Complement activation by SARS-CoV- 2 vaccines and the effect of anti-vector antibodies

ABSTRACT

Novel vaccine platforms against SARS-CoV- 2 are in large-scale use, but interactions of complement with the 3 major vaccines have been little studied. In this work, we studied whether ChAdOx1 (AstraZeneca), mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines activate the human complement system. Complement C3 activation by the vaccine preparations was determined by Western blotting (WB) and the terminal complement complex (TCC) levels by ELISA in sera from individuals with different vaccination status or disease history. Antibody (IgG) titers against ChAdOx1 vector and the human adenovirus 2 hexon (hAdV2) protein were measured by EIA, and IgGs from high-and low-titre sera were purified by MelonGel filtration ChAdOx1 strongly activated C3 and TCC in a dose-dependent manner. Activation was inhibited by Mg-EGTA indicating classical pathway activation. Sera containing antibodies to hAdV2 or with vaccination-induced antibodies against ChAdOx1 enhanced complement activation in a dose-dependent manner. mRNA-1273 activated C3, but to a lesser extent. Activation occurred via the AP but did not lead to TCC formation. No C3 activation or TCC formation by BNT162b2 was detected. The three studied vaccines differed in their ability to activate complement. ChAdOx1 induced a robust complement activation, which correlated with the amount of anti-vector antibodies in the individual sera. Surprisingly, the two lipid nanoparticle mRNA vaccines (mRNA-1273 and BNT162b2) differed in their ability to activate complement. In addition to the role of complement as an endogenous adjuvant in vaccination, complement activation by vaccines may be involved in potential side effects or in determining variations in vaccine efficacy.