Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant

Abstract

The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

Fig. 1. Level of specific IgG antibodies against receptor-binding domain (RBD) in different vaccination groups.

Comparison of anti-RBD against G614 SARS-CoV-2 (a) and variants of concern (b–d) presented as binding antibody units (BAU)/ml. Symbols represent individual subjects and horizontal black lines indicate the median. The cutoff-value (dashed red line) and number of fold differences of median between groups are indicated. For each group, the number of samples (N = ) and median antibody titers are shown below the X-axis. In the last group, convalescent donors (prior history of infection) were color-coded based on receiving one (purple) or two doses (blue) of mRNA vaccines. Whiskers indicate the interquartile range. Two-sided Mann–Whitney U test was used and P < 0.05 was considered statistically significant and marked with red color.

Fig. 2. Plasma neutralization activity against SARS-CoV-2 in different vaccination groups.

Plasma neutralizing titers against Beta, Delta and Omicron variants of concern compared to the G614 virus (a–d). The figure shows the comparisons of 90% neutralizing titer (NT90) values in samples collected before vaccination and after different types of vaccinations. Symbols represent individual subjects and horizontal black lines indicate the median. For each group, the number of samples (N = ) and median antibody titers are shown below the X-axis. The dashed red line indicates the titer cutoff-value (≥1:10). The inactivated vaccine 3rd dose group was color-coded based on <85 days (dark blue) or >85 days (green). In the last group, convalescent donors (prior history of infection) were color-coded based on receiving one (purple) or two doses (blue) of mRNA vaccine. Whiskers indicate the interquartile range. Two-sided Mann–Whitney U test was used and P < 0.05 was considered statistically significant and marked with red color.

Fig. 3. Specific memory B and T cell responses in different vaccination groups.

Receptor-binding domain (RBD)-specific, IgG producing memory B cell (a) and spike ectodomain 1 (S1)-specific T cell (b–d) responses in different groups of vaccinated individuals. Symbols represent individual subjects and horizontal black lines indicate the median. The cutoff-value (dashed red line) and number of fold differences of median between groups are indicated. As the median number of RBD-specific cells was 0 for two groups, the number of fold change differences compared to inactivated vaccine + one dose mRNA vaccine was estimated to be more than the highest calculated value (>73.1-fold). For each group, the number of samples (N = ) and median number of specific B cells or T cells are shown below the X-axis. In the last group, convalescent donors were color-coded based on receiving one (purple) or two doses (cyan) of mRNA vaccines. Whiskers indicate the interquartile range. Two-sided Mann–Whitney U test was used and P < 0.05 was considered statistically significant and marked with red color. IL-2: interleukin 2, IFN-γ: Interferon gamma.