Immunogenicity and safety of an intradermal ChAdOx1 nCoV-19 boost in a healthy population

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Two doses of an inactivated SARS-CoV-2 vaccine (CoronaVac) have been shown to be insufficient to protect against variants of concern (VOCs), while viral vector vaccines remain protective against the infection. Herein, we conducted a preliminary study to evaluate the safety and immunity in an adult population who received the conventional 2 dosage-regimen of inactivated SARS-CoV-2 vaccine; with an additional intradermal ChAdOx1 nCoV-19 reciprocal dosage (1:5). An Intramuscular ChAdOx1 nCoV-19 booster was also included as a control. Immediate and delayed local reactions were frequently observed in the fractional intradermal boost, but systemic side effects were significantly decreased compared to the conventional intramuscular boost. The anti-RBD-IgG levels, the neutralising function against delta variants, and T cell responses were significantly increased after boosting via both routes. Interestingly, the shorter interval elicited higher immunogenicity compared to the extended interval. Taken together, a reciprocal dosage of intradermal ChAdOx1 nCoV-19 booster reduces systemic adverse reactions and enhances non inferiority humoral and cellular immune responses compared to a full dose of intramuscular boosting. These findings provide for an effective vaccine management during the shortages of vaccine supply.

Fig. 1. CONSORT chart of study design and volunteer recruitment.

Healthy volunteers who had been vaccinated with two doses of CoronaVac were recruited into the study. 94 participants were enrolled and randomised into 3 study groups. Group 1 participants were received a full dose of ChAdOx1 nCoV-19 intramuscularly. Group 2 and Group 3 volunteers were vaccinated intradermally with a fractional dose of the viral vector vaccine. The interval between completed primary series of CoronaVac and the booster was 4–8 weeks in Group 1 and 2 but was > 8–12 weeks in Group 3. ID intradermal, IM intramuscular.

Fig. 2. Solicited local adverse reactions at 30 min and 7 days after boosting.

Full dose of intramuscular (Group 1, blue) and one in five doses of intradermal viral vector vaccines were given 4–8 weeks after completed vaccination with two doses of inactivated SARS-CoV-2 (Group2, orange). Some of the vaccinated individuals were boosted with a fractional dose of intradermal viral vector 8–12 weeks after completing two doses of the inactivated vaccine (Group3, yellow). a The immediate local reactions were observed within 30 min after injection. b Seven days after boosting, local adverse events were recorded to compare between booster groups. c The margins of local reaction size were measured and recorded as millimetres (mm).

Fig. 3. Solicited systemic adverse reactions in 7 days after boosting.

One in five dosages of viral vector vaccine was delivered intradermally 4–8 weeks (Group2) and 8–12 weeks (Group3) after 2 doses of inactivated SARS-CoV-2 vaccines. Intramuscular viral vector boost, with a 4–8-week interval after the last vaccination (Group 1), was also included as controls. a The systemic adverse events were graded as per medical requirements and presented as percentages. The self-limited, systemic reactions were grade 1 (green). The reactions requiring medications were grade 2 (orange), and those needing medical attention were grade 3 (red). No grade 3 reactions were observed. b Systemic reactions were plotted separately to compare the three vaccinated groups.

Fig. 4. Antibody responses and neutralising function after boosting.

The fractional dose of the viral vector vaccine was delivered intradermally, 4–8 weeks (Group2) and 8–12 weeks (Group3) after two doses of inactivated SARS-CoV-2 vaccines. Intramuscular viral vector boosting was also given at 4–8 weeks after the last vaccination (Group 1). The blood samples were collected before (D0) and after the booster dose for 14, 28 days (D14, D28). a Serum samples were analyzed using CMIA to measure anti-RBD IgG. b Neutralising function of antibodies against the delta variant were tested using PRNT. Each symbol represents one participant, and the number is the geometric mean with 95% CI (n = 30–34 volunteers). Statistical significance was determined using Kruskal–Wallis test, with Dunn’s multiple comparisons test between vaccinated groups (a) and between time points (b). *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.0001, ns non significance.

Fig. 5. T cell responses after the booster.

All volunteers were previously vaccinated with two doses of inactivated SARS-CoV-2 vaccines. After 4–8 weeks (Group2) and 8–12 weeks (Group3), the fractional dose of a viral vector vaccine was delivered intradermally; as a booster dose. A full dose of intramuscular viral vector booster was also given at 4–8 weeks after their last vaccination (Group 1). Blood was taken before (D0) and after the booster dose for 14, 28 days (D14, D28). The blood samples were processed to obtain PBMCs. The fresh PBMCs were stimulated with S1 peptide pools before measuring IFN-γ secreted cells, using ELISpot. PHA, was included as a positive control. Media was used in unstimulated controls. Each symbol represents one participant, and the number is the median of each group with 95% CI (n = 30–34 volunteers). Statistical significance was determined using Kruskal–Wallis test, with Dunn’s multiple comparisons test between vaccinated groups. **p ≤ 0.01.

Fig. 6. Effector cytokine production of S1-specific CD8 + T cells after boosting.

All volunteers were previously vaccinated with two doses of inactivated SARS-CoV-2 vaccines. After 4–8 weeks (Group2) and 8–12 weeks (Group3), the fractional dose of a viral vector vaccine booster was delivered intradermally. A full dose of intramuscular viral vector booster was also given at 4–8 weeks as a control (Group 1). Blood was taken before (D0) and after the booster dose for 14, 28 days (D14, D28). The blood samples were processed to obtain PBMCs. The frozen PBMCs were thawed and stimulated with S1 peptide pools. The cells were stained and analysed using flow cytometry. a Representative flow plot shows CD8 + T cell and CD4 + T cell populations. b Percentage of CD8 + T cells before and after the booster dose. c CD8 + T cells were then selected for S1-specific IFN-γ producing cells. d Percentage of S1-specific IFN-γ producing CD8 + T cell responses at D0, D14, and D28. e Representative flow plot shows CD8 + T cells producing S1-specific TNF-α. f S1-specific TNF-α producing CD8 + T cells. Each symbol represents one participant presenting as a median with 95% CI (n = 30–34 volunteers). Statistical significance was determined using Kruskal–Wallis test, with Dunn’s multiple comparisons test between vaccinated groups. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.

Fig. 7. Effector cytokine production of S1-specific CD4 + T cells after boosting.

All volunteers were previously completed with two doses of inactivated SARS-CoV-2 vaccines. A full dose of intramuscular viral vector booster was given at 4–8 weeks after their last vaccination (Group 1). After 4–8 weeks (Group2) and 8–12 weeks (Group3), the fractional dose of a viral vector vaccine booster was delivered intradermally. Blood was taken before (D0) and after the booster dose for 14, 28 days (D14, D28). The blood samples were processed to obtain PBMCs. The frozen PBMCs were thawed and stimulated with S1 peptide pools. The cells were stained and analysed using flow cytometry. a Representative flow plot shows CD8 + T cell and CD4 + T cell populations. b Percentage of CD4 + T cells before and after the booster dose. c CD4 + T cells were then selected for S1-specific IFN-γ producing cells. d Percentage of S1-specific IFN-γ producing CD4 + T cell responses at D0, D14 and D28. e Representative flow plot shows CD4 + T cells producing S1-specific TNF-α. f S1-specific TNF-α producing CD4 + T cells. Each symbol represents one participant presenting as a median with 95% CI (n = 30–34 volunteers). Statistical significance was determined using Kruskal–Wallis test, with Dunn’s multiple comparisons test between vaccinated groups. *p ≤ 0.05; **p ≤ 0.01.