Background/Objectives: Understanding the behavior of B cells during infection and vaccination is important for determining protective humoral immunity. We evaluated the profile of humoral immunity and B cell pool in individuals who were acutely infected with SARS-CoV-2, recovered from COVID-19, or received two doses of the AZD1222 vaccine. Methods: Peripheral blood mononuclear cells (PBMCs) from these individuals were subjected to in vitro stimulation to promote differentiation of B cells into antibody-secreting cells (ASC), and the ELISpot evaluated the abundance of pan and SARS-CoV-2 Spike S1-reactive IgG+ ASC. Stimulated PBMCs were characterized using flow cytometry. Culture supernatants were assessed for soluble B cell-activating factors. The IgA and IgG for the S1 were evaluated by ELISA. Results: The recovered individuals displayed a robust S1 ASC compared to acute and vaccinated. Although the frequency of total B cells or B-cell subsets did not vary among the groups, plasma cells were increased in naïve and double-negative B cells in the acute, recovered, and vaccinated. Similar IgA and IgG production appeared to be present in the acute and recovered. During vaccination, more IgG is produced than IgA. In acute patients, BAFF levels were positively correlated with total B cells and IgG+ plasma cells, but negatively correlated with IgA+ plasma cells. Conclusions: The vaccination and natural infection with COVID-19 induce a differential profile and functionality of B cells. We suggest that new vaccines against COVID-19 incorporate molecular adjuvants that regulate B lymphocyte functionality and consider the beneficial aspects of the IgA response in addition to IgG.