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.

Safety and Immunogenicity of a 100 μg mRNA-1273 Vaccine Booster for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

“…The incidence of local or systemic adverse reactions was overall higher after the 100 µg booster injection than has been observed in previous studies after the second dose of the primary series and the authorized 50 µg mRNA-1273 booster dose. 5, 7 These comparisons must be made with caution, as the two booster dose levels of mRNA-1273 (100 µg and 50 µg) were not evaluated head-to-head in the same study, study participants were aware they were receiving a higher booster dose and the interval between the primary series and the 100 µg booster dose (∼11 months) was different compared to the interval for the 50 µg booster dose (∼7.2 months) 7 .…”

“…The neutralizing antibody titers against the ancestral SARS-CoV-2 and the Delta variant following the 100 µg booster dose were higher than the titers after the authorized 50 µg booster dose which was evaluated in a separate phase 2 study 7 . The two different dose levels (50 and 100 µg) were not evaluated head-to-head in the same study as a pre-specified objective that would enable direct comparison of the antibody response and were administered in different intervals from the primary series of mRNA-1273 which could also influence the neutralizing antibody titer levels post-boost.…”

“…The mRNA-1273 booster dose was a lipid nanoparticle containing mRNA encoding the spike glycoprotein of the Wuhan-HU-1 isolate of SARS-CoV-2. 7 The booster dose of mRNA-1273 was administered at a dose level of 100 µg mRNA in a 0.5 mL volume.…”

“…The details of the immunogenicity assays and the statistical analysis are in the Supplementary Appendix. Data from an separate phase 2 study (mRNA-P201, NCT04405076) where participants received a 50 µg mRNA-1273 booster dose are included 7 .…”

“…In 2021, the Delta variant (B.1.617.2) became dominant in multiple regions and caused breakthrough infections and disease, especially in individuals who were not recently immunized 5 . Vaccine authorization was expanded in many countries to include a 50 µg mRNA- 1273 booster dose, at least six months after completion of the primary immunization, to boost the immune response against SARS-CoV-2 7 . A booster dose has been shown to further prevent COVID-19 and the durability of the booster dose effectiveness is being evaluated.…”