Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses.

PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

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.

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.

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.

A new mathematical model to identify contacts with recent and remote latent tuberculosis.

Tuberculosis (TB) elimination programmes need to target preventive treatment to groups with an increased risk of TB activation, such as individuals with a latent tuberculosis infection (LTBI) acquired recently. Current diagnostic tests for LTBI have poor predictive values for TB activation and there is, at present, no reference method to evaluate new LTBI diagnostic and prognostic tools. Thus, our objective was to develop a mathematical model, independent of currently available diagnostic tests, to estimate the individual probability of recent and/or remote LTBI. Estimations of recent LTBI were based on the contagiousness of index case, proximity and time of exposure, and environmental factors. Estimation of remote LTBI was based on country of origin, previous stays in high-risk environments or known exposure to TB. Individual probabilities were calculated and compared with tuberculin skin test (TST) and interferon-γ release assay results for 162 contacts of 42 index TB cases. Probabilities of remote LTBI were 16% for European/American contacts and 38% for African/Asian contacts. The probability of recent LTBI was 35% for close contacts to smear microscopy positive index cases. A higher probability of remote LTBI was seen among TST-positive contacts. This model may, with further validation, be used as an independent tool to evaluate new diagnostic markers for recent LTBI.

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.