Establishing the safety, tolerability and immunogenicity of intradermal delivery of mRNA SARS-CoV-2 vaccine in healthy adults

The intradermal route is a highly effective way to administer vaccines. The
vaccine is deposited right into the papillary dermis which is rich in antigen
presenting cells. As a consequence, a fractional vaccine dose introduced
directly into the papillary dermis (intradermal administration, ID) might be as
effective as the intramuscular administration of the full standard dose to
achieve a protective immune response. Especially in circumstances of limited
vaccine stockpiles, vaccination with a fractional dose through the intradermal
route can be applied as a dose-sparing strategy. Because the vaccine is
administered much more superficially, the local side effects, such as redness
and induration, are more visible at the site of injection than after
intramuscular injection.

Globally the race to national mass vaccination campaigns to protect against
infection with SARS-CoV-2 has started. The first registered mRNA COVID vaccines
are currently in limited supply leading to a selection of those who receive the
vaccine, instead of vaccinating everyone. Production limitations threaten to
delay the roll-out of the national vaccination campaigns. In preclinical
studies the intradermal route has been shown to be a very effective way for
mRNA vaccine administration. If the intradermal route would be a safe and
effective route for a fractional dose of the mRNA COVID vaccine, many more
people could be vaccinated with the same limited amount of vaccine.

To enable the implementation of the intradermal injection technique in mass
vaccination campaigns by relatively untrained technicians, we also will
evaluate the performance of a needle specifically designed for highly accurate
and easy-to-use intradermal administration.

An extra stage (stage 4) has been added in which participants from stage 3
(non-inferiority study) and an extra group of healthy volunteers, will receive
a booster with mRNA-1273.

Primary objectives:
- to describe tolerability, safety and immunogenicity in healthy adults of the
intradermal delivery of one or two fractional doses of 10 µg and 20 µg
mRNA-1273 LPN vaccine (Moderna).
- to compare the immunogenicity in healthy adults of the intradermal delivery
of two fractional dosis of 20 µg mRNA-1273 LPN with that of two doses of 20 µg
mRNA-1273 vaccine through intramuscular delivery on Day 43.
- to determine non-inferiority of the virus neutralising antibody response
elicited by intradermal delivery by means of standard needle and syringe of
mRNA-1273 vaccine in healthy adults after two fractional doses of 20 µg with
the responses to two doses of 100 µg mRNA-1273 vaccine through intramuscular
delivery on Day 43
- to determine non-inferiority of the virus neutralising antibody response
elicited by intradermal delivery by means of U-needle and syringe of mRNA-1273
vaccine in healthy adults after two fractional doses of 20 µg with the
responses to two doses of 100 µg mRNA-1273 vaccine through intramuscular
delivery on Day 43*
- to determine the antibody-response after revaccination with standard dose
(1/2 of primary dose) and fractional dose (1/5th of primary dose) of mRNA-1273
on Day 29 after revaccination

Secondary objectives:
- to describe the kinetics of the humoral immune responses elicited by
intradermal or intramuscular delivery of mRNA-1273 vaccine in healthy adults
after 1 and 2 fractional doses of 20 µg, and standard intramuscular delivery of
100 µg
- to compare the size of the dermal bleb after intradermal delivery with the
standard needle and with the U-needle
- to document symptomatic and asymptomatic infection with SARS-CoV-2

Exploratory objectives:
- to describe the nasal mucosal immune response elicited by intradermal or
intramuscular delivery of mRNA-1273 vaccine in healthy adults after 1 or 2
fractional doses of 20 µg, and standard intramuscular delivery of 100 µg
- to describe the glycosylation of SARS-CoV-2 antibodies elicited by
intradermal or intramuscular delivery of mRNA-1273 vaccine in healthy adults
after 1 or 2 fractional doses of 20 µg, and standard intramuscular delivery of
100 µg.
- to describe the T follicular helper cell kinetics elicited by intradermal or
intramuscular delivery of mRNA-1273 vaccine in healthy adults after 1 or 2
fractional doses of 20 µg, and standard intramuscular delivery of 100 µg.
- to describe the memory B-cell and plasma cell response elicited by
intradermal delivery of mRNA-1273 vaccine in healthy adults after 1 or 2
fractional doses of 20 µg, and standard intramuscular delivery of 100 µg.
- to describe several coagulation factors in response to the intradermal and
intramuscular mRNA-1273 vaccination, such as fibrinogen, factors II, V, VII,
VIII, IX, X, XI and inhibitors (protein C, protein S, antithrombin),
activation/inhibition complexes, platelet factors and general coagulation and
fibrinolysis tests. These will be measured with chromogenous coagulation tests,
ELISA and mass spectrometry

This is a Phase 1/Phase 2a open-label, randomised- controlled, dose-escalation,
proof-of-concept vaccine study in healthy adults.

This study will evaluate the safety, tolerability, and immunogenicity of the
intradermal delivery two different fractional doses of mRNA-1273 vaccine:
- as a 2-dose schedule separated by 28 days
- up to 2 different dose levels: 10 and 20 µg

The study consists of 4 study stages.
- Stage 1: to establish tolerability, safety and immunogenicity of two doses of
10 µg of mRNA-1273 through intradermal injection
- Stage 2: to establish tolerability, safety and immunogenicity of two doses of
20 µg of mRNA-1273 through intradermal injection and to compare this with two
fractional doses of 20 µg of mRNA-1273 administered through the intramuscular
route
- Stage 3: to determine non-inferiority of two fractional doses of 20 µg of
mRNA-1273 through the intradermal route (group a standard technique, group b
u-needle) compared to two standard doses of 100 µg of mRNA-1273 administered
through the intramuscular route.
- Stage 4: to determine the antibody-response of standard and fractional dose
mRNA-1273 in participants of Stage 3, who received a fractional primary vaccins
dose, and additionally recruited healthy participants who received a standard
vaccine dose as primairy vaccination

The study is unblinded to the participant, investigator and other site staff as
the route of administration differs. The study will blinded to the laboratory
staff. Dependent upon safety generated during the course of this study, it is
possible that groups may be started at the next highest dose, groups may not be
started, groups may be terminated early, and/or groups may be added at the same
dose

Stage 1-2-3
Intervention group:
group a: Participants will receive 10 µg or 20 µg mRNA-1273 vaccine followed by
a second dose on day 28 through the intradermal route (standard technique).
group b: Participants will receive 10 µg or 20 µg mRNA-1273 vaccine followed by
a second dose on day 28 through the intradermal route (U-needle).
Comparison group:
Participants will receive 20 µg or 100 µg mRNA-1273 vaccine followed by a
second dose on day 28 through the intramuscular route

Booster study (stage 4)
Intervention group:
participants from stage 3 who received a fractional priming vaccine dose (n=90)
are randomised 1:1 to receive again a fractional vaccine dose of a standard
dose as booster
Comparison group:
Participants from stage 3 who received the standard vaccine dose (n=45) will
receive the standard booster
Comparison group:
Participants who are recruited for stage 4 and who have received the standard
vaccine dose as primary vaccine, will now receive the fractional dose as
booster

The safety of COVID-19 Vaccine Moderna has been evaluated in an ongoing Phase 3
randomised, placebo-controlled, observer-blind clinical trial conducted in the
United States involving 30,351 participants 18 years of age and older who
received at least one dose of COVID-19 Vaccine Moderna (n=15,185) or placebo
(n=15,166) (NCT04470427). After intramuscular injection of 100 µg mRNA-1273,
the most frequently reported adverse reactions were pain at the injection site
(92%), fatigue (70%), headache (64.7%), myalgia (61.5%), arthralgia (46.4%),
chills (45.4%), nausea/vomiting (23%), axillary swelling/ tenderness (19.8%),
fever (15.5%), injection site swelling (14.7%) and redness (10%). Adverse
reactions were usually mild or
moderate in intensity and resolved within a few days after vaccination.
Overall, there was a higher incidence of some adverse reactions in younger age
groups: the incidence of axillary swelling/tenderness, fatigue, headache,
myalgia, arthralgia, chills, nausea/vomiting and fever was higher in adults
aged 18 to < 65 years than in those aged 65 years and above. Local and systemic
adverse reactions were more frequently reported after Dose 2 than after Dose 1.
The frequency of anaphylactic reactions is estimated to be around 1:100,000
[CDC]. Three cases of Bell*s palsy have been reported in the vaccine group and
one in the placebo group.

Since a smaller fractional dose is applied with intradermal injection, it is
expected that the systemic side effects will be less. However, local side
effects may be more pronounced with more redness, swelling, pain, and
potentially necrosis and scarring at the injection site. Also swelling of the
axillary lymph nodes may be more pronounced. The risk of anaphylactic reaction
is probably lower because of the intradermal route. The participants may
acquired virus neutralising antibodies after intradermal vaccination.
Participation does not interfere with possible access to future COVID
vaccinations.
The outcome of this study may have important health benefits for the population
at large. If intradermal delivery of an one-fifth fractional dose of mRNA-1273
is safe and immunogenic, the population-wide benefits of higher vaccine
coverage would outweigh the lower efficacy of fractionated dosing for
individual vaccinees.