BCG as a case study for precision vaccine development: lessons from vaccine heterogeneity, trained immunity, and immune ontogeny

Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces “heterologous” protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed “trained immunity.” In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TB-specific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG’s innate immune activation, suggesting that aspects of BCG’s effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines

HCI policy and the smart city

While the idea of the ‘Smart City’ has attracted increasing attention from academia, industry, and government this interest has largely had a technical and technological focus. This paper identifies some of the important political and policy challenges facing the idea, the discourse, of a ‘smart city’ as a means to optimise HCI input into the ‘smart city’ debate. It then addresses that gap by detailing a research project that explored how experts in smart city research and development in the UK context responded to this policy challenge. Experts were asked questions regarding their prior experience with the “smart city”, their understandings of what it means for a city to be smart, and what policy potentials they've recognised in the smart city. The paper analyses and offers a synthesis of the responses collected throughout the research with the current policies concerning various smart city proximity, thereby providing a critical assessment of the values underlying the smart city. The paper aims to explore and present some of the policy possibilities for UK smart cities that are potentially useful for politicians, policy makers, planners, academics, and technology companies. I believe that these perspectives for policy development can be used to inform responsible development, spatially and socially inclusive technologies, and ultimately more resilient and liveable cities

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases

IL-9 Induces VEGF Secretion from Human Mast Cells and IL-9/IL-9 Receptor Genes Are Overexpressed in Atopic Dermatitis

Interleukin 9 (IL-9) has been implicated in mast cell-related inflammatory diseases, such as asthma, where vascular endothelial growth factor (VEGF) is involved. Here we report that IL-9 (10–20 ng/ml) induces gene expression and secretion of VEGF from human LAD2. IL-9 does not induce mast cell degranulation or the release of other mediators (IL-1, IL-8, or TNF). VEGF production in response to IL-9 involves STAT-3 activation. The effect is inhibited (about 80%) by the STAT-3 inhibitor, Stattic. Gene-expression of IL-9 and IL-9 receptor is significantly increased in lesional skin areas of atopic dermatitis (AD) patients as compared to normal control skin, while serum IL-9 is not different from controls. These results imply that functional interactions between IL-9 and mast cells leading to VEGF release contribute to the initiation/propagation of the pathogenesis of AD, a skin inflammatory disease

Exploring the asymmetric complementarity between external knowledge search and management innovation

This paper hypothesizes about and tests the conditions under which firms experience substitutional and complementary effects from the synchronous deployment of innovation search—in the form of external knowledge sourcing, and management innovation—in the form of new organizational processes, practices, and structures, on innovative performance. Theoretically, this represents an interesting puzzle as the extant literature offers two contradictory explanations regarding their synchronous effects, built on fundamentally different problem-solving mechanisms that expose distinct managerial challenges for coordinating external search activities. Specifically, we predict the existence of a substitutional effect between external search depth and management innovation, and a complementary effect between external search breadth and management innovation. We found strong evidence relevant to our theoretical predictions. Our study offers new theoretical insights regarding the synchronicity of innovation search and management innovation

Maternal and fetal circulating sKL and ET-1 levels as function of normal labor at term

Objectives. To determine whether labor is associated with alterations of the levels of soluble c-kit ligand (sKL) and endothelin-1 (ET-1) in maternal plasma and umbilical cord blood. Methods. The sKL and ET-1 levels were investigated in umbilical cord and maternal plasma on the day of delivery in 18 pregnant women with vaginal delivery during labor, 18 non-pregnant women and 9 pregnant women before cesarean delivery, using an ELISA assay. Results. Umbilical cord plasma sKL levels were significantly higher than the maternal plasma in both types of delivery (p=0.0001, p<0.0001, respectively). However, maternal plasma ET-1 levels in the presence of labor were significantly higher than the cesarean delivery group (p<0.0001). No difference was noted for sKL and ET-1 in umbilical cord vessels of both groups. Furthermore, a highly significant inverse correlation was documented between the individual levels of cord plasma ET-1 and the levels of cord plasma sKL (r=-0.6269, p=0.0054). Conclusions. The sKL levels found in umbilical cord plasma are consistent with the pleiotropic effects of sKL in facilitating the transition of the fetus to the neonatal stage. The reduced ET-1 maternal plasma levels, compared to non-pregnant women, probably are indicative of a putative mechanism for embryo protection from vasoconstriction sequelae. This assumption is strengthened by the corresponding ET-1 levels in umbilical cord plasma. © 2011 Informa UK, Ltd

Brief report: "Allergic symptoms" in children with autism spectrum disorders. more than meets the eye?

Many children with Autism Spectrum Disorders (ASD) have either family and/or personal history of "allergic symptomatology", often in the absence of positive skin or RAST tests. These symptoms may suggest mast cell activation by non-allergic triggers. Moreover, children with mastocytosis or mast cell activation syndrome (MCAS), a spectrum of rare diseases characterized by increased number of activated mast cells in many organs, appear to have ASD at a rate tenfold higher (1/10 children) than that of the general population (1/100 children). Mast cell activation by allergic, infectious, environmental and stress-related triggers, especially perinatally, would release pro-inflammatory and neurotoxic molecules. We speculate these could disrupt the gut-blood-brain barriers, thus contributing to brain inflammation and ASD pathogenesis. Increased mast cell responsiveness may define at least a subgroup of ASD subjects, who could benefit from inhibition of mast cell activation. © 2011 Springer Science+Business Media, LLC