SARS-Cov-2 Vaccination in Patients with Inborn Errors of Immunity in Latvia: Immune Response and Reasons for Refusal of Recommended Vaccination. Summary of the Doctoral Thesis

Abstract

Inborn errors of immunity (IEI) are a heterogeneous group of rare diseases characterized by immune system dysregulation. The most common type of IEI is predominantly antibody deficiencies (PAD), with selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID) being the most frequently observed. Vaccination is particularly important for PAD patients due to their increased risk of infections; however, their humoral immune response to vaccines may be impaired. Nevertheless, T-cell responses can provide protection even when antibody production is limited. The aim of this study is to investigate the humoral and T-cell immune response to the SARS-CoV-2 antigen in PAD patients, as well as the association of immune responses with disease phenotype and severity. Additionally, the study examines the reasons for refusal of recommended SARS-CoV-2 vaccination among IEI patients in Latvia. This dissertation is structured as a series of four sequential publications. In the first part, the prevalence of IEI in Latvia was analyzed using patient medical records. The second and third parts assessed the humoral and T-cell SARS-CoV-2-specific response in PAD (CVID and SIgAD) patients, as well as cytokine profile following SARS-CoV-2 antigen stimulation, using enzyme-linked immunosorbent assay, interferon-? release assay, and xMAP technology. In the fourth part, semi-structured interviews and thematic analysis were used to explore the reasons why IEI patients refused recommended SARS-CoV-2 vaccination. The point prevalence of IEI in Latvia in December 2020 was 7.1 per 100 000 inhabitants. The level of SARS-CoV-2-specific IgG antibodies in CVID patients was lower (5.47 ratio, IQR = 4.08) compared to healthy controls (9.43 ratio, IQR = 2.13) (p < 0.05). No statistically significant difference was found in SARS-CoV-2-specific T-cell and cytokine responses between patients with CVID, SIgAD, or the control group (p > 0.05). After SARS-CoV-2 antigen stimulation, patients with serum autoantibodies exhibited an increase in IL-4 levels, as well as initially higher IL-4 and TNF-? levels (p < 0.05). Moreover, IL-10 levels differed significantly in patients with lymphadenopathy (p < 0.05), hepatomegaly (p < 0.01), and splenomegaly (p < 0.01). Patients with a low proportion of switched memory B cells exhibited a more pronounced increase in TNF-? levels compared to other groups (p < 0.01). Five key themes influencing IEI patients’ decision to avoid vaccination were identified: (1) Fear and uncertainty, (2) Risk–benefit assessment, (3) External influence from others, (4) Distrust and unwillingness to comply, (5) Beliefs about COVID-19 vaccines and vaccination in general. The prevalence of IEI in Latvia is similar to other European countries, but Latvia has a lower proportion of PAD. The T-cell response to the SARS-CoV-2 antigen in CVID and SIgAD patients did not differ from that of the control group, but the humoral response in CVID patients was reduced. Changes in the levels of several cytokines (IL-4, IL-10, IL-21, TNF-?) following SARS-CoV-2 antigen stimulation were associated with clinical or immunological disease phenotypes. While most reasons for vaccine hesitancy among IEI patients were similar to those observed in the general population, disease-specific factors were also identified: the belief that vaccination is contraindicated in patients with immunodeficiency, as well as the perception that SARS-CoV-2 vaccination is unnecessary for those receiving immunoglobulin replacement therapy.