Pfizer-BioNTech and Moderna mRNA Vaccines Elicit Different Antibody Responses

There are currently 3 coronavirus vaccines approved by the US Food and Drug Administration (FDA) under Emergency Use Authorization. These are the Pfizer-BioNTech, Moderna, and Janssen vaccines.

In December 2021, the US Centers for Disease Control and Prevention (CDC) recommended the Pfizer-BioNTech and Moderna mRNA vaccines over the Janssen citing concerns over blood clotting and the superior protection provided by the mRNA vaccines.

However, the 2 US-approved mRNA vaccines are not interchangeable. New research, published yesterday in Science Translational Medicine, found notable differences in the epitope-specific responses of the Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines. The distinct antibody and killer T-cell responses elicited suggest a “mix-and-match” heterologous boosting approach may offer the most robust protection.

The study included 73 participants, 28 of whom received the Moderna vaccine and 45 who received Pfizer-BioNTech. Because real-world data suggests the 2 mRNA vaccines differ in their ability to prevent infection, the investigators analyzed whether they elicited similar Fc profiles.

Fc receptors (FcRs) bind to antibodies that have attached to infectious pathogens, stimulating the antibody to generate an adequate immune response to the antigen. Fc-mediated effector functions have been shown to enhance protection against COVID-19 after vaccination or infection.

Both mRNA vaccines induced strong humoral immune responses to SARS-CoV-2 variants of concern, with equivocal IgG and IgM binding titers. Differences emerged in the epitope-specific responses, with greater receptor-binding domain (RBD)- and N-terminal domain-specific IgA concentrations in Moderna vaccine recipients. Moderna recipients also had increased natural killer T-cell activation and antibodies eliciting neutrophil antibody depletion.

RBD-specific antibody depletion emphasized the prevalence of non-RBD-specific antibody effector function, deployed at different concentrations in the Pfizer-BioNTech and Moderna vaccines. The investigators believe this explains the different Fc-mediated effector concentrations observed between the 2 mRNA vaccines.

Univariate comparisons across each antigen and Fc-profile measurements revealed FcR-binding antibodies for all 3 VOCs were comparable between Pfizer-BioNTech and Moderna. However, there were elevated IgA concentrations in Moderna recipients, and elevated IgM and IgG levels in Pfizer-BioNTech recipients.

As the Delta and Omicron variants caused unprecedented numbers of breakthrough infections, causing vaccine protection against infection to plumet, new vaccination strategies need to be examined. The different epitope recognition and antibody mediated functional properties observed in the Pfizer-BioNTech and Moderna vaccines suggest mixing and matching initial vaccine series and booster shots may provide the highest level of protection.

Previous studies have confirmed that heterologous boosting is not only safe, but may actually increase immune response. The FDA and CDC authorized mix-and-match boosting last fall, but have yet to formally recommend heterologous booster doses over homologous boosters.