Study explores differential antibody-mediated effector functions evoked by two mRNA-based COVID-19 vaccines

By Neha MathurAug 2 2022Reviewed by Aimee Molineux

In a recent study published in Science Translational Medicine, researchers evaluated the differential humoral immune response to two coronavirus disease 2019 (COVID-19) vaccines - messenger ribonucleic acid (mRNA)-1273 and BNT162b2.

Background

In their phase III clinical trials, BNT162b2 and mRNA-1273 showed 94.1 and 95% vaccine effectiveness (VE) against the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain D614G, respectively. Against the Delta variant, their VE declined and reached 40% and 75% in the BNT162b2 and mRNA-1273 vaccinees, respectively. Researchers proposed that the observed decline could be driven by differences in vaccine formulation, dosage, or boosting delay.

However, it is yet unknown whether similar differences exist across other SARS-CoV-2 variants of concern (VOCs). Moreover, studies have shown that real-world VE could differ for vaccines based on the same platform (e..g., mRNA platform).

The emergence of SARS-CoV-2 VOCs with the potential to evade natural and vaccine-induced immunity makes it urgent to evaluate immune responses beyond vaccine-induced neutralizing antibodies. Therefore, studies must evaluate and establish the significance of additional antibody functions beyond neutralization.

Studies have shown that fragment, crystallizable (Fc)-mediated effector functions confer protection against SARS-CoV-2 after vaccination and infection. They have been associated with reducing the disease severity rather than transmission; thus, these effector functions might prevent a disease already attenuated by vaccination rather than blocking the initial infection. There is a growing body of evidence suggesting that adenoviral vaccine platforms evoke strong Fc-mediated effector functions linked to protection against human immunodeficiency virus (HIV) or malaria. However, little is known about whether mRNA vaccine platforms elicit similar effector functions to prevent COVID-19.

About the study

In the present study, researchers enrolled 73 hospital workers who had received a two-dose regimen of either mRNA-1273 or BNT162b2 to profile the functional capacity of humoral immune responses. The team measured Fc profiles and performed univariate comparisons across each antigen. Further, they log-transformed antibody titers and Z-scored each measurement. They also used Mann-Whitney U tests corrected for multiple comparisons by the Benjamini-Hochberg (BH) method.

Lastly, the researchers used multivariate analysis to further refine vaccine-specific signatures with unsupervised principal components analysis (PCA). They supervised least absolute shrinkage and selection operator (LASSO) feature selection coupled to partial least squares discriminant analysis (PLSDA) to visualize how overall antibody profiles differed across the vaccines.

Study findings

While 28 study participants had received mRNA-1273, 45 received BNT162b2, but both vaccines were administered intramuscularly. The dose amounts varied, with 30 micrograms (μg) of BNT162b2 and 100 μg of mRNA-1273 delivered three and four weeks apart. The researchers obtained samples on an average of 19 days after the second vaccination. They diagnosed prior mild SARS-CoV-2 infection in 7% and 2% of mRNA-1273– and BNT162b2-vaccinated individuals, respectively. While 48% of mRNA-1273–vaccinated reported fever following the second vaccination, 45% of BNT162b2-vaccinated participants also had a fever after receiving a second dose.

Both vaccines induced robust humoral immune responses to the ancestral SARS-CoV-2 strain and against all its VOCs, especially Beta and Delta. However, mRNA-1273 recipients had higher concentrations of receptor binding domain (RBD)- and N-terminal domain (NTD)–specific immunoglobulin (Ig)A, indicating differences in epitope-specific, Fc-mediated antibody responses. These individuals also had increased antibodies eliciting neutrophil phagocytosis and natural killer (NK) cell activation compared to the BNT162b2 recipients. RBD-specific antibody depletion highlighted the different roles of non–RBD-specific antibody effector functions induced across the mRNA vaccines, providing evidence elucidating the differential Fc-mediated effector functions.

On the PCA plot, BNT162b2-vaccinated antibody profiles accumulated on the bottom right side, whereas mRNA vaccine profiles showed separation along the PC1. Additionally, LASSO-PLSDA analysis identified two unique mRNA vaccine profiles. The mRNA-1273 vaccine profiles showed five selectively enhanced features, including NTD-specific IgA1, Fc-gamma receptors (FcγR)2A, and FcγR2B binding, and RBD-specific IgA1 and IgG2.

Conclusions

Despite their similar composition, the authors observed that  mRNA-1273 and BNT162b2 elicited immune responses with understated differences, which also provided insights into potential differences in protective immunity conferred by the two vaccines. In the current study, although both mRNA vaccines elicited similar functional antibodies to the VOCs, the BNT162b2 vaccine induced an IgM- and IgG-biased profile while the mRNA-1273 vaccine induced a more class-switched IgA- and IgG-driven profile. Three feature clusters were specifically enhanced among mRNA-1273–immunized individuals compared with BNT162b2 recipients - NTD recognition, IgA immunity, and specific antibody effector functions.

Future studies should evaluate whether these differences account for any biological variation in real-world protection. It is also unclear whether these differences are attributable to differences in vaccine composition, dosage, or delays in boosting. Nevertheless, the study data highlights the potential of mRNA vaccines to drive Fc effector functions that could be tuned to attain selective responses to particular pathogens.