Elevated CD21low B Cell Frequency Is a Marker of Poor Immunity to Pfizer-BioNTech BNT162b2 mRNA Vaccine Against SARS-CoV-2 in Patients with Common Variable Immunodeficiency.

PURPOSE: Limited data is available on the effect of COVID-19 vaccination in immunocompromised individuals. Here, we provide the results from vaccinating a single-center cohort of patients with common variable immunodeficiency (CVID). METHODS: In a prospective, open-label clinical trial, 50 patients with CVID and 90 age-matched healthy controls (HC) were analyzed for SARS-CoV-2 spike antibody (Ab) production after one or two doses of the Pfizer-BioNTech BNT162b2 mRNA vaccine. Additionally, in selected patients, SARS-CoV-2 spike-specific T-cells were assessed. RESULTS: A potent vaccine-induced anti-spike-specific IgG Ab response was observed in all the HC. In contrast, only 68.3% of the CVID patients seroconverted, with median titers of specific Ab being 83-fold lower than in HC. In fact, only 4/46 patients (8.6%) of patients who were seronegative at baseline reached the threshold for an optimal response (250 U/mL). Using the EUROclass definition, patients with either a reduced proportion, but not absolute counts, of switched memory B-cells or having an increased frequency of CD21low B-cells generally generated poor vaccine responses. Overall, CVID-patients had reduced spike-specific IFN-γ positive CD4+ T cell responses 2 weeks after the second dose, compared to HC. The total CD4 and CD4 central memory cell counts correlated with humoral immunity to the vaccine. CONCLUSIONS: CVID patients with low frequency of switched memory B-cells or an increased frequency of CD21low B-cells according to the EUROclass definition demonstrated poor responses to Pfizer-BioNTech BNT162b2 mRNA vaccination. Cellular immune responses were significantly affected, affirming that the defect in CVID is not limited to humoral immunity.

Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene.

Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.

Vitamin d levels affect outcome in pediatric hematopoietic stem cell transplantation.

The importance of vitamin D in immunologic processes has recently emerged, but whether it has any impact on the course of allogeneic hematopoietic stem cell transplantation (HSCT) has not been determined. Reports indicate that HSCT recipients, particularly children, often suffer from vitamin D deficiency. This study investigated the role of vitamin D in 123 children undergoing HSCT from 2004 to 2011. Vitamin D (ie, serum calcidiol) was analyzed in collected cryostored samples. Patients were grouped according to pre-HSCT calcidiol level: insufficient (<50 nm/L, n = 38) and sufficient (≥50 nm/L, n = 85). Older children who underwent transplants from January through June and children of Middle Eastern or African origin were more commonly found in the insufficient group. Acute grades II to IV graft-versus-host disease occurred more frequently in the vitamin D sufficient group (47% versus 30%, P = .05), whereas no difference was demonstrated for chronic graft-versus-host disease. The neutrophil granulocytes rose significantly faster in the vitamin D sufficient group. No difference in lymphocyte counts, immunoglobulin levels, or infectious disease burden during the first year post-HSCT were observed. Among children with malignancies, overall survival was significantly better in the sufficient group (87% versus 50%, P = .01). In addition, rejection (0% versus 11%, P = .06) and relapse (4% versus 33%, P = .03) rates were lower in patients with sufficient vitamin D levels. To conclude, vitamin D may have an important impact on the outcome of pediatric HSCT, particularly in patients with malignant disease. Further studies investigating whether vitamin D acts as an immunomodulator or is merely a surrogate marker of patient health or nutritional status are warranted.

Serum levels of 25-hydroxyvitamin D and the CYP3A biomarker 4ß-hydroxycholesterol in a high-dose vitamin D supplementation study.

The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolizing CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomized to either placebo or high-dose (4000 IU/day) vitamin D for 12 months. One hundred sixteen patients were included in the final analyses, and serum samples collected 6 months after study start were analyzed. At this time point, 25-hydroxyvitamin D levels were found to range between 10 and 284 nM. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4ß-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene. There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4ß-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4ß-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration.

Product Choice Affects Risk of False-Positive Hepatitis B Virus Serology During Immunoglobulin Replacement Therapy.

Hepatitis B virus (HBV) core antigen antibodies passively transferred from immunoglobulin products used for replacement or immunomodulation may lead to unnecessary antiviral treatment for patients who are also starting immunosuppressive treatment. We have systematically assessed the contents of 93 commercial immunoglobulin batches and show that there are consistent product-specific differences in the levels of HBV core antigen antibodies and that choice of immunoglobulin product may have an impact on false-positivity rates.

A comparison of Campath and Thymoglobulin as part of the conditioning before allogeneic hematopoietic stem cell transplantation.

BACKGROUND: In vivo T-cell depletion with anti-thymocyte globulin is a commonly used strategy for the prevention of graft-versus-host disease (GVHD) and to avoid rejection after hematopoietic stem cell transplantation (HSCT). METHODS: We compared 36 patients given Campath (alemtuzumab) as part of the conditioning with a matched cohort of 72 patients receiving Thymoglobulin (TMG). Most patients had a hematologic malignancy beyond first remission. Median age was 55 (1-67). The majority of patients had an unrelated donor (70%) and 82% were given peripheral blood stem cells. Most patients received reduced-intensity conditioning. RESULTS: Graft failure occurred in 8% of the patients in each group. No difference in time-to-engraftment of neutrophils and platelets was found. The cumulative incidence of acute GVHD of any grade was 34% and 53% (P = 0.07), and the incidence of chronic GVHD was 46% and 25% in the Campath and TMG groups, respectively. In multivariate analysis, a low antibody dose was associated with acute and chronic GVHD and Campath was correlated with chronic GVHD. No differences in transplant-related mortality (28% vs. 18%), overall survival (54% vs. 58%), and relapse-free survival (39% vs. 43%) were found between the two groups. No difference in the proportion of T and B lymphocytes during the first year after HSCT was found. CONCLUSIONS: TMG and Campath as part of the conditioning result in similar outcome. Campath was associated with less acute but more chronic GVHD.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial.

BACKGROUND: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. METHODS: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FINDINGS: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. INTERPRETATION: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. FUNDING: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via FcgammaRIIa.

Dendritic cells (DCs) process and present bacterial and endogenous lipid antigens in complex with CD1 molecules to T cells and invariant natural killer T (NKT) cells. However, different types of DCs, such as blood myeloid DCs and skin Langerhans cells, exhibit distinct patterns of CD1a, CD1b, CD1c, and CD1d expression. The regulation of such differences is incompletely understood. Here, we initially observed that monocyte-derived DCs cultured in an immunoglobulin-rich milieu expressed CD1d but not CD1a, CD1b, and CD1c, whereas DCs cultured in the presence of low levels of immunoglobulins had an opposite CD1 profile. Based on this, we tested the possibility that immunoglobulins play a central role in determining these differences. IgG depletion and intravenous immunoglobulin (IVIg) add-in experiments strongly supported a role for IgG in directing the CD1 expression profile. Blocking experiments indicated that this effect was mediated by FcgammaRIIa (CD32a), and quantitative polymerase chain reaction data demonstrated that regulation of the CD1 profile occurred at the gene expression level. Finally, the ability of DCs to activate CD1-restricted NKT cells and T cells was determined by this regulatory effect of IgG. Our data demonstrate an important role for FcgammaRIIa in regulating the CD1 antigen presentation machinery of human DCs.

Are Vitamin D3 Tablets and Oil Drops Equally Effective in Raising S-25-Hydroxyvitamin D Concentrations? A Post-Hoc Analysis of an Observational Study on Immunodeficient Patients.

BACKGROUND: Vitamin D3 supplements are available as tablets or oil drops, but there is no consensus as to whether either of these preparations is more effective than the other. METHODS: We compared the effectiveness of tablets versus oil in raising S-25-hydroxyvitamin D (S-25-OHD) in plasma by re-analyzing data from a previously performed observational study in which immunodeficient patients with S-25-OHD concentrations <75 nmol/L were randomly prescribed vitamin D3 tablets (1600 IU/day) or vitamin D3 oil-drops (1500 IU/day) for twelve months. Tablets and oil were compared for the effect on S-25-OHD concentrations after 3-5 months and antibiotic use. RESULTS: Data on S-25-OHD after ≥ 3 months was available for 137 patients treated with tablets and 69 with oil drops. Both groups exhibited a significant increase in S-25-OHD-oil-drops from 55 to 86 nmol/L and tablets from 52 to 87 nmol/L-with no difference between groups (p = 0.77). In a subgroup of patients without immunoglobulin replacement, vitamin D3 supplementation with oil drops (n = 34) but not with tablets (n = 60) resulted in significantly lower antibiotic administration (p < 0.001 and p = 0.58). CONCLUSION: Vitamin D3 supplementation with tablets and oil drops were equally efficient in raising S-25-OHD concentrations. Only oil drops caused a reduction in antibiotic consumption in immuno-deficient patients who did not receive immunoglobulin replacement.

Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies.

BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

The Pneumocell-study: Vaccination of IgG1- and IgG2-deficient patients with Prevnar13.

BACKGROUND: Patients with IgG-deficiency often suffer from repeated bacterial infections with S. pneumoniae. Since there is a lack of knowledge regarding whether IgG-deficient patients would benefit from conjugate pneumococcal vaccination, we set out to evaluate the effect of Prevnar13 vaccination in IgG1- and/or IgG2-deficient patients. METHOD: We designed a small pilot-study including IgG1- and/or IgG2-deficient patients (n=10) and age- and sex-matched healthy controls (n=10). Serum, plasma and heparin-blood were collected prior to vaccination, as well as 1, 2 and 4weeks post vaccination, and the levels of opsonophagocytic activity (Opa) titers and anti-pneumococcal IgG-antibodies were analyzed. RESULTS: Patients generally had lower Opa-titers than controls for most serotypes, but they exhibited an almost normal vaccine response to serotypes 6A and 6B. Notably, 5/10 patients showed vaccine-response to at least one serotype. Most patients reached the presumably protective levels of Opa-titers ≥8 and anti-pneumococcal IgG levels of 0.35µg/ml by 4weeks post-vaccination for a majority of the serotypes. CONCLUSION: Our results show that vaccination of IgG-deficient patients with Prevnar13 is likely to have a clinical benefit. Our initial findings will provide a framework for future vaccine-trials in this vulnerable patient group. Registered at www.clinicaltrials.gov as NCT01847781.

Vitamin D3 Supplementation and Antibiotic Consumption - Results from a Prospective, Observational Study at an Immune-Deficiency Unit in Sweden.

BACKGROUND: Vitamin D supplementation has been proposed to improve clinical symptoms during respiratory tract infections (RTIs), but results from randomized, placebo-controlled trials (RCT) are inconclusive. Previously, we performed an RCT in patients with various immune-disorders and observed that supplementation with 4000 IU vitamin D/day during 12 months significantly reduced antibiotic consumption and RTIs. This formed the basis for new guidelines at our unit; i.e. patients with insufficient levels of 25-hydroxyvitamin D (≤75 nmol/L) are now offered vitamin D supplementation. The aim of this prospective follow-up study was to evaluate the outcome of these new recommendations with regard to antibiotic consumption in our unit. METHOD: 277 patients with insufficiency were supplemented with vitamin D3, 1500-1600 IU/day for 12 months. Each patient was its own control and data on antibiotic consumption was monitored 12 months before and 12 months after initiation of vitamin D3 supplementation. RESULTS: Vitamin D3 supplementation resulted in a significantly reduced antibiotic consumption, from 20 to 15 days/patient (p<0.05). The number of antibiotic-free patients increased from 52 to 81 after vitamin D3 supplementation; OR 1.79; 95% CI 1.20-2.66 (p<0.01). The number of antibiotic-prescriptions decreased significantly, a finding that mainly was attributed to a reduction of respiratory tract antibiotics (p<0.05). Subgroup analysis showed that only patients without immunoglobulin substitution (n = 135) had a significant effect of vitamin D supplementation. CONCLUSION: Vitamin D3 supplementation of 1600 IE /day is safe to use in immunodeficient patients with 25-OHD levels less than 75 nmol/L and significantly reduced the antibiotic consumption in patients without immunoglobulin substitution.

Vitamin D supplementation improves well-being in patients with frequent respiratory tract infections: a post hoc analysis of a randomized, placebo-controlled trial.

BACKGROUND: The aim of this study was to test the hypothesis that vitamin D supplementation improves well-being in patients with frequent respiratory tract infections (RTIs). We performed a post hoc analysis of a randomized, placebo-controlled and double-blind study in which patients with frequent RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124). At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study. RESULTS: The majority of patients, both placebo- and vitamin D treated, stated that they had felt 'better' during the study; 52% in the placebo group and 70% in the vitamin D group, relative risk 1.3 (95% CI 1.0-1.8; p = 0.06, Fisher's exact test). Statement of better well-being was associated with an increase in 25-hydroxyvitamin D (25-OHD) levels (p < 0.001). In contrast, worse well-being was associated with unchanged 25-OHD levels. Notably, a 25-OHD level above 100 nmol/L at the study end was associated with a higher chance of having a better well-being (p < 0.01). Four patients on anti-depressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25-OHD levels from low levels at study-start. CONCLUSION: Vitamin D supplementation to patients with frequent RTIs might be beneficial, not only for infections, but also for their general well-being. However, given the post hoc design of this study, these findings need to be confirmed in additional clinical trials before firm conclusions can be drawn. TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01131858), registered March 22, 2010.

Vitamin D supplementation to patients with frequent respiratory tract infections: a post hoc analysis of a randomized and placebo-controlled trial.

BACKGROUND: Vitamin D is considered to be important for a healthy immune system. The aim of this study was to test the hypothesis that vitamin D supplementation reduces number of respiratory tract infections (RTIs) and prolong the time to the first RTI in adult patients with frequent RTIs. METHODS: We performed a post hoc analysis of a randomized, placebo-controlled and double-blinded study, where adult patients with a high burden of RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124 in the per protocol cohort presented here). RESULTS: Vitamin D supplementation increased the probability to stay free of RTI during the study year (RR 0.64, 95% CI 0.43-0.94). Further, the total number of RTIs was also reduced in the vitamin D-group (86 RTIs) versus placebo (120 RTIs; p = 0.05). Finally, the time to the first RTI was significantly extended in the vitamin D-group (HR 1.68, 95% CI 1.03-2.68, p = 0.0376). CONCLUSION: Vitamin D supplementation was found to significantly increase the probability of staying infection free during the study period. This finding further supports the notion that vitamin D-status should be monitored in adult patients with frequent RTIs and suggests that selected patients with vitamin D deficiency are supplemented. This could be a safe and cheap way to reduce RTIs and improve health in this vulnerable patient population. The original trial was registered at http://www.clinicaltrials.gov (NCT01131858).

Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D(3) are associated with an increased risk of respiratory tract infections (RTIs). Clinical trials with vitamin D(3) against various infections have been carried out but data are so far not conclusive. Thus, there is a need for additional randomised controlled trials of effects of vitamin D(3) on infections. OBJECTIVE: To investigate if supplementation with vitamin D(3) could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs. DESIGN: A double-blind randomised controlled trial. SETTING: Karolinska University Hospital, Huddinge. PARTICIPANTS: 140 patients with antibody deficiency (selective IgA subclass deficiency, IgG subclass deficiency, common variable immune disorder) and patients with increased susceptibility to RTIs (>4 bacterial RTIs/year) but without immunological diagnosis. INTERVENTION: Vitamin D(3) (4000 IU) or placebo was given daily for 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was an infectious score based on five parameters: symptoms from respiratory tract, ears and sinuses, malaise and antibiotic consumption. Secondary endpoints were serum levels of 25-hydroxyvitamin D(3), microbiological findings and levels of antimicrobial peptides (LL-37, HNP1-3) in nasal fluid. RESULTS: The overall infectious score was significantly reduced for patients allocated to the vitamin D group (202 points) compared with the placebo group (249 points; adjusted relative score 0.771, 95% CI 0.604 to 0.985, p=0.04). LIMITATIONS: A single study centre, small sample size and a selected group of patients. The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level. CONCLUSIONS: Supplementation with vitamin D(3) may reduce disease burden in patients with frequent RTIs.