A Study Of Factors Underlying BCG Immunogenicity Differences Across Countries: The Influence Of DNA Methylation Patterns And Antigen Presenting Cells

Introduction: The protective efficacy of the BCG vaccine against pulmonary tuberculosis varies across the globe and is lower in countries near the equator. Previous studies have shown disparate immunogenicity profiles after infant BCG vaccination in The United Kingdom, Malawi, The Gambia and Indonesia. Pre-exposure to environmental mycobacteria and maternal or infant coinfections are one of the mechanisms that could explain these variations. Exact molecular mechanisms that drive sustained differences in BCG immunogenicity are not known. Methods and Hypothesis: In this study we aimed to investigate molecular mechanisms that drive differences in BCG immunogenicity. We hypothesised that differential DNA methylation or dynamic phenotypes of antigen presenting cells contribute to underlying differences in BCG immunogenicity. We used samples from South African, Ugandan and UK BCG vaccinated infants to investigate their BCG-induced immune responses. In South Africa we compared DNA methylation profiles between high and low BCG responders. In the UK and Uganda, we compared BCG specific immune responses and DNA methylation profiles between both countries. Lastly, in Uganda, we investigated longitudinal changes in dendritic cell phenotypes. Results: We found that differential DNA methylation of immune pathways such as T cell activation, or potassium and calcium channel Signalling is associated with variation in BCG immunogenicity in South African infants. The 4 comparison of immune responses between UK and Ugandan infants revealed that Ugandan infants have a strong inflammatory response to BCG, but levels of TH1 and TH2 cytokines are similar. The analysis of DNA methylation between these countries revealed that genes of B cell activation pathway are more methylated in Uganda, whereas genes of TGFb regulatory pathways are more methylated in the UK. The analysis of antigen presenting cells revealed that key dendritic cell populations are absent at birth and develop within the first year of life. We also highlight that cytomegalovirus (CMV), Epstein-Barr virus (EBV) and maternal latent tuberculosis infection (LTBI) have profound effects on dendritic cell phenotypes. Implications: These results point towards a role for DNA methylation in the regulation of BCG immune responses, however, in vitro studies focusing on highlighted gene candidates and pathways should be conducted. Small differences in immunogenicity profiles after BCG vaccination in the UK and Uganda suggest that BCG efficacy in these countries should be similar, an area requiring a further investigation. The absence of dendritic cells at birth should be investigated and the kinetics of their development within the first week of life examined. Special attention should be paid to the development of vaccines or treatments for CMV, EBV and LTBI, as these pathogens modulate DC phenotypes

Ormianie polscy, co dalej?

Stenogram dyskusji przedstawicieli środowiska ormiańskiego w Polsce, która odbyła się 8 czerwca 2009 r. w Krakowie, jako druga część konferencji naukowej Armenica Cracoviensia. Organizatorami panelu byli: Komisja Wschodnioeuropejska Polskiej Akademii Umiejętności, Wydział Historyczny Uniwersytetu Jagiellońskiego oraz Fundacja Kultury i Dziedzictwa Ormian Polskich

Zawał serca z zamknięciem pnia lewej tętnicy wieńcowej u chorego z zespołem Leriche’a

We present the case of a 55 year-old male admitted to Malopolskie Centrum Sercowo-Naczyniowe PAKS in Chrzanów with diagnosis of anterior wall myocardial infarction (STEMI). We decided to treat the patient invasively because of presence of chest pain, persistent ST elevation and signs of haemodinamical instability. As it revealed later patient needed combination of PCI of left main/left anterior descending artery with PTA of iliac artery. Kardiol Pol 2012; 70, 1: 92–9

Global and regional burden of attributable and associated bacterial antimicrobial resistance avertable by vaccination: modelling study

Introduction Antimicrobial resistance (AMR) is a global health threat with 1.27 million and 4.95 million deaths attributable to and associated with bacterial AMR, respectively, in 2019. Our aim is to estimate the vaccine avertable bacterial AMR burden based on existing and future vaccines at the regional and global levels by pathogen and infectious syndromes. Methods We developed a static proportional impact model to estimate the vaccination impact on 15 bacterial pathogens in terms of reduction in age-specific AMR burden estimates for 2019 from the Global Research on Antimicrobial Resistance project in direct proportion to efficacy, coverage, target population for protection, and duration of protection of existing and future vaccines. Results The AMR burden avertable by vaccination in 2019 was highest for the WHO Africa and South-East Asia regions, for lower respiratory infections, tuberculosis, and bloodstream infections by infectious syndromes, and forMycobacterium tuberculosisandStreptococcus pneumoniaeby pathogen. In the baseline scenario for vaccination of primary age groups against 15 pathogens, we estimated vaccine-avertable AMR burden of 0.51 (95% UI 0.49–0.54) million deaths and 28 (27–29) million disability-adjusted life-years (DALYs) associated with bacterial AMR, and 0.15 (0.14–0.17) million deaths and 7.6 (7.1–8.0) million DALYs attributable to AMR globally in 2019. In the high-potential scenario for vaccination of additional age groups against seven pathogens, we estimated vaccine-avertable AMR burden of an additional 1.2 (1.18–1.23) million deaths and 37 (36–39) million DALYs associated with AMR, and 0.33 (0.32–0.34) million deaths and 10 (9.8–11) million DALYs attributable to AMR globally in 2019. Conclusion Increased coverage of existing vaccines and development of new vaccines are effective means to reduce AMR, and this evidence should inform the full value of vaccine assessments

Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination

© 2018, The Author(s). Bacillus Calmette–Guérin (BCG) is the only licensed vaccine for tuberculosis (TB) and induces highly variable protection against pulmonary disease in different countries. We hypothesised that DNA methylation is one of the molecular mechanisms driving variability in BCG-induced immune responses. DNA methylation in peripheral blood mononuclear cells (PBMC) from BCG vaccinated infants was measured and comparisons made between low and high BCG-specific cytokine responders. We found 318 genes and 67 pathways with distinct patterns of DNA methylation, including immune pathways, e.g. for T cell activation, that are known to directly affect immune responses. We also highlight signalling pathways that could indirectly affect the BCG-induced immune response: potassium and calcium channel, muscarinic acetylcholine receptor, G Protein coupled receptor (GPCR), glutamate signalling and WNT pathways. This study suggests that in addition to immune pathways, cellular processes drive vaccine-induced immune responses. Our results highlight mechanisms that require consideration when designing new TB vaccines.European Commission within Horizon2020 TBVAC2020 (Grant No. H2020 PHC-643381); National Institutes of Health grant RO1-AI065653, European and Developing Countries Clinical Trial Partnership, Aeras, and the Bill and Melinda Gates Foundation through Grand Challenges in Global Health grant 37772 (“Biomarkers of Protective Immunity against TB in the context of HIV/AIDS in Africa”)

Update on the global epidemiology of intussusception: a systematic review of incidence rates, age distributions and case-fatality ratios among children aged <5 years, before the introduction of rotavirus vaccination.

BACKGROUND: In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception-a rare bowel disorder-has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings. METHODS: We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions. RESULTS: We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13-56) in Africa to 90 (9-380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100-2000 hospital admissions). CONCLUSION: Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates

Mortality reduction benefits and intussusception risks of rotavirus vaccination in 135 low-income and middle-income countries: a modelling analysis of current and alternative schedules.

BACKGROUND: Infant rotavirus vaccines have led to substantial reductions in hospital admissions and deaths due to gastroenteritis, but some studies have reported an elevated risk of intussusception, a rare bowel disorder. This analysis aimed to provide evidence on the potential mortality reduction benefits and intussusception risks of current rotavirus vaccination schedules, and to explore whether alternative schedules could have advantages. METHODS: All 135 low-income and middle-income countries, defined by gross national income per capita of less than US$12 236 in the 2018 fiscal year, were included in the model. Mortality reduction benefits and intussusception risks of rotavirus vaccination were modelled by use of an Excel-based static cohort model with a finely disaggregated age structure. Numbers of rotavirus gastroenteritis deaths and intussusception deaths in each week of age were calculated for all infants born in the year 2015 between birth and age 5·0 years, with and without restrictions on age at administration. Benefit-risk ratios (rotavirus gastroenteritis deaths prevented per excess intussusception death) and other indicators were calculated for two vaccination schedules currently recommended by WHO and 16 alternative schedules. Of these schedules, it was assumed that between one and three doses would be given; the first dose of the rotavirus vaccine would be co-administered with either BCG or diphtheria-tetanus-pertussis (DTP)1; and the second or third dose would be co-administered with either DTP1, DTP2, DTP3, or measles (Meas)1. FINDINGS: A three-dose schedule co-administered with DTP (without age restrictions) could prevent about 74 000 (95% uncertainty interval 59 000-100 000) rotavirus gastroenteritis deaths (38% reduction) and could lead to 201 (77-550) excess intussusception deaths (1·4% increase) compared with no vaccination, resulting in a benefit-risk ratio of 369:1 (160:1-895:1). The benefit-risk ratio was most favourable when the relative risk of intussusception was assumed to decline with the national under-5 mortality rate (2386:1) and least favourable with pessimistic assumptions about access to hospital for intussusception treatment (168:1). Schedules that involve giving the first dose with BCG and the second with DTP1 had the fewest excess intussusception deaths and most favourable benefit-risk ratios. INTERPRETATION: Rotavirus vaccines have a favourable benefit-risk profile in LMICs. Neonatal schedules have the potential to prevent more rotavirus gastroenteritis deaths and cause fewer excess intussusception deaths than the schedules currently recommended by WHO, but more efficacious rotavirus vaccines would be needed to achieve more substantial mortality reduction benefits. FUNDING: Bill & Melinda Gates Foundation