Effective vaccine coverage is urgently needed to tackle the COVID-19 pandemic. Inactivated vaccines have been introduced in many countries for emergency usage, but have only provided limited protection. Heterologous vaccination is a promising strategy to maximise vaccine immunogenicity. Here, we conducted a phase I, randomised control trial to observe the safety and immunogenicity after an intradermal boost, using a fractional dosage (1:5) of BNT162b2 mRNA vaccine in healthy participants in Songkhla, Thailand. In total, 91 volunteers who had been administered with two doses of inactivated SARS-CoV-2 (CoronaVac) were recruited into the study, and then randomised (1:1:1) to received different regimens of the third dose. An intramuscular booster with a full dose of BNT162b2 was included as a conventional control, and a half dose group was included as reciprocal comparator. Both, immediate and delayed adverse events following immunisation (AEFI) were monitored. Humoral and cellular immune responses were examined to observe the booster effects. The intradermal booster provided significantly fewer systemic side effects, from 70% down to 19.4% (p < 0.001); however, they were comparable to local reactions with the conventional intramuscular booster. In the intradermal group after receiving only one fifth of the conventional dosage, serum Anti-RBD IgG was halved compared to the full dose of an intramuscular injection. However, the neutralising function against the Delta strain remained intact. T cell responses were also less effective in the intradermal group compared to the intramuscular booster. Together, the intradermal booster, using a fractional dose of BNT162b2, can reduce systemic reactions and provides a good level and function of antibody responses compared to the conventional booster. This favourable intradermal boosting strategy provides a suitable alternative for vaccines and effective vaccine management to increase the coverage during the vaccine shortage.

Depending on the intensity and duration of SARS-CoV-2 infection, the host immune response plays a significant role in immunological protection. Here, we studied the regulatory T-cell (Treg) response in relation to kinetic change and cytokine production in patients with mild COVID-19. Nineteen SARS-CoV-2-positive patients were recruited, and blood was collected at four time points, i.e., seven days after admission, after discharge, and one and three months after recovery. CD3⁺CD4⁺CD25⁺CD127^low was marked as the Treg population, with IL-10 and TGF-β used to study cytokine-producing Tregs. IFN-γ-producing CD8⁺ T cells were observed for an effector response. The Treg percentage in patients with mild COVID-19 increased during hospitalization compared to during the recovery period. Peripheral blood mononuclear cells (PBMCs) were quantified, and the T-cell response was characterized by re-stimulation with S1 and N peptides. IL-10 and TGF-β were produced by CD25⁺CD127^low T cells during the active infection phase, especially with N peptide stimulation. Compared to N peptide stimulation, S1 peptide stimulation provided superior IFN-γ-secreting CD8⁺ T-cell responses. Our results suggest that while IFN-γ⁺CD8⁺ T cells confer antiviral immunity, cytokine-producing Tregs may have a substantial role in regulating inflammatory responses in mild SARS-CoV-2 infection. Novel vaccine development may also consider enhancing T-cell repertoires.

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.

A practical booster vaccine is urgently needed to control the coronavirus disease (COVID-19) pandemic. We have previously reported the safety and immunogenicity of a fractional intradermal booster, using the BNT162b2 mRNA vaccine in healthy volunteers who had completed two doses of inactivated SARS-CoV-2 vaccine. In this study, an intramuscular booster at full dosage was used as a control, and a half-dose vaccination was included for reciprocal comparison. Detailed T-cell studies are essential to understand cellular responses to vaccination. T-cell immunity was examined using S1 peptide restimulation and flow cytometry. The fractional dose (1:5) of the BNT162b2 mRNA vaccine enhanced antigen-specific effector T-cells, but the responses were less remarkable compared to the intramuscular booster at full dosage. However, the intradermal regimen was not inferior to the intramuscular booster a month after boosting. An intradermal booster using only one-fifth of the standard dosage could provide comparable T-cell responses with the fractional intramuscular booster. This work confirms the efficacy of intradermal and fractional vaccination in terms of T-cell immunogenicity in previously immunised populations.

This study aimed to evaluate the antibody and cellular responses to different coronavirus 2019 (COVID-19) vaccination regimens in patients with cirrhosis and to assess the antibody response after a vaccine booster. We conducted a prospective observational study of 89 patients with cirrhosis and 41 healthy volunteers who received two COVID-19 vaccine doses. Next, we prospectively evaluated 24 patients with cirrhosis who received a booster COVID-19 vaccine dose. In both studies, blood samples were collected before and 4 weeks after vaccination, and anti-spike receptor-binding domain protein IgG levels, T-cell phenotypes, and effector functions were assessed. The heterologous vaccine regimen (CoronaVac [SV]/AstraZeneca [AZ]) produced a better antibody response and CD4+IFNg+ T cell response compared to homogeneous vaccine regimens. The antibody response after the second dose of the vaccine was similar in patients with cirrhosis and healthy volunteers. Patients who received a booster dose of the mRNA vaccine had significantly increased antibody titers compared to those who received the AZ vaccine. In patients with cirrhosis, heterologous vaccination with SV/AZ resulted in a better immune response than the AZ/AZ and SV/SV regimens. Moreover, a booster dose of the mRNA vaccine led to a greater increase in antibody titers compared to the AZ vaccine.

Reports on vaccine immunogenicity in patients with systemic autoimmune rheumatic diseases (SARDs) have been inconclusive. Here, we report the immunogenicity of heterologous prime-boost with an inactivated vaccine followed by an adenoviral vector vaccine in patients with SARDs using anti-RBD antibodies, neutralizing capacity against Omicron BA.2 [plaque-reduction neutralization test (PRNT)], T cell phenotypes, and effector cytokine production at 4 weeks after vaccination. SARD patients had lower median (IQR) anti-RBD-IgG levels and neutralizing function against the Omicron BA.2 variant than the healthy group (p = 0.003, p = 0.004, respectively). T cell analysis revealed higher levels of IFN-γ- and TNF-α-secreting CD4 + T cells (p < 0.001, p = 0.0322, respectively) in SARD patients than in the healthy group. Effector cytokine production by CD8 + T cells was consistent with Th responses. These results suggest that this vaccine regimen revealed mildly impaired humoral response while preserving cellular immunogenicity and may be an alternative for individuals for whom mRNA vaccines are contraindicated.