Establishing Immunogenicity and Safety of Needle-free Intradermal Delivery of mRNA COVID-19 Vaccine (MILESTONE)

Establishing Immunogenicity and Safety of Needle-free Intradermal Delivery by Solid Micro Needle Skin Patch of mRNA SARS-CoV-2 Vaccine as a Revaccination Strategy in Healthy Volunteers

COVID-19 vaccines are limited in supply, especially in low- and middle-income countries, leading to substantial morbidity and mortality. Despite the COVID-19 Vaccines Global Access (COVAX) Facility initiated by the WHO to provide vaccine access for low-income countries, probably 80% of the vaccine needs of participating countries will not be met soon.

In addition, there is an increasing demand for revaccination of the population globally, because of waning immunity which will further limit vaccine supplies. Exploring dose-sparing techniques, could therefore provide the solution to immunise more people with the same vaccine stockpile.

The intramuscular injection (IM) is the standard inoculation route of vaccines. However, the skin (dermis) is much richer in antigen presenting dendritic cells than muscle. As a consequence, a fractional vaccine dose introduced directly into the dermis (intradermal administration, ID) might be as effective as the intramuscular administration of the full standard dose to achieve a protective immune response. This principle has recently been demonstrated for the ID dermal delivery of one-fifth fractional dose mRNA-1273 (Spikevax, Moderna) vaccine.

However, needle-based immunisation has several limitations. Fear of needles makes immunisation a stressful event. In addition, needle stick injuries, as well as unsafe injection practices carry serious health risks. Therefore, the development of needle-free delivery has been identified as an important goal in global health care. The WHO reported that microneedle vaccine delivery is top priority and requires additional research to explore the benefits in more detail. A big advantage of intradermal delivery via a solid needle patch is not only the absence of needles and pain since no nerves are at the proximity where the needles are presented, but also the local delivery close to immune cells as with the above mentioned intradermal injection enables a much lower dose as compared to IM dosing. And since with the patch a larger skin surface is involved as compared to intradermal injection, even lower doses are possibly still immunogenic.

In this study, we will investigate the immunogenicity and safety in healthy volunteers of the needle-free intradermal delivery of a single fractional dose of 20µg mRNA-1273 LNP vaccine (Spikevax, Moderna) more than 3 months after primary vaccination with Comirnaty (Pfizer) vaccine and/or after having contracted COVID-19.

Study Overview

• Status: Recruiting
• Conditions: COVID-19; Vaccination; Infection
• Intervention / Treatment: Device: solid microneedle skin patch; Biological: mRNA-1273; Device: standard needle

Detailed Description

Objectives Primary objective

• to describe immunogenicity and safety in healthy volunteers of the needle-free intradermal delivery of a single fractional dose of 20µg mRNA-1273 LNP vaccine (Spikevax, Moderna) more than 3 months after primary vaccination with Comirnaty (Pfizer) vaccine and/or after have contracted COVID-19.

Secondary objectives

• to describe the kinetics of the SARS-CoV-2 anti-Spike1 (S1) and Region Binding Domain (RBD) IgG binding antibodies elicited by needle-free intradermal or intramuscular delivery of mRNA-1273 vaccine in healthy volunteers after a single fractional dose of 20µg mRNA-1273 LNP vaccine
• to describe the kinetics of the SARS-CoV-2 neutralising antibodies elicited by needle-free intradermal or intramuscular delivery of mRNA-1273 vaccine in healthy volunteers after a single fractional dose of 20µg mRNA-1273 LNP vaccine

Exploratory objectives:

• to describe the kinetics of memory B-cell and plasma cell responses elicited by needle-free intradermal or intramuscular delivery of mRNA-1273 vaccine of a single fractional dose of 20µg mRNA-1273 LNP vaccine (Spikevax, Moderna)
• to describe the interferon-gamma release in whole blood in response to SARS-CoV 2 peptides after needle-free intradermal or intramuscular delivery of mRNA-1273 vaccine of a single fractional doses of 20µg mRNA-1273 LNP vaccine (Spikevax, Moderna)

Study design:

This is a Phase 2a, open-label, randomised-controlled, proof-of-concept vaccine study

Study population:

Healthy volunteers aged 18 - 40 years who have been vaccinated with Comirnaty (Pfizer) vaccine at least 3 months before

Intervention group:

Participants will receive 20 µg of mRNA-1273 vaccine through the needle-free intradermal route using a micro-needle delivery system.

Control group:

Participants will receive 20 µg of mRNA-1273 vaccine through the intramuscular route

Main study parameters/endpoints:

• Solicited local reactions and systemic events self-reported by diary on a daily basis over a 2-week period, telephone interview on D4, as well as by on site visits on D15 and D29
• Adverse events (AEs) until two weeks after administration
• Serious AEs (SAEs) until six months after administration
• Seroconversion for anti-spike IgG antibodies (D29)
• Geometric mean concentrations (GMC) for anti-spike IgG antibodies (D1, D29)

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Anna H Roukens, MD PhD; Phone Number: +31715262613; Email: a.h.e.roukens@lumc.nl
• Study Contact Backup: Name: Leo G Visser, MD PhD; Phone Number: +31715262613; Email: l.g.visser@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Recruiting
    • Leiden University Medical Center
    • Contact: Anna H Roukens, MD, PhD; Phone Number: +31715262613; Email: a.h.e.roukens@lumc.nl
    • Contact: Leo G Visser, MD, PhD; Phone Number: +31715262613; Email: l.g.visser@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previously vaccinated with Comirnaty (Pfizer) and/or previously contracted COVID-19 at least 3 months before inclusion
• Healthy participants who are determined by medical history and clinical judgment of the investigator to be eligible for inclusion in the study. Healthy participants with preexisting stable disease, defined as disease not requiring significant change in therapy or hospitalisation for worsening disease during the 6 weeks before enrolment, can be included.
• Participants who are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other study procedures.
• Participants are willing to postpone their regular COVID-19 revaccination upon invitation by the municipal health center or general practitioner until four weeks after receiving the intervention (after the last sampling of D29).
• Capable of giving personal signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Exclusion Criteria:

• Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the study intervention(s).
• Receipt of medications intended to prevent COVID-19.
• Previous microbiological diagnosis of COVID-19.
• Previous COVID-19 vaccination other than Comirnaty (Pfizer)
• Individuals at high risk for severe COVID-19 (e.g. BMI > 40, diabetes, heart- end/or lung disease), who are planned to receive COVID vaccine within the next two months.
• Immunosuppressed individuals with known or suspected immunodeficiency, as determined by history.
• Individuals with an active autoimmune disease requiring therapeutic intervention.
• Receipt of systemic or topical corticosteroids.
• Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
• Women who are pregnant or breastfeeding.
• Planned pregnancy within four weeks after injection.
• Positive serological test for SARS-CoV-2 anti-N IgM and/or IgG antibodies at screening visit.
• SARS-CoV-2 PCR-positive mid-turbinate/throat swab at the screening before receipt of the vaccine dose.
• Participation in other studies involving study intervention within 28 days prior to study entry and/or during study participation.
• Receipt of any other non-study vaccine within 28 days, before receipt of the study dose.
• Anticipated receipt of any other non-study vaccine within 28 days, after the study dose administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention group - intradermal vaccination with patch; Participants will receive 20 µg of mRNA-1273 vaccine through the intradermal route using a solid micro needle delivery system	Device: solid microneedle skin patch; intradermal vaccination with a skin patch; Biological: mRNA-1273; administration of mRNA-1273 vaccine
ACTIVE_COMPARATOR: Control group - intramuscular vaccination with standard needle; Participants will receive 20 µg of mRNA-1273 vaccine through the intramuscular route	Biological: mRNA-1273; administration of mRNA-1273 vaccine; Device: standard needle; intramuscular vaccination with a standard needle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-CoV-2-spike protein-specific binding IgG antibody levels	SARS-CoV-2-spike protein-specific binding IgG antibody levels	3 months
adverse events	local and systemic reactions after intradermal vaccination with a solid microneedle patch	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS CoV 2 neutralizing antibody levels	SARS CoV 2 neutralizing antibody levels	3 months
Number of Spike-protein specific proliferating B-cells, plasma cells and B-memory cells	Number of Spike-protein specific proliferating B-cells, plasma cells and B-memory cells	6 months
INF-gamma concentration and other cytokine responses after over-night incubation	INF-gamma concentration and other cytokine responses after over-night incubation	3 months

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Anna H Roukens, MD PhD, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): May 1, 2022
• Primary Completion (ANTICIPATED): September 1, 2022
• Study Completion (ANTICIPATED): May 1, 2023

Study Registration Dates

• First Submitted: April 6, 2022
• First Submitted That Met QC Criteria: April 6, 2022
• First Posted (ACTUAL): April 7, 2022

Study Record Updates

• Last Update Posted (ACTUAL): April 22, 2022
• Last Update Submitted That Met QC Criteria: April 14, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: NL80101.058.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No