Abstract
9 min readLetters25 October 2022Safety and Immunogenicity of Intradermal Fractional Dose Administration of the mRNA-1273 Vaccine: A Proof-of-Concept StudyFREEGeert V.T. Roozen, MD, Margaretha L.M. Prins, MD, Rob van Binnendijk, PhD, Gerco den Hartog, PhD, Vincent P. Kuiper, MD, Corine Prins, BSc, Jacqueline J. Janse, MSc, Annelieke C. Kruithof, PhD, Mariet C.W. Feltkamp, MD, PhD, Marjan Kuijer, Frits R. Rosendaal, MD, PhD, Meta Roestenberg, MD, PhD, Leo G. Visser, MD, PhD, and Anna H.E. Roukens, MD, PhDGeert V.T. Roozen, MDDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.), Margaretha L.M. Prins, MDDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.), Rob van Binnendijk, PhDDepartment of Immune Surveillance, National Institute for Public Health and the Environment, Bilthoven, the Netherlands (R.V., G.D., M.K.), Gerco den Hartog, PhDDepartment of Immune Surveillance, National Institute for Public Health and the Environment, Bilthoven, the Netherlands (R.V., G.D., M.K.), Vincent P. Kuiper, MDDepartment of Parasitology, Leiden University Medical Center, Leiden, the Netherlands (V.P.K., J.J.J.), Corine Prins, BScDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.), Jacqueline J. Janse, MScDepartment of Parasitology, Leiden University Medical Center, Leiden, the Netherlands (V.P.K., J.J.J.), Annelieke C. Kruithof, PhDDepartment of Infectious Diseases, Leiden University Medical Center, and Centre for Human Drug Research, Leiden, the Netherlands (A.C.K.), Mariet C.W. Feltkamp, MD, PhDDepartment of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands (M.C.F.), Marjan KuijerDepartment of Immune Surveillance, National Institute for Public Health and the Environment, Bilthoven, the Netherlands (R.V., G.D., M.K.), Frits R. Rosendaal, MD, PhDDepartment of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (F.R.R.), Meta Roestenberg, MD, PhDDepartment of Infectious Diseases and Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands (M.R.), Leo G. Visser, MD, PhDDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.), and Anna H.E. Roukens, MD, PhDDepartment of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-2089 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: There is an urgent need for fair and equitable access to safe and effective COVID-19 vaccines. Intradermal (ID) delivery is a dose-sparing technique that can be used to immunize more people with the same limited vaccine stockpile (1). The papillary dermis contains a higher density of antigen-presenting cells than muscle tissue; therefore, ID delivery of a fractional vaccine dose into this skin layer can be as effective as intramuscular (IM) administration of the standard dose (2).Objective: To assess the safety, tolerability, and immunogenicity of ID fractional dose administration of the mRNA-1273 (Moderna) vaccine as a potential dose-sparing strategy.Methods and Findings: We conducted a proof-of-concept, dose-escalation, open-label, randomized controlled trial in a tertiary medical center in Leiden, the Netherlands. Participants were recruited in April and May 2021 from a database of people who had previously shown interest in participating in upcoming COVID-19 vaccine trials. Eligible participants were healthy adults aged 18 to 30 years with no history of COVID-19. At every visit, participants were screened for past SARS-CoV-2 infection via serologic testing and polymerase chain reaction and were excluded from further participation if results were positive.In part one, 10 participants received 10 mcg of mRNA-1273 vaccine (0.05 mL [one tenth of the standard dose]) intradermally at days 1 and 29. In part two, 30 participants were randomly assigned in a 1:1 ratio to receive a 20-mcg dose of mRNA-1273 (0.01 mL [one fifth of the standard dose]) either intradermally or intramuscularly at days 1 and 29. All ID vaccinations were administered using a Becton Dickinson U-100 Micro-Fine insulin syringe with an integrated 29G needle.Diaries were used to collect self-reported local and systemic adverse events for 14 days after every vaccination (Supplement Sections A and B). Concentrations of IgG- and IgA-binding antibodies against SARS-CoV-2 spike S1 and receptor-binding domain (RBD) and virus neutralization titers were measured at day 36, day 43, and month 7 (Figure).Figure. Serum anti–SARS-CoV-2 antibody concentrations.Each symbol represents a sample from an individual participant at a certain time point. Error bars represent geometric mean concentrations with 95% CIs. anti-N = anti-nucleocapsid; anti-RBD = anti–receptor-binding domain; anti-S1 = anti–spike S1; AU = arbitrary unit; BAU = binding antibody unit; ID = intradermal; IM = intramuscular; LLoQ = lower limit of quantitation; NF50 = neutralizing factor at 50% normalized against an international reference serum. A, B, and C. Anti–SARS-CoV-2 serum IgG concentrations for anti-S1 (A), anti-RBD (B), and anti-N (C), assessed by bead-based immunoassay and reported in BAUs per milliliter. Data at day 1 (before receipt of the first vaccination), day 29 (before receipt of the second vaccination), day 36 (1 week after receipt of the second vaccination), day 43 (2 weeks after receipt of the second vaccination), and month 7 (half a year after receipt of the second vaccination) are reported for the 10-mcg ID dose, the 20-mcg ID dose, and the 20-mcg IM dose. Horizontal dashed lines represent the cutoff for seropositivity (10 BAU/mL for anti-S1, 30 BAU/mL for anti-RBD, and 14 BAU/mL for anti-N). D. Wild-type SARS-CoV-2 (Wuhan strain) microneutralization assay. NF50 is reported in international units per milliliter. The conversion rate from titer to international units was 1 / 4.064. The horizontal dashed line represents the LLoQ at 15 IU/mL (titer of 62). Values with an NF50 below the LLoQ were set to 2 IU/mL (titer of 10). Values above the upper limit of quantitation (n = 2 in the 20-mcg ID group and 1 in the 20-mcg IM group at day 43) were set to 2953 IU/mL (titer of 12 000). E, F, and G. Anti–SARS-CoV-2 serum IgA concentrations for anti-S1 (E), anti-RBD (F), and anti-N (G), assessed by bead-based immunoassay and reported in AUs per milliliter. Data at days 1, 29, 36, and 43 are reported for the 10-mcg ID dose, the 20-mcg ID dose, and the 20-mcg IM dose. Download figure Download PowerPoint Thirty-eight of 40 participants remained in the study through day 43, and 31 remained through month 7. The main reasons for premature study termination were COVID-19 or receipt of an additional vaccination elsewhere (Supplement Section C).The average wheal sizes after the first and second 10-mcg ID vaccinations were 8 mm (SD, 1) and 7 mm (SD, 1), respectively. For the 20-mcg dose, the average wheal sizes were 8 mm (SD, 1) and 10 mm (SD, 1), respectively, for the first and second vaccinations.No serious adverse events occurred. The most commonly reported adverse events were short-lasting and consisted of mild pain, itching, erythema, and swelling at the injection site (Table; Supplement Sections E and F). One participant in the 20-mcg ID group reported severe erythema of more than 10 cm in diameter and moderate swelling. This lasted 6 days and was self-limiting and well tolerated (Supplement Section G).Table. Local and Systemic Adverse Events Related to Vaccination*All participants showed robust antibody responses at day 43 that were still detectable at month 7. The binding antibody responses for anti-S1 IgG, anti-RBD IgG, and neutralizing antibodies showed similar patterns (Figure, A to D; Supplement Sections H and I). At day 43, geometric mean concentrations of neutralizing antibody were 1115 IU/mL (95% CI, 669 to 1858 IU/mL) for the 10-mcg group, 1300 IU/mL (CI, 941 to 1796 IU/mL) for the 20-mcg ID group, and 1052 IU/mL (CI, 733 to 1509 IU/mL) for the 20-mcg IM group. The IgA responses were similar between groups, independent of dose or method of administration (Figure, E to G; Supplement Section J).Discussion: Intradermal delivery of a 2-dose regimen of mRNA-1273 vaccine at 10 or 20 mcg was safe, was well tolerated, and induced durable antibody responses.This study has 2 limitations. First, although the IgG, IgA, and neutralizing antibody concentrations were highest in the 20-mcg ID group, the sample size did not allow demonstration of statistically significant superiority of ID over IM injection. Second, only healthy volunteers aged 18 to 30 years were included, so the findings on safety and immunogenicity may not apply to the general population.Although true vaccine efficacy depends on several factors, antibody concentrations measured after fractional dose vaccination in our trial are within the ranges that correlated with high levels of protection in the mRNA-1273 phase 3 trial (3). This is especially true for the 20-mcg ID group.In conclusion, the safety and immunogenicity results from this trial strongly support advancement of the investigation of ID vaccination with the mRNA-1273 vaccine.References1. Roozen GVT, Roukens AHE, Roestenberg M. COVID-19 vaccine dose sparing: strategies to improve vaccine equity and pandemic preparedness. Lancet Glob Health. 2022;10:e570-e573. [PMID: 35303466] doi:10.1016/S2214-109X(22)00075-4 CrossrefMedlineGoogle Scholar2. Nicolas JF, Guy B. Intradermal, epidermal and transcutaneous vaccination: from immunology to clinical practice. Expert Rev Vaccines. 2008;7:1201-14. [PMID: 18844594] doi:10.1586/14760584.7.8.1201 CrossrefMedlineGoogle Scholar3. Gilbert PB, Montefiori DC, McDermott AB, et al; Immune Assays Team. Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science. 2022;375:43-50. [PMID: 34812653] doi:10.1126/science.abm3425 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands (G.V.R., M.L.P., C.P., L.G.V., A.H.R.)Department of Immune Surveillance, National Institute for Public Health and the Environment, Bilthoven, the Netherlands (R.V., G.D., M.K.)Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands (V.P.K., J.J.J.)Department of Infectious Diseases, Leiden University Medical Center, and Centre for Human Drug Research, Leiden, the Netherlands (A.C.K.)Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands (M.C.F.)Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (F.R.R.)Department of Infectious Diseases and Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands (M.R.)Note: The protocol was approved by the Medical Ethical Committee Leiden, Den Haag, Delft (NL 76702.058.21).Acknowledgment: The authors thank all of the trial participants for their contributions and the members of the data safety monitoring board for their invaluable advice. They also thank all of the people who donated to the crowdfunding that supported the trial. The authors acknowledge the support of CEPI and the participation of Viroclinics for performance of the neutralization assay. Finally, the authors thank the Centre for Human Drug Research for its collaboration and its assistance in the recruitment of participants.Financial Support: The trial was supported by crowdfunding (Wake Up to Corona) set up by the Leiden University Fund. The funder had no influence on the design or conduct of the trial and did not influence the manuscript.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-2089.Data Sharing Statement: The following data and supporting documents will be made available with publication: deidentified participant data and informed consent form (e-mail, a.h.e.[email protected]nl). These will be made available to researchers whose proposed use of the data has been approved, for any purpose, with a signed data access agreement (restrictions: none).Corresponding Author: Geert V.T. Roozen, Department of Infectious Diseases C5-P, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; e-mail, G.V.T.[email protected]nl.Previous Posting: This manuscript was posted as a preprint on medRxiv on 28 July 2021. doi:10.1101/2021.07.27.21261116This article was published at Annals.org on 25 October 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics LatestKeywordsAdverse eventsAntibodiesCOVID-19Confidence intervalsErythemaImmunityIntradermal injectionsPainSafetyVaccines ePublished: 25 October 2022 CopyrightCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...
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