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SARS-CoV-2 infection elicits a cross-reactive and back boosting immune response from prior exposure to any of the human seasonal coronaviruses (HCoVs), but is has yet to be determined whether this response is associated with fatal outcome of severe COVID-19 disease. In a cohort of 58 hospitalized patients, we have shown that heterologous immune responses are associated with increased disease severity. Here, we report that a lower anti-spike IgG ratio of SARS-CoV-2 to HCoVs, in particular to the human coronavirus 229E, correlates with decreased neutralizing antibody titers, and is associated with a fatal disease course. These results support the hypothesis that pre-existing humoral immunity to spike antigens of HCoVs may impair an efficient immune response during COVID-19.

Effective vaccination is a key element in the exit strategy from the current severe acute respiratory syndrome—CoV coronavirus-2 (SARS-CoV-2) pandemic, and may also offer protection against severe disease from future variants of concern. Here, we prospectively monitored T-cell responses over time, using ELISpot interferon-γ (INF-y) release assays, and B-cell responses, using serological tests, after vaccination and booster with BioNTech/Pfizer mRNA (Pfizer) and Janssen vector (Janssen/Johnson & Johnson) vaccines in hospital health care workers. Vaccine recipients were divided into seropositive and seronegative individuals at baseline, in order to determine the effect of natural immunity on vaccine-induced immune kinetics. We found that convalescent individuals mounted higher spike-specific INF-y-secreting T-cell responses and B-cell-mediated IgG responses, after receiving the Janssen vaccine or the first dose of the Pfizer vaccine. IgG levels corresponded to the virus neutralization capacity as measured by VNT assay. At 8 months postvaccination, spike-specific cellular immunity waned to low levels in individuals with or without prior natural immunity, whereas waning of humoral immunity occurred predominantly in naive individuals. The booster shot effectively reinduced both cellular and humoral immune responses. To conclude, our data supports the implemented single-dose mRNA booster strategy employed in the Netherlands. Furthermore, the level of pre-existing natural immunity may be factored into determining the optimal time window between future booster vaccines.

Background: A new coronavirus, SARS-CoV-2, has recently emerged to cause a human pandemic. Data on SARS-CoV-2 specific T-cell responses is scarce, but various studies suggest a suppressed T-cell mediated immunity in patients with COVID-19. Methods: The objective of the present study was to determine functional T-cell responses to SARS-CoV-2 antigens (mosaic surface protein and nucleoprotein), by using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay, in patients with RT-PCR confirmed COVID-19. T-cell immune responses were evaluated in patients with severe disease admitted to the intensive care unit (ICU), patients with moderate disease treated on the pulmonary ward and healthy volunteers. Findings: More than half of the 19 COVID-19 patients sampled at ≥14 days after the onset of symptoms showed a significant T-cell response against the nucleoprotein. A subgroup of nine (47%) of these 19 COVID-19 patients showed a delayed or reduced T-cell response against the nucleoprotein and showed significant lower reactivity against the mitogen control stimulant. Interpretation: As none of the healthy controls had more than nine IFN-γ spot forming cells specific for the SARS-CoV-2 nucleoprotein, 10 or more spots was determined to be indicative for COVID-19 disease. The SARS-CoV-2 nucleoprotein ELISpot of patient samples taken more than three weeks after the start of symptoms showed a high diagnostic sensitivity for COVID-19 disease. T-cell response in a subgroup of COVID-19 patients was suboptimal and supports previous studies in which patients with COVID-19 were associated with a suppressed T-cell mediated immunity. Funding Statement: N/A Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The regional Medical Research Ethics Committees United approved the study (Nieuwegein, the Netherlands; MEC-U: NL73618.100.20).

Background: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an opportunistic infection across the tropics. Here, we provide a systematic overview of imported human cases in a non-endemic country over a 25-year period. Methods: All 55 Dutch microbiology laboratories were contacted in order to identify all B. pseudomallei positive cultures from 1990 to 2018. A response rate of 100% was achieved. Additionally, a systematic literature search was performed, medical-charts reviewed, and tissue/autopsy specimens were re-assessed. Results: Thirty-three travelers with melioidosis were identified: 70% male with a median-age of 54 years. Risk factors were present in most patients (n = 23, 70%), most notably diabetes (n = 8, 24%) and cystic fibrosis (n = 3, 9%). Countries of acquisition included Thailand, Brazil, Indonesia, Panama, and The Gambia. Disease manifestations included pneumonia, intra-abdominal abscesses, otitis externa, genitourinary, skin-, CNS-, and thyroid gland infections. Twelve (36%) patients developed sepsis and/or septic shock. Repeat episodes of active infection were observed in five (15%) and mortality in four (12%) patients. Post-mortem analysis showed extensive metastatic (micro)abscesses amongst other sites in the adrenal gland and bone marrow. Conclusions: The number of imported melioidosis is likely to increase, given rising numbers of (immunocompromised) travelers, and increased vigilance of the condition. This first systematic retrospective surveillance study in a non-endemic melioidosis country shows that imported cases can serve as sentinels to provide information about disease activity in areas visited and inform pre-travel advice and post-travel clinical management.

QuantiFERON (QFT) results near the cut-off are subject to debate. We aimed to investigate which borderline QFT results were due to Mycobacterium tuberculosis (Mtb)-specific responses or to test variability.In a contact investigation, tuberculin skin test (TST), QFT and T-SPOT.TB (T-SPOT) were performed in 785 BCG-unvaccinated contacts. Contacts with a low-negative (0.15), borderline (0.15-0.35), low-positive (0.35-0.70) or high-positive QFT (≥0.70 IU/mL) were compared with respect to exposure, TST and T-SPOT results. Development of active tuberculosis was assessed.Borderline QFT results occurred in threefold excess over test variability (p = 0.0027). In contacts with low-negative, borderline or positive QFT results, a positive TST occurred in 24.9%, 62.1% and 91.4% (p 0.0001) and a positive T-SPOT result in 6.3%, 41.3% and 86.4%, respectively (p 0.0001). Two-third (20/29) of contacts with a borderline and 14/16 (88%) with a low-positive QFT had a positive TST and/or T-SPOT, indicating probable Mtb-infection. During 12 years of follow-up, seven patients were diagnosed with active tuberculosis, two of whom after a low-positive QFT.In this study, most borderline and low-positive QFT results were Mtb-specific, showing the biological significance of a borderline QFT. The clinical relevance, however, will be most distinct in patients who are or will be immunocompromised.

Advanced age was the only risk factor for false-negative IGRAs in this study of active tuberculosis http://ow.ly/Cvp5G

T-SPOT. TB is a specific assay for the diagnosis of tuberculosis. The assay needs to be performed with freshly isolated cells, and interpretation requires training. T-SPOT. TB has been used in various clinical-epidemiological settings, but so far no studies have evaluated the effect of interobserver variation in test reading. Our aim was to evaluate variation between different observers in reading T-SPOT. TB results. The study was nested within an ongoing cohort study, in which part of the T-SPOT. TB had been performed with frozen material. Culture plates were read visually by four different observers from two laboratories and by two automated readers. Of 313 T-SPOT. TB assays, 235 were performed with fresh cells and 78 were performed with frozen cells. No significant difference was found between results obtained with fresh cells and those obtained with frozen cells. The percentage of positive results varied between readers by maximally 15%; five/six raters were within a 6% difference in positive results. Analysis of the observed interrater differences showed that some individuals systematically counted more spots than others did. Because test interpretation includes subtraction of background values, this systematic variance had little influence on interindividual differences. The test result as positive or negative varied between independent raters, mainly due to samples with values around the cutoff. This warrants further study regarding determinants affecting the reading of T-SPOT. TB .