Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity.

PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID). METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed. RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines. CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

Congenital and acquired defects of immunity: An ever-evolving story.

Inborn errors of immunity (IEI), also referred to as primary immunodeficiencies (PID), are disorders that, for the most part, result from mutations in genes involved in immune host defense and immune regulation. With the increased availability of high-throughput DNA sequencing and improved genomic data interpretation, the number of newly identified genes associated with IEI has exponentially increased over the last decade. Here, we focus on the newly described IEI associated with severe COVID-19 and SASH3 deficiency, the most recently reported IEI with impaired T-cell receptor (TCR) signaling.

Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity.

BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity.

BACKGROUND: In mid-December 2020, Israel started a nationwide mass vaccination campaign against coronavirus disease 2019 (COVID-19). In the first few weeks, medical personnel, elderly citizens, and patients with chronic diseases were prioritized. As such, patients with primary and secondary immunodeficiencies were encouraged to receive the vaccine. Although the efficacy of RNA-based COVID-19 vaccines has been demonstrated in the general population, little is known about their efficacy and safety in patients with inborn errors of immunity (IEI). OBJECTIVE: Our aim was to evaluate the humoral and cellular immune response to COVID-19 vaccine in a cohort of patients with IEI. METHODS: A total of 26 adult patients were enrolled, and plasma and peripheral blood mononuclear cells were collected from them 2 weeks following the second dose of Pfizer-BioNTech COVID-19 vaccine. Humoral response was evaluated by testing anti-SARS-CoV-2 spike (S) receptor-binding domain and antinucleocapsid antibody titers and evaluating neutralizing ability by inhibition of receptor-binding domain-angiotensin-converting enzyme 2 binding. Cellular immune response was evaluated by using ELISpot, estimating IL-2 and IFN-γ secretion in response to pooled SARS-CoV-2 S- or M-peptides. RESULTS: Our cohort included 18 patients with a predominantly antibody deficiency, 2 with combined immunodeficiency, 3 with immune dysregulation, and 3 with other genetically defined diagnoses. Twenty-two of them were receiving immunoglobulin replacement therapy. Of the 26 patients, 18 developed specific antibody response, and 19 showed S-peptide-specific T-cell response. None of the patients reported significant adverse events. CONCLUSION: Vaccinating patients with IEI is safe, and most patients were able to develop vaccine-specific antibody response, S-protein-specific cellular response, or both.

Immunological deficiencies: more frequent than they seem to be.

OBJECTIVE: A review article was carried out, addressing the clinical and epidemiological characteristics of immune system deficiencies, which are associated with or predispose to recurrent infectious processes, autoimmune diseases, auto inflammatory diseases, or neoplasms, and which are classified as inborn errors of immunity (IEI) and secondary immunodeficiencies (SID). Emphasis was placed on the classification of the main signs and symptoms for each organ and system, which will serve as warning signs, to guide the pediatrician in the investigation of the main IEI. In addition, the main secondary changes in the immune system triggered by infections (with emphasis on COVID-19), drugs, chronic diseases, metabolic and nutritional disorders were identified. SOURCES OF DATA: This review included articles published in the last five years and that were identified in the MEDLINE platform (PubMed). SUMMARY OF FINDINGS: The recurrence of infectious processes, associated with the severity of the condition and/or unusual profile of the infectious agent, always related to the age range of symptom onset, are the most important findings for suspected diagnosis. CONCLUSIONS: Considering this scenario, immunity disorders should be part of the investigation carried out by the general pediatrician, whether they are the innate errors of immunity (primary immunodeficiencies) or secondary immunodeficiencies, so that the diagnosis is attained as early as possible and therapeutic measures are implemented, reducing the morbidity and mortality of these patients.