Impfung gegen ms biontech

List von authors.Lindsey R. Baden, M.D., Hana M. Elastisch 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. Girlfriend Creech, M.D., john McGettigan, M.D., Shishir Khetan, M.D., Nathan Segall, M.D., Joel Solis, M.D., Adam Brosz, M.D., Carlos Fierro, M.D., Howard Schwartz, M.D., catalent Neuzil, M.D., Lawrence Corey, M.D., peter Gilbert, Ph.D., Holly Janes, Ph.D., Dean Follmann, Ph.D., mar 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.et al.,

A complete list von members von the COVE Study kopieren, gruppe is provided an the Supplementary Appendix, available at uvcdeals.com.

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Drs. Baden und El Sahly added equally zu this article.


Metrics


Abstract

Background

Vaccines room needed kommen sie prevent coronavirus disease 2019 (Covid-19) und to defend persons that are hinweisen high risk zum complications. Die mRNA-1273 vaccine ist a lipid nanoparticle–encapsulated mRNA-based vaccine the encodes the prefusion stabilized full-length spike protein des the serious acute respiratory tract syndrome covid 2 (SARS-CoV-2), ns virus that reasons Covid-19.

Methods

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Download a PDF of the research Summary.

This bühne 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across ns United States. Persons hinweisen high risk zum SARS-CoV-2 epidemic or that complications were randomly assigned an a 1:1 ratio to receive 2 intramuscular injections von mRNA-1273 (100 μg) or placebo 28 work apart. Ns primary ende point was prevention of covid19 illness through onset hinweisen least 14 work after the second injection bei participants who had notfall previously to be infected v SARS-CoV-2.

Results

The psychological enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio kommen sie receive either vaccine or placebo (15,210 participants bei each group). Much more than 96% of participants obtained both injections, und 2.2% had proof (serologic, virologic, or both) von SARS-CoV-2 infection hinweisen baseline. Symptomatic covid-19 illness was confirmed in 185 participants in the placebo group (56.5 von 1000 person-years; 95% trust interval , 48.7 kommen sie 65.3) and an 11 participants an the mRNA-1273 gruppe (3.3 von 1000 person-years; 95% CI, 1.7 kommen sie 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 kommen sie 96.8%; p Severe covid19 occurred bei 30 participants, through one fatality; all 30 were an the placebo group. Moderate, transient reactogenicity after inoculation occurred an ext frequently an the mRNA-1273 group. Significant adverse occasions were rare, and the incidence was similar bei the 2 groups.

Conclusions

The mRNA-1273 vaccine verified 94.1% efficacy hinweisen preventing covid19 illness, consisting of severe disease. Aside from transient local and systemic reactions, no safety involves were identified. (Funded über the Biomedical progressed Research and Development Authority and the national Institute von Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)

Introduction


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QUICK TAKEEfficacy und Safety of mRNA-1273 SARS-CoV-2 Vaccine 02:31

The emergence in December 2019 of a novel coronavirus, ns severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had devastating consequences globally. Manage measures together as die use of masks, physics distancing, testing von exposed or symptomatic persons, call tracing, and isolation schutz helped limit die transmission where they have been rigorously applied; however, these actions have been variably implemented und have showed insufficient in impeding ns spread of coronavirus disease 2019 (Covid-19), die disease caused über SARS-CoV-2. Vaccines are needed to reduce die morbidity and mortality verbunden with Covid-19, and multiple platforms have been involved in the quick development of vaccine candidates.1-9

The mRNA vaccine platform has advantages as a pandemic-response strategy, given its flexibility und efficiency bei immunogen design and manufacturing. Earlier arbeit had suggested that ns spike protein of the coronavirus responsible weil das the 2002 SARS outbreak was a perfect target zum protective immunity.10 plenty of vaccine candidates in various stages des development are jetzt being evaluated.11-13 shortly after the SARS-CoV-2 genetic sequence was determined in January 2020, mRNA-1273, a lipid-nanoparticle (LNP)–encapsulated mRNA vaccine expressing the prefusion-stabilized spike glycoprotein, was developed von Moderna und the Vaccine research Center punkt the national Institute des Allergy und Infectious illness (NIAID), in ~ the national Institutes von Health (NIH).14 die mRNA-1273 vaccine demonstrated protection in animal-challenge experiments15 und encouraging safety and immunogenicity bei early-stage human testing.1,4 die efficacy and safety des another mRNA vaccine, BNT162b2, was recently demonstrated.16

The coronavirus Efficacy (COVE) phase 3 trial was launched in late July 2020 to assess ns safety and efficacy des the mRNA-1273 vaccine in preventing SARS-CoV-2 infection. In independent data and safety monitoring board determined that die vaccine met ns prespecified efficacy criteria hinweisen the zuerst interim analysis. We report die primary evaluation results von this continuous pivotal schritt 3 trial.


Trial Oversight

This bühne 3 randomized, stratified, observer-blinded, placebo-controlled psychological enrolled adults an medically stable condition at 99 U.S. Sites. Participants got the zuerst trial injection betwee July 27 und October 23, 2020. Ns trial zu sein being conducted in accordance v the international Council zum Harmonisation des Technical Requirements for Pharmaceuticals for Human Use, great Clinical practice guidelines, and applicable government regulations. Ns central institutional review board approved die protocol and the consent forms. All participants provided written informed consent prior to enrollment. Safety ist reviewed von a protocol safety review team weekly und by an independent data und safety monitoring board top top a constant basis. Ns trial Investigational neu Drug sponsor, Moderna, was responsible zum the in its entirety trial entwurf (with intake from the Biomedical advanced Research and Development Authority, ns NIAID, the covid-19 Prevention Network, und the psychological cochairs), site selection and monitoring, und data analysis. Investigators space responsible for charme collection. A clinical writer funded über Moderna assisted in drafting die manuscript zum submission. The authors vouch for the accuracy and completeness von the data und for ns fidelity von the psychological to the protocol. Die trial is ongoing, und the investigators continue to be unaware of participant-level data. Designated mannschaft members in ~ Moderna schutz unblinded accessibility to die data, zu facilitate user interface with die regulatory agencies und the data und safety security board; all other trial staff und participants stay unaware des the treatment assignments.

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Participants, Randomization, und Data Blinding

Eligible participants were persons 18 years von age or older v no known history of SARS-CoV-2 infection und with areas or situations that placed them at in appreciable risk von SARS-CoV-2 infection, a high risk des severe Covid-19, or both. Inclusion und exclusion criteria room provided in the protocol (available with ns full text des this article punkt uvcdeals.com). To enhance die diversity of the trial population bei accordance with Food und Drug management Draft Guidance, site-selection und enrollment procedures were adjusted kommen sie increase die number von persons native racial und ethnic minorities in the trial, in addition to the persons at risk for SARS-CoV-2 infection an the neighborhood population. The upper limit zum stratification of enrolled participants considered kommen sie be “at risk zum severe illness” at raffinesse was raised from 40% to 50%.17

Participants to be randomly assigned an a 1:1 ratio, through die use of a centralized interactive response an innovation system, zu receive vaccine or placebo. Assignment was stratified, on the basis of age und Covid-19 complications danger criteria, into ns following risk groups: people 65 years of age or older, people younger than 65 years of age that were hinweisen heightened hazard (at risk) zum severe Covid-19, and persons younger than 65 years von age there is no heightened hazard (not weist risk). Attendees younger 보다 65 years of age were categorized as having risk zum severe covid19 if castle had hinweisen least one of the following risk factors, based on the Centers zum Disease Control und Prevention (CDC) criteria obtainable at die time of trial design: chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma); cardiac an illness (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension); severe weight problems (body mass index ≥40); diabetes (type 1, form 2, or gestational); liver disease; or infection with the human immunodeficiency virus.18

Vaccine sheep preparation und administration to be performed von pharmacists und vaccine administrators that were aware des treatment assignments yet had no other role bei the conduct des the trial. Once ns injection was completed, only trial staff who were unaware von treatment assignments perform assessments and interacted with the participants. Accessibility to ns randomization code was strikt controlled at die pharmacy. The data und safety monitoring board reviewed efficacy charme at the group level und unblinded safety säule at ns participant level.

Trial Vaccine

The mRNA-1273 vaccine, noted as a sterile flüssig at a concentration des 0.2 mg von milliliter, was administered von injection into die deltoid muscle according to a two-dose regimen. Injections were given 28 work apart, an the very same arm, bei a volume of 0.5 ml include 100 μg von mRNA-1273 or saline placebo.1 Vaccine mRNA-1273 was stored at 2° kommen sie 8°C (35.6° zu 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses can be held bei syringes for up kommen sie 8 hours punkt room temperature prior to administration.

Safety Assessments

Safety assessments contained monitoring des solicited local and systemic adverse events zum 7 job after every injection; unsolicited disadvantage reactions zum 28 work after each injection; adverse occasions leading kommen sie discontinuation native a dose, indigenous participation in the trial, or both; and medically attended adverse events und serious adverse events from job 1 through day 759. Adverse occasion grading criteria und toxicity tables are described an the protocol. Cases von Covid-19 and severe covid19 were continuously monitored über the data and safety security board indigenous randomization onward.

Efficacy Assessments

The primary ende point was the efficacy von the mRNA-1273 vaccine in preventing a zuerst occurrence des symptomatic covid19 with onset weist least 14 days after die second injection bei the per-protocol population, among participants who were seronegative at baseline. End points were judged by in independent adjudication committee that was unaware of group assignment. Covid19 cases were identified as occurring in participants that had weist least two of the complying with symptoms: fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or neu olfactory or basic disorder, or together occurring bei those who had hinweisen least one respiratory authorize or symptom (including cough, shortness of breath, or clinical or radiographic evidence des pneumonia) and at the very least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if ns participant was hospitalized) that was positive zum SARS-CoV-2 über reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed zum the presence von SARS-CoV-2–binding antibodies specific to ns SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) und had a nasopharyngeal swab zum SARS-CoV-2 RT-PCR experimentation (Viracor, Eurofins Clinical Diagnostics) before each injection. SARS-CoV-2–infected volunteers were complied with daily, zu assess symptom severity, zum 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab zum RT-PCR testing and a blood sample weil das identifying serologic evidence of SARS-CoV-2 epidemic were collected from participants v symptoms des Covid-19.

The consistency des vaccine efficacy at the primary end point was evaluated across various subgroups, including period groups (18 to Supplementary Appendix, available hinweisen uvcdeals.com).

Statistical Analysis

For analysis of the primary end point, ns trial was designed zum the null hypothesis that the efficacy von the mRNA-1273 vaccine ist 30% or less. A total of 151 instances of covid-19 would carry out 90% energie to recognize a 60% reduction in the peril rate (i.e., 60% vaccine efficacy), with two plan interim analyses punkt approximately 35% und 70% des the target pistole number von cases (151) und with a one-sided O’Brien–Fleming boundary zum efficacy and an overall one-sided verfehlt rate of 0.025. Die efficacy des the mRNA-1273 vaccine could be demonstrated hinweisen either the interim or ns primary analysis, performed when die target total number von cases had actually been observed. Die Lan–DeMets alpha-spending function was used zum calculating efficacy boundaries weist each analysis. Hinweisen the zuerst interim analysis on november 15, 2020, vaccine efficacy had been demonstrated an accordance with die prespecified statistical criteria. Die vaccine efficacy estimate, based on a total des 95 adjudicated cases (63% des the target total), was 94.5%, through a one-sided p value von less 보다 0.001 kommen sie reject the null hypothesis that vaccine efficacy would be 30% or less. Ns data und safety surveillance board referral to the oversight group and the trial sponsor was that die efficacy findings should be mutual with ns participants and the neighborhood (full einzelheiten are available an the protocol and statistical evaluation plan).

Vaccine efficacy was assessed in the complete analysis population (randomized participants who received weist least one dose von mRNA-1273 or placebo), ns modified intention-to-treat population (participants bei the complete analysis population who had no immunologic or virologic proof of covid19 on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, v no major protocol deviations). The primary efficacy end point in the interim und primary analyses was assessed an the per-protocol population. Participants were evaluated in the therapy groups kommen sie which they were assigned. Vaccine efficacy was defined as die percentage reduction an the peril ratio zum the primary ende point (mRNA-1273 vs. Placebo). A stratified Cox proportional hazards modell was used to assess die vaccine efficacy of mRNA-1273 as contrasted with placebo bei terms des the portion hazard reduction. (Details regarding ns analysis von vaccine efficacy room provided bei the techniques section of the Supplementary Appendix.)

Safety was assessed an all participants bei the solicited safety population (i.e., those that received punkt least one injection und reported a solicited disadvantage event). Descriptive summary charme (numbers und percentages) weil das participants with any type of solicited disadvantage events, unsolicited adverse events, unsolicited major adverse events, serious adverse events, median attended adverse events, and adverse events leading kommen sie discontinuation von the injections or withdrawal from ns trial room provided von group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) space provided zum the percentages des participants with solicited adverse events. Unsolicited adverse events are presented follow to ns Medical Dictionary weil das Regulatory activities (MedDRA), ausführung 23.0, desired terms and system organ class categories.

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To meet ns regulatory agencies’ requirement of a average follow-up duration des at least 2 month after completion des the two-dose regimen, a 2nd analysis was performed, with in efficacy säule cutoff date of november 21, 2020. This 2nd analysis ist considered die primary analysis des efficacy, with a total des 196 adjudicated covid19 cases in the per-protocol population, i m sorry exceeds ns target pistole number von cases (151) specified in the protocol. This was in increase from die 95 situations observed hinweisen the zuerst interim analysis dünn cutoff on november 11, 2020. Outcomes from ns primary analysis are presented an this report. Succeeding analyses are taken into consideration supplementary.