Establishing immunogenicity and safety of needle-free intradermal delivery by nanoporous ceramic skin patch of mRNA SARS-CoV-2 vaccine as a revaccination strategy in healthy volunteers

Introduction: Nanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher vaccine acceptance, which is important for future mass vaccination campaigns to control outbreaks, such as COVID-19, and for public vaccination in general. In this study we investigated the safety and immunogenicity of needle-free intradermal delivery of a fractional third or fourth dose of mRNA-1273 vaccine by npMNA. Methods: This study was an open-label, randomised-controlled, proof-of-concept study. Healthy adults were eligible if they had received a primary immunisation series against SARS-CoV-2 with two doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) mRNA vaccine. A history of a COVID-19 infection or booster vaccination with mRNA-1273 or BNT162b2 was allowed if it occurred at least three months before inclusion. Participants were randomised in a 1:1 ratio to receive 20 µg mRNA-1273 vaccine, either through npMNA patch applied on the skin (ID-patch group), or through intramuscular (IM) injection (IM-control group). Primary outcomes were reactogenicity up to two weeks after vaccination, and fold-increase of SARS-CoV-2 spike S1-specific IgG antibodies 14 days post-vaccination. Results: In April 2022, 20 participants were enroled. The geometric mean concentration (GMC) did not increase in the ID-patch group after vaccination, in contrast to the IM-control group (GMC was 1,006 BAU/mL (95% CI 599–1,689), 3,855 (2,800–5,306), and 3,513 (2,554–4,833) at day 1, 15 and 29, respectively). In addition, SARS-CoV-2-specific T cell responses were lower after ID vaccination through npMNA. Conclusion: Needle-free delivery of 20 µg mRNA-1273 vaccine by npMNA failed to induce antibody and T cell responses. As this is a potentially very useful vaccination method, it is important to determine which adjustments are needed to make this npMNA successful. Clinical trial registry (on ClinicalTrial.gov): NCT05315362

Discrepancy between Mycobacterium tuberculosis-Specific Gamma Interferon Release Assays Using Short and Prolonged In Vitro Incubation▿

The sensitivities of various gamma interferon release assays (IGRAs) for the detection of past latent Mycobacterium tuberculosis infection are not known. In this study, we aimed to assess the effects of various IGRA formats and in vitro incubation periods on test outcome. The results of the tuberculin skin test (TST) were compared with those of the QuantiFERON-TB Gold in-tube (QFT-GIT) test, an overnight enzyme-linked immunospot assay (ELISPOT), and a 6-day lymphocyte stimulation test (LST) by using the same M. tuberculosis-specific peptides and samples from 27 TST-positive persons with a history of exposure to M. tuberculosis, 4 patients cured of tuberculosis (TB), and 9 TST-negative controls. Among the TST-positive persons, the LST was more frequently positive (92%; P < 0.01) than either the QFT-GIT test (33%) or ELISPOT (46%). While good agreement was observed between the QFT-GIT test and ELISPOT (κ = 0.71) and between TST and LST (κ = 0.78), the agreement between TST or LST, on the one hand, and the QFT-GIT test or ELISPOT, on the other, was poor. These data indicate that the QFT-GIT test and overnight ELISPOT are less sensitive for the detection of past latent TB than the 6-day LST. The observed discrepancies between these IGRAs are most likely related to differences in incubation periods. Whether TST-positive persons with positive LST results but negative QFT-GIT and ELISPOT results are at risk for the development of TB needs to be elucidated before short-incubation IGRAs can be used for the screening of individuals for latent TB before immunosuppressive treatment

Use of Enzyme-Linked Immunospot Assay with Mycobacterium tuberculosis- Specific Peptides for Diagnosis of Recent Infection with M. tuberculosis after Accidental Laboratory Exposure

This report of an accidental exposure to Mycobacterium tuberculosis in a microbiological laboratory illustrates the value of gamma interferon enzyme-linked immunospot assay using peptides of ESAT-6, CFP-10, TB37.6, and TB7.7 for the diagnosis of latent infection. In particular, positive responses to peptides 2 to 6 of TB37.6 were observed exclusively in recently infected persons

New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

16 páginas, 8 figuras. Disponoble información suplementaria en: http://www.nature.com/srepNew strategies are needed to develop better tools to control TB, including identification of novel antigens for vaccination. Such Mtb antigens must be expressed during Mtb infection in the major target organ, the lung, and must be capable of eliciting human immune responses. Using genome-wide transcriptomics of Mtb infected lungs we developed data sets and methods to identify IVE-TB (in-vivo expressed Mtb) antigens expressed in the lung. Quantitative expression analysis of 2,068 Mtb genes from the predicted first operons identified the most upregulated IVE-TB genes during in-vivo pulmonary infection. By further analysing high-level conservation among whole-genome sequenced Mtb-complex strains (n = 219) and algorithms predicting HLA-class-Ia and II presented epitopes, we selected the most promising IVE-TB candidate antigens. Several of these were recognized by T-cells from in-vitro Mtb-PPD and ESAT6/CFP10-positive donors by proliferation and multi-cytokine production. This was validated in an independent cohort of latently Mtb-infected individuals. Significant T-cell responses were observed in the absence of IFN-γ-production. Collectively, the results underscore the power of our novel antigen discovery approach in identifying Mtb antigens, including those that induce unconventional T-cell responses, which may provide important novel tools for TB vaccination and biomarker profiling. Our generic approach is applicable to other infectious diseases.We acknowledge funding by EC HORIZON2020 TBVAC2020 (Grant Agreement No. 643381); EC ITN FP7 VACTRAIN project (the text represents the authors’ views and does not necessarily represent a position of the Commission who will not be liable for the use made of such information), The Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038); European Research Council (ERC TB-ACCELERATE Grant Agreement No. 638553). Funding was also supplied by the Ministerio de Economía y Competitividad (Spanish Government) research grant SAF2013-43521-R, and the European Research Council (ERC) (638553-TB-ACCELERATE) (to IC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Comparison of Mantoux and QuantiFERON TB Gold Tests for Diagnosis of Latent Tuberculosis Infection in Army Personnel

The tuberculin skin test (TST) was compared with QuantiFERON-TB Gold in-tube (QFT-GIT) test for the diagnosis of tuberculosis in non-Mycobacterium bovis BCG-vaccinated military personnel. Among subjects positive by TST, 44.4% of recruits were positive by QFT-GIT compared with 11.5% subjects tested after missions abroad, suggesting that most TST conversions in the latter group were caused by nontuberculous mycobacteria

Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

Immunogenetics and cellular immunology of bacterial infectious disease

Abnormalities suggestive of latent tuberculosis infection on chest radiography; how specific are they?

Background: Several radiological features have been reported in association with latent tuberculosis infection (LTBI) but it has not been studied which are specific. The aim of this study was to evaluate allegedly characteristic abnormalities on chest radiography (CXR) in patients with LTBI compared to uninfected controls. Methods: From 236 patients tested with QuantiFERON-TB Gold In-Tube (QFT), the CXR was re-evaluated in a blinded fashion for fibrotic scarring, (non-)calcified nodules and pleural thickening. LTBI was defined as presence of a positive QFT result and/or positive tuberculin skin test result stratified by Bacille Calmette-Guérin-vaccination status. Results: Any predefined abnormality of LTBI was observed in 116/236 (49.2%) patients, the frequency not being different between groups. However, the specificity for LTBI of a fibrotic scar ≥ 2 cm2 was 100% [95% CI: 92.0%–100%] and of a calcified nodule ≥1.5 mm was 95.7% [95% CI: 85.2%–99.5%]. The frequency of non-calcified nodules and pleural thickening did not differ between groups. Conclusion: Only a fibrotic scar ≥ 2 cm2 and/or a calcified nodule ≥1.5 mm were significantly associated with LTBI. This finding is clinically relevant mainly in patients who are at significant risk of TB reactivation and in whom indirect diagnostic tests may be unreliable. Keywords: Latent tuberculosis, Thoracic radiography, Diagnostic imaging, Sensitivity, Specificity, Pulmonary nodul

Additional file 1: of The effects of a psychological intervention directed at optimizing immune function: study protocol for a randomized controlled trial

SPIRIT_Checklist. (DOC 254 kb