Trial design and participants
We initially conducted an open-label clinical trial of Phase 1, Dosage-Escalation, MRNA-1273 involving participants aged 18 to 55 years.2 In which we evaluated doses of 25 g, 100 μg and 250 g. We then expanded the hearing to include participants who were 56 years of age or older and divided into two subgroups: 56 to 56 years of age and 711 years of age or older. Due to clinically significant systemic reactogenicity in participants aged 18 to 55 years at 250-icig doses, we gave older participants a dose of 25 μg or 100 g.
The hearing was conducted at the Washington Institute of Health Research, Seattle’s Kaiser Parment, Emory University School of Medicine Medicine in Atlanta and the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center in Bethesda, Maryland. The registered adults were healthy and provided informed informed consent prior to any study procedures. By testing blood or nasal samples prior to registration we did not check for evidence of past or present SARS-Cove-2 infection. The criteria for full eligibility, trial design, conduct, observation and details of statistical analysis are described in the protocol, which is available on NEJM.org with the full text of this article.
mRNA-1273 vaccine
The MRNA-1273 vaccine was coded by researchers at the NIAID Vaccine Research Center and Modernna in Cambridge, Massachusetts. The vaccine encodes a stable version of the SARS-Covy-2 full-length spike glycoprotein trimmer, S-2P, which has been modified to include two volatile substitutes at the top of the central helix in the S2 subunit. MRNAs are contained in lipid nanoparticles at a concentration of 0.5 mg per milliliter and diluted with normal saline to achieve the final target vaccine concentration.
Study observation
NIAID served as the trial sponsor and made all decisions regarding study design and implementation. Vaccine investigators reviewed new drug application and protocol improvements by the Food and Drug Administration and the Institutional Review Board at Adwara, which served as an institutional review board for all study sites. The Independent Data and Safety Monitoring Committee reviewed the interim security reports.
Modern has provided MRNA-1273 for use in this trial but has not provided any financial support. Moderna staff contributed to the development of the protocol, contributed to investigative new drug application, and participated in weekly team meetings related to the study.
Ames, the statistical and data integration center for the study, developed a statistical analysis plan and analyzed all data. Data reports, which were generated from the raw data by the Statistical and Data Compilation Center, were provided to all authors and were available. The manuscript was written by full authors, with the first two authors serving as overall lead authors. All authors guarantee the completeness and accuracy of the data and adherence to the study of the protocol. No one who is not an author contributed to the writing of the manuscript.
Trial proceedings
The mRNA-1273 vaccine was given as a 0.5 ml intramuscular injection into the deltoid on days 1 and 29 of the study; The same dose of vaccine was given on both days. Follow-up visits were scheduled 7 and 14 days after the administration of each dose of vaccine and on the 57th day, respectively. A standard toxicity standard was used to grade adverse events (Table S1 in the Supplementary Appendix available on NEJM.org). Requested local and systemic adverse events were collected for 7 days after each vaccination, facilitated by the use of memory aids. Data on unadvised adverse events and use of new drugs were collected during 57 days. Collection of samples, as well as monitoring for adverse events in the medical presence, development of new chronic medical conditions, and severe adverse events, was to continue for 1 year. After the last dose. These preliminary findings will be updated with final safety and immunogenicity data when the results become available.
After initial safety data from the first phase of the study became available from participants aged 18 and 55,2 The onset of administration of mRNA-1273 was initiated sequentially in a subgroup of participants aged 56 to 70 years at a 25-doseg dose, followed by initiation of a 100-doseg dose. Since participants in this subgroup did not meet any stagnant rules after completing the eighth day, the vaccine administration was gradually started iated in a subgroup of participants aged 711 years or older, who were started on a 25-doseg dose, whose Was made after the start. 100-doseg dose.
Evaluation of antibody response
We performed an enzyme-linked immunosorbent assay (ELISA) for the amount of binding IgG responses on S-2P containing ASP (D) residue at the 614 position (initial Wuhan-1 strain sequence).8) And on receptor-binding domains at days 1, 15, 29, 36, 43, and 57. (The receptor-binding domain is part of the SARS-COV-2 virus that is located on its spike domain and it links with the body’s receptors to infect cells.) A SARS-COV-2 native spike-pseudotype lentivirus reporter single-round-off -Infection neutralization assay (Pseudovirus neutralization assay) was simultaneously used to assess vaccine-induced neutralization activity against variant 614D. Time points. Day States Vaccine-induced neutralization was evaluated using the p11-gly (14114g) polygonal variant with the second pseudovirus neutralization chamber, as 141114g strain became the mainstay in the United States and around the world.9 (Details are provided in the Details section in the Supplementary Appendix.)
Three neutralization methods of live viruses were used: first, SARS-Cavi-2 nanoluciferous high-throughput neutralization assay (N. luch HTNA), which uses a virus that represents the reporter gene nanuluciferous (NLUC).10; Second, the attention reduction neutralization test MNGreen (FRNT-MNG), which uses the recombinant SARS-CoV-2 expressing the fluorescent reporter gene EMNGRIN.11; And third, a SARS-Cavi-2 plaque-replication neutralization test (PRNT) AC, which uses a wild-type virus. We used nLuc HTNA to analyze samples on participants 1, 29, and 43 from participants aged 56 years and older and who received 100-ડોg doses. We used the FRNT-mNG segment to analyze samples received on days 1, 29, and 43 from all participants in the two age and dose subgroups. For this preliminary report, due to the time-intensive nature of the PRNT compartment and to enhance the useful information that can be obtained from its use, we assisted PRNT for the presence of SARS-COV-2 on samples obtained on 1 and 43 from participants. Received only 100-doseg dose. We have used the previous report as a comparison of participants aged 18 to 55 years in the 100-μg subgroup, as well as the results of the controls for controlling the controllant serum.2 The severity of Covid-19 illness was known for 38 of these controls and was classified as mild in 63% of participants, moderate to severe in 22% (15% admitted to hospital who required intensive care, ventilation or both).
Evaluation of T-cell responses
Intracellular cytokine-staining aces were performed for the dose of antigen-specific T-cell responses against spike proteins at 1, 29, and 43 days. (Details are given in the Supplementary Appendix.)
Statistical analysis
The safety analysis included all participants who received at least one dose of mRNA-1273. Immunogenicity results excluded 29 participants who received only a single dose of the vaccine after 29 days of sampling. No other data points were missing. Seroconversion was defined as a baseline increase in antibody titers by a factor of 4 or more. The geometric medium was calculated by converting the data points and calculating the mean and 95% confidence interval on the log-transformed data. The g-transformed mean and converted back to the original scale after a 95% confidence interval. We used the student’s t-test to calculate confidence intervals. Interim analysis of study subgroups was predetermined to inform critical decisions about vaccine development.
