Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response in adults with predominantly antibody deficiency

Abstract

Background: Patients with predominantly antibody deficiency (PAD) have lower anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody levels after initial 2-dose SARS-CoV-2 vaccination than healthy controls do; however, the anti-spike antibody responses and neutralization function in patients with PAD following subsequent immunizations remain understudied.

Objective: We sought to characterize anti-spike antibody responses in adults with PAD over the course of 5 SARS-CoV-2 vaccine doses and identify diagnostic and immunophenotypic risk factors for low antibody response.

Methods: We evaluated anti-spike antibody levels in 117 adult patients with PAD and 192 adult healthy controls following a maximum of 5 SARS-CoV-2 immunizations. We assessed neutralization of the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant and analyzed infection outcomes.

Results: The patients with PAD had significantly lower mean anti-spike antibody levels after 3 SARS-CoV-2 vaccine doses than the healthy controls did (1,439.1 vs 21,890.4 U/mL [P < .0001]). Adults with secondary PAD, severe primary PAD, and high-risk immunophenotypes had lower mean anti-spike antibody levels following vaccine doses 2, 3, and/or 4 but not following vaccine dose 5. Compared with patients with mild and moderate PAD, patients with severe PAD had a higher rate of increase in anti-spike antibody levels over 5 immunizations. A strong positive correlation was observed between anti-spike antibody levels and neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Most infections were managed on an outpatient basis.

Conclusions: In all of the patients with PAD, anti-spike antibody levels increased with successive SARS-CoV-2 immunizations and were correlated with neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Secondary PAD, severe primary PAD, and high-risk immunophenotypes were correlated with lower mean anti-spike antibody levels following vaccine doses 2 through 4. Patients with severe PAD had the highest rate of increase in anti-spike antibody levels over 5 immunizations. These data suggest a clinical benefit to sequential SARS-CoV-2 immunizations, particularly among high-risk patients with PAD.

Keywords: CD19+ B cells; CD4+ T cells; Omicron BA.5 variant; Predominantly antibody deficiency; SARS-CoV-2; anti-spike antibody; class-switched memory B cells; common variable immunodeficiency; neutralization; rituximab.

Fig 1

Mean anti-spike antibody levels following 3 SARS-CoV-2 vaccine doses in adults with PAD versus in healthy controls. SARS-CoV-2 anti-spike antibody levels (in U/mL), shown in log scale as geometric means, adjusted for time from last vaccination. A, Levels compared between healthy adult controls (HCs) (gray circles [n = 192]) and all adult patients with PAD (red circles [n = 117]) after vaccination doses 1 to 3, as indicated. B, Levels compared between adult HCs (gray circles [n = 192]) and adult patients with primary PAD (red circles [n = 104]) after vaccination doses 1 to 3, as indicated. Symbols represent unique individuals, bars represent adjusted geometric means (95% CIs) of total indicated patients (n), and shading represents the assay’s lower limit of reactivity. ∗P < .05 by analysis of covariance analysis.

Fig 2

Mean anti-spike antibody levels following 5 SARS-CoV-2 vaccine doses, compared between patients with PAD by clinical disease type. SARS-CoV-2 anti-spike antibody levels (in U/mL), shown in log scale as geometric means, adjusted for time from last vaccination. A, Levels compared between adult patients with secondary PAD (purple circles [n = 13]), and adult patients with primary PAD (red circles [n = 104]), after vaccination doses 2 to 5, as indicated. B, Symbols with bars represent adjusted geometric means (±95% CIs) of the patients with mild (green circles), moderate (orange circles), and severe (red circles) primary PAD, and the dotted line indicates mean SARS-CoV-2 anti-spike antibody levels in adult healthy controls (HCs) following vaccine dose 3 as a reference. C, Patients segregated by disease severity after vaccine dose 2 (n = 57), dose 3 (n = 64), dose 4 (n = 47), and dose 5 (n = 26) in adult patients with mild (green circles [n = 24]), moderate (orange circles [n = 33]), and severe (red circles [n = 47]) primary PAD. Symbols represent unique individuals, bars represent adjusted geometric means (±95% CIs) of the total indicated patients (n), respectively; shading represents the assay’s lower limit of reactivity, and the dotted line indicates mean SARS-CoV-2 anti-spike antibody levels in adult healthy controls (HCs) following vaccine dose 3 as a reference. ∗P < .05 by analysis of covariance analysis. In post hoc analysis, statistical significance was driven by differences between the groups with severe versus mild and moderate PAD.

Fig 3

Mean anti-spike antibody levels following 5 SARS-CoV-2 vaccine doses, compared between patients with PAD by immunophenotype. SARS-CoV-2 anti-spike antibody levels (in U/mL) in adult patients with PAD, shown in log scale as geometric means, adjusted for time from last vaccination, at postvaccine time points, as indicated. Segregated by patients with PAD with absolute B-cell counts higher than 90 cells/μL (blue circles and line) and absolute B-cell counts of 90 cells/μL or lower (orange circles and line) (A), absolute T-cell counts higher than 419.0 cells/μL (blue circles and line) and absolute T-cell counts of 419.0 cells/μL or lower (orange circles and line) (B), and class-switched memory B-cell frequency of at least 2.0% of CD19⁺ cells (blue circles and line) and class-switched memory B-cell frequency less than 2.0% of CD19⁺ cells (orange circles and line) (C). Symbols with bars represent adjusted geometric means (±95% CIs) of the total set of patients, and the dotted line indicates mean SARS-CoV-2 anti-spike antibody levels in adult healthy controls (HCs) following vaccine dose 3 as a reference. ∗P < .05 by analysis of covariance analysis.

Fig 4

Mean anti-spike antibody levels following 5 SARS-CoV-2 vaccine doses, compared between patients with PAD by clinical confounder. SARS-CoV-2 anti-spike antibody levels (in U/mL) in adult patients with primary PAD, shown in log scale as geometric means, adjusted for time from last vaccination, at postvaccine time points, as indicated. Segregated by patients with PAD who received prior rituximab therapy (orange circles and line) and did not receive prior rituximab therapy (blue circles and line) (A), received prior IgRT (orange circles and line) and did not receive prior IgRT (blue circles and line) (B), received prior tixagevimab and cilgavimab (Evusheld [orange circles and line]) and did not receive prior Evusheld (blue circles and line) (C), and had prior SARS-CoV-2 infection (orange circles and line) and did not have prior SARS-CoV-2 infection (blue circles and line) (D). Symbols with bars represent adjusted geometric means (±95% CIs) of the total set of patients, and the dotted line indicates mean SARS-CoV-2 anti-spike antibody levels in adult healthy controls (HCs) following vaccine dose 3 as reference. ∗P < .05 by analysis of covariance analysis.

Fig 5

Linear mixed model of SARS-CoV-2 vaccine response among patients with PAD by clinical disease severity. Linear mixed model of mean anti–SARS-CoV-2 spike antibody levels following vaccine doses, as indicated, in patients with primary PAD, stratified by clinical disease severity (mild in green, moderate in orange, and severe in red). Shaded areas represent ±95% CIs. Further adjustment for time since vaccination, use of tixagevimab and cilgavimab, IgRT (mg/kg per month), and prior SARS-CoV-2 infection did not significantly change these findings (see Table E3).