at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infec- MA 02115, or at lbaden@bwh.harvard.edu. tion or its complications were randomly assigned in a 1:1 ratio to receive two intra- *A complete list of members of the COVE muscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The pri - Study Group is provided in the Supple- mentary Appendix, available at NEJM.org. mary 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 Drs. Baden and El Sahly contributed equal- ly to this article. SARS-CoV-2. This article was published on December 30, RESULTS 2020, at NEJM.org. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to DOI: 10.1056/NEJMoa2035389 receive either vaccine or placebo (15,210 participants in each group). More than Copyright © 2020 Massachusetts Medical Society. 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 ill- ness was confirmed in 185 participants in the placebo group (56.5 per 1000 person- years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA- 1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 partici- pants, with one fatality; all 30 were in the placebo group. Moderate, transient re- actogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.) n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e he emergence in December 2019 of a in medically stable condition at 99 U.S. sites. novel coronavirus, the severe acute respi- Participants received the first trial injection be- Tratory syndrome coronavirus 2 (SARS- tween July 27 and October 23, 2020. The trial is CoV-2), has had devastating consequences glob- being conducted in accordance with the Inter- ally. Control measures such as the use of masks, national Council for Harmonisation of Techni- A Quick Take physical distancing, testing of exposed or symp- cal Requirements for Pharmaceuticals for Hu- is available at tomatic persons, contact tracing, and isolation man Use, Good Clinical Practice guidelines, NEJM.org have helped limit the transmission where they have and applicable government regulations. The cen- been rigorously applied; however, these actions tral institutional review board approved the have been variably implemented and have proved protocol and the consent forms. All partici- insufficient in impeding the spread of coronavi- pants provided written informed consent be- rus disease 2019 (Covid-19), the disease caused by fore enrollment. Safety is reviewed by a protocol SARS-CoV-2. Vaccines are needed to reduce the safety review team weekly and by an indepen- morbidity and mortality associated with Covid-19, dent data and safety monitoring board on a and multiple vaccine platforms have been involved continual basis. The trial Investigational New 1-9 in the rapid development of vaccine candidates. Drug sponsor, Moderna, was responsible for The mRNA vaccine platform has advantages the overall trial design (with input from the as a pandemic-response strategy, given its f lexi- Biomedical Advanced Research and Develop- bility and efficiency in immunogen design and ment Authority, the NIAID, the Covid-19 Pre- manufacturing. Earlier work had suggested that vention Network, and the trial cochairs), site the spike protein of the coronavirus responsible selection and monitoring, and data analysis. for the 2002 SARS outbreak was a suitable target Investigators are responsible for data collection. for protective immunity. Numerous vaccine can- A medical writer funded by Moderna assisted didates in various stages of development are now in drafting the manuscript for submission. The 11-13 being evaluated. Shortly after the SARS-CoV-2 authors vouch for the accuracy and complete- genetic sequence was determined in January ness of the data and for the fidelity of the trial 2020, mRNA-1273, a lipid-nanoparticle (LNP)– to the protocol. The trial is ongoing, and the encapsulated mRNA vaccine expressing the pre- investigators remain unaware of participant- fusion-stabilized spike glycoprotein, was developed level data. Designated team members within by Moderna and the Vaccine Research Center at Moderna have unblinded access to the data, to the National Institute of Allergy and Infectious facilitate interface with the regulatory agencies Diseases (NIAID), within the National Institutes and the data and safety monitoring board; all of Health (NIH). The mRNA-1273 vaccine dem- other trial staff and participants remain un- onstrated protection in animal-challenge experi- aware of the treatment assignments. ments and encouraging safety and immunoge- 1,4 Participants, Randomization, and Data nicity in early-stage human testing. The efficacy Blinding and safety of another mRNA vaccine, BNT162b2, was recently demonstrated. Eligible participants were persons 18 years of age The Coronavirus Efficacy (COVE) phase 3 trial or older with no known history of SARS-CoV-2 was launched in late July 2020 to assess the infection and with locations or circumstances safety and efficacy of the mRNA-1273 vaccine in that put them at an appreciable risk of SARS- preventing SARS-CoV-2 infection. An independent CoV-2 infection, a high risk of severe Covid-19, data and safety monitoring board determined or both. Inclusion and exclusion criteria are pro- that the vaccine met the prespecified efficacy vided in the protocol (available with the full text criteria at the first interim analysis. We report the of this article at NEJM.org). To enhance the di- primary analysis results of this ongoing pivotal versity of the trial population in accordance with phase 3 trial. Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from M e th o ds racial and ethnic minorities in the trial, in addi- Trial Oversight tion to the persons at risk for SARS-CoV-2 infec- This phase 3 randomized, stratified, observer- tion in the local population. The upper limit for blinded, placebo-controlled trial enrolled adults stratification of enrolled participants considered n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Safety Assessments to be “at risk for severe illness” at screening was increased from 40% to 50%. Safety assessments included monitoring of solic- Participants were randomly assigned in a 1:1 ited local and systemic adverse events for 7 days ratio, through the use of a centralized interactive after each injection; unsolicited adverse reac- response technology system, to receive vaccine or tions for 28 days after each injection; adverse placebo. Assignment was stratified, on the basis events leading to discontinuation from a dose, of age and Covid-19 complications risk criteria, from participation in the trial, or both; and into the following risk groups: persons 65 years medically attended adverse events and serious of age or older, persons younger than 65 years of adverse events from day 1 through day 759. Ad- age who were at heightened risk (at risk) for se- verse event grading criteria and toxicity tables vere Covid-19, and persons younger than 65 years are described in the protocol. Cases of Covid-19 of age without heightened risk (not at risk). Par- and severe Covid-19 were continuously moni- ticipants younger than 65 years of age were cate- tored by the data and safety monitoring board gorized as having risk for severe Covid-19 if they from randomization onward. had at least one of the following risk factors, Efficacy Assessments based on the Centers for Disease Control and Pre- vention (CDC) criteria available at the time of trial The primary end point was the efficacy of the design: chronic lung disease (e.g., emphysema, mRNA-1273 vaccine in preventing a first occur- chronic bronchitis, idiopathic pulmonary fibro- rence of symptomatic Covid-19 with onset at sis, cystic fibrosis, or moderate-to-severe asthma); least 14 days after the second injection in the cardiac disease (e.g., heart failure, congenital per-protocol population, among participants who coronary artery disease, cardiomyopathies, or pul- were seronegative at baseline. End points were monary hypertension); severe obesity (body mass judged by an independent adjudication committee index [the weight in kilograms divided by the that was unaware of group assignment. Covid-19 square of the height in meters] ≥40); diabetes cases were defined as occurring in participants (type 1, type 2, or gestational); liver disease; or in- who had at least two of the following symptoms: fection with the human immunodeficiency virus. fever (temperature ≥38°C), chills, myalgia, head- Vaccine dose preparation and administration ache, sore throat, or new olfactory or taste dis- were performed by pharmacists and vaccine ad- order, or as occurring in those who had at least ministrators who were aware of treatment as- one respiratory sign or symptom (including cough, signments but had no other role in the conduct shortness of breath, or clinical or radiographic of the trial. Once the injection was completed, evidence of pneumonia) and at least one naso- only trial staff who were unaware of treatment pharyngeal swab, nasal swab, or saliva sample assignments performed assessments and inter- (or respiratory sample, if the participant was acted with the participants. Access to the ran- hospitalized) that was positive for SARS-CoV-2 domization code was strictly controlled at the by reverse-transcriptase–polymerase-chain-reac- pharmacy. The data and safety monitoring board tion (RT-PCR) test. Participants were assessed for reviewed efficacy data at the group level and the presence of SARS-CoV-2–binding antibodies unblinded safety data at the participant level. specific to the SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) Trial Vaccine and had a nasopharyngeal swab for SARS-CoV-2 The mRNA-1273 vaccine, provided as a sterile RT-PCR testing (Viracor, Eurofins Clinical Di- liquid at a concentration of 0.2 mg per milliliter, agnostics) before each injection. SARS-CoV-2– was administered by injection into the deltoid infected volunteers were followed daily, to assess muscle according to a two-dose regimen. Injec- symptom severity, for 14 days or until symptoms tions were given 28 days apart, in the same arm, resolved, whichever was longer. A nasopharyn- in a volume of 0.5 ml containing 100 μg of geal swab for RT-PCR testing and a blood sam- mRNA-1273 or saline placebo. Vaccine mRNA- ple for identifying serologic evidence of SARS- 1273 was stored at 2° to 8°C (35.6° to 46.4°F) at CoV-2 infection were collected from participants clinical sites before preparation and vaccination. with symptoms of Covid-19. No dilution was required. Doses could be held in The consistency of vaccine efficacy at the pri- syringes for up to 8 hours at room temperature mary end point was evaluated across various before administration. subgroups, including age groups (18 to <65 years n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e of age and ≥65 years), age and health risk for mate, based on a total of 95 adjudicated cases severe disease (18 to <65 years and not at risk; (63% of the target total), was 94.5%, with a 18 to <65 years and at risk; and ≥65 years), sex one-sided P value of less than 0.001 to reject the (female or male), race and ethnic group, and risk null hypothesis that vaccine efficacy would be for severe Covid-19 illness. If the number of 30% or less. The data and safety monitoring participants in a subgroup was too small, it was board recommendation to the oversight group combined with other subgroups for the sub- and the trial sponsor was that the efficacy find- group analyses. ings should be shared with the participants and A secondary end point was the efficacy of the community (full details are available in the mRNA-1273 in the prevention of severe Covid-19 protocol and statistical analysis plan). as defined by one of the following criteria: respi- Vaccine efficacy was assessed in the full analy- ratory rate of 30 or more breaths per minute; sis population (randomized participants who re- heart rate at or exceeding 125 beats per minute; ceived at least one dose of mRNA-1273 or pla- oxygen saturation at 93% or less while the par- cebo), the modif ied intention-to-treat population ticipant was breathing ambient air at sea level or (participants in the full analysis population who a ratio of the partial pressure of oxygen to the had no immunologic or virologic evidence of fraction of inspired oxygen below 300 mm Hg; Covid-19 on day 1, before the first dose), and the respiratory failure; acute respiratory distress syn- per-protocol population (participants in the mod- drome; evidence of shock (systolic blood pressure ified intention-to-treat population who received <90 mm Hg, diastolic blood pressure <60 mm Hg, two doses, with no major protocol deviations). or a need for vasopressors); clinically significant The primary efficacy end point in the interim acute renal, hepatic, or neurologic dysfunction; and primary analyses was assessed in the per- admission to an intensive care unit; or death. protocol population. Participants were evaluated Additional secondary end points included the in the treatment groups to which they were as- efficacy of the vaccine at preventing Covid-19 signed. Vaccine efficacy was defined as the per- after a single dose or at preventing Covid-19 ac- centage reduction in the hazard ratio for the cording to a secondary (CDC), less restrictive primary end point (mRNA-1273 vs. placebo). A case definition: having any symptom of Covid-19 stratified Cox proportional hazards model was and a positive SARS-CoV-2 test by RT-PCR (see used to assess the vaccine efficacy of mRNA-1273 Table S1 in the Supplementary Appendix, avail- as compared with placebo in terms of the per- able at NEJM.org). centage hazard reduction. (Details regarding the analysis of vaccine efficacy are provided in the Statistical Analysis Methods section of the Supplementary Appendix.) For analysis of the primary end point, the trial Safety was assessed in all participants in the was designed for the null hypothesis that the solicited safety population (i.e., those who re- efficacy of the mRNA-1273 vaccine is 30% or ceived at least one injection and reported a solic- less. A total of 151 cases of Covid-19 would pro- ited adverse event). Descriptive summary data vide 90% power to detect a 60% reduction in the (numbers and percentages) for participants with hazard rate (i.e., 60% vaccine efficacy), with two any solicited adverse events, unsolicited adverse planned interim analyses at approximately 35% events, unsolicited severe adverse events, serious and 70% of the target total number of cases adverse events, medically attended adverse (151) and with a one-sided O’Brien–Fleming events, and adverse events leading to discontinu- boundary for efficacy and an overall one-sided ation of the injections or withdrawal from the error rate of 0.025. The efficacy of the mRNA- trial are provided by group. Two-sided 95% exact 1273 vaccine could be demonstrated at either the confidence intervals (Clopper–Pearson method) interim or the primary analysis, performed when are provided for the percentages of participants the target total number of cases had been ob- with solicited adverse events. Unsolicited adverse served. The Lan–DeMets alpha-spending func- events are presented according to the Medical tion was used for calculating efficacy boundar- Dictionary for Regulatory Activities (MedDRA), ver- ies at each analysis. At the first interim analysis sion 23.0, preferred terms and system organ on November 15, 2020, vaccine eff icacy had been class categories. demonstrated in accordance with the prespeci- To meet the regulatory agencies’ requirement of fied statistical criteria. The vaccine efficacy esti- a median follow-up duration of at least 2 months n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine 30,420 Participants underwent randomization (1:1) 15,210 Were assigned to receive 15,210 Were assigned to receive two doses of mRNA-1273, placebo 100 μg each 15,185 Were included in the 15,181 Received at least one 15,170 Received at least one 15,166 Were included in the safety analysis dose and were included dose and were included safety analysis in the full analysis set in the full analysis set 29 Did not receive any 40 Did not receive any injection injection 14,550 Were included in the 14,598 Were included in the modified intention-to- modified intention-to- treat population treat population 631 Were SARS-CoV-2–positive 572 Were SARS-CoV-2–positive at baseline or had missing at baseline or had missing data and were excluded data and were excluded 416 Were excluded from per-protocol analysis 525 Were excluded from per-protocol analysis 6 Received an incorrect mRNA injection 7 Received incorrect injection 168 Discontinued without receiving dose 2 231 Discontinued without receiving dose 2 93 Received dose 2 outside dose 2 window 109 Received dose 2 outside dose 2 window 138 Did not receive dose 2, or were out 154 Did not receive dose 2, or were out of window for per-protocol analysis of window for per-protocol analysis 11 Had other major deviations from protocol 24 Had other major deviations from protocol 14,134 Were included in the 14,073 Were included in the per-protocol analysis per-protocol analysis Figure 1. Randomization and Analysis Populations. The data cutoff for the primary analysis occurred on November 25, 2020. The full analysis population consisted of participants who un- derwent randomization and received at least one dose of mRNA-1273 or placebo; the modified intention-to-treat population comprised participants in the full analysis population who had no immunologic or virologic evidence of Covid-19 on day 1, before the first dose; and the per-protocol analysis population included participants in the modified intention-to-treat population who received two doses, with no major protocol deviations. The safety population included all participants who received at least one injection. Among partici- pants who received an incorrect injection, three participants in the mRNA-1273 group received at least one dose of placebo and no dose of mRNA-1273 and were included in the placebo safety population, and three received one dose of placebo and one dose of mRNA-1273 and were included in the mRNA-1273 safety population; in the placebo group all seven received mRNA-1273 and were included in the mRNA-1273 safety population. Participants who received dose 2 outside the window for the per-protocol analysis are those who did not receive the second dose between 7 days before and 14 days after day 29. after completion of the two-dose regimen, a sec- sented in this report. Subsequent analyses are ond analysis was performed, with an efficacy considered supplementary. data cutoff date of November 21, 2020. This second analysis is considered the primary analy- R e s u l t s sis of efficacy, with a total of 196 adjudicated Trial Population Covid-19 cases in the per-protocol population, which exceeds the target total number of cases Between July 27, 2020, and October 23, 2020, a (151) specified in the protocol. This was an in- total of 30,420 participants underwent random- crease from the 95 cases observed at the first ization, and the 15,210 participants in each interim analysis data cutoff on November 11, group were assigned to receive two doses of ei- 2020. Results from the primary analysis are pre- ther placebo or mRNA-1273 (100 μg) (Fig. 1). n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Table 1. Demographic and Clinical Characteristics at Baseline.* Placebo mRNA-1273 Total Characteristics (N=15,170) (N=15,181) (N=30,351) Sex — no. of participants (%) Male 8,062 (53.1) 7,923 (52.2) 15,985 (52.7) Female 7,108 (46.9) 7,258 (47.8) 14,366 (47.3) Mean age (range) — yr 51.3 (18–95) 51.4 (18–95) 51.4 (18–95) Age category and risk for severe Covid-19 — no. of participants (%)† 18 to <65 yr, not at risk 8,886 (58.6) 8,888 (58.5) 17,774 (58.6) 18 to <65 yr, at risk 2,535 (16.7) 2,530 (16.7) 5,065 (16.7) ≥65 yr 3,749 (24.7) 3,763 (24.8) 7,512 (24.8) Hispanic or Latino ethnicity — no. of participants (%)‡ Hispanic or Latino 3,114 (20.5) 3,121 (20.6) 6,235 (20.5) Not Hispanic or Latino 11,917 (78.6) 11,918 (78.5) 23,835 (78.5) Not reported and unknown 139 (0.9) 142 (0.9) 281 (0.9) Race or ethnic group — no. of participants (%)‡ White 11,995 (79.1) 12,029 (79.2) 24,024 (79.2) Black or African American 1,527 (10.1) 1,563 (10.3) 3,090 (10.2) Asian 731 (4.8) 651 (4.3) 1,382 (4.6) American Indian or Alaska Native 121 (0.8) 112 (0.7) 233 (0.8) Native Hawaiian or Other Pacific Islander 32 (0.2) 35 (0.2) 67 (0.2) Multiracial 321 (2.1) 315 (2.1) 636 (2.1) Other 316 (2.1) 321 (2.1) 637 (2.1) Not reported and unknown 127 (0.8) 155 (1.0) 282 (0.9) Baseline SARS-CoV-2 status — no. of participants (%)§ Negative 14,598 (96.2) 14,550 (95.8) 29,148 (96.0) Positive 337 (2.2) 343 (2.3) 680 (2.2) Missing data 235 (1.5) 288 (1.9) 523 (1.7) Baseline RT-PCR test — no. of participants (%) Negative 14,923 (98.4) 14,917 (98.3) 29,840 (98.3) Positive 95 (0.6) 87 (0.6) 182 (0.6) Missing data 152 (1.0) 177 (1.2) 329 (1.1) Baseline bAb anti–SARS-CoV-2 assay — no. of participants (%) Negative 14,726 (97.1) 14,690 (96.8) 29,416 (96.9) Positive 303 (2.0) 305 (2.0) 608 (2.0) Missing data 141 (0.9) 186 (1.2) 327 (1.1) Risk factor for severe Covid-19 — no. of participants (%) Chronic lung disease 744 (4.9) 710 (4.7) 1,454 (4.8) Significant cardiac disease 744 (4.9) 752 (5.0) 1,496 (4.9) Severe obesity 1,021 (6.7) 1,025 (6.8) 2,046 (6.7) Diabetes 1,440 (9.5) 1,435 (9.5) 2,875 (9.5) Liver disease 96 (0.6) 100 (0.7) 196 (0.6) Human immunodeficiency virus infection 87 (0.6) 92 (0.6) 179 (0.6) n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Table 1. (Continued.) Placebo mRNA-1273 Total Characteristics (N=15,170) (N=15,181) (N=30,351) Body-mass index¶ No. of participants 15,007 14,985 29,992 Mean ±SD 29.3±6.7 29.3±6.9 29.3±6.8 * Internet-based randomization was used to assign participants to treatment groups on the basis of information entered by the investigator regarding the participant’s age and coexisting conditions. Percentages are based on the full analysis population; baseline demographics and characteristics for the per-protocol population are provided in the Supplementary Appendix. Percentages may not total 100 because of rounding. The abbreviation bAb denotes binding antibody concentration, and RT-PCR reverse-transcriptase polymerase chain reaction. † Risk was based on a stratification factor from the Internet-based interactive response system used for randomization; participa nts who were younger than 65 years of age were categorized as at risk for severe Covid-19 illness if they had at least one of the risk factors specified in the trial protocol at screening. ‡ Race or ethnic group was reported by the participant. Participants could be included in more than one category. § Baseline SARS-CoV-2 status was positive if there was immunologic or virologic evidence of previous illness with Covid-19, as defined by a positive RT-PCR test or a positive bAb against SARS-CoV-2 nucleocapsid assay result that was above the limit of detection or by a lower limit of quantification at day 1. Baseline SARS-CoV-2 status was negative if there was a negative RT-PCR test and negative bAb against SARS-CoV-2 assay result at day 1. ¶ The body-mass index is the weight in kilograms divided by the square of the height in meters. More than 96% of participants received the sec- proportions were generally representative of U.S. ond dose (Fig. S1). Common reasons for not re- demographics, including 10.2% Black or African ceiving the second dose were withdrawal of American and 20.5% Hispanic or Latino. Evi- consent (153 participants) and the detection of dence of SARS-CoV-2 infection at baseline was SARS-CoV-2 by PCR before the administration present in 2.3% of participants in the mRNA- of the second dose on day 29 (114 participants: 1273 group and in 2.2% in the placebo group, as 69 in the placebo group and 45 in the mRNA- detected by serologic assay or RT-PCR testing. 1273 group). The primary efficacy and safety Safety analyses were performed in the per-protocol and safety populations, respectively. Of the partici- Solicited adverse events at the injection site oc- pants who received a first injection, 14,073 of curred more frequently in the mRNA-1273 group those in the placebo group and 14,134 in the than in the placebo group after both the first mRNA-1273 group were included in the primary dose (84.2%, vs. 19.8%) and the second dose efficacy analysis; 525 participants in the placebo (88.6%, vs. 18.8%) (Fig. 2 and Tables S3 and S4). group and 416 in the mRNA-1273 group were In the mRNA-1273 group, injection-site events excluded from the per-protocol population, in- were mainly grade 1 or 2 in severity and lasted cluding those who had not received a second a mean of 2.6 and 3.2 days after the first and dose by the day 29 data cutoff (Fig. 1). As of second doses, respectively (Table S5). The most November 25, 2020, the participants had a me- common injection-site event was pain after in- dian follow-up duration of 64 days (range, 0 to jection (86.0%). Delayed injection-site reactions 97) after the second dose, with 61% of partici- (those with onset on or after day 8) were noted pants having more than 56 days of follow-up. in 244 participants (0.8%) after the first dose Baseline demographic characteristics were and in 68 participants (0.2%) after the second balanced between the placebo group and the dose. Reactions were characterized by erythema, mRNA-1273 vaccine group (Table 1 and Table S2). induration, and tenderness, and they resolved The mean age of the participants was 51.4 years, over the following 4 to 5 days. Solicited sys- 47.3% of the participants were female, 24.8% temic adverse events occurred more often in the were 65 years of age or older, and 16.7% were mRNA-1273 group than in the placebo group younger than 65 years of age and had predispos- after both the first dose (54.9%, vs. 42.2%) and ing medical conditions that put them at risk for the second dose (79.4%, vs. 36.5%). The severity severe Covid-19. The majority of participants of the solicited systemic events increased after were White (79.2%), and the racial and ethnic the second dose in the mRNA-1273 group, with n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Grade 1 Grade 2 Grade 3 A Local Events Any Adverse Event Pain Erythema Swelling Lymphadenopathy B Systemic Events Any Adverse Fever Headache Fatigue Myalgia Arthralgia Nausea Chills Event or Vomiting Figure 2. Solicited Local and Systemic Adverse Events. Shown is the percentage of participants who had a solicited local or systemic adverse event within 7 days after injection 1 or injection 2 of either the placebo or the mRNA-1273 vaccine. an increase in proportions of grade 2 events tively (Table S5). Both solicited injection-site and (from 16.5% after the first dose to 38.1% after systemic adverse events were more common the second dose) and grade 3 events (from 2.9% among younger participants (18 to <65 years of to 15.8%). Solicited systemic adverse events in the age) than among older participants (≥65 years mRNA-1273 group lasted a mean of 2.6 days and of age). Solicited adverse events were less com- 3.1 days after the first and second doses, respec- mon in participants who were positive for SARS- n engl j med nejm.org Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 Placebo, dose 1 mRNA-1273, dose 1 Placebo, dose 2 mRNA-1273, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 1 Placebo, dose 2 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 1 mRNA-1273, dose 2 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Placebo, dose 1 Placebo, dose 2 mRNA-1273, dose 1 mRNA-1273, dose 2 Percentage of Participants Percentage of Participants Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine CoV-2 infection at baseline than in those who incidence of these adverse events according to were negative at baseline (Tables S6 and S7). vaccine group was not affected by age. The frequency of unsolicited adverse events, Efficacy unsolicited severe adverse events, and serious adverse events reported during the 28 days after After day 1 and through November 25, 2020, a injection was generally similar among partici- total of 269 Covid-19 cases were identified, with pants in the two groups (Tables S8 through S11). an incidence of 79.8 cases per 1000 person-years Three deaths occurred in the placebo group (one (95% confidence interval [CI], 70.5 to 89.9) from intraabdominal perforation, one from car- among participants in the placebo group with diopulmonary arrest, and one from severe sys- no evidence of previous SARS-CoV-2 infection. temic inflammatory syndrome in a participant For the primary analysis, 196 cases of Covid-19 with chronic lymphocytic leukemia and diffuse were diagnosed: 11 cases in the vaccine group bullous rash) and two in the vaccine group (one (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0) from cardiopulmonary arrest and one by sui- and 185 cases in the placebo group (56.5 per cide). The frequency of grade 3 adverse events in 1000 person-years; 95% CI, 48.7 to 65.3), indi- the placebo group (1.3%) was similar to that in cating 94.1% efficacy of the mRNA-1273 vaccine the vaccine group (1.5%), as were the frequencies (95% CI, 89.3 to 96.8%; P<0.001) for the preven- of medically attended adverse events (9.7% vs. tion of symptomatic SARS-CoV-2 infection as 9.0%) and serious adverse events (0.6% in both compared with placebo (Fig. 3A). Findings were groups). Hypersensitivity reactions were report- similar across key secondary analyses (Table ed in 1.5% and 1.1% of participants in the vac- S16), including assessment starting 14 days after cine and placebo groups, respectively (Table S12). dose 1 (225 cases with placebo, vs. 11 with Bell’s palsy occurred in the vaccine group (3 par- mRNA-1273, indicating a vaccine efficacy of ticipants [<0.1%]) and the placebo group (1 partici- 95.2% [95% CI, 91.2 to 97.4]), and assessment pant [<0.1%]) during the observation period of including participants who were SARS-CoV-2 the trial (more than 28 days after injection). seropositive at baseline in the per-protocol anal- Overall, 0.5% of participants in the placebo ysis (187 cases with placebo, vs. 12 with mRNA- group and 0.3% in the mRNA-1273 group had 1273; one volunteer assigned to receive mRNA- adverse events that resulted in their not receiving 1273 was inadvertently given placebo], indicating the second dose, and less than 0.1% of partici- a vaccine efficacy of 93.6% [95% CI, 88.6 to pants in both groups discontinued participation 96.5]). Between days 1 and 42, seven cases of in the trial because of adverse events after any Covid-19 were identified in the mRNA-1273 dose (Table S8). No evidence of vaccine-associated group, as compared with 65 cases in the placebo enhanced respiratory disease was noted, and group (Fig. 3B). fewer cases of severe Covid-19 or any Covid-19 A key secondary end point evaluated the effi- were observed among participants who received cacy of mRNA-1273 at preventing severe Covid- mRNA-1273 than among those who received 19. Thirty participants in the trial had severe placebo (Tables S13 and S14). Adverse events Covid-19; all 30 were in the placebo group (indi- that were deemed by the trial team to be related cating vaccine efficacy of 100% [95% CI, could to the vaccine or placebo were reported among not be estimated to 1.0]), and one death among 4.5% of participants in the placebo group and these participants was attributed to Covid-19 8.2% in the mRNA-1273 group. The most com- (Table S16). The vaccine efficacy to prevent mon treatment-related adverse events (those re- Covid-19 was consistent across subgroups strati- ported in at least 1% of participants) in the pla- fied by demographic and baseline characteristics cebo group and the mRNA-1273 group were (Fig. 4): age groups (18 to <65 years of age and fatigue (1.2% and 1.5%) and headache (0.9% and ≥65 years), presence of risk for severe Covid-19, 1.4%). In the overall population, the incidence of sex, and race and ethnic group (non-Hispanic treatment-related severe adverse events was White and communities of color). Among par- higher in the mRNA-1273 group (71 participants ticipants who were positive for SARS-CoV-2, by [0.5%]) than in the placebo group (28 partici- serologic or virologic testing, at baseline (337 in pants [0.2%]) (Tables S8 and S15). The relative the placebo group and 343 in the mRNA-1273 n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e A Per-Protocol Analysis Vaccine Efficacy Incidence Rate (95% CI) (95% CI) 3.5 % per 1000 person-yr 3.0 Placebo 56.5 (48.7–65.3) mRNA-1273 94.1 (89.3–96.8) 3.3 (1.7–6.0) Placebo 2.5 2.0 1.5 1.0 0.5 mRNA-1273 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days since Randomization No. at Risk Placebo 14,073 14,073 14,073 14,072 13,416 12,992 12,361 11,147 9474 6563 3971 1172 0 mRNA-1273 14,134 14,134 14,134 14,133 13,483 13,073 12,508 11,315 9684 6721 4094 1209 0 B Modified Intention-to-Treat Analysis Vaccine Efficacy Incidence Rate 3.5 (95% CI) (95% CI) Placebo % per 1000 person-yr 3.0 Placebo 79.8 (70.5–89.9) mRNA-1273 93.0 (88.9–95.6) 5.6 (3.4–8.8) 2.5 2.0 1.5 1.0 0.5 mRNA-1273 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days since Randomization No. at Risk Placebo 14,598 14,590 14,567 14,515 13,806 12,352 12,694 11,450 9736 6729 4067 1200 0 mRNA-1273 14,550 14,543 14,532 14,504 13,825 13,398 12,791 11,573 9911 6871 4179 1238 0 Placebo mRNA-1273 Covid-19 Onset (N= 14,598) (N= 14,550) Randomization to 14 days after dose 1 11 14 Days after dose 1 to dose 2 35 2 Dose 2 to 14 days after dose 2 19 Starting 14 days after dose 2 204 12 269 19 Total (any time after randomization) n engl j med nejm.org Cumulative Event Rate (%) Cumulative Event Rate (%) Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine the placebo group, which suggests that mRNA- Figure 3 (facing page). Vaccine Eff icacy of mRNA-1273 1273 is likely to have an effect on preventing to Prevent Covid-19. severe illness, which is the major cause of health Shown is the cumulative incidence of Covid-19 events in the primary analysis based on adjudicated assess- care utilization, complications, and death. The ment starting 14 days after the second vaccination in finding of fewer occurrences of symptomatic the per-protocol population (Panel A) and after ran- SARS-CoV-2 infection after a single dose of domization in the modified intention-to-treat popula- mRNA-1273 is encouraging; however, the trial tion (Panel B) (see the Supplementary Appendix). The was not designed to evaluate the efficacy of a dotted line in Panel A indicates day 42 (14 days after vaccination 2), when the per-protocol follow-up began, single dose, and additional evaluation is war- and arrows in both panels indicate days 1 and 29, when ranted. injections were administered. Tick marks indicate cen- The magnitude of mRNA-1273 vaccine effi- sored data. Vaccine efficacy was defined as 1 minus the cacy at preventing symptomatic SARS-CoV-2 in- hazard ratio (mRNA vs. placebo), and the 95% confi- fection is higher than the efficacy observed for dence interval was estimated with the use of a stratified Cox proportional hazards model, with Efron’s method vaccines for respiratory viruses, such as the in- of tie handling and with treatment group as a covariate, activated inf luenza vaccine against symptomatic, with adjustment for stratification factor. Incidence was virologically confirmed disease in adults, for defined as the number of events divided by number of which studies have shown a pooled efficacy of participants at risk and was adjusted by person-years. 59%. This high apparent efficacy of mRNA- Symptomatic Covid-19 case accrual for placebo and vac- cine in the modified intention-to-treat population is dis- 1273 is based on short-term data, and waning of played (does not include asymptomatic cases of SARS- efficacy over time has been demonstrated with CoV-2 detected at the day 29 by nasopharyngeal swab). other vaccines. Also, the efficacy of the vaccine was tested in a setting of national recommenda- group), one case of Covid-19 was diagnosed by tions for masking and social distancing, which RT-PCR testing in a placebo recipient and no may have translated into lower levels of infec- cases were diagnosed in mRNA-1273 recipients tious inoculum. The eff icacy of mRNA-1273 is in (Table S17). Among participants who were nega- line with that of the recently reported BNT162b2 tive for SARS-CoV-2 at baseline (by RT-PCR or mRNA vaccine. The COVE trial is ongoing, and antibody testing), in addition to symptomatic longitudinal follow-up will allow an assessment Covid-19 cases 39 (0.3%) in the placebo group of efficacy changes over time and under evolving and 15 (0.1%) in the mRNA-1273 group had epidemiologic conditions. nasopharyngeal swabs that were positive for Overall, the safety of the mRNA-1273 vaccine SARS-CoV-2 by RT-PCR at the second dose visit regimen and platform is reassuring; no unex- (surveillance swab) but had no evidence of pected patterns of concern were identified. The Covid-19 symptoms (Table S18). reactogenicity associated with immunization with mRNA-1273 in this trial is similar to that 1,4 in the phase 1 data reported previously. Over- D i s c u s s ion all, the local reactions to vaccination were mild; The COVE trial provides evidence of short-term however, moderate-to-severe systemic side ef- efficacy of the mRNA-1273 vaccine in preventing fects, such as fatigue, myalgia, arthralgia, and symptomatic SARS-CoV-2 infection in a diverse headache, were noted in about 50% of partici- adult trial population. Of note, the trial was pants in the mRNA-1273 group after the second designed for an infection attack rate of 0.75%, dose. These side effects were transient, starting which would have necessitated a follow-up peri- about 15 hours after vaccination and resolving in od of 6 months after the two vaccine doses to most participants by day 2, without sequelae. accrue 151 cases in 30,000 participants. The The degree of reactogenicity after one dose of pandemic trajectory accelerated in many U.S. mRNA-1273 was less than that observed for the regions in the late summer and fall of 2020, re- recently approved recombinant adjuvanted zoster sulting in rapid accrual of 196 cases after a vaccine and after the second mRNA-1273 dose 21,22 median follow-up of 2 months. It is important to was similar to that of the zoster vaccine. note that all the severe Covid-19 cases were in Delayed injection-site reactions, with an onset n engl j med nejm.org T he n e w e n g l a n d j o u r n a l of m e d i cin e Placebo mRNA-1273 Subgroup (N=14,073) (N=14,134) Vaccine Efficacy (95% CI) no. of events/total no. All patients 185/14,073 11/14,134 94.1 (89.3–96.8) Age ≥18 to <65 yr 156/10,521 7/10,551 95.6 (90.6–97.9) ≥65 yr 29/3552 4/3583 86.4 (61.4–95.2) Age, risk for severe Covid-19 18 to <65 yr, not at risk 121/8403 5/8396 95.9 (90.0–98.3) 94.4 (76.9–98.7) 18 to <65 yr, at risk 35/2118 2/2155 86.4 (61.4–95.2) ≥65 yr 29/3552 4/3583 Sex Male 87/7462 4/7366 95.4 (87.4–98.3) 93.1 (85.2–96.8) Female 98/6611 7/6768 At risk for severe Covid-19 90.9 (74.7–96.7) Yes 43/3167 4/3206 No 142/10,906 7/10,928 95.1 (89.6–97.7) Race and ethnic group 93.2 (87.1–96.4) White 144/8916 10/9023 Communities of color 41/5132 1/5088 97.5 (82.2–99.7) 0 25 50 75 100 Figure 4. Vaccine Eff icacy of mRNA-1273 to Prevent Covid-19 in Subgroups. The efficacy of the RNA-1273 vaccine in preventing Covid-19 in various subgroups in the per-protocol population was based on adjudicated assessments starting 14 days after the second injection. Vaccine efficacy, defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo), and 95% confidence intervals were estimated with the use of a stratified Cox proportional hazards model, with Efron’s method of tie handling and with the treatment group as a covariate, adjusting for stratification factor if applicable. Race and ethnic group categories shown are White (non- Hispanic) and communities of color (all others, including those whose race and ethnicity were both reported as un- known, were not reported, or were both missing at screening). Data for communities of color were pooled owing to limited numbers of participants in each racial or ethnic group, to ensure that the subpopulations would be large enough for meaningful analyses. 8 days or more after injection, were uncommon. immune response and eosinophilic pulmonary The overall incidence of unsolicited adverse infiltration on histopathological examination. events reported up to 28 days after vaccination Of note, preclinical testing of mRNA-1273 and and of serious adverse events reported through- other SARS-CoV-2 vaccines in advanced clinical out the entire trial was similar for mRNA-1273 evaluation has shown a Th1-skewed vaccine re- 15,26-28 and placebo. A risk of acute hypersensitivity is sponse and no pathologic lung infiltrates. sometimes observed with vaccines; however, no Whether mRNA-1273 vaccination results in en- such risk was evident in the COVE trial, although hanced disease on exposure to the virus in the the ability to detect rare events is limited, given long term is unknown. the trial sample size. The anecdotal finding of a Key limitations of the data are the short dura- slight excess of Bell’s palsy in this trial and in tion of safety and efficacy follow-up. The trial is the BNT162b2 vaccine trial arouses concern that ongoing, and a follow-up duration of 2 years is it may be more than a chance event, and the planned, with possible changes to the trial de- possibility bears close monitoring. sign to allow participant retention and ongoing The mRNA-1273 vaccine did not show evi- data collection. Another limitation is the lack of dence in the short term of enhanced respiratory an identified correlate of protection, a critical disease after infection, a concern that emerged tool for future bridging studies. As of the data from animal models used in evaluating some cutoff, 11 cases of Covid-19 had occurred in the SARS and Middle East respiratory syndrome mRNA-1273 group, a finding that limits our 23-25 (MERS) vaccine constructs. A hallmark of ability to detect a correlate of protection. As enhanced respiratory disease is a Th2-skewed cases accrue and immunity wanes, it may be- n engl j med nejm.org Effic ac y a nd Sa fe t y of mR NA-1273 SA R S- CoV-2 Vaccine Supported by the Office of the Assistant Secretary for Pre- come possible to determine such a correlate. In paredness and Response, Biomedical Advanced Research and addition, although our trial showed that mRNA- Development Authority (contract 75A50120C00034) and by the 1273 reduces the incidence of symptomatic National Institute of Allergy and Infectious Diseases (NIAID). The NIAID provides grant funding to the HIV Vaccine Trials SARS-CoV-2 infection, the data were not suffi- Network (HVTN) Leadership and Operations Center (UM1 cient to assess asymptomatic infection, although AI 68614HVTN), the Statistics and Data Management Center our results from a preliminary exploratory anal- (UM1 AI 68635), the HVTN Laboratory Center (UM1 AI 68618), the HIV Prevention Trials Network Leadership and Operations ysis suggest that some degree of prevention may Center (UM1 AI 68619), the AIDS Clinical Trials Group Leader- be afforded after the first dose. Evaluation of the ship and Operations Center (UM1 AI 68636), and the Infectious incidence of asymptomatic or subclinical infec- Diseases Clinical Research Consortium leadership group 5 (UM1 AI148684-03). tion and viral shedding after infection are under Disclosure forms provided by the authors are available with way, to assess whether vaccination affects infec- the full text of this article at NEJM.org. tiousness. The relatively smaller numbers of A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. cases that occurred in older adults and in par- We thank the participants in the trial and the members of the ticipants from ethnic or racial minorities and mRNA-1273 trial team (listed in the Supplementary Appendix) the small number of previously infected persons for their dedication and the contributions to the trial, and the members of the data and safety monitoring board (Richard J. who received the vaccine limit efficacy evalua- Whitley [chair], University of Alabama School of Medicine; Abdel tions in these groups. Longer-term data from Babiker, MRC Clinical Trials Unit at University College, London; the ongoing trial may allow a more careful Lisa A. Cooper, Johns Hopkins University School of Medicine and Bloomberg School of Public Health; Susan S. Ellenberg, University evaluation of the vaccine efficacy in these of Pennsylvania; Alan Fix, Vaccine Development Global Program groups. Pregnant women and children were ex- Center for Vaccine Innovation and Access PATH; Marie Griffin, cluded from this trial, and additional evaluation Vanderbilt University Medical Center; Steven Joffe, Perelman School of Medicine, University of Pennsylvania; Jorge Kalil, Heart of the vaccine in these groups is planned. Institute, Hospital das Clínicas da Faculdade de Medicina da Uni- Within 1 year after the emergence of this versidade de São Paulo; Myron M. Levine, University of Maryland School of Medicine; Malegapuru W. Makgoba, University of Kwa- novel infection that caused a pandemic, a patho- Zulu-Natal; Anastasios A. Tsiatis, North Carolina State University; gen was determined, vaccine targets were identi- Renee H. Moore, Emory University); and Sally Hunsberger [Execu- fied, vaccine constructs were created, manufac- tive Secretary], NIAID) for their hard work, support, and guidance of the trial; and the adjudication committee (Richard J. Hamill turing to scale was developed, phase 1 through [chair], Baylor College of Medicine; Lewis Lipsitz, Harvard Medi- phase 3 testing was conducted, and data have cal School; Eric S. Rosenberg, Massachusetts General Hospital; been reported. This process demonstrates what and Anthony Faugno, Tufts Medical Center) for their critical and timely review of the trial data. We also acknowledge the contri- is possible in the context of motivated collabora- bution from the mRNA-1273 Product Coordination Team from tion among key sectors of society, including aca- the Biomedical Advanced Research and Development Authority demia, government, industry, regulators, and the (BARDA) (Robert Bruno, Richard Gorman, Holli Hamilton, Gary Horwith, Chuong Huynh, Nutan Mytle, Corrina Pavetto, Xiaomi larger community. Lessons learned from this Tong, and John Treanor), and Joanne E. Tomassini (JET Scien- endeavor should allow us to better prepare for tific), for assistance in writing the manuscript for submission, the next pandemic pathogen. and Frank J. Dutko, for editorial support (funded by Moderna). Appendix The authors’ full names and academic degrees are as follows: Lindsey R. Baden, M.D., Hana M. El Sahly, M.D., Brandon Essink, M.D., Karen Kotloff, M.D., Sharon Frey, M.D., Rick Novak, M.D., David Diemert, M.D., Stephen A. Spector, M.D., Nadine Rouphael, M.D., C. Buddy Creech, M.D., John McGettigan, M.D., Shishir Khetan, M.D., Nathan Segall, M.D., Joel Solis, M.D., Adam Brosz, M.D., Car- los Fierro, M.D., Howard Schwartz, M.D., Kathleen Neuzil, M.D., Larry Corey, M.D., Peter Gilbert, Ph.D., Holly Janes, Ph.D., Dean Follmann, Ph.D., Mary Marovich, M.D., John Mascola, M.D., Laura Polakowski, M.D., Julie Ledgerwood, D.O., Barney S. Graham, M.D., Hamilton Bennett, M.S., Rolando Pajon, Ph.D., Conor Knightly, M.P.H., Brett Leav, M.D., Weiping Deng, Ph.D., Honghong Zhou, Ph.D., Shu Han, Ph.D., Melanie Ivarsson, Ph.D., Jacqueline Miller, M.D., and Tal Zaks, M.D. The authors’ affiliations are as follows: Brigham and Women’s Hospital (L.R.B.), Boston, and Moderna, Cambridge (H.B., R.P., C.K., B.L., W.D., H.Z., S.H., M.I., J. 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Published: Dec 30, 2020

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