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

Spyros Chalkias, Howard Schwartz, Biliana Nestorova, Jing Feng, Ying Chang, Honghong Zhou, Frank J Dutko, Darin K Edwards, David Montefiori, Rolando Pajon, Brett Leav, Jacqueline M Miller, Rituparna Das, Spyros Chalkias, Howard Schwartz, Biliana Nestorova, Jing Feng, Ying Chang, Honghong Zhou, Frank J Dutko, Darin K Edwards, David Montefiori, Rolando Pajon, Brett Leav, Jacqueline M Miller, Rituparna Das

Abstract

Importance: Due to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed.

Objectives: Evaluate safety and immunogenicity of 100-µg of mRNA-1273 booster dose in adults.

Design: Open-label, Phase 2/3 study.

Setting: Multicenter study at 8 sites in the U.S.

Participants: The mRNA-1273 100-µg booster was administered to adults who previously received a two dose primary series of 100-µg mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier.

Intervention: Lipid nanoparticle containing 100-µg of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1).

Main outcomes and measures: Solicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated.

Results: The 100-µg booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-µg mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-µg booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-µg booster of mRNA-1273.

Conclusions and relevance: The 100-µg mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-µg booster dose compared to the authorized booster dose level in adults (50-µg). mRNA-1273 100-µg booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065.

Key points: Question: What is the safety and immunogenicity of a booster dose of 100 µg of mRNA-1273 in adults who previously received the primary series of mRNA-1273?Findings: In this open-label, Phase 2/3 study, the 100 µg booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 µg booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 µg booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants.Meaning: mRNA-1273 100 µg booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.

Figures

Figure 1:
Figure 1:
CONSORT Flow Diagram Trial profile. Participants who received two doses of mRNA-1273 in Phase 3 COVE trial were offered a booster injection of 100 μg of mRNA-1273 in this Phase 2/3, Part B, study. Eligibility to receive the booster included participants who completed 6 months of follow-up after the last injection received in the Phase 3 COVE trial. The screen failure rate will be presented for the entire study at the end-of-study analysis.
Figure 2:
Figure 2:
Solicited Local and Systemic Adverse Reactions Shown are the percentages of participants who had a solicited local or systemic adverse reaction within 7 days after the second injection of 100 μg of mRNA-1273 of the primary series (n=14691; Phase 3 COVE trial), after the injection of a mRNA-1273 booster 50 μg dose (n=167; Phase 2 study mRNA-1273-P201) or after the injection of a 100 μg mRNA-1273 booster dose (n=303; the study reported here). In the phase 3 COVE trial, there were Grade 4, solicited systemic reports of fever (13/14,682;

Figure 3:

Neutralizing antibody titers (pseudovirus assay;…

Figure 3:

Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100…

Figure 3:
Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100 μg booster of mRNA-1273 or the second dose of mRNA-1273 in the phase 3 COVE trial The neutralizing antibody titers in the pseudovirus assay against the D614G virus (panel A) and against the Delta variant (panel B) are shown for serum samples collected pre-booster and 28 days after the 100 μg mRNA-1273 booster (blue) and from the historical control group (COVE, Phase 3) at baseline and 28 days after the second dose of mRNA-1273 (green). The dots show the results from individual serum samples. The horizontal lines in the middle of the boxes show the median titers. The boxes extend from the 25th percentile to the 75th percentile. The whiskers were determined using the Tukey method. The tops of the whiskers show the 75th percentile plus 1.5 times the IQR (the difference between the 25th and 75th percentiles). The bottoms of the whiskers show the 25th percentile minus 1.5 times the IQR. a The Delta-specific neutralizing antibody titers were not measured at COVE baseline. The Delta-specific neutralizing antibody titers at the pre-vaccination baseline (COVE baseline) for the historical control group were imputed based on the pre-dose 1 SARS-CoV-2 status; when SARS-CoV-2 status was negative, antibody titers were imputed as <LLOQ at pre-dose 1 of primary series.

Figure 3:

Neutralizing antibody titers (pseudovirus assay;…

Figure 3:

Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100…

Figure 3:
Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100 μg booster of mRNA-1273 or the second dose of mRNA-1273 in the phase 3 COVE trial The neutralizing antibody titers in the pseudovirus assay against the D614G virus (panel A) and against the Delta variant (panel B) are shown for serum samples collected pre-booster and 28 days after the 100 μg mRNA-1273 booster (blue) and from the historical control group (COVE, Phase 3) at baseline and 28 days after the second dose of mRNA-1273 (green). The dots show the results from individual serum samples. The horizontal lines in the middle of the boxes show the median titers. The boxes extend from the 25th percentile to the 75th percentile. The whiskers were determined using the Tukey method. The tops of the whiskers show the 75th percentile plus 1.5 times the IQR (the difference between the 25th and 75th percentiles). The bottoms of the whiskers show the 25th percentile minus 1.5 times the IQR. a The Delta-specific neutralizing antibody titers were not measured at COVE baseline. The Delta-specific neutralizing antibody titers at the pre-vaccination baseline (COVE baseline) for the historical control group were imputed based on the pre-dose 1 SARS-CoV-2 status; when SARS-CoV-2 status was negative, antibody titers were imputed as <LLOQ at pre-dose 1 of primary series.
Figure 3:
Figure 3:
Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100 μg booster of mRNA-1273 or the second dose of mRNA-1273 in the phase 3 COVE trial The neutralizing antibody titers in the pseudovirus assay against the D614G virus (panel A) and against the Delta variant (panel B) are shown for serum samples collected pre-booster and 28 days after the 100 μg mRNA-1273 booster (blue) and from the historical control group (COVE, Phase 3) at baseline and 28 days after the second dose of mRNA-1273 (green). The dots show the results from individual serum samples. The horizontal lines in the middle of the boxes show the median titers. The boxes extend from the 25th percentile to the 75th percentile. The whiskers were determined using the Tukey method. The tops of the whiskers show the 75th percentile plus 1.5 times the IQR (the difference between the 25th and 75th percentiles). The bottoms of the whiskers show the 25th percentile minus 1.5 times the IQR. a The Delta-specific neutralizing antibody titers were not measured at COVE baseline. The Delta-specific neutralizing antibody titers at the pre-vaccination baseline (COVE baseline) for the historical control group were imputed based on the pre-dose 1 SARS-CoV-2 status; when SARS-CoV-2 status was negative, antibody titers were imputed as <LLOQ at pre-dose 1 of primary series.
Figure 3:
Figure 3:
Neutralizing antibody titers (pseudovirus assay; ID50) before and 28 days after the 100 μg booster of mRNA-1273 or the second dose of mRNA-1273 in the phase 3 COVE trial The neutralizing antibody titers in the pseudovirus assay against the D614G virus (panel A) and against the Delta variant (panel B) are shown for serum samples collected pre-booster and 28 days after the 100 μg mRNA-1273 booster (blue) and from the historical control group (COVE, Phase 3) at baseline and 28 days after the second dose of mRNA-1273 (green). The dots show the results from individual serum samples. The horizontal lines in the middle of the boxes show the median titers. The boxes extend from the 25th percentile to the 75th percentile. The whiskers were determined using the Tukey method. The tops of the whiskers show the 75th percentile plus 1.5 times the IQR (the difference between the 25th and 75th percentiles). The bottoms of the whiskers show the 25th percentile minus 1.5 times the IQR. a The Delta-specific neutralizing antibody titers were not measured at COVE baseline. The Delta-specific neutralizing antibody titers at the pre-vaccination baseline (COVE baseline) for the historical control group were imputed based on the pre-dose 1 SARS-CoV-2 status; when SARS-CoV-2 status was negative, antibody titers were imputed as <LLOQ at pre-dose 1 of primary series.

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Source: PubMed

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