Breakthrough Infection After a Primary Series of COVID-19 Vaccination Induces Stronger Humoral Immunity and Equivalent Cellular Immunity to the Spike Protein Compared with Booster Shots

<b>Background:</b> The long-term immune implications of administering more than four doses of COVID-19 vaccine and the impact of breakthrough infections are not fully understood. <b>Research Design and Methods:</b> We conducted a follow-up cohort study on Japanese healthcare workers who received more than three doses of the BNT162b2 vaccine. We assessed both the anti-SARS-CoV-2 antibody titer and cellular immunity in 429 participants and investigated the numbers, types, and brands of COVID-19 vaccines administered, as well as the episodes of COVID-19 infections after the third dose. <b>Results:</b> Individuals who received three total doses of vaccines with BTI episodes demonstrated higher antibody titers than those who received four total doses of vaccines with no BTIs. The cellular immune responses between these two groups were comparable. <b>Conclusions:</b> These findings suggest that BTIs occurring after the primary series of COVID-19 vaccinations (first to third dose) induced humoral immunity to the spike protein that is greater than that induced by booster doses (fourth or fifth dose) and elicit cellular immunity to the spike protein comparable to that of booster doses.