Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles

Abstract

The successful development of several 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, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

Figure.1. mRNA-1273 and BNT162b2 COVID-19 vaccines induce similar SARS-CoV-2 D614G WT antibody profiles.

(A) Heatmap summarizes SARS-Cov-2 WT S, RBD, NTD, S1, and S2-specific IgG1, IgG2, IgG3, IgA1, and IgM titers, Fc measurements, and functional assays such, Antibody-dependent complement deposition (ADCD), cellular phagocytosis (ADCP) and neutrophil phagocytosis (ADNP), and NK cell activation (ADNKA, CD107a surface expression, and MIP-1β or IFNγ production) for each subject in BNT162b2 or mRNA-1273 arm. Titers and FcRs were first logtransformed and all measurements were z-scored. (B-C) Univariate comparisons of (B) antibody titers and FcRs binding for SARS-CoV-2 WT S, RBD, NTD, S1 and S2, as well as (C) S-specific antibody-mediated effector functions, such as ADCD, ADCP, ADNP and ADNKA, between BNT162b2 (blue) and mRNA-1273 (red) vaccines recipients. Mann-Whitney U-test corrected for multiple comparisons by the Benjamini-Hochberg (BH) method, was used. The adjusted p < 0.001 ***, p < 0.01 **, p < 0.05 *. (D) The 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, FcRs, and functional measurements. All shown links are positive correlations.

Figure.2. mRNA-1273 and BNT162b2 vaccines induce a comparable antibody profile across alpha, beta, and gamma SARS-CoV-2 VOCs.

(A-B) Univariate comparisons of antibody titers and FcRs binding for SARS-CoV-2 VOCs, such as Alpha B.1.1.17, Beta B.1.351 and Gamma P1, as well as (B) antibody-dependent, cellular (ADCP) and neutrophil phagocytosis (ADNP), in BNT162b2 (blue) and mRNA-1273 (red) vaccinated individuals. Mann-Whitney U-test corrected for multiple comparison with the Benjamini-Hochberg (BH) method was used. The adjusted p < 0.001 ***, p < 0.01 **, p < 0.05 *. (C) LASSO-PLSDA model 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, FcRs, and functional measurements. All shown links are positive correlations.

Figure.3. mRNA vaccines are able to induce the high level of Spike-specific antibody binding to FcRs across all SARS-CoV-2 VOCs

(A-C) Univariate comparisons of (A) RBD-specific, (B) S-specific IgG1, IgG2, IgG3, IgA1, and IgM titers and FcR bindings across SARS-CoV-2 WT and VOCs, such as Alpha B.1.1.7, beta B.1.351, Gamma P1, Kappa B.1.617.1 and Delta B.1.617.2, between the BNT162b2 (blue) and mRNA-1273 (red) vaccine recipients and convalescent individuals (green). (C) Delta B.1.617.2 S- and RBD- specific antibody titers and FcR binding between BNT162b2 (blue) and mRNA-1273 (red) vaccinees and convalescent individuals (green). Comparisons were made for each variant using Wilcoxon rank-sum test and corrected for multiple comparison using the BenjaminiHochberg (BH) method. The adjusted p < 0.001 ***, p < 0.01 **, p < 0.05 *.

Figure.4.. RBD-specific antibody depletion differently influences the antibody-mediated monocytes and neutrophils phagocytosis across SARS-CoV-2 VOCs.

(A) Comparisons of antibody-mediated cellular (ADCP) and neutrophil (ADNP) phagocytosis across SARS-CoV-2 WT and VOC, such as Alpha B.1.1.7, beta B.1.351, Gamma P1, Epsilon B.1.427 and Iota B.1426 Spikes, between pre-depletion (RBD+) and post RBD-specific antibody depletion (RBD-) serum samples across from BNT162b2 (blue) and mRNA-1273 (red) vaccine recipients and convalescent individuals (green). The paired t-test corrected for multiple comparison by the Benjamini-Hochberg (BH) method was used. The adjusted p < 0.001 ***, p < 0.01 **, p < 0.05 *.