Humoral immune response characterization of heterologous prime-boost vaccination with CoronaVac and BNT162b2

Abstract

Background: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven to be a successful strategy for prevent severe infections. CoronaVac and BNT162b2 are the most used vaccines worldwide, but their use in heterologous vaccination schedules is still subjected to evaluation.

Methods: Fifty healthy individuals who received heterologous prime-boost vaccination with CoronaVac and BNT162b2 were enrolled in a post-vaccination serological follow-up longitudinal prospective study. We evaluated specific serum anti-receptor binding domain (RBD) IgG antibody levels, and their capacity to block RBD-ACE2 interaction with a surrogate neutralization assay. In 20 participants, we assessed antibody binding kinetics by surface plasmon resonance, and Fc-mediated functions by ADCC and ADCP reporter assays.

Results: Our baseline seronegative cohort, displayed seroconversion after two doses of CoronaVac and an important decrease in serum anti-RBD IgG antibodies levels 80 days post-second dose. These levels increased significantly early after the third dose with BNT162b2, but 73 days after the booster we found a new fall. Immunoglobulin functionalities showed a similar behavior.

Conclusions: The heterologous prime-boost vaccination with CoronaVac and BNT162b2 generated an impressive increase in serum anti-RBD specific antibody levels followed by a drop. Nevertheless, these titers remained well above those found in individuals only vaccinated with CoronaVac in the same elapsed time. Serum IgG levels showed high correlation with antibody binding analysis, their capacity to block RBD-ACE2 interaction, and Fc-effectors mechanisms. Our work sheds light on the humoral immune response to heterologous vaccination with CoronaVac and BNT162b2, to define a post-vaccination correlate of protection against SARS-CoV-2 infection and to discuss the scheduling of future vaccine boosters in general population.

Keywords: Binding kinetics; Fc-mediated functions; Heterologous vaccination; Humoral immune response; SARS-CoV-2.

Fig. 1

Serum anti-RBD IgG levels at different times in the cohort follow-up. Serum samples of the same 50 individuals that received heterologous prime-boost vaccination with CoronaVac and BNT162b2 were evaluated at different times, except for t₄ where 41 of them were studied. Bars and numbers above them represent the median values of each time point and numbers in parentheses are the interquartile ranges. The number of individuals evaluated at each time point is presented on the base of each bar. Bars corresponding to serum samples obtained after the third dose are presented in grey. Comparisons between groups were carried out using Friedman's test and Dunn's multiple comparison post-hoc test. ^**p = 0.01–0.001, ^***p < 0.001. BAU, binding antibody units.

Fig. 2

Comparison between serum anti-RBD IgG levels and their capacity to block RBD-ACE2 interaction at different times in the cohort follow-up. Lines show the individual evolution over time of the serum anti-RBD IgG levels (A) and their capacity to block RBD-ACE2 interaction (B) for every participant in the cohort (n = 50). Numbers represents median values with the interquartile range in parentheses. Both datasets show a similar behavior over time in most of the evaluated cases. Comparisons between groups were carried out using Friedman's test and Dunn's multiple comparison post-hoc test. ^**p = 0.01–0.001, ^***p < 0.001. BAU, binding antibody units; AU, arbitrary units.

Fig. 3

Comparison of anti-RBD total antibodies measured by SPR and anti-RBD IgG measured by ELISA, in serum samples of 20 individuals selected from the cohort and collected at different times. The levels of total specific antibodies measured by SPR after 1 min dissociation are presented at different times with grey lines showing the individual evolution over time, and the corresponding sensorgrams as stacked insets on the left (A). Sensorgrams are presented after subtracting pre-vaccination data collected at t₀ and for clarity, curves are presented with the same color code as in Fig. S5. For comparison, the results obtained by ELISA with the same 20 selected individuals are presented (B) with the same representation as in Fig. 2. Both in SPR and ELISA, pre-vaccination data (at t₀) correspond to zero (not shown due to logarithmic representation of y-axis). RU, resonance units; BAU, binding antibody units.

Fig. 4

Fc-mediated functions and RBD-ACE2 binding inhibition of specific serum anti-RBD immunoglobulins. Figure shows ADCC (A) and ADCP (B) Fc-mediated functions of serum anti-RBD immunoglobulin in 20 individuals early after two doses of Coronavac (t₁) and after heterologous booster with BNT162b2 (t₃). Endpoint titers were calculated by interpolating the reciprocal of serum dilutions to baseline, whose values were determined for each plate as the mean signal in absence of serum plus three standard deviations. Inhibition of RBD-ACE2 binding (C) and serum anti-RBD IgG levels (D) were measured in the same samples, showing a similar behavior over time. Comparison of the RBD-ACE2 binding inhibition activity against SARS-CoV-2 Wuhan and Omicron variants were carried out by sVNT in these 20 samples (E). Numbers represents median values and the interquartile range (in parentheses). Comparisons between groups were carried out using Wilcoxon test. *p < 0.05, ^**p = 0.01–0.001, ^***p < 0.001. BAU, binding antibody units; AU, arbitrary units.