Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults

Abstract

Background: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age.

Methods: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart.

Results: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells.

Conclusions: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).

Copyright © 2020 Massachusetts Medical Society.

Figures

Figure 1. Solicited Systemic and Local Adverse Events within 7 Days after Receipt of mRNA-1273.

Shown are data for older participants in the two age subgroups (56 to 70 years and ≥71 years) and the two dose subgroups (25 μg and 100 μg). The severity of solicited adverse events was graded as mild, moderate, or severe on the basis of definitions that are detailed in Table S1 in the Supplementary Appendix. Dashes indicate that the adverse event was not reported in any participant.

Figure 2. SARS-CoV-2 Antibody-Binding and Neutralization Responses.

Shown are reciprocal end-point binding IgG titers on receptor-binding domain (RBD) enzyme-linked immunosorbent assay (ELISA) (Panel A), along with titers to 614D on the pseudovirus neutralization assay at a 50% inhibitory dilution (ID50) (Panel B), on the focus reduction neutralization test mNeonGreen assay (FRNT-mNG ID50) (Panel C), and on plaque-reduction neutralization testing (PRNT80) (Panel D). PRNT80 results were available only for the participants who had received the 100-μg dose of the mRNA-1273 vaccine on days 1 and 43. Boxes denote interquartile ranges, and horizontal bars denote median end-point titers. Whisker end points denote the maximum and minimum values below or above the median at 1.5 times the interquartile range. The shaded portion on the right side of each panel indicates one or two categories of reference values: antibody titers from 41 controls who had donated convalescent serum (Panels A and B) and antibody titers from participants between the ages of 18 and 55 years who had received the 100-μg dose of mRNA-1273 (Panels A through D).

Figure 3. CD4 T-Cell Responses to the S1 Peptide Pool after Receipt of mRNA-1273.

Shown are the percentages of CD4 T cells that produced the indicated cytokines in the two age subgroups (56 to 70 years or ≥71 years) after stimulation with the SARS-CoV-2 S1 peptide pool. Type 1 helper T (Th1) cells are shown in Panel A, and type 2 helper T (Th2) cells are shown in Panel B. A total of 40 participants who were enrolled in the study (10 participants in each of the two age and dose subgroups) were tested at each time point, except for 1 participant who was between the ages of 56 and 70 years and who did not receive the second 25-μg dose and so did not contribute data after day 29. In Panel A, the boxes indicate interquartile ranges. Details regarding the T-cell calculations are provided in the Supplementary Appendix. TNF-α denotes tumor necrosis factor α.