Comparing the immunogenicity of intradermal and intramuscular vaccination of elderly with BNT162b2 XBB.1.5: An equivalent dose study.

Publication date: Sep 15, 2025

Aging coincides with a decline in immune functioning, whereby elderly become less responsive to vaccination. Alternative vaccination strategies, including administration into the skin, may improve immunogenicity and efficacy. Here, we investigated the immunogenicity of intradermal (ID) administration of a fractional dose of a COVID-19 vaccine in elderly (75 years and older) compared to standard intramuscular (IM) administration of an equivalent dose. Between November and December 2023, 48 adults aged 75-86 were randomized (1:1:1, n = 16/group) to receive either 20 μg of the BNT162b2 XBB. 1.5 vaccine via ID injection, using a microneedle, or 20 μg via IM injection, or the standard 30 μg dose via IM injection (NCT05977127). The primary endpoint was the geometric mean concentration (GMC) of SARS-CoV-2 Spike-specific IgG at day 28 post-vaccination. Secondary endpoints included the serum ACE2 binding inhibition at day 28, as well as incidence of local and systemic adverse events (AEs), recorded during the first 28 days post-vaccination. Exploratory outcomes included longitudinal immunogenicity assessments in serum and nasal mucosal lining fluid, on days 0, 28 and 122 and whole blood transcriptome profiling on day 0 and 1. At day 28 post-vaccination, no differences were found in serum anti-Spike IgG and ACE2 binding inhibition capacity between all three groups. Longitudinal analysis revealed parallel trends across groups in serum and mucosal IgG, IgA and ACE2 inhibition response. While ID vaccination induced a distinct blood transcriptomic profile compared to IM administration, no specific pathways were found that were differentially regulated. Mild and self-limiting local AEs were observed in all ID vaccinated participants, in contrast to IM vaccinated participants. No differences were found in antibody level and functionality following ID and IM administration of 20 μg BNT162b2 XBB. 1.5 vaccine in elderly, while IM administration was less reactogenic than ID administration.

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