ABSTRACT
Characterizing the antibody epitope profiles of messenger RNA (mRNA)-based vaccines against SARS-CoV-2 can aid in elucidating the mechanisms underlying the antibody-mediated immune responses elicited by these vaccines. This study investigated the distinct antibody epitopes toward the SARS-CoV-2 spike (S) protein targeted after a 2-dose primary series of mRNA-1273 followed by a booster dose of mRNA-1273 or a variant-updated vaccine among serum samples from clinical trial adult participants. Multiple S-specific epitopes were targeted after primary vaccination; while signal decreased over time, a booster dose after >6 months largely revived waning antibody signals. Epitope identity also changed after booster vaccination in some subjects, with 4 new S-specific epitopes detected with stronger signals after boosting than with primary vaccination. Notably, the strength of antibody responses after booster vaccination differed by the exact vaccine formulation, with variant-updated mRNA-1273.211 and mRNA-1273.617.2 booster formulations inducing significantly stronger S-specific signals than a mRNA-1273 booster.
ABSTRACT
BackgroundOmicron-containing bivalent boosters are available worldwide. Results of a large, randomized, active-controlled study are presented. MethodsThis phase 3, randomized, observer-blind, active-controlled trial in the United Kingdom evaluated the immunogenicity and safety of 50-g doses of omicron-BA.1-monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50-g mRNA-1273 administered as boosters in individuals [≥]16 years. Participants had previously received 2 doses of any authorized/approved Covid-19 vaccine with or without an mRNA vaccine booster. Safety and immunogenicity were primary objectives; immunogenicity was assessed in all participants, with analysis conducted based on prior infection status. Incidence of Covid-19 post-boost was a secondary (mRNA-1273.214) or exploratory (mRNA-1273.529) objective. ResultsIn part 1 of the study, 719 participants received mRNA-1273.529 (n=362) or mRNA-1273 (n=357); in part 2, 2813 received mRNA-1273.214 (n=1418) or mRNA-1273 (n=1395). Median durations (months [range]) between the most recent Covid-19 vaccine and study boosters were similar in the mRNA-1273.529 (4.0 [1.5-8.9]) and mRNA-1273 (4.1 [3.0-5.6]) (part 1), and mRNA-1273.214 (5.5 [0.4-13.3] and mRNA-1273 (5.4 [0.2-10.6]) groups (part 2). Both mRNA-1273.529 and mRNA-1273.214 elicited superior neutralizing antibody responses against omicron BA.1 with geometric mean ratios (95% CI) of 1.68 (1.45-1.95) and 1.53 (1.41-1.67) compared to mRNA-1273 at Day 29 post-boost. Although the study was not powered to assess relative vaccine efficacy, the incidence rates/1000 person years (95% CI) of Covid-19 trended lower with mRNA-1273.529 (670.5 [528.3-839.3]) than mRNA-1273 (769.3 [615.4-950.1]) and mRNA-1273.214 (633.0 [538.1-739.7]) than mRNA-1273 (711.6 [607.5-828.5]). Sequence analysis in part 2 showed that this was driven by lower incidence of Covid-19 in the mRNA-1273.214 cohort with BA.2 and BA.4 sublineages but not BA.5 sublineages. All study boosters were well-tolerated. ConclusionThe bivalent omicron BA.1 containing booster elicited superior neutralizing antibody responses against omicron BA.1 with acceptable safety results consistent with the BA.1 monovalent vaccine. Incidence rates for Covid-19 were numerically lower in participants who received mRNA-1273.214 compared to the original booster vaccine mRNA-1273, driven by the BA.2 and BA.4 sublineages.
Subject(s)
COVID-19ABSTRACT
Background: Information on the safety and immunogenicity of the omicron BA.4/BA.5-containing bivalent booster mRNA-1273.222 are needed. Methods In this ongoing, phase 2/3 trial, 50-μg mRNA-1273.222 (25-μg each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-μg mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-μg) primary series and first booster (50-μg) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost. Results Participants received 50-μg of mRNA-1273 (n=376) or mRNA-1273.222 (n=511) as second booster doses. Omicron BA.4/BA.5 and ancestral SARS-CoV-2 D614G neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after mRNA-1273.222 (2324.6 [1921.2-2812.7] and 7322.4 [6386.2-8395.7]) were significantly higher than mRNA-1273 (488.5 [427.4-558.4] and 5651.4 (5055.7-6317.3) respectively, at day 29 post-boost in participants with no prior SARS-CoV-2-infection. A randomly selected subgroup (N=60) of participants in the mRNA-1273.222 group also exhibited cross-neutralization against the emerging omicron variants BQ.1.1 and XBB.1. No new safety concerns were identified with mRNA-1273.222. Vaccine effectiveness was not assessed in this study; in an exploratory analysis 1.6% of mRNA-1273.222 recipients had Covid-19 post-boost. Conclusion The bivalent omicron BA.4/BA.5-containing vaccine mRNA-1273.222 elicited superior neutralizing antibody responses against BA.4/BA.5 compared to mRNA-1273, with no safety concerns identified.
Subject(s)
COVID-19ABSTRACT
We previously presented day 29 interim safety and immunogenicity results from a phase 2/3 study comparing the Omicron-BA.1-containing bivalent vaccine mRNA-1273.214 (50-µg) to the 50-µg mRNA-1273 booster in adults who previously received the mRNA-1273 primary series (100-µg) and mRNA-1273 first booster (50-µg) dose. Here we present day 91 post-booster results. Participants were sequentially enrolled to receive 50-µg of mRNA-1273 (n = 376) or mRNA-1273.214 (n = 437) as second booster doses. In participants with no pre-booster severe acute respiratory syndrome coronavirus 2-infection (SARS-CoV-2), mRNA-1273.214 elicited Omicron-BA.1-neutralizing antibody titers that were significantly higher (964.4 [834.4-1114.7]) than those of mRNA-1273 (624.2 [533.1-730.9]) and similar between boosters against ancestral SARS-CoV-2 at day 91. mRNA-1273.214 also induced higher binding antibody responses against Omicron BA.1 and alpha, gamma and delta variants than mRNA-1273. Safety profiles were similar for both vaccines. The Omicron-BA.1 bivalent vaccine induced improved antibody persistence compared to mRNA-1273.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses of these vaccines and the development of new variant-derived ones. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs). It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS-CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naive B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.
Subject(s)
Breast Neoplasms , Lymphoma, B-CellABSTRACT
ABSTRACT Background Updated vaccination strategies against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern are needed. Interim results of the safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster candidate are presented. Methods In this ongoing, phase 2/3 trial, the 50-μg bivalent vaccine mRNA-1273.214 (25-μg each ancestral Wuhan-Hu-1 and omicron B.1.1.529 spike SARS-CoV-2 mRNAs) was compared to the authorized 50-μg mRNA-1273 booster in adults who previously received 2-dose primary series of 100-μg mRNA-1273 and a first booster dose of 50-μg mRNA-1273 at least 3 months prior. Primary objectives were safety and reactogenicity, and immunogenicity of 50-μg mRNA-1273.214 compared with 50-μg mRNA-1273. Immunogenicity data 28 days after the booster dose are presented. Results Four hundred thirty-seven and 377 participants received 50-μg of mRNA-1273.214, or mRNA-1273, respectively. Median time between first and second booster doses of mRNA-1273.214 and mRNA-1273 were similar (136 and 134 days, respectively). In participants with no prior SARS-CoV-2 infection, observed omicron neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after the mRNA-1273.214 and mRNA-1273 booster doses, were 2372.4 (2070.6−2718.2) and 1473.5 (1270.8−1708.4) respectively and the model-based GMT ratio (97.5% confidence interval) was 1.75 (1.49−2.04). All pre-specified non-inferiority (ancestral SARS-CoV-2 with D614G mutation [D614G] GMT ratio; ancestral SARS-CoV-2 [D614G] and omicron seroresponse rates difference) and superiority primary objectives (omicron GMT ratio) for mRNA-1273.214 compared to mRNA-1273 were met. Additionally, mRNA-1273.214 50-μg induced a potent neutralizing antibody response against omicron subvariants BA.4/BA.5 and higher binding antibody responses against alpha, beta, gamma, delta and omicron variants. Safety and reactogenicity profiles were similar and well-tolerated for both vaccines groups. Conclusion The bivalent vaccine mRNA-1273.214 50-μg was well-tolerated and elicited a superior neutralizing antibody response against omicron, compared to mRNA-1273 50-μg, and a non-inferior neutralizing antibody response against the ancestral SARS-CoV-2 (D614G), 28 days after immunization, creating a new tool as we respond to emerging SARS-CoV-2 variants.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have caused multiple waves of infection globally. This phase 2/3 study evaluated the safety and immunogenicity of the bivalent vaccine candidate mRNA-1273.211 (equal mRNA amounts of ancestral SARS-CoV-2 and Beta variant spike proteins) as 50-µg (n=300) and 100-µg (n=595) first booster doses approximately 8.8-9.8 months after the mRNA-1273 primary series. The mRNA-1273.211 booster (50 and 100-µg) elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and the Beta variant than that after the second mRNA‑1273 dose. Antibody responses after the 50-µg mRNA-1273.211 booster dose were also higher than that after a 50-µg mRNA-1273 booster dose for the ancestral SARS-CoV-2, Beta, Omicron and Delta variants (28 days after the booster dose) and for the ancestral SARS-CoV-2, Beta and Omicron (180 days after the booster dose), and the immunogenicity objectives were met. The safety and reactogenicity profile of the mRNA-1273.211 booster (50-µg) was comparable to mRNA-1273 (50-µg). These results indicate that bivalent booster vaccines can induce potent and durable antibody responses providing a new tool in response to emerging variants. Trial registration: https://www.clinicaltrials.gov NCT04927065
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-g 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-g booster was administered to adults who previously received a two dose primary series of 100-g mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. Intervention: Lipid nanoparticle containing 100-g 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-g 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-g 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-g 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-g booster of mRNA-1273. Conclusions and Relevance: The 100-g mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2 and reactogenicity was higher with the 100-g booster dose compared to authorized booster dose level in adults (50-g). mRNA-1273 100-g booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065