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

  1. Spyros Chalkias
  2. Howard Schwartz
  3. Biliana Nestorova
  4. Jing Feng
  5. Ying Chang
  6. Honghong Zhou
  7. Frank J. Dutko
  8. Darin K. Edwards
  9. David Montefiori
  10. Rolando Pajon
  11. Brett Leav
  12. Jacqueline M. Miller
  13. Rituparna Das

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

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.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2022.03.04.22271830: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Upon meeting eligibility criteria and providing consent to enroll into the current Phase 2/3 trial, participants received a single booster dose of 100 µg mRNA-1273 on Day 1.
    Sex as a biological variablenot detected.
    RandomizationThe historical control group consisted of 584 participants who received a primary series of 2 doses of mRNA- 1273 100 µg and were included in the random sub-cohort for Immunogenicity of the phase 3 COVE trial2, 13, 14.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are several limitations of this study. The evaluation of a 100 µg booster was open- label, and the study was not designed to evaluate booster doses at varying intervals or compare different booster dose levels head-to-head. Additionally, neutralization results from different groups were not generated in the lab at the same time, the historical control group is not the same group of participants enrolled in the present study, and the study was not designed to evaluate vaccine effectiveness. However, neutralizing antibody responses have been correlated to reduction of risk for breakthrough COVID-19.12, 21, 22 The strengths of the study include that over 300 participants received a booster dose, allowing for a robust evaluation of possible adverse reactions, and the antibody response against SARS-CoV-2 variants was evaluated. The same laboratory was used to perform all neutralizing antibody assessments in a formally validated assay. The results from this study provide evidence that a 100 µg mRNA-1273 booster dose administered at least 6 months after the primary series induces a robust immune response against the ancestral SARS-CoV-2 and against variants of concern. The results also suggest that the 100 µg booster dose enhances the breadth of the neutralizing antibody response and elicits even numerically higher neutralizing antibody titers against antigenically divergent variants compared to a 50 µg booster dose. Although observed to have a clinically-acceptable safety pro...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04927065RecruitingA Study to Evaluate the Immunogenicity and Safety of mRNA Va…
    NCT04405076CompletedDose-Confirmation Study to Evaluate the Safety, Reactogenici…
    NCT04470427Active, not recruitingA Study to Evaluate Efficacy, Safety, and Immunogenicity of …

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2022.03.04.22271830 on medRxiv