The fourth vaccination with a non-SARS-CoV-2 variant adapted vaccine fails to increase the breadth of the humoral immune response.

Escape mutations in the spike protein of SARS-CoV-2 are a major reason for Omicron breakthrough infections. After basal vaccination only very low titers of Omicron neutralizing antibodies are present. However, booster vaccinations induce higher titers against the Omicron variant. The neutralization of the Delta and Omicron variants by sera obtained 6 months after 3rd vaccination and 2 weeks or 6 months after 4th vaccination with a monovalent RNA vaccine (Spikevax) was analyzed. It was observed for the Omicron variant that 6 months after the fourth vaccination, the titer returns to the same very low neutralizing capacity as 6 months after the third vaccination. The Delta variant neutralizing capacity wanes with a comparable kinetic although the titers are higher as compared to the Omicron variant. This indicates that the fourth vaccination with a monovalent vaccine based on the ancestral isolate neither affects the kinetic of the waning nor the breadth of the humoral response.