Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was associated with high morbidity in patients with predominant antibody deficiency (PAD). For a study, researchers sought to determine the antibody response to the SARS-CoV-2 vaccine in PAD patients and to identify vaccine response correlations. Investigators compared the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients to matched healthy controls at baseline, 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or 2 doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and 4 to 6 weeks after an additional dose immunization, if received. PAD patients showed lower mean anti-spike antibody levels after the first round of SARS-CoV-2 vaccinations than healthy controls (140.1 vs. 547.3 U/mL; P=.02). Patients with severe original PAD (e.g., common variable immunodeficiency with autoinflammatory consequences) and secondary PAD (e.g., B-cell depletion treatment) had the lowest mean anti-spike antibody levels. Low CD4+T helper cells, low CD19+ total B cells, and low class-switched memory (CD27+IgD/M–) B cells were immune to a low anti-spike antibody response. Furthermore, a low (100 U/mL) anti-spike antibody response was linked to prior B-cell depletion therapy, both at any point in the past (odds ratio=5.5; CI, 1.5-20.4; P=.01) and proximal to vaccination (odds ratio=36.4; CI, 1.7-791.9; P=.02). In a sample of 31 PAD patients, supplementary dose immunization with an mRNA vaccine boosted mean anti-spike antibody levels (76.3 U/mL before to 1065 U/mL after the extra dosage; P<.0001). Patients with secondary and severe primary PAD, defined by low T helper cells, low B cells, and low class-switched memory B cells, had an inadequate antibody response to SARS-CoV-2 immunization, which improved in most patients after a second dose vaccination.