A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine

Abstract

Background: Vaccines are urgently needed to prevent the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed the safety and immunogenicity of vaccine candidate mRNA-1273, encoding the prefusion-stabilized spike protein of SARS-CoV-2.

Methods: This phase 2, randomized, observer-blind, placebo-controlled trial was conducted at 8 sites in the USA, in healthy adults aged ≥18 years with no known history or risk of SARS-CoV-2 infection, and had not previously received an investigational CoV vaccine or treatment. Participants were stratified into two age cohorts (≥18-<55 and ≥55) and were randomly assigned (1:1:1) to either 50 or 100 µg of mRNA-1273, or placebo administered as two intramuscular injections 28 days apart. The primary outcomes were safety, reactogenicity, and immunogenicity assessed by anti-SARS-CoV-2-spike binding antibody level (bAb). Secondary outcome was immunogenicity assessed by SARS-CoV-2 neutralizing antibody (nAb) response.

Results: Between 29 May and 8 July 2020, 600 participants were randomized, 300 per age cohort. The most common solicited adverse reactions were pain at injection site, headache, and fatigue following each vaccination in both age cohorts. One serious adverse event deemed unrelated by the site investigator occurred 33 days post-vaccination one. mRNA-1273 induced bAb and nAb by 28 days post-vaccination one that were higher at the 100 µg dose relative to the 50 µg dose; this difference was less apparent post-vaccination two. Binding antibodies and nAb increased substantially by 14 days following the second vaccination (day 43) to levels exceeding those of convalescent sera and remained elevated through day 57.

Conclusions: Vaccination with mRNA-1273 resulted in significant immune responses to SARS-CoV-2 in participants 18 years and older, with an acceptable safety profile, confirming the safety and immunogenicity of 50 and 100 µg mRNA-1273 given as a 2 dose-regimen. ClinicalTrials.gov; NCT04405076.

Keywords: COVID-19; Immunogenicity; Phase 2; SARS-CoV-2; Safety; Vaccine; mRNA-1273.

Fig. 1

Trial profile. Percentages are based on the number of randomized participants in the study. ^aConfirmed adverse event of SARS-CoV-2 infection. ^bConsidered a serious adverse event due to community-acquired pneumonia that led to study vaccine discontinuation that occurred on day 33 and resolved on day 58, outside the primary endpoint evaluation of unsolicited AEs through 28 days after each injection. ^cn = 92, 90, and 95 for both bAb and nAb in placebo, 50 µg and 100 µg mRNA-1273 groups, respectively. ^dn = 94, 95, and 94 for bAb and 89, 89, and 91 for nAb in placebo, 50 µg and 100 µg mRNA-1273 groups, respectively. The “other” reasons for study vaccine discontinuations included 3 false positive COVID-19 infection results reported from central labs and 1 participant that reported a positive COVID-19 infection result from an external lab at day 15.

Fig. 2

Solicited local and systemic adverse reactions within 7 days post-vaccinations one and two in each cohort. Percentages of participants with solicited local and systemic adverse reactions by dose, grade and vaccination in cohorts 1 and 2. Percentages are based on the solicited safety set comprising all participants who were randomly assigned, received any study vaccine and submitted any solicited adverse reaction data. In the eDiary, rash was not reported by grade. Lymphadenopathy included any localized axillary swelling or tenderness ipsilateral to the vaccination arm. Dashes indicate no reported data for the adverse reactions. CI = Confidence intervals.

Fig. 3

SARS-CoV-2-spike binding and neutralizing antibody responses. Percentage of participants in the per-protocol set having SARS-CoV-2-specific bAb (A) and nAb (B) at the corresponding visit days. Antibody values below the LLOQ were replaced by 0.5 × LLOQ. Values greater than the ULOQ were converted to the ULOQ. For visit day 29, visit window (−3/+7 days) was used to define per-protocol. If the visit (day 29) was disrupted and could not be completed at day 29 (−3/+7 days) as a result of the COVID-19 pandemic, the window was extended to day 29 + 21 days. The 95% CI were calculated based on the t-distribution of the log-transformed values for GMT and GM levels, then back transformed to the original scale for presentation. The bAb values reported are ELISA concentrations µg/ml and nAb values are MN₅₀ titers (LLOQ = 91.1 and ULOQ = 2031.9). Seroconversion rate at the participant level was defined as a change of nAb titer from below the LLOQ to ≥LLOQ, or a 4-times or higher ratio in participants with pre-existing nAb. Human convalescent sera collected from COVID-19 symptomatic patients at least 15 days post-infection confirmed by RT-PCR, and tested by MN (n = 32) and by ELISA (n = 119) served as reference control titers. ^aResponses in participants who received placebo averaged across days, study vaccine group and cohorts. ^b95% CIs were not estimable. Number of participants in the per-protocol set with SARS-CoV-2-specific nAb levels at the corresponding visit. bAb = binding antibody, BL = baseline, Conv = convalescent sera, ELISA = Enzyme-Linked Immunosorbent Assay, GM = geometric mean, LLOQ = lower limit of quantification, MN = microneutralization, nAb = neutralizing antibody, Pbo = placebo, ULOQ = upper limit of quantification.