Introduction

Coronaviruses are medium-sized, enveloped, positive-stranded RNA viruses named for their crown-like appearance under the electron microscope [1]. Viruses in this family played an important role in human health long before the COVID-19 pandemic, responsible for both nonspecific upper respiratory tract infections and specific viral syndromes like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In 2019, cases of coronavirus-induced pneumonia clustered in the Hubei Province of China. This started out as a local outbreak in Wuhan but soon spread internationally, developing into a global pandemic. The implicated virus was designated SARS-CoV-2, and the disease that virus caused was named COVID-19.

Clinically, COVID-19 infections can range from asymptomatic to life threatening. Several factors place infected patients at higher risk for poor outcomes, including increasing age, obesity, and chronic disease [2, 3]. Among the many chronic diseases that may lead to more severe infection are inborn errors of immunity (IEI), a collection of diseases which lead to immunodeficiency and immune dysregulation. The earliest survey of 94 patients with IEI observed 10% mortality and found that risk factors for severe disease in the general public also affected outcomes in patients with IEI [4]. A recently published review of the literature supports that mortality among most IEI diagnosis subgroups ranges from 4 to 16% [5]. One large collection reported that the case fatality rate could be as high as 100 times the general population among patients 0–19 years of age. Patients with disrupted type I interferon (IFN) immunity in particular have worse outcomes [6,7,8,9].

The first COVID-19 vaccines became available in 2020, and since their introduction, vaccines have proven to be critically important to decreasing both SARS-CoV-2 spread and COVID-19 disease severity. There have been obvious concerns regarding how well vaccines work in patients with IEI. Few studies have been performed, and the highly varied nature of the more than 450 IEI disorders make generalization across disorders impossible. IEI patients can have lower rates of seroconversion compared to healthy controls, though responses tend to improve with additional (third dose) vaccine administrations or when given in the setting of previous COVID-19 infection [5, 10,11,12,13]. In addition to antibody responses to COVID-19 vaccination, T-cell responses have proven to be important [14, 15]. Pham and colleagues found that most patients with IEI were able to mount at least a T-cell response to vaccination, even if their humoral immune response to vaccination was lackluster [16]. These findings suggested the importance of COVID-19 vaccination even in patients with severe humoral immune defects, as these patients may benefit from adaptive cellular immune responses even in the absence of a functioning humoral immune system.

Regardless of laboratory-observed vaccination responses, an important consideration for both IEI patients and practicing immunologists is the real-world effectiveness of vaccination against SARS-CoV-2. A previous large healthcare claims study of vaccinated patients found that most infections after vaccination resulting in hospitalization and/or death occurred in patients with primary and secondary immunodeficiencies, but no data were presented regarding just primary IEI patients [17]. A small single-center study of COVID-19 outcomes in 113 IEI patients who predominantly had CVID, hypogammaglobulinemia, and agammaglobulinemia observed that COVID-19-related hospitalization occurred in 40% of unvaccinated patients versus 4% in vaccinated patients, suggesting a dramatic protective effect of vaccination [18].

Overall, COVID-19 vaccines have proven safe in the general population, although mild local and systemic reactions are common such as pain, lymphadenopathy, headache, and fever. Although severe events are possible, including myocarditis, pericarditis, anaphylaxis, and thromboembolic events, these serious adverse events are rare [19, 20]. Little is known about the safety of COVID-19 vaccines in patients with IEI. For example, patients with autoinflammatory IEIs may fear that vaccination could precipitate a disease flare, requiring increased immunosuppression or hospitalization. Indeed, the rarity of many IEI conditions and the relative recency of COVID-19 disease has made it difficult for professional organizations, the normal adjudicators of such questions, to be able to determine if there are unique or increased risks for these patients. In fact, the 2021 consensus statement from the European Alliance of Associations for Rheumatology and the American College of Rheumatology on diagnosis and management of type 1 interferonopathies expresses agnosticism, stating “whether vaccines against COVID-19 have the potential to provoke a disease flare is unknown” and “there are currently no data to back specific recommendations” [21].

In this study, we investigated the real-world safety and effectiveness of vaccination in IEI patients. Our findings demonstrate that COVID-19 vaccination is safe and effective in a large, phenotypically diverse, and multinational IEI registry including more than 1000 patients.

Materials and Methods

This study was performed as a collaboration between Cincinnati Children’s Hospital, the US Immunodeficiency Network (USIDNET), the Clinical Immunology Society, and additional physicians who contributed patient data. We created a COVID-19-specific registry database as part of the USIDNET for the collection of IEI patient data related to SARS-CoV-2 infection and/or SARS-CoV-2 vaccination. This REDCap database was used to house de-identified clinical patient data submitted by immunologists worldwide. The study was approved as exempt research by the Cincinnati Children’s Hospital institutional review board (IRB ID: 2021–0406). Members of the Clinical Immunology Society (CIS) were invited by email to contribute patient data via entry into the registry database. The database opened for entries on January 1, 2022, and closed on August 19, 2022.

Patients of any age with IEI and COVID-19/SARS-CoV-2 infection, COVID-19 vaccination, or both were eligible for inclusion. Diagnoses were linked to International Union of Immunological Societies (IUIS) subcategories by phenotypic or molecular defect as entered by the clinician [22]. All types of COVID-19/SARS-CoV-2 infections and complications were eligible for inclusion—asymptomatic, acute, long COVID, and multisystem inflammatory syndrome in children or adults (MIS-C/MIS-A). In addition to basic demographics and information on the nature of the subject’s IEI and relevant medical comorbidities, data were collected on hospitalization, requirement of ICU care, and patient survival. For patients who had COVID-19 vaccination, data were collected on vaccine side effects, need for escalation of IEI treatment in relation to vaccination, and healthcare utilization.

Primary outcomes of interest were (1) adverse vaccine effects and (2) real-world vaccine effectiveness in preventing hospitalization, ICU admission, and death. Adverse vaccine effects were determined by analyzing reported need for medical care in association with vaccination (emergency, outpatient, and inpatient environments), evaluating for significant changes to patients’ immunology medication regimen, examining for development of vaccine-induced myocarditis and anaphylaxis, and reviewing reported adverse effects beyond expected pain and fever for up to 3 days. Real-world vaccine effectiveness was assessed by comparison of reported hospital admission, ICU admission, and death in patients with at least one vaccine dose versus those without. Consideration of the timing of a COVID-19 infection in relation to vaccination was built into the analysis. For example, subjects who had a COVID-19 infection prior to vaccination were analyzed differently from subjects with first infection after vaccination.

We report descriptive statistics for the study population, including medians for continuous variables and counts and percentages for categorical variables. Categorical variables were compared using the Pearson chi-square test. Logistic regression analysis for outcomes of non-ICU hospitalization, ICU hospitalization, and death against vaccination status was performed both unadjusted and adjusted for potential confounding factors. Confounders considered in the adjusted models were age, obesity, kidney disease, lung disease, immunosuppressive medication use in the previous 3 months, neuromuscular disease, tracheostomy status, heart disease, sickle cell disease, and diabetes. Confounders that occurred infrequently in the data set (< 20 times each in the entire cohort)—namely, neuromuscular disease, tracheostomy, heart disease, diabetes, and sickle cell disease—were grouped together into a composite risk factor binary variable. For all these confounders, we assumed nonresponse on the survey instrument to be equivalent to a “no” answer, as not all fields were required for submission of a patient entry. All analysis was performed using Stata 17.0 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).

Results

Patients

A total of 1245 subjects were entered in the registry (Table 1). Of these, 806 (64.7%) had received at least one vaccine against COVID-19. The type of vaccine received was reported for 80.7% of vaccinated patients: the majority of patients received mRNA-based vaccines (84.0%) followed by viral vector (10.9%) and protein subunit vaccines (5.1%). Seven-hundred twenty-five received two or more vaccinations. Males were slightly predominant (53%), and patients were mostly Caucasian (70.1%) and from the USA (63.5%). Demographic characteristics were generally similar between the unvaccinated and vaccinated groups. Major exceptions were age (vaccinated patients tended to be older) and country of the treating medical center (higher percentage of vaccinated patients in US centers). The burden of comorbidities including lung disease, obesity, diabetes, and other conditions was similar between the groups, although the proportion of patients with history of bone marrow transplant (n = 96) was higher in the vaccinated group (8.9% compared to 5.5%).

Table 1 Demographic characteristics of subjects in the USIDNET registry
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A wide variety of IEI phenotypes and molecular diagnoses were represented in the cohort (Fig. 1). Most patients (n = 793, 63.7%) had antibody defects, predominantly CVID, hypogammaglobulinemia, and agammaglobulinemia. Combined immune deficiencies, syndrome-associated and otherwise, together made up the second largest category (n = 163, 13.1%). Disorders of immune dysregulation, including primary immune regulatory disorders and genetic disorders associated with hemophagocytic lymphohistiocytosis (HLH) or Epstein-Barr virus (EBV) susceptibility, were also well represented (n = 106, 8.5%). Forty-six patients had autoinflammatory disorders. There were 27 patients with chronic granulomatous disease (CGD) and 16 patients with other disorders of phagocyte function or number. Remaining categories are shown in Fig. 1. Note that 33 patients did not have enough information recorded to be categorized into a specific grouping. The breakdown of molecular diagnoses is given in Table 2 and included close to 150 different genetic diagnoses. The genetic disorders in the registry with 10 or more patients reported included pathogenic changes in ADA, CD40L, ATM, WAS, BTK, TNFRSF13B, CTLA4, XIAP, and 22q11 deletion.

Fig. 1
figure 1

Patient diagnoses in USIDNET registry, categorized by International Union of Immunologic Societies (IUIS) schema. General IUIS categories further subclassified based on phenotype or genetic defect. Abbreviations: SCID, severe combined immune deficiency; CID, combined immune deficiency; A-T, ataxia-telangiectasia; WAS, Wiskott-Aldrich syndrome; CHARGE, coloboma/heart defects/atresia choanae/growth retardation/genital abnormalities/ear abnormalities; NEMO, nuclear factor-kappa B essential modulator deficiency; CVID, common variable immune deficiency; hypogamma, hypogammaglobulinemia; agamma, agammaglobulinemia; Comp. Def., complement deficiency; SAD, specific antibody deficiency; Subclass Def., IgG subclass deficiency; IgA Def., IgA deficiency; HLH/EBV Susc., hemophagocytic lymphohistiocytosis and EBV susceptibility; ALPS, autoimmune lymphoproliferative syndrome; IPEX, immune dysregulation/polyendocrinopathy/enteropathy/X-linked syndrome; VEO-IBD, very early onset inflammatory bowel disease; CGD, chronic granulomatous disease; MSMD, Mendelian susceptibility to mycobacterial disease; Cong. Neut., congenital neutropenia; Marrow Fail., bone marrow failure; Viral Predisp., predisposition to severe viral infection

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Table 2 Molecular defects of subjects in the USIDNET COVID-19 registry as entered and categorized by registering clinicians
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Vaccine Complications

Adverse events reported after vaccination are listed in Table 3. Of the 806 patients who received at least one vaccine, only 17 were reported to seek medical care in the outpatient clinic (n = 9) or emergency room (n = 8) for a vaccine-related complication. One patient was hospitalized in association with the COVID-19 vaccine. This patient had a diagnosis of hyper-IgM syndrome and a history of recurrent cytopenias and developed an exacerbation of pre-existing autoimmune hemolytic anemia after his first COVID-19 mRNA vaccine.

Table 3 Vaccine safety in the IEI cohort (n = 806)
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Twenty-five patients were reported as having adverse effects secondary to the vaccines, with several having more than one listed complaint. Common issues included fatigue (8 patients), myalgia (5 patients), arthralgia (3 patients), and headache (3 patients). Most adverse effects were mild and self-limited, although one patient, a teenage girl with CVID, developed a serum sickness-like reaction after mRNA vaccination which required an outpatient physician visit and treatment with oral antihistamines. Seven patients required either increased immunosuppression or a change in antibiotic regimen after vaccination as detailed in Table 3. It is not clear what role vaccination may have played in many of these events, and some (e.g., onset of diabetes, gallstones) seem likely unrelated. There were no cases of anaphylaxis or vaccine-related myocarditis. MIS-C/MIS-A was reported to occur in one patient following vaccination. This patient had his second COVID vaccination, followed by a mild COVID-19 infection 6 days later. He then developed MIS-C approximately 6 weeks after the infection and required ICU care. His unusual presentation led to a genetic workup, and ultimately, this patient was diagnosed with familial HLH due to pathogenic variants in STXBP2.

COVID-19/SARS-CoV-2 Infection

Sixty-six percent (n = 823) of the patients in the USIDNET cohort experienced SARS-CoV-2 infections (Table 4). Of these, the majority (89.2%) were acute/symptomatic. MIS-C/MIS-A was reported in 7/823 patients (0.8%); these patients’ ages ranged from 2 to 24 years (median 11 years). The underlying IEI diagnoses in patients with MIS-C/MIS-A were X-linked agammaglobulinemia (n = 2), hyper-IgM syndrome (n = 2), interferonopathy (n = 1), inherited bone marrow failure (n = 1), and APECED (n = 1). Long COVID was reported in 13/823 patients (1.6%). One-hundred and fifty-one patients (18.4% of those infected) received monoclonal antibodies to prevent or treat COVID-19, and 41 (5.0% of those infected) received convalescent plasma. One-hundred and fifty-six IEI patients infected with SARS-CoV-2 required hospitalization (19.0% of those infected), 47 required ICU care (5.7%), and 28 died (3.4%) (Fig. 2). Characteristics of the 28 patients who died are given in Table 5. Most deceased patients had multiple comorbidities. The cause(s) of death for most adult patients included COVID-19, pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), or multiorgan failure. Sepsis was more commonly reported as an additional or only cause of death in pediatric patients, with Escherichia coli and Stenotrophomonas maltophilia identified in 2 patients.

Table 4 SARS-CoV-2 infection outcomes in the IEI cohort and effect of vaccination. Data are presented as column totals/percentages for outcomes of infection and hospitalization, ICU admission, and death among those infected
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Fig. 2
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Hospitalization, ICU admission, and death among the USIDNET registry cohort. Categorization was adapted from International Union of Immunological Societies (IUIS) phenotypic classification. Age quartile (years) is based on patient age at time of COVID-19 infection. Three infected patients lacked data on age. COVID-19 risk factors included history of lung disease, immunosuppressive medication use in the 3 months preceding infection, obesity, and renal disease. Additionally, a measure of “other risk factors” was determined, representing a composite of uncommonly observed risk factors in the cohort—neuromuscular disease, tracheostomy, heart disease, sickle cell disease, and diabetes. Any patient with at least one of these uncommonly observed risk factors was counted for this measure. Vaccination was determined as receipt of at least one COVID-19 vaccine prior to SARS-CoV-2 infection. Sixty-six patients lacked adequate information on timing of vaccination relative to infection and were not included

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Table 5 Characteristics of deceased patients
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Hospitalization, ICU admission, and death rates varied by IUIS diagnosis group (Fig. 2). The highest rates were observed in patients with innate immune defects with hospitalization observed in 44%, ICU admission observed in 22%, and death observed in 11% of these patients. Patients with combined immune deficiencies, immune dysregulation, and autoinflammatory disorders also had higher rates of hospitalization, ICU admission, and death (Fig. 2). Lower rates were observed in patients with antibody deficiencies, and the lowest rates were observed in patients with phagocyte deficiencies and complement deficiencies, with no ICU admissions or deaths observed in those two patient groups. Rates of hospitalization, ICU admission, and death were higher in patients with comorbidities and in patients in the oldest age quartile (Fig. 2).

Effect of Vaccination on COVID-19 Outcomes

Of 806 patients who received one or more vaccinations against SARS-CoV-2, 216 patients received vaccination prior to COVID-19/SARS-CoV-2 infection, 541 were vaccinated after infection, and timing of vaccination was not clear in the remaining patients. Patients who received vaccination after SARS-CoV-2 infection were counted in the unvaccinated group for analyses, and subjects with uncertain timing of vaccination relative to infection were excluded.

Rates of hospitalization, ICU admission, and death were all proportionately lower in the patients who received one or more vaccinations prior to COVID-19/SARS-CoV-2 infection (Fig. 2, Table 4). Twenty of 216 (9.3%) IEI patients who received one or more vaccinations prior to COVID-19 were hospitalized, compared with 132/541 (24.4%) who had not received at least one vaccine (p < 0.001). Six of 216 (2.8%) vaccinated patients were admitted to the ICU, compared with 41 of 541 (7.6%) unvaccinated patients (p = 0.013). Five of 216 (2.3%) vaccinated patients died, and 23 of 541 (4.3%) unvaccinated patients died (p = 0.202).

In unadjusted logistic regression analysis (Table 6), not having at least one COVID-19 vaccine prior to first COVID-19/SARS-CoV-2 infection significantly increased the odds of non-ICU admission by a factor of 3.16 (95% CI (1.92–5.22), p < 0.001) and the odds of ICU admission by a factor of 2.87 (95% CI (1.20–6.86), p = 0.018). Although the odds of death were also increased in the unvaccinated group, this difference was not statistically significant.

Table 6 Logistic regression analysis for COVID-19-related hospitalization, ICU admission, and death
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Similarly, we performed regression analysis for the same outcomes, but adjusting for the potential confounders age, obesity, renal disease, immunosuppressive medication use, lung disease, and other composite risk factors (Table 6). Not having at least one COVID-19 vaccine prior to first COVID-19 infection significantly increased the odds of non-ICU admission (OR 3.84, 95% CI (2.28–6.49), p < 0.001) and ICU admission (OR 3.61, 95% CI (1.48–8.79), p = 0.005). While odds of death were increased in the nonvaccinated group (OR 2.30, 95% CI (0.85–6.28)), this difference was not statistically significant (p = 0.103. There was also a small but significant effect on the odds of hospitalization, ICU admission, and death for each increase in year of age (Table 6). Lung disease significantly impacted risk of hospitalization, and immunosuppressive medication use significantly impacted risk of ICU admission and death.

Discussion

This is the largest registry report of COVID-19 vaccination and/or infection in IEI patients (n = 1245) to date. The disease burden in this multinational cohort of patients was diverse, with representation of even very rare diseases in each IUIS category.

Our study demonstrates that SARS-CoV-2 infections were most commonly mild in this phenotypically diverse patient population. Over 95% of patients can be expected to survive COVID-19. However, a significant proportion of infected IEI patients required hospitalization (19%) and ICU care (5.7%), and a minority did succumb (3.4%). The observed COVID-19 death rate in this large IEI registry cohort, which is largely US based, is higher than the US COVID-19 death rate in general (1.1%) and approaches that seen in medically underserved Ecuador (3.6%) [23]. Similar to previous studies, we observed that patients with innate immune defects, combined immunodeficiencies, disorders of immune dysregulation, and autoinflammatory disorders appear to have higher rates of severe complications of COVID-19 compared to patients with antibody deficiencies, phagocyte disorders, and complement deficiencies [4, 5, 24]. However, previous reports have included higher complication and death estimates in the IEI population than observed in our registry cohort. A recent systematic review on COVID-19 in patients with primary immunodeficiency found a case fatality rate of 9% and hospitalization rate of 49% [24]. These differences may be due to the different populations of the patients, with US patients representing a minority of patients in the review versus 63.5% of our USIDNET registry cohort. Abolhassani and colleagues performed a review of the COVID-19/IEI literature and found severe COVID-19 presentations in 21.5% of IEI patients and COVID-19-related mortality in 8.3% [7]. Of note, however, many of these cases of SARS-CoV-2 infection occurred prior to the widespread availability of vaccinations, and the Abolhassani cohort included more innate immune deficiencies which have been linked to more severe outcomes. A study based in the UK by Shields and colleagues found even higher rates of hospitalization (53.3%) and case fatality (39.2%), although this cohort included patients with secondary immune deficiencies in addition to IEI patients [25]. In contrast, an Italian IEI/COVID-19 study by Milito and colleagues reported a comparable infection mortality rate (3.8%) to that observed in our cohort [26] as did the Cousins study (3%) although the latter found a much larger difference in odds of hospitalization [18]. As before, the heterogeneity in these estimates is likely secondary to various confounding effects—temporal factors such as predominant SARS-CoV-2 variant at different times and increasing access to vaccination over time, cohort-level factors including diagnosis breakdown, and varying inclusion–exclusion criteria.

Vaccination in the IEI population was noted in our study to be quite effective in preventing COVID-19 general hospitalization and ICU admission, with > 3.5 times increased odds ratios for these outcomes in the unvaccinated group compared to those with at least one vaccine dose in adjusted regression analyses. Notably, the odds of death were not significantly decreased in the COVID-19 vaccinated group—a fact that is likely attributable to the generally low numbers of deaths in the cohort (28 patients), and even lower number of vaccinated deaths (5 patients), affecting statistical power.

Adverse effects of vaccination were generally mild and occurred in < 3.5% of vaccinated patients, further supporting the use of COVID-19 vaccination in patients with IEI. For the few vaccinated patients who required escalation of care after vaccination, it is not clear whether or how the vaccination event itself may have contributed to this. Importantly, there were no cases of anaphylaxis or vaccine-induced myocarditis in the cohort, though this does not rule out the occurrence. Myocarditis has been reported following a third mRNA vaccination in a 17-year-old male with CVID, for instance, and anaphylaxis would certainly be expected to occur in a minority of patients [27].

Limitations of the study include several inherent in registry-based observational research. These include recall bias on the part of clinicians filling out the survey, as well as ascertainment bias in terms of cases included. Additionally, respondents entered surveys at one point in time and were unable to update their entries later. Thus, information on repeat COVID-19 infections/outcomes and repeat COVID-19 vaccinations/outcomes was not captured. To facilitate analysis, subjects with more than one COVID-19 vaccine were pooled with those receiving only one, although it is reasonable to suppose that the degree of protection was different between these groups. Finally, the study design precluded evaluating for differences in rates of SARS-CoV-2 infection in vaccinated and unvaccinated patients. However, the apparent impact of vaccination on improving COVID-19 outcomes and the generally observed safety are important observations that may encourage hesitant IEI patients (up to 42%) to receive vaccination [28].

In summary, our study of a largely US-based registry cohort demonstrates that SARS-CoV-2 infections are mild in most patients with IEI but can be severe, and the percentages of serious COVID-19 outcomes (hospitalization, ICU care, or death) in this medically vulnerable group remain substantial. Vaccination appears safe and effective in decreasing serious outcomes among patients with diverse IEI.