An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

We conducted a phase 1, dose-escalation, open-label clinical trial designed to determine the safety, reactogenicity, and immunogenicity of mRNA-1273. Eligible participants were healthy adults 18 to 55 years of age who received two injections of trial vaccine 28 days apart at a dose of 25 μg, 100 μg, or 250 μg. On the basis of the results obtained in patients at these dose levels, additional groups were added to the protocol; those results will be reported in a subsequent publication. Participants were not screened for SARS-CoV-2 infection by serology or polymerase chain reaction before enrollment. The trial was conducted at the Kaiser Permanente Washington Health Research Institute in Seattle and at the Emory University School of Medicine in Atlanta. The protocol, available with the full text of this article at NEJM.org, permitted interim analyses to inform decisions regarding vaccine strategy and public health; this interim analysis reports findings through day 57. Full details of the trial design, conduct, oversight, and analyses can be found in the protocol and statistical analysis plan (available at NEJM.org).

The trial was reviewed and approved by the Advarra institutional review board, which functioned as a single board and was overseen by an independent safety monitoring committee. All participants provided written informed consent before enrollment. The trial was conducted under an Investigational New Drug application submitted to the Food and Drug Administration. The vaccine was codeveloped by researchers at the National Institute of Allergy and Infectious Diseases (NIAID, the trial sponsor) and at Moderna (Cambridge, MA). Moderna was involved in discussions of the trial design, provided the vaccine candidate, and, as part of the writing group, contributed to drafting the manuscript. The Emmes Company, as a subcontractor to the NIAID, served as the statistical and data coordinating center, developed the statistical analysis plan, and performed the analyses. The manuscript was written entirely by the authors, with the first author as the overall lead author, the fourth author as the lead NIAID author, and the last two authors as senior authors (details are provided in the Supplementary Appendix, available at NEJM.org). The authors had full access to the data reports, which were prepared from the raw data by the statistical and data coordinating center, and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

The mRNA-1273 vaccine candidate, manufactured by Moderna, encodes the S-2P antigen, consisting of the SARS-CoV-2 glycoprotein with a transmembrane anchor and an intact S1–S2 cleavage site. S-2P is stabilized in its prefusion conformation by two consecutive proline substitutions at amino acid positions 986 and 987, at the top of the central helix in the S2 subunit.8 The lipid nanoparticle capsule composed of four lipids was formulated in a fixed ratio of mRNA and lipid. The mRNA-1273 vaccine was provided as a sterile liquid for injection at a concentration of 0.5 mg per milliliter. Normal saline was used as a diluent to prepare the doses administered.

The vaccine was administered as a 0.5-ml injection in the deltoid muscle on days 1 and 29; follow-up visits were scheduled for 7 and 14 days after each vaccination and on days 57, 119, 209, and 394. The dose-escalation plan specified enrollment of four sentinel participants in the 25-μg group, followed by four sentinel participants in the 100-μg group, followed by full enrollment of those two dose groups. If no halting rules were met after all participants in those two dose groups completed day 8, four sentinel participants in the 250-μg group were enrolled, followed by the remainder of that dose group.

Participants recorded local and systemic reactions, using a memory aid, for 7 days after each vaccination. Participants were not instructed to routinely use acetaminophen or other analgesics or antipyretics before or after the vaccinations but were asked to record any new medications taken. Adverse events were graded according to a standard toxicity grading scale (Table S1 in the Supplementary Appendix).9

Assessment of SARS-CoV-2 Binding Antibody and Neutralizing Responses

Binding antibody responses against S-2P and the isolated receptor-binding domain, located in the S1 subunit, were assessed by enzyme-linked immunosorbent assay (ELISA). Vaccine-induced neutralizing activity was assessed by a pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA) and by live wild-type SARS-CoV-2 plaque-reduction neutralization testing (PRNT) assay. ELISA and PsVNA were performed on specimens collected from all participants on days 1, 15, 29, 36, 43, and 57. Because of the time-intensive nature of the PRNT assay, for this report of the interim analysis, results were available only for the day 1 and day 43 time points in the 25-μg and 100-μg dose groups.

For comparison of the participants’ immune responses with those induced by SARS-CoV-2 infection, 41 convalescent serum specimens were also tested. The assays were performed at the NIAID Vaccine Research Center (ELISA and PsVNA) and the Vanderbilt University Medical Center (PRNT).

T-cell responses against the spike protein were assessed by an intracellular cytokine–staining assay, performed on specimens collected at days 1, 29, and 43. For this report of the interim analysis, results were available only for the 25-μg and 100-μg dose groups. These assays were performed at the NIAID Vaccine Research Center. (See the Supplementary Appendix for details of all assay methods and for characteristics of the convalescent serum specimens.)

Results of immunogenicity testing of the 45 enrolled participants excluded findings for day 36, day 43, and day 57 for 3 participants who did not receive the second vaccination and for time points at which specimens were not collected (in the 100-μg group: 1 participant at day 43 and day 57; in the 250-μg group: 1 participant at day 29 and 1 at day 57). Confidence intervals of the geometric means were calculated with the Student’s t distribution on log-transformed data. Seroconversion as measured by ELISA was defined as an increase by a factor of 4 or more in antibody titer over baseline.