A Proof-of-Concept Study for an Intradermal Dose-Sparing Strategy: Non-Inferior Immunogenicity and Improved Systemic Tolerability of Fractional-Dose ChAdOx1-S SARS-CoV-2 Vaccine Compared to Intramuscular Administration
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Abstract
Background: The global shortage of SARS-CoV-2 vaccines and the necessity for repeated booster doses highlight an urgent need for dose-sparing strategies. The intradermal (ID) route, leveraging the skin’s rich immune network, is highly attractive due to the high density of antigen-presenting cells (APCs) in the dermis, offering the potential to induce a robust immune response with a reduced antigen dose. This study was conducted to establish a Proof-of-Concept (PoC) for the feasibility of an ID fractional dose strategy.
Objective: This study aimed to establish a proof-of-concept for an ID dose-sparing strategy. Primary
objectives were to evaluate the safety, tolerability, and immunogenicity of a fractional ID dose (0.1 mL,
1 x 1010 viral particles) compared to the standard IM dose (0.5 mL, 5 x1010 viral particles) as a booster in healthy adults.
Methods: This was a comparative, prospective, open-label, volunteer-controlled trial. Healthy adults (18-60 years old) who had previously completed a two-dose regimen of inactivated SARS-CoV-2 vaccine (Sinovac) were assigned to receive the ChAdOx1-S vaccine as a 3rd dose booster. The IM full dose group received 0.5 mL, 5 x 1010 vp, while the ID fractional dose group received 0.1 mL, 1 x 1010 vp. Safety, tolerability, and immunogenicity (Anti-S RBD antibody titers, converted to BAU/mL) were evaluated at Day 0 and Day 14 post-vaccination.
Results: A total of 60 volunteers were included. The Geometric Mean Titer (GMT) of Anti-S RBD antibodies was 10,203 BAU/mL (95%CI: 7,698 to 13,524) in the ID group and 10,337 BAU/mL (95%CI: 8,078 to 13,225) in the IM group. The GMT ratio (ID/IM) was 0.99 (95%CI: 0.77 to 1.27), which exceeded the pre-specified non-inferiority margin (0.67), demonstrating statistical non-inferiority of the fractional ID dose. The ID group demonstrated a favorable safety profile with significantly lower incidence of systemic adverse events (AEs) (e.g., Myalgia 10 % vs. 40 %, Headache 5 % vs. 30 %) compared to the IM group. Local reactions like erythema (91 % vs. 11.1 %) and swelling (72 % vs. 11.1 %) were more common with ID administration.
No serious adverse events were reported.
Conclusion: The ID administration of a one-fifth fractional dose of the ChAdOx1-S vaccine produces a robust, non-inferior immune response with a superior systemic safety profile. This study establishes a vital PoC for a Dose-Sparing strategy using viral vector vaccines. Beyond vaccine scarcity, the demonstrated efficiency of the ID route holds vast potential for future application in anti-cancer immunotherapy, specifically with personalized cancer vaccines.
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