Tolerability, safety and immunogenicity of intradermal delivery of a fractional dose mRNA-1273 SARS-CoV-2 vaccine in healthy adults as a dose sparing strategy

  1. Geert V.T. Roozen
  2. Margaretha L.M. Prins
  3. Rob van Binnendijk
  4. Gerco den Hartog
  5. Vincent P. Kuiper
  6. Corine Prins
  7. Jacqueline J. Janse
  8. Annelieke C. Kruithof
  9. Mariet C.W. Feltkamp
  10. Marjan Kuijer
  11. Frits R. Rosendaal
  12. Meta Roestenberg
  13. Leo G. Visser
  14. Anna H.E. Roukens

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Abstract

Background

There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy.

Methods

We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals.

Findings

Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273.

Interpretation

Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.

Funding

The trial was supported by crowdfunding (Wake Up to Corona).

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  1. ScreenIT

    SciScore for 10.1101/2021.07.27.21261116: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All participants provided written informed consent.
    IRB: The PIENTER-Corona study was approved by the medical ethical committee MED-U, Nieuwegein, the Netherlands and registered in NTR (https://www.trialregister.nl/trial/8473).
    Sex as a biological variablenot detected.
    RandomizationStudy design and participants: This study was designed as a proof-of-concept, dose-escalation, open-label, randomized-controlled vaccine trial (IDSCOVA) conducted at the Leiden University Medical Center in collaboration with the Centre for Human Drug Research in the Netherlands.
    BlindingInvestigators and participants were not blinded; laboratory personnel was blinded for the study groups.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Participants were screened for SARS-CoV-2 infection by serology [SARS-CoV-2 anti-N IgG antibodies (Liaison by Diasorin, Sallugia, Italy) and SARS-CoV-2 PCR of a mid-turbinate/throat swab and excluded when positive.
    anti-N IgG
    suggested: None
    All sera were tested for the presence of specific IgG antibodies against the nucleoprotein, Spike S1 protein and the receptor binding domain (RBD), located in the S1 subunit using a bead-based multiplex immunoassay (MIA) based on Luminex technology, as previously described.
    MIA
    suggested: None
    In addition, we used MIA for detection of anti-nucleocapsid (anti-N) antibodies in parallel to assess any occurrence of SARS-CoV-2 infection following vaccination.
    anti-nucleocapsid ( anti-N )
    suggested: None
    Software and Algorithms
    SentencesResources
    All analyses were conducted using IBM SPSS Statistics for Windows, version 25.0. Armonk, New York: IBM Corp.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)
    Graphs were made by using GraphPad Prism version 9.0.1 for Windows, GraphPad software, San Diego, California.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    This study has some limitations. Although the concentrations of anti-S1 IgG were higher at each time point, the limited sample size did not allow to demonstrate superiority of intradermal delivery over intramuscular injection. In addition, since we included healthy volunteers aged 18-30 years old, the results on safety and immunogenicity may not apply to the general population. Finally, the longevity of the immune response past day 43 was not assessed, as some participants opted for receiving the regular vaccine through the national COVID-19 vaccination program at day 57. Although the relative importance of neutralization antibodies with regard to protection from COVID-19 has not yet been fully characterized, high levels of neutralising antibodies have been shown in early preclinical Rhesus macaque studies22, in convalescent individuals23,24 and in recently reported vaccine trials.25,26 Additional measurements of neutralising antibodies and T-cell responses will be performed at a later part and will provide more information on the robustness and longevity of the immune response. In conclusion, we show that the ID administration of 10 µg and 20 µg mRNA-1273 vaccine resulted in a robust, homogeneous, immune response with an acceptable safety profile in healthy adults aged 18-30 years. These safety and immunogenicity results support advancement of the investigation of the intradermal route for administration of the fractional doses of the mRNA-1273 vaccine to later-stage clinica...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

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  2. Version published to 10.1101/2021.07.27.21261116v1 on medRxiv