Safety and Immunogenicity of the Third Booster Dose with Inactivated, Viral Vector, and mRNA COVID-19 Vaccines in Fully Immunized Healthy Adults with Inactivated Vaccine

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2), in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7-alpha, B.1.351-beta, and B.1.617.2-delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of IFN-ɣ secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.

Keywords: booster; clinical trial; inactivated vaccine; mRNA vaccine; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); third dose; viral vector vaccine.

Figure 1

Reactogenicity of a booster dose of SARS-CoV-2 vaccines within 7 days of vaccination. A booster dose of the inactivated vaccine BBIBP (A), viral vector vaccine AZD1222 (B), and mRNA vaccine BNT162b2 (C). The percentages of participants who recorded local, systemic, and any adverse events are shown on the Y-axis. Fever was defined as mild: 38.0 °C to <38.5 °C; moderate: 38.5 °C to <39.0 °C; severe: ≥39.0 °C. For local and systemic symptoms, grading was classified as mild—easily tolerated with no limitation on regular activity; moderate—some limitation of daily activity; severe—unable to perform regular daily activity [19].

Figure 2

Antibody responses against SARS-CoV-2 assay. The circulating total immunoglobulin anti-RBD of SARS-CoV-2 (U/mL) (A). The circulating IgG-specific RBD of SARS-CoV-2 (BAU/mL) (B). IgG anti-N of SARS-CoV-2 index (S/C) (C). IgA anti-S1 of SARS-CoV-2 ratio (S/C) (D). The serum samples were obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose. Lines represent GMTs (95% CI); ns indicates no statistical difference; p < 0.0001 (****).

Figure 3

Neutralization activities against wild-type and SARS-CoV-2 variants measured by surrogate virus neutralization test (sVNT). The serum samples obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose were compared. The neutralizing activities against SARS-CoV-2 Wide-type (A), Alpha (B.1.1.7) (B), Beta (B.1.351) (C), and Delta (B.1.617.2) (D) were shown. Lines represent medians with interquartile ranges (IQR); ns indicates no significant difference; p-value < 0.001 (***), 0.0001 (****).

Figure 4

SARS-CoV-2-stimulating IFN-ɣ assay. The heparinized samples were obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose and incubated in a QFN blood collection tube for 21 h. The plasma fraction was evaluated by QFN IFN-ɣ ELISA. The IFN-ɣ produced by CD4-specific Ag1 (A). The IFN-ɣ produced by CD4- and CD8-specific Ag2 (B). Lines represent medians (IQR); ns indicates no significant difference; p < 0.05 (*), 0.0001 (****).