Safety and immunogenicity of intradermal administration of fractional dose CoronaVac(®), ChAdOx1 nCoV-19 and BNT162b2 as primary series vaccination

There is a limited supply of COVID-19 vaccines, with less than 20% of eligible populations in low-income countries having received one dose. Intradermal delivery of fractional dose vaccines is one way to improve global vaccine access, but no studies have reported data on intradermal delivery of COVID-19 primary series vaccination. We conducted a pilot study to examine the safety and immunogenicity of three intradermal primary series regimens – heterologous regimen of CoronaVac and ChAdOx1 (CoronaVac-ChAdOx1), homologous regimen of ChAdOx1 (ChAdOx1-ChAdOx1), and homologous regimen of BNT162b2 (BNT162b2-BNT162b2). Each dose was 1/5(th) or 1/6(th) of the standard dose. Two additional exploratory arms of intradermal vaccination for the second dose following an intramuscular first dose of ChAdOx1 and BNT162b2 were included. Intradermal vaccination was found to be immunogenic and safe. The antibody responses generated by the intradermal primary series were highest in the BNT162b2 arms. The anti-receptor binding domain (anti-RBD) IgG concentration following fractional dose intradermal vaccination was similar to that of standard dose intramuscular vaccination of the same regimen for all study arms except for BNT162b2. The BNT162b2 intradermal series generated a lower antibody concentration than the reference intramuscular series, despite generating the highest antibody concentration of all three intradermal primary series regimens. Neutralizing antibody responses against the SARS-CoV-2 ancestral strain were consistent with what was observed for anti-RBD IgG, with lower titers for SARS-CoV-2 variants. Neutralizing titers were lowest against the omicron variant, being undetectable in about a quarter of study participants. T-cell responses against spike- and nucleocapsid-membrane-open reading frame proteins were also detected following intradermal vaccination. Adverse effects following intradermal vaccination were generally comparable with post-intramuscular vaccination effects. Taken together, our data suggest that intradermal vaccination using 1/5(th) or 1/6(th) of standard COVID-19 intramuscular vaccination dosing were immunogenic with tendency of lower systemic adverse reactions than intramuscular vaccination. Our findings have implications in settings where COVID-19 vaccines are in shortage.