Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial

Abstract

Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6-8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 ( NCT04405076 ). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.

Fig. 1. Trial profile for phase 2, parts A and B.

Participants who received two doses of mRNA-1273 in part A were offered a booster injection of 50 µg of mRNA-1273 in part B. Completion of part A was defined as participants who completed 6 months of follow-up after the last injection received in part B (open-label phase). Data cutoff was 11 June 2021. *15 participants declined to receive a booster of 50 μg of mRNA-1273; ^†14 participants declined to receive a booster of 50 μg of mRNA-1273.

Fig. 2. Solicited adverse reactions within 7 days after booster injection.

a, Solicited local adverse reactions. b, Solicited systemic adverse reactions. The percentage of participants in the solicited safety set who reported local (a) or systemic (b) solicited adverse reactions is shown for 330 participants who received a booster dose of mRNA-1273 (50 μg) after a primary series of two doses of 50 µg or 100 µg of mRNA-1273 in part B; 198 participants who received a booster dose of mRNA-1273 (50 μg) after a primary series of two doses of 100 µg of mRNA-1273 in part B; and 14,691 participants who received two doses of 100 µg of mRNA-1273 in the phase 3 COVE trial. The percentages of participants who submitted any data for the adverse event within 7 days after the booster injection or the second dose during the primary series are shown. Grade 1 adverse reactions are indicated by gray bars, grade 2 adverse reactions by blue bars and grade 3 adverse reactions by red bars.

Fig. 3. nAb titers (pseudovirus ID₅₀; D614G) after the primary series and after a booster injection of 50 µg of mRNA-1273 (per-protocol set).

The nAb titers in the pseudovirus assay against the D614G virus are shown for serum samples collected in part A at baseline, 28 days after the first dose of mRNA-1273, 28 days after the second dose of mRNA-1273 and in part B before the booster injection of 50 µg of mRNA-1273 (pre-booster) and 28 days after the booster injection. Titers from the group that received two priming doses of 50 µg of mRNA-1273 are shown in green, and those from the group that received two priming doses of 100 µg of mRNA-1273 are shown in blue. The dots show the results from individual serum samples. The tops of the bars show the GMTs. The whiskers were determined using the Tukey method. The tops of the whiskers show the 75th percentile minus the IQR (the difference between the 25th and 75th percentiles). The bottoms of the whiskers show the 25th percentile minus the IQR. Antibody values in the pseudovirus assay reported as below the LLOQ (18.5) were replaced by 0.5× LLOQ. Values that were greater than the ULOQ (45,118) were changed to the ULOQ if actual values were not available.