Development and application of the direct mycobacterial growth inhibition assay: a systematic review

Introduction: First described by Wallis et al. in 2001 for the assessment of TB drugs, the direct mycobacterial growth inhibition assay (MGIA) offers a tractable ex vivo tool measuring the combined influences of host immunity, strain virulence and intervention effects. Over the past 13 years, we have led efforts to adapt the direct MGIA for the assessment of TB vaccines including optimisation, harmonisation and validation of BCG vaccine-induced responses as a benchmark, as well as assay transfer to institutes worldwide. Methods: We have performed a systematic review on the primary published literature describing the development and applications of the direct MGIA from 2001 to June 2023 in accordance with the PRISMA reporting guidelines. Results: We describe 63 studies in which the direct MGIA has been applied across species for the evaluation of TB drugs and novel TB vaccine candidates, the study of clinical cohorts including those with comorbidities, and to further understanding of potential immune correlates of protection from TB. We provide a comprehensive update on progress of the assay since its conception and critically evaluate current findings and evidence supporting its utility, highlighting priorities for future directions. Discussion: While further standardisation and validation work is required, significant advancements have been made in the past two decades. The direct MGIA provides a potentially valuable tool for the early evaluation of TB drug and vaccine candidates, clinical cohorts, and immune mechanisms of mycobacterial control. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023423491

The humoral immune response to BCG vaccination

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity

Determinants of COVID-19 immunisation uptake in a country with high mortality and a low vaccination rate

Background Research concerned with attitudes towards COVID-19 vaccination in upper middle-income countries such as Bosnia and Herzegovina (B&H) is scarce. Currently, B&H has the lowest number of fully vaccinated adults in Europe, and the highest cumulative number of COVID-19 deaths and SARS-CoV-2 infected individuals. The aim of our study was to examine the factors associated with COVID-19 vaccination status in B&H. Methods An online survey among 1304 B&H adults was conducted in October 2021 evaluating vaccine acceptance, together with socio-demographic variables, attitudes and beliefs related to COVID-19 vaccination. Results The results from a binary logistic regression indicate that those who believed that the COVID-19 vaccine was effective were 45 times more likely to be vaccinated compared to those who did not. We also show that those who had received childhood immunisations were 41 times more likely to be vaccinated against COVID-19 compared to those who had never been previously immunised. Other significant factors were related to respondents’ trust in government institutions and healthcare policymakers as well as trust in public healthcare workers. Conclusion We suggest that future vaccination campaigns should be aimed at educating the public regarding the importance and safety of vaccines, together with strengthening trust in the public health system

A mycobacterial growth inhibition assay (MGIA) for bovine TB vaccine development

Human tuberculosis remains a significant cause of mortality and morbidity throughout the world. The global economic impact of bovine TB is considerable. An effective vaccine would be the most cost-effective way to control both epidemics, particularly in emerging economies. TB vaccine research would benefit from the identification of an immune correlate of protection with which vaccines could be gated at both preclinical and clinical levels. In-vitro mycobacterial growth inhibition assays (MGIA) are functional assays that include most aspects of the complex host immune response to mycobacteria, and they may serve as functional immune correlates for vaccine development. We applied to cattle an MGIA that was developed for use with human and murine samples. Several technical difficulties were encountered while transferring it to the cattle model. However, our data demonstrate that the assay was not discriminatory in cattle and further work is needed before using it for bovine TB vaccine development

Supporting diverse Pacific NW marine data access needs via the NANOOS Visualization system (NVS) and data services

Serving PNW users via the ANANOOS Visualization System: Data integration and management

Rapid Implementation of Telerehabilitation for Pediatric Patients During COVID-19

The COVID-19 pandemic necessitated a sudden limitation of in-person outpatient occupational and physical therapy services for most patients at a large, multisite pediatric hospital located in the Midwest, United States.  To ensure patient and staff safety, the hospital rapidly shifted to deliver most of these services via telerehabilitation. The purposes of this study were to (1) describe the rapid implementation of telerehabilitation during the COVID-19 pandemic, (2) describe the demographic characteristics of patients who continued in-person services and those who received telerehabilitation, and (3) evaluate the therapists’ perceptions of telerehabilitation for physical and occupational therapy. Most of the children (83.4% of n=1352) received telerehabilitation services. A family was more likely to choose to continue in-person visits if their child was <1-year-old, had a diagnosis of torticollis, received serial casting, or was post-surgical. Occupational and physical therapy therapists (n=9) completed surveys to discern their perceptions of the acceptability of telerehabilitation, with most reporting that telerehabilitation was as effective as in-person care. &nbsp

Generalizability of SPRINT Results to the U.S. Adult Population

Background In SPRINT (Systolic Blood Pressure Intervention Trial), a systolic blood pressure (SBP) goal of <120 mm Hg resulted in lower cardiovascular disease (CVD) risk compared with an SBP goal of <140 mm Hg. Objectives The purpose of this study was to estimate the prevalence, number, and characteristics of U.S. adults meeting SPRINT eligibility criteria and determine the broader population to whom SPRINT could be generalized. Methods We conducted a cross-sectional, population-based study using data from the National Health and Nutrition Examination Survey, 2007 to 2012. The SPRINT inclusion criteria were age ≥50 years, SBP 130 to 180 mm Hg depending on the number of antihypertensive medication classes being taken, and high CVD risk (history of coronary heart disease, estimated glomerular filtration rate of 20 to 59 ml/min/1.73 m2, 10-year CVD risk ≥15%, or age ≥75 years). Exclusion criteria were diabetes, history of stroke, >1 g in 24 h of proteinuria daily, heart failure, estimated glomerular filtration rate <20 ml/min/1.73 m2, or receiving dialysis. Treated hypertension was defined by self-reported use of medication to lower blood pressure with ≥1 class of antihypertensive medication identified through a pill bottle review. Results Overall, 7.6% (95% confidence interval [CI]: 7.0% to 8.3%) or 16.8 million (95% CI: 15.7 to 17.8 million) U.S. adults, and 16.7% (95% CI: 15.2% to 18.3%) or 8.2 million (95% CI: 7.6 to 8.8 million) adults with treated hypertension met the SPRINT eligibility criteria. Among both the overall U.S. population and adults with treated hypertension, the percentage meeting SPRINT eligibility criteria increased with older age, was higher among males than females, and was higher among non-Hispanic whites compared with non-Hispanic blacks or Hispanics. Of U.S. adults eligible for SPRINT, 51.0% (95% CI: 47.8% to 54.1%) or 8.6 million (95% CI: 8.0 to 9.1 million) were not treated for hypertension. Conclusions A substantial percentage of U.S. adults meet the eligibility criteria for SPRINT

A Top-Down Approach to Estimating Spatially Heterogeneous Impacts of Development Aid on Vegetative Carbon Sequestration

Since 1945, over $4.9 trillion dollars of international aid has been allocated to developing countries. To date, there have been no estimates of the regional impact of this aid on the carbon cycle. We apply a geographically explicit matching method to estimate the relative impact of large-scale World Bank projects implemented between 2000 and 2010 on sequestered carbon, using a novel and publicly available data set of 61,243 World Bank project locations. Considering only carbon sequestered due to fluctuations in vegetative biomass caused by World Bank projects, we illustrate the relative impact of World Bank projects on carbon sequestration. We use this information to illustrate the geographic variation in the apparent effectiveness of environmental safeguards implemented by the World Bank. We argue that sub-national data can help to identify geographically heterogeneous impact effects, and highlight many remaining methodological challenges

Meeting report: 5th Global Forum on TB Vaccines, 20-23 February 2018, New Delhi India

The 5th Global Forum on TB Vaccines was held in New Delhi, India from 20 to 23 February 2018. This was the largest Global Forum on TB Vaccines to date with nearly 350 participants from more than 30 countries. The program included over 60 speakers in 12 special, plenary and breakout sessions and 72 posters. This Global Forum brought a great sense of momentum and excitement to the field. New vaccines are in clinical trials, new routes of delivery are being tested, novel assays and biomarker signatures are being developed, and the results from the first prevention of infection clinical trial with the H4:IC31 vaccine candidate and BCG revaccination were presented. Speakers and participants acknowledged the significant challenges that the TB vaccine R&D field continues to face - including limited funding, and the need for novel effective vaccine candidates and tools such as improved diagnostics and biomarkers to accurately predict protective efficacy. New solutions and approaches to address these challenges were discussed. The following report presents highlights from talks presented at this Global Forum. A full program, abstract book and presentations (where publicly available) from the Forum may be found at tbvaccinesforum.org

Distinct Transcriptional and Anti-Mycobacterial Profiles of Peripheral Blood Monocytes Dependent on the Ratio of Monocytes: Lymphocytes.

The ratio of monocytes and lymphocytes (ML ratio) in peripheral blood is associated with tuberculosis and malaria disease risk and cancer and cardiovascular disease outcomes. We studied anti-mycobacterial function and the transcriptome of monocytes in relation to the ML ratio. Mycobacterial growth inhibition assays of whole or sorted blood were performed and mycobacteria were enumerated by liquid culture. Transcriptomes of unstimulated CD14 + monocytes isolated by magnetic bead sorting were characterised by microarray. Transcript expression was tested for association with ML ratio calculated from leucocyte differential counts by linear regression. The ML ratio was associated with mycobacterial growth in vitro (β = 2.23, SE 0.91, p = 0.02). Using sorted monocytes and lymphocytes, in vivo ML ratio (% variance explained R(2) = 11%, p = 0.02) dominated over in vitro ratios (R(2) = 5%, p = 0.10) in explaining mycobacterial growth. Expression of 906 genes was associated with the ML ratio and 53 with monocyte count alone. ML-ratio associated genes were enriched for type-I and -II interferon signalling (p = 1.2 × 10(− 8)), and for genes under transcriptional control of IRF1, IRF2, RUNX1, RELA and ESRRB. The ML-ratio-associated gene set was enriched in TB disease (3.11-fold, 95% CI: 2.28-4.19, p = 5.7 × 10(− 12)) and other inflammatory diseases including atopy, HIV, IBD and SLE. The ML ratio is associated with distinct transcriptional and anti-mycobacterial profiles of monocytes that may explain the disease associations of the ML ratio