SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

Abstract

Background Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

The Immune Response to SARS-CoV-2 Vaccination: Insights Learned From Adult Patients With Common Variable Immune Deficiency

“…In a recent paper, a high percentage of fully immunized CVID patients developed anti-Spike IgG, at significantly lower levels than in the healthy control group (26). Our data (27) in CVID patients immunized with BNT162b2 SARS-CoV-2 mRNA vaccine contrasted with the high frequency of response reported in the cohorts illustrated above. We show that only 20% of CVID patients developed both anti-Spike IgG and IgA antibodies, and one patient responded with IgG only.…”

“…Since vaccination became available, Italian CVID patients, as well as CVID from other countries, were immunized mostly with mRNA COVID-19 vaccines. Four groups have recently reported immune responses to vaccines in patients with inborn errors of immunity, including CVID patients (24)(25)(26)(27). In the study by Hagin et al, 70% of the adult patients with predominantly antibody deficiency developed specific humoral and T-cell responses after 2 doses of SARS-CoV-2 mRNA vaccine.…”

“…Impaired maturation of B-cells might occur also at the pre-GC stage, leading to a strongly reduced number of B cells in the periphery (33). Upon vaccination, CVID patients did not generate classical and activated MBCs, but SARS-CoV-2 vaccination induced only ATM B cells with low binding capacity to Spike protein (27). It has been suggested that ATM B cells are short-lived activated cells, in the process of differentiating into plasma cells.…”

Persistent B cell memory after SARS-CoV-2 vaccination is functional during breakthrough infections

“…A third vaccine dose is necessary for all those individuals with primary and secondary immunodeficiency, immune-suppressive treatments, chemotherapy, bone marrow transplantation, or advanced age; these individuals may be unable to generate protective levels of antibodies and sufficient numbers of memory B and T cells ( Salinas et al., 2021 ; Fernandez Salinas et al., 2021 ). The strength of our paper is the demonstration that B cell immunity does not wane and reacts as expected in vaccinated subjects independently from the time of immunization and the level of serum-specific antibodies at the time of infection.…”

Patient with agammaglobulinemia produces anti-SARS-CoV-2 reactive T-cells after CoronaVac vaccine

“… [16] Interestingly, particularly for XLA patients, immunization with the mRNA-based vaccine BNT162b2 (Pfizer Biontech) resulted in a robust T-cell response comparable to healthy donors. [ 17 , 18 ]…”