mRNA-1273 and BNT162b2 COVID-19 vaccines elicit antibodies with differences in Fc-mediated effector functions

Abstract

The successful development of several coronavirus disease 2019 (COVID-19) vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants that are able to evade vaccine-induced neutralizing antibodies, real-world vaccine efficacy has begun to show differences across the two approved mRNA platforms, BNT162b2 and mRNA-1273; these findings suggest that subtle variation in immune responses induced by the BNT162b2 and mRNA-1273 vaccines may confer differential protection. Given our emerging appreciation for the importance of additional antibody functions beyond neutralization, we profiled the postboost binding and functional capacity of humoral immune responses induced by the BNT162b2 and mRNA-1273 vaccines in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to variants of concern. However, differences emerged across epitope-specific responses, with higher concentrations of receptor binding domain (RBD)- and N-terminal domain-specific IgA observed in recipients of mRNA-1273. Antibodies eliciting neutrophil phagocytosis and natural killer cell activation were also increased in mRNA-1273 vaccine recipients as compared to BNT162b2 recipients. RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector functions induced across the mRNA vaccines. These data provide insights into potential differences in protective immunity conferred by these vaccines.

Fig. 1.

mRNA-1273 and BNT162b2 COVID-19 vaccines induce similar SARS-CoV-2 D614G-specific antibody profiles. (A) A heatmap is shown summarizing SARS-CoV-2 D614G spike protein, RBD, NTD, S1, and S2-specific IgG1, IgG2, IgG3, IgA1, and IgM titers, Fc measurements, and functional assays (antibody-dependent complement deposition (ADCD), cellular phagocytosis (ADCP) and neutrophil phagocytosis (ADNP), and NK cell activation (ADNKA, CD107a surface expression, and MIP-1β or IFN-γ production) for each participant in the mRNA-1273 (n = 28) and BNT162b2 (n = 45) vaccine arms of the study. Titers and FcRs were first log-transformed, and all measurements were z-scored. (B and C) Univariate comparisons between BNT162b2 (blue) and mRNA-1273 (red) vaccine recipients are shown for (B) antibody titers and FcγR binding for SARS-CoV-2 D614G spike protein-, RBD-, NTD-, S1-, and S2-specific antibodies, as well as (C) spike protein-specific antibody-mediated effector functions. Vertical bars in (B) depict median values. Mann-Whitney U-tests corrected for multiple comparisons by the Benjamini-Hochberg (BH) method were used. The adjusted p < 0.001 ***, p < 0.01 **, p < 0.05 *. (D) A least Absolute Shrinkage Selection Operator (LASSO) was used to select antibody features that contributed most to the discriminate subjects vaccinated with BNT162b2 or mRNA-1273. A partial least square discriminant analysis (PLSDA) was used to visualize samples. LASSO selected features were ranked based on their Variable of Importance (VIP) score, and the loadings of the latent variable 1 (LV1) were visualized in a bar graph. (E) A co-correlate network of the LASSO selected features was built using a threshold of absolute Spearman rho greater than 0.7 and BH-adjusted p-value lower than 0.01. Nodes were colored based on the type of measurement; titers are shown in yellow, FcγRs are shown in green, and functional measurements are shown in gray. All shown links are positive correlations.

Fig. 2.

mRNA-1273 and BNT162b2 vaccines induce a comparable antibody profile across Alpha, Beta, and Gamma SARS-CoV-2 VOCs. (A and B) Univariate comparisons of (A) antibody titers and FcγR binding for SARS-CoV-2 Alpha, Beta, and Gamma VOCs as well as (B) ADCP and ADNP activity are shown for BNT162b2 (blue) and mRNA-1273 (red) vaccinated individuals. Vertical bars in (A) depict median values. Mann-Whitney U-tests corrected for multiple comparisons with the Benjamini-Hochberg (BH) method were used. Adjusted p-values are indicated as ***p < 0.001, **p < 0.01, and *p < 0.05. (C) A LASSO-PLSDA model is shown including all variant measurements. LASSO selected features were ranked based on their Variable of Importance (VIP) score, and the loadings of the latent variable 1 (LV1) were visualized in a bar graph. (D) A co-correlate network of the LASSO-selected features was built using a threshold of absolute Spearman rho greater than 0.7 and BH-adjusted p-value lower than 0.01. Nodes were colored based on the type of measurement; titers are shown in yellow, FcγRs are shown in green, and functional measurements are shown in gray. All shown links are positive correlations.

Fig. 3.. mRNA vaccines are able to induce high spike protein-specific antibody binding to FcRs across all SARS-CoV-2 VOCs.

Univariate comparisons between BNT162b2 (blue) vaccine recipients, mRNA-1273 (red) vaccine recipients, and convalescent individuals (green) are shown for RBD-specific (top row) and full-length spike (S) protein-specific (bottom row) IgG1, IgG2, IgG3, IgA1, and IgM titers as well as FcγR binding. Comparisons are shown for SARS-CoV-2 D614G and indicated VOCs. Lines connect median values for each cohort. Comparisons were made for each variant using Wilcoxon rank-sum tests and corrected for multiple comparisons using the Benjamini Hochberg (BH) method. T Adjusted p-values are indicated as ***p < 0.001, **p < 0.01, and *p < 0.05.

Fig. 4.

RBD-specific antibody depletion influences antibody-mediated monocyte and neutrophil phagocytosis following vaccination and infection. (A) Antibody-mediated cellular phagocytosis (ADCP), (B) antibody-mediated neutrophil phagocytosis (ADNP), (C) antibody-mediated NK activation (ADNKA) and (D) antibody-mediated complement deposition (ADCD), activity specific to the spike protein were compared across SARS-CoV-2 D614G and Alpha, Beta, Gamma, and Delta variants. Comparisons were made between pre-depletion (RBD+) and post-RBD-specific antibody depletion (RBD-) serum samples from BNT162b2 (blue) and mRNA-1273 (red) vaccine recipients and convalescent individuals (green). All data were Z-scored. A paired t test, corrected for multiple comparisons by the Benjamini-Hochberg (BH) method, was used to identify differences in non-depleted and depleted plasma. Adjusted p-values are indicated as ***p < 0.001, **p < 0.01, and *p < 0.05.