Intradermal administration of low-dose mRNA COVID-19 vaccine induces strong immune response, study finds

Scientists in the Netherlands recently conducted an open-level, randomized-controlled trial to evaluate the safety and immunogenicity of fractional intradermal doses of the mRNA-based coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 (Moderna).

The trial findings reveal that the fractional dose regimen of the Moderna vaccine is well tolerated and safe and is capable of inducing robust antibody responses in vaccine recipients. The study is currently available on the medRxiv* preprint server.


Since its emergence in December 2019 in China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, has infected 195 million people and claimed 4.1 million lives globally. The continuous emergence of novel viral variants with higher infectivity, pathogenicity, and immune evasion ability have made the pandemic an enormous threat to mankind. To save the world from the major health and socioeconomic crisis, rapid and large-scale vaccination is highly required.

Although several COVID-19 vaccines with good efficacy are currently rolling out globally, a large proportion of the world population is still unvaccinated because of limited vaccine supply. One of the potential approaches to overcome vaccine shortage is a dose-sparing strategy that allows intradermal delivery of low-dose vaccines.

In the current study, the scientists have investigated the safety and immunogenicity of the Moderna-developed COVID-19 vaccine mRNA-1273 following fractional-dose intradermal administration. Studies conducted in real-world pandemic settings have demonstrated that the two doses of 100 µg vaccine provide more than 90% protection against COVID-19 when administered intramuscularly.  

Study design

In the first part of the study, two doses of 10 µg mRNA-1273 vaccine were administered intradermally to 10 individuals at an interval of 28 days. Similarly, in the second part, two doses of 20 µg mRNA-1273 were intradermally administered to 30 individuals at the same interval. The vaccine recipients were healthy adults aged 18 to 30 years who tested negative for SARS-CoV-2 in both serological and PCR-based testing.

To compare the immunogenicity of intradermal regimen, plasma samples collected from individuals who received the standard 100 µg doses of the mRNA-1273 intramuscularly were also analyzed.

Safety profile

No acute adverse reaction was noticed among vaccine recipients within 30 minutes following vaccination.

Local reactions

About 70% of participants who received the 10 µg-dose reported having pain at the injection site after 1st vaccination. After 2nd vaccination, the most commonly reported local reactions were mild erythema, pain, and itching at the injection site.

The most common local reactions related to the first vaccination with the 20 µg-dose were itching and erythema at the injection site. One participant mentioned having a large erythema of more than 10 cm that lasted for 6 days. In general, recurrence of erythema and swelling was observed 8 – 10 after the 1st vaccination with 10/20 µg dose. After the 2nd vaccination, the most commonly reported reactions were local pain and erythema. Overall, intradermal administration of 20 µg of vaccine-induced more local adversities than intramuscular administration.

Systemic reactions

Among recipients of a 10 µg vaccine dose, only one reported moderate headache after 1st vaccination. However, among the recipients of 20 µg vaccine dose, the most common systemic adversities were headache and fatigue after the 1st and 2nd vaccination.


After the 1st vaccine dose, all participants became seropositive. None of the participants exhibited detectable anti-nucleoprotein antibodies, indicating that the antibody response is induced by vaccination and not by natural infection.

Among participants who received 10 µg vaccine dose, the levels of IgG-specific anti-S1 and anti-RBD antibodies increased rapidly after both 1st and 2nd immunization. As expected, recipients of the 20µg vaccine dose showed higher anti-S1, and anti-RBD titers post 2nd vaccination. However, the titers detected after intramuscular immunization with 20 µg vaccine were significantly lower than that in intradermal immunization.

In intradermally immunized participants, the antibody titers were 14 – 20-fold higher than that in convalescent plasma. Moreover, antibody titers detected after intradermal administration of 10/20 µg dose and intramuscular administration of 20 µg dose were equivalent to those who received 100 µg dose intramuscularly.

Study significance

The study demonstrates that intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine is sufficient to induce robust antibody response with an acceptable safety profile in healthy adults aged 18 – 30 years. These observations highlight the significance of the intradermal route of vaccine delivery as a potential dose-sparing strategy to overcome vaccine shortage.

The main advantage of intradermal vaccine administration is that the papillary dermis contains high levels of antigen-presenting dendritic cells. Moreover, the presence of multiple plexus systems in the dermal lymphatic system enables effective transport of vaccine antigen and antigen-presenting cells to regional lymph nodes. Collectively, these processes lead to more efficient activation of B cells and T cells and induction of immune responses.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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