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The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior. In CD8 + T cells, spike-dependent ACE2-mediated signaling suppresses immunological synapse (IS) formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This cross-sectional survey explored the attitudes and the reasons, as well their associated factors, for receiving the second booster dose of the COVID-19 vaccine among a sample of all old adults and of people with chronic medical conditions attending two randomly selected immunization centers in Naples (Italy). A total of 438 questionnaires were collected. The majority were male (55.1%) and the median age was 71 years. A higher perception of the vaccine's utility, measured with a 10-point Likert type scale, has been observed among males, individuals with a higher perception that COVID-19 is a severe illness, with a higher self-awareness of being at risk of infection, and with a higher trust in the information received. The most reported reasons for receiving the second booster dose included protection of themselves and of their family members from getting COVID-19, fear of acquiring the disease, and having a physician's recommendation. Younger participants, married/cohabitant, and with a higher perception that COVID-19 is a severe illness were more likely to have indicated protecting themselves and their family members as reason for receiving the booster dose. Respondents with a chronic medical condition, with a higher perception that COVID-19 is a severe illness, with a lower trust in the information received, and informed by physicians were more likely to have received the vaccine because they perceived of being at risk of getting a severe form of the SARS-CoV-2 infection. Physicians should play a pivotal role in stressing the importance of the second booster dose and in helping individuals to make decisions.

Background: This present survey sought to investigate the level of knowledge and the attitudes pertaining the monkeypox (mpox) virus infection among a sample of health care workers (HCWs) in Italy, as well as the possible role of different factors on these outcomes., Methods: The cross-sectional survey was performed from July through October, 2022 at four randomly selected hospitals located in Southern Italy., Results: The questionnaire was completed by 421 HCWs, for an overall 59% response rate. Less than two-thirds were able to define the disease and the correct answer of the transmission mechanisms ranged from 22.8% for contact with contaminated objects to 75.8% through close contact with body fluids. Only 4% and 12.8% indicated HCWs and elderly/frail/people with underlying immune deficiencies as risk groups. The mean overall score of the knowledge assessment on mpox was 3.4 (0-9). The multivariate logistic regression analysis showed that HCWs with a lower number of years of working experience and those who had acquired information about mpox from scientific journals were more likely to have a higher level of knowledge. The average score of the perception of the severity of the disease was 6.3. A similar score with a value of 6.1 has been observed for the statement that mpox is a serious problem for the population. Regarding the level of concern about contracting mpox, the mean score was 5.1. Only 10.5% reported that they feel that this disease can be prevented, with an overall mean score of 6.5. Almost all HCWs reported that they are still living as usual, with no modification of their behavior for fear of contracting the mpox. The results of the multivariate logistic regression model showed that women, HCWs with a higher level of knowledge about mpox, and those who needed additional information about mpox were more likely to have a higher level of perception of the severity of the disease., Conclusion: This survey has demonstrated that HCWs had an unsatisfactory level of knowledge toward mpox and only nearly half showed positive attitudes. Strategic health training programs should be made so that knowledge can be acquired., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miraglia del Giudice, Della Polla, Folcarelli, Napoli, Angelillo and The Collaborative Working Group.)

This cross-sectional survey investigated the knowledge, attitudes, and practices concerning the COVID-19 vaccination for pregnant women among midwives in Italy and the associated factors. Midwives with at least five years of midwifery education and who had received information about the COVID-19 vaccination from official government organizations or scientific journals were more likely to know in which trimester this vaccine can be administered. A higher perceived utility of this vaccination was observed among midwives working in the public sector, in those concerned by being infected by SARS-CoV-2, who have received at least one dose of this vaccination, in those who considered COVID-19 a severe disease for pregnant women and their fetus, and who believed that the vaccination is safe. One-third of the midwives routinely provided information and half recommended this vaccination. Midwives with more years of activity, who received information about the vaccination from official government organizations or scientific journals, those who had never assisted patients with SARS-CoV-2, and those who believed in midwives' role in COVID-19 prevention were more likely to routinely provide information. Participants who perceived a higher utility of this vaccination, those who believed in midwives' role in COVID-19 prevention, those who received information from official government organizations or scientific journals were more likely to routinely provide a recommendation for the vaccine. Midwives' knowledge must be improved for ensuring that they communicate and recommend the vaccination to their patients.

Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe-by-design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much-needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi-step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, a panel of AOP-derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The purposes of this cross-sectional study were to determine the knowledge, attitudes, and behaviors about COVID-19 and its vaccination among 313 individuals experiencing homelessness in Italy and to identify the associated factors. A total of 20.5% identified the virus as a causative agent for COVID-19 and 44.2% identified how the SARS-CoV-2 infection wastransmitted. Those living in homeless shelters were more likely to have this knowledge. Concerns about the safety of the COVID-19 vaccine werehigher in those who were younger, with secondary school as the highest level of education, who practiced Christianity, and who did not believe that COVID-19 was a severe disease. A total of 83.9% received the vaccination. Those who were older, who had correct knowledge, whoperceived to be at a higher risk of getting the disease, and who had a lower concern about the vaccine side effects were more likely to have received the vaccination. The primary reasons for accepting the COVID-19 vaccine were that it wasa preventive measure and that it wasmandatory; those unvaccinated indicated, as the main reasons, a fear of side effects and that it wasnot useful. A relationship and communication between healthcare professionals and this hard-to-reach population are needed, with the implementation of educational and information programs.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving,the newly emerged Omicron variant being the dominant strain worldwide, and this has raised concerns about vaccine efficacy. The purposes of this survey were to examine the extent to which healthcare workers (HCWs) intend to receive a second booster dose of the COVID-19 vaccine and the factors that influence their willingness to accept it., Methods: The study was conducted among HCWs who were randomly selected from four public hospitals in the Campania region, Southern Italy., Results: A total of 496 HCWs answered the questionnaire (a response rate of 61.2%). Among the respondents, 20.8% indicated a score of 10, using a 10-point Likert-type scale, regarding the usefulness of a second COVID-19 vaccine booster dose. Physicians, HCWs who believed that COVID-19 was a severe disease, and those who have acquired information about the second booster dose from scientific journals were more likely to have this positive attitude. Slightly more than half of HCWs self-reported willingness to receive a second booster dose. Respondents who believe that HCWs are at higher risk of being infected by SARS-CoV-2, those who have a higher belief that COVID-19 is a severe disease, and those who have a higher belief that a second booster dose is useful were more willing to receive a second booster dose. The main reasons for those who had a positive intention were to protect their family members and patients, whereas, the main reasons for not getting vaccinated or for uncertainty were that the dose does not offer protection against the emerging variants and the fear of its side effects. HCWs of younger age, physicians, those who have a higher belief that a second booster dose is useful, and those who were willing to receive a second booster dose were more likely to recommend the booster dose to their patients., Conclusion: This study's findings highlight the necessity for designing and implementing educational interventions for improving second booster dose uptake and beliefs among HCWs and their capacity to recommend the vaccine to the patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Della Polla, Miraglia del Giudice, Folcarelli, Napoli, Angelillo and The Collaborative Working Group.)

In recent years, a growing interest in the characterization of the molecular basis of psoriasis has been observed. However, despite the availability of a large amount of molecular data, many pathogenic mechanisms of psoriasis are still poorly understood. In this study, we performed an integrated analysis of 23 public transcriptomic datasets encompassing both lesional and uninvolved skin samples from psoriasis patients. We defined comprehensive gene co-expression network models of psoriatic lesions and uninvolved skin. Moreover, we curated and exploited a wide range of functional information from multiple public sources in order to systematically annotate the inferred networks. The integrated analysis of transcriptomics data and co-expression networks highlighted genes that are frequently dysregulated and show aberrant patterns of connectivity in the psoriatic lesion compared with the unaffected skin. Our approach allowed us to also identify plausible, previously unknown, actors in the expression of the psoriasis phenotype. Finally, we characterized communities of co-expressed genes associated with relevant molecular functions and expression signatures of specific immune cell types associated with the psoriasis lesion. Overall, integrating experimental driven results with curated functional information from public repositories represents an efficient approach to empower knowledge generation about psoriasis and may be applicable to other complex diseases., (© 2022. The Author(s).)

Background: Pregnant women, especially those with comorbidities, compared to those non-pregnant, have higher risk of developing a severe form of COVID-19. However, COVID-19 vaccine uptake is very low among them., Methods: An anonymous questionnaire was administered to randomly selected women 18 years of age that were currently pregnant or had just given birth between September 2021 and May 2022 in the geographic area of Naples. Vaccine hesitancy was assessed using the vaccine hesitancy scale (VHS)., Results: A total of 385 women participated. Women who had not been infected by SARS-CoV-2 and who needed information about vaccination against COVID-19 had a higher perceived risk of being infected with SARS-CoV-2. More than half (54.3%) of the women were very afraid of the potential side effects of the COVID-19 vaccination on the fetus. There was higher concern of the side effects of the vaccine on the fetus among those who did not have a graduate degree, those with high-risk pregnancy, those who had not been infected by SARS-CoV-2, those who were more concerned that they could be infected by SARS-CoV-2, those who did not know that this vaccination was recommended for them, and those trusting mass media/internet/social networks for information. Only 21.3% were vaccinated when pregnant, mostly women with a university degree, those who had been infected by SARS-CoV-2 before pregnancy, those who did not need information, and those who acquired information about the vaccination from gynecologists. Almost three-quarters (71.9%) were willing to receive the vaccination and those more likely were those with a university degree, those who have had at least one relative/cohabitant partner/friend who had been infected by SARS-CoV-2, those who were more concerned that they could be infected by SARS-CoV-2, and those who were not extremely concerned of the side effects of the vaccine on the fetus. A total of 86.4% were highly hesitant. Highly hesitant were respondents who did not get a graduate degree, those less concerned that they could be infected by SARS-CoV-2, and those trusting mass media/internet/social networks for information., Conclusion: Public health efforts and education campaigns for pregnant women are needed for changing their perception patterns and for supporting gynecologists in promoting the uptake of this vaccination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miraglia del Giudice, Folcarelli, Napoli, Corea, Angelillo and The Collaborative Working Group.)

Almost 140 years of industrial exploitation have severely degraded the environment of Bagnoli Coroglio (BC), the westernmost neighborhood of the city of Naples (Italy). In this peculiar area, however, geogenic processes overlap with the impact of human activities, making it difficult to distinguish between anthropogenic and geogenic pollution sources. This is particularly true for Arsenic, the concentration of which in the marine sediments largely exceeds the tolerable level for human health and the background value for local pyroclastics. After several studies have used traditional tools based on multivariate statistics, this article attempts at tackling the problem via numerical modeling, which provides a deeper insight into the physics that governs the pollution process. Therefore, we use a particle tracking model to assess whether arsenic levels in the seabed can be affected by the influx of thermal water from an artificial channel outfalling at the westernmost part of the coast The climatic forcings that drive the marine circulation are simplified to basic "scenarios", in which wind and waves are stationary in strength and direction. Since the simulation time is much less than the contamination timescale, the comparison between numerical results and measurements is essentially qualitative and concerns the shape of contamination contours. It was found the primary forcing that enables seabed pollution is the tidal circulation, which, moreover, acts continuously in time. Quantitative arguments based on regression analysis suggest the discharge of thermal water explains almost a quarter of the observed pollution, which is consistent with previous research based on multivariate statistics., (Copyright © 2022. Published by Elsevier Ltd.)

Background: This study was designed to evaluate vaccination hesitancy and behaviors among parents of children with chronic conditions., Methods: This cross-sectional study was conducted from June to December 2021 in three public hospitals in southern Italy. Data were collected using a face-to-face interview of parents of children up to 17 years of age with at least one chronic condition., Results: Of the 532 parents approached, 444 agreed to participate, with a response rate of 83.4%. Almost half of parents (43%) knew that children with chronic diseases are at greater risk of complications from VPDs, and 21.6% knew all the vaccinations available in Italy. Additionally, 55.9% felt that vaccine-preventable diseases (VPDs) are very dangerous for their children, and 28.7% were very worried about the side effects of vaccines. The result of the Parent Attitudes about Childhood Vaccine (PACV) score indicated that 23.2% of parents were hesitant about vaccinations. Parental vaccine hesitancy was significantly more common among parents who had female children, among those who did not know the recommended vaccinations, among those who had a higher concern of potential side effects of the vaccines, among those who believed that the administration of the vaccinations was not useful, and among who received information on recommended vaccination from the internet, social and mass media., Conclusions: Important efforts by policy makers and healthcare providers must be implemented to counter vaccine hesitancy among parents.

The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group., Competing Interests: GD is a previous employee and holds shares in the GSK group of companies. AM is an employee of Valneva Austria GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aradottir Pind, Thorsdottir, Magnusdottir, Meinke, Del Giudice, Jonsdottir and Bjarnarson.)

Objectives: The aims of this cross-sectional study were to investigate why parents decide to vaccinate, as well as the determinants, their children aged 5-11 years against COVID-19 in Italy., Methods: The survey was conducted from January through May 2022. All parents/guardians who came in randomly selected days to immunization centers for the administration of the first dose of the COVID-19 vaccine to their child were asked to complete a questionnaire about socio-demographic characteristics, attitudes toward COVID-19 infection and vaccination, reason(s) regarding their decision to vaccinate their child, and source(s) of information., Results: A total of 358 questionnaires were collected. Parent's perception that COVID-19 is a severe illness for the child, assessed using a 10-point Likert scale, was 7.5. The overall mean scores of the risk perception for their child of having the COVID-19 before and after the vaccination were 8.1 and 6.3. A significantly higher parents' level of risk perception for their child of having the COVID-19 after the vaccination has been observed among those not having a university degree, those with the child having at least one chronic medical condition, and those who perceived that COVID-19 is a severe illness for the child. The mean value of respondent trust in the information provided by the pediatricians on a 10-point scale Likert type was 7.6. Female, not having a university degree, higher perception that COVID-19 is a severe disease, not having received information about the vaccination from pediatricians, and needing information had a significantly higher concern of side effects after the vaccination. The most common reasons for vaccinating their children included wanting to protect the child against COVID-19, to attend the school with less risk, to prevent the transmission to family members, and to practice sport and other activities with less risks. Participants with a university degree were more likely to have vaccinated their child for attending the school and practicing sport and other activities with less risks., Conclusions: More publicity should be promoted among parents of children aged 5-11 years which would increase the coverage rates and thus lower the transmission of SARS-CoV-2 and reduce the occurrence of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Napoli, Miraglia del Giudice, Corea, Folcarelli and Angelillo.)

Although the simple diffusion model can effectively describe the movement of eukaryotic cells on a culture surface observed at relatively low sampling frequency, at higher sampling rates more complex models are often necessary to better fit the experimental data. Currently available models can describe motion paths by involving additional parameters, such as linearity or directional persistence in time. However sometimes difficulties arise as it is not easy to effectively evaluate persistence in presence of a directional bias. Here we present a procedure which helps solve this problem, based on a model which describes displacement as the vectorial sum of three components: diffusion, persistence and directional bias. The described model has been tested by analysing the migratory behaviour of simulated cell populations and used to analyse a collection of experimental datasets, obtained by observing cell cultures in time lapse microscopy. Overall, the method produces a good description of migration behaviour as it appears to capture the expected increase in the directional bias in presence of wound without a large concomitant increase in the persistence module, allowing it to remain as a physically meaningful quantity in the presence of a directional stimulus., Competing Interests: The authors have declared that no competing interests exist.

Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.

The molecular effects of exposures to engineered nanomaterials (ENMs) are still largely unknown. In classical inhalation toxicology, cell composition of bronchoalveolar lavage (BAL) is a toxicity indicator at the lung tissue level that can aid in interpreting pulmonary histological changes. Toxicogenomic approaches help characterize the mechanism of action (MOA) of ENMs by investigating the differentially expressed genes (DEG). However, dissecting which molecular mechanisms and events are directly induced by the exposure is not straightforward. It is now generally accepted that direct effects follow a monotonic dose-dependent pattern. Here, we applied an integrated modeling approach to study the MOA of four ENMs by retrieving the DEGs that also show a dynamic dose-dependent profile (dddtMOA). We further combined the information of the dddtMOA with the dose dependency of four immune cell populations derived from BAL counts. The dddtMOA analysis highlighted the specific adaptation pattern to each ENM. Furthermore, it revealed the distinct effect of the ENM physicochemical properties on the induced immune response. Finally, we report three genes dose-dependent in all the exposures and correlated with immune deregulation in the lung. The characterization of dddtMOA for ENM exposures, both for apical endpoints and molecular responses, can further promote toxicogenomic approaches in a regulatory context.

Despite remarkable efforts of computational and predictive pharmacology to improve therapeutic strategies for complex diseases, only in a few cases have the predictions been eventually employed in the clinics. One of the reasons behind this drawback is that current predictive approaches are based only on the integration of molecular perturbation of a certain disease with drug sensitivity signatures, neglecting intrinsic properties of the drugs. Here we integrate mechanistic and chemocentric approaches to drug repositioning by developing an innovative network pharmacology strategy. We developed a multilayer network-based computational framework integrating perturbational signatures of the disease as well as intrinsic characteristics of the drugs, such as their mechanism of action and chemical structure. We present five case studies carried out on public data from The Cancer Genome Atlas, including invasive breast cancer, colon adenocarcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and prostate adenocarcinoma. Our results highlight paclitaxel as a suitable drug for combination therapy for many of the considered cancer types. In addition, several non-cancer-related genes representing unusual drug targets were identified as potential candidates for pharmacological treatment of cancer.

The recent advancements in toxicogenomics have led to the availability of large omics data sets, representing the starting point for studying the exposure mechanism of action and identifying candidate biomarkers for toxicity prediction. The current lack of standard methods in data generation and analysis hampers the full exploitation of toxicogenomics-based evidence in regulatory risk assessment. Moreover, the pipelines for the preprocessing and downstream analyses of toxicogenomic data sets can be quite challenging to implement. During the years, we have developed a number of software packages to address specific questions related to multiple steps of toxicogenomics data analysis and modelling. In this review we present the Nextcast software collection and discuss how its individual tools can be combined into efficient pipelines to answer specific biological questions. Nextcast components are of great support to the scientific community for analysing and interpreting large data sets for the toxicity evaluation of compounds in an unbiased, straightforward, and reliable manner. The Nextcast software suite is available at: ( https://github.com/fhaive/nextcast)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

COVID-19 vaccination has been extended to include children aged 5-11 years. This cross-sectional survey evaluated parental COVID-19 vaccine willingness and hesitancy, and associated factors, for their children aged 5-11 years with chronic conditions. A telephone survey was conducted from 14 December 2021 to 4 January 2022. The questionnaire assessed participants' socio-demographic and health-related information, attitudes towards COVID-19 infection, hesitancy, by using the PACV-5 (Parent Attitudes About Childhood Vaccines Survey Tool), and sources of information. A total of 430 answers were collected anonymously. Respondents with no cohabitant who had been infected by SARS-CoV-2 and having been vaccinated against COVID-19 had a higher concern about the severity of COVID-19. The parents' perceived risk that the child could be infected by SARS-CoV-2 was higher in those more concerned about the severity of COVID-19, with an older child, and who had at least one cohabitant positive for COVID-19. Only 38.8% parents were willing to vaccinate their children against COVID-19. Parents who did not need additional information, those with higher education, those who have been vaccinated against COVID-19, those whose child was older, who had received information on this vaccination from physicians, with higher self-reported concern about the severity of COVID-19, and who had a higher perceived risk that their child could be infected by SARS-CoV-2, expressed a greater willingness to vaccinate their child. Overall, 26.3% were high-hesitant, with a PACV-5 score ≥ 7. Respondents who did not get the COVID-19 vaccine, were less educated, with a lower concern about severity of COVID-19, and with a lower perceived risk that their child could be infected by SARS-CoV-2, were more likely to be high-hesitant. New policies and educational programs regarding COVID-19 vaccination for children with chronic conditions are needed to reduce hesitancy and increase vaccination uptake.

The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs., (© The Author(s) 2021. Published by Oxford University Press.)

DNA microarray data preprocessing is of utmost importance in the analytical path starting from the experimental design and leading to a reliable biological interpretation. In fact, when all relevant aspects regarding the experimental plan have been considered, the following steps from data quality check to differential analysis will lead to robust, trustworthy results. In this chapter, all the relevant aspects and considerations about microarray preprocessing will be discussed. Preprocessing steps are organized in an orderly manner, from experimental design to quality check and batch effect removal, including the most common visualization methods. Furthermore, we will discuss data representation and differential testing methods with a focus on the most common microarray technologies, such as gene expression and DNA methylation., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Motivation: Network analysis is a powerful approach to investigate biological systems. It is often applied to study gene co-expression patterns derived from transcriptomics experiments. Even though co-expression analysis is widely used, there is still a lack of tools that are open and customizable on the basis of different network types and analysis scenarios (e.g. through function accessibility), but are also suitable for novice users by providing complete analysis pipelines., Results: We developed VOLTA, a Python package suited for complex co-expression network analysis. VOLTA is designed to allow users direct access to the individual functions, while they are also provided with complete analysis pipelines. Moreover, VOLTA offers when possible multiple algorithms applicable to each analytical step (e.g. multiple community detection or clustering algorithms are provided), hence providing the user with the possibility to perform analysis tailored to their needs. This makes VOLTA highly suitable for experienced users who wish to build their own analysis pipelines for a wide range of networks as well as for novice users for which a 'plug and play' system is provided., Availability and Implementation: The package and used data are available at GitHub: https://github.com/fhaive/VOLTA and 10.5281/zenodo.5171719., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Continuum robots (CR) have been recently shown capable of micron-scale motion resolutions. Such motions are achieved through equilibrium modulation using indirect actuation for altering either internal preload forces or changing the cross-sectional stiffness along the length of a continuum robot. Previously reported, but unexplained, turning point behavior is modeled using two approaches. An energy minimization approach is first used to explain the source of this behavior. Subsequently, a kinematic model using internal constraints in multi-backbone CRs is used to replicate this turning point behavior. An approach for modeling the micro-motion differential kinematics is presented using experimental data based on the solution of a system of linear matrix equations. This approach provides a closed-form approximation of the empirical micro-motion kinematics and could be easily used for real-time control. A motivating application of image-based biopsy using 3D optical coherence tomography (OCT) is envisioned and demonstrated in this paper. A system integration for generating OCT volumes by sweeping a custom B-mode OCT probe is presented. Results showing high accuracy in obtaining 3D OCT measurements are shown using a commercial OCT probe. Qualitative results using a miniature probe integrated within the robot are also shown. Finally, closed-loop visual servoing using OCT data is demonstrated for guiding a needle into an agar channel. Results of this paper present what we believe is the first embodiment of a continuum robot capable of micro and macro motion control for 3D OCT imaging. This approach can support the development of new technologies for CRs capable of surgical intervention and micro-motion for ultra-precision tasks.

The primary goal of vaccination is the prevention of pathogen-specific infection. The indirect consequences may include maintenance of homeostasis through prevention of infection-induced complications; trained immunity that re-programs innate cells to respond more efficiently to later, unrelated threats; slowing or reversing immune senescence by altering the epigenetic clock, and leveraging the pool of memory B and T cells to improve responses to new infections. Vaccines may exploit the plasticity of the immune system to drive longer-term immune responses that promote health at a broader level than just the prevention of single, specific infections. In this perspective, we discuss the concept of "immune fitness" and how to potentially build a resilient immune system that could contribute to better health. We argue that vaccines may contribute positively to immune fitness in ways that are only beginning to be understood, and that life-course vaccination is a fundamental tool for achieving healthy aging., (© 2021. The Author(s).)

Affinity measurement is a fundamental step in the discovery of monoclonal antibodies (mAbs) and of antigens suitable for vaccine development. Innovative affinity assays are needed due to the low throughput and/or limited dynamic range of available technologies. We combined microfluidic technology with quantum-mechanical scattering theory, in order to develop a high-throughput, broad-range methodology to measure affinity. Fluorescence intensity profiles were generated for out-of-equilibrium solutions of labelled mAbs and their antigen-binding fragments migrating along micro-columns with immobilized cognate antigen. Affinity quantification was performed by computational data analysis based on the Landau probability distribution. Experiments using a wide array of human or murine antibodies against bacterial or viral, protein or polysaccharide antigens, showed that all the antibody-antigen capture profiles (n = 841) generated at different concentrations were accurately described by the Landau distribution. A scale parameter W , proportional to the full-width-at-half-maximum of the capture profile, was shown to be independent of the antibody concentration. The W parameter correlated significantly (Pearson's r [ p- value]: 0.89 [3 × 10 -8 ]) with the equilibrium dissociation constant K D , a gold-standard affinity measure. Our method showed good intermediate precision (median coefficient of variation: 5%) and a dynamic range corresponding to K D values spanning from ~10 -7 to ~10 -11 Molar. Relative to assays relying on antibody-antigen equilibrium in solution, even when they are microfluidic-based, the method's turnaround times were decreased from 2 days to 2 h. The described computational modelling of antibody capture profiles represents a fast, reproducible, high-throughput methodology to accurately measure a broad range of antibody affinities in very low volumes of solution., Competing Interests: SB, FB, GV, PLS, CJB, GDG, DM and OF are (or were at the time of writing) employees of the GSK group of companies. AC and AM participated in a post graduate studentship program at GSK at the time of the study. GDG, DM and OF report ownership of GSK shares and/or restricted GSK shares as part of his/her employee remuneration at the time of writing., (© 2021 The Authors.)

The COVID-19 disease led to an unprecedented health emergency, still ongoing worldwide. Given the lack of a vaccine or a clear therapeutic strategy to counteract the infection as well as its secondary effects, there is currently a pressing need to generate new insights into the SARS-CoV-2 induced host response. Biomedical data can help to investigate new aspects of the COVID-19 pathogenesis, but source heterogeneity represents a major drawback and limitation. In this work, we applied data integration methods to develop a Unified Knowledge Space (UKS) and used it to identify a new set of genes associated with SARS-CoV-2 host response, both in vitro and in vivo. Functional analysis of these genes reveals possible long-term systemic effects of the infection, such as vascular remodelling and fibrosis. Finally, we identified a set of potentially relevant drugs targeting proteins involved in multiple steps of the host response to the virus., (© The Author(s) 2021. Published by Oxford University Press.)

Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomography/computed tomography (PET/CT) scanning using tissue-specific and non-specific radioligands together with transcriptomic analysis of muscle biopsies in a clinical model systematically and prospectively comparing vaccine-induced immune/inflammatory responses. 109 male participants received a single immunization with licensed preparations of either AS04-adjuvanted hepatitis B virus vaccine (AHBVV); MF59C-adjuvanted (ATIV) or unadjuvanted seasonal trivalent influenza vaccine (STIV); or alum-OMV-meningococcal B protein vaccine (4CMenB), followed by a PET/CT scan (n = 54) or an injection site muscle biopsy (n = 45). Characteristic kinetics was observed with a localized intramuscular focus associated with increased tissue glycolysis at the site of immunization detected by 18 F-fluorodeoxyglucose (FDG) PET/CT, peaking after 1-3 days and strongest and most prolonged after 4CMenB, which correlated with clinical experience. Draining lymph node activation peaked between days 3-5 and was most prominent after ATIV. Well defined uptake of the immune cell-binding radioligand 11 C-PBR28 was observed in muscle lesions and draining lymph nodes. Kinetics of muscle gene expression module upregulation reflected those seen previously in preclinical models with a very early (~6hrs) upregulation of monocyte-, TLR- and cytokine/chemokine-associated modules after AHBVV, in contrast to a response on day 3 after ATIV, which was bracketed by whole blood responses on day 1 as antigen presenting, inflammatory and innate immune cells trafficked to the site of immunization, and on day 5 associated with activated CD4+ T cells. These observations confirm the use of PET/CT, including potentially tissue-, cell-, or cytokine/chemokine-specific radioligands, is a safe and ethical quantitative technique to compare candidate vaccine formulations and could be safely combined with biopsy to guide efficient collection of samples for integrated whole blood and tissue systems vaccinology in small-scale but intensive human clinical models of immunization and to accelerate clinical development and optimisation of vaccine candidates, adjuvants, and formulations., Competing Interests: PD and GG are employees of the GSK group of companies, and report receiving restricted shares of the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Win, Weiner 3rd, Listanco, Patel, Sharma, Greenwood, Maertzdorf, Mollenkopf, Pizzoferro, Cole, Bodinham, Kaufmann, Denoel, Del Giudice and Lewis.)

The COVID-19 pandemic is a shocking reminder of how our world would look in the absence of vaccination. Fortunately, new technologies, the pace of understanding new and existing pathogens, and the increased knowledge of the immune system allow us today to develop vaccines at an unprecedented speed. Some of the vaccine technologies that are fast-tracked by the urgency of COVID-19 may also be the answer for other health priorities, such as antimicrobial resistance, chronic infections, and cancer, that the post-COVID-19 world will urgently need to face. This perspective analyzes the way COVID-19 is transforming vaccinology and the opportunities for vaccines to have an increasingly important role in health and well-being., Competing Interests: Competing interest statement: All authors are full-time employees of the GlaxoSmithKline group of companies. This work was sponsored by GlaxoSmithKline Biologicals SA., (Copyright © 2021 the Author(s). Published by PNAS.)

Long-term effects of Covid-19 disease are still poorly understood. However, similarities between the responses to SARS-CoV-2 and certain nanomaterials suggest fibrotic pulmonary disease as a concern for public health in the next future. Cross-talk between nanotoxicology and other relevant disciplines can help us to deploy more effective Covid-19 therapies and management strategies., Competing Interests: The authors report no declarations of interest., (© 2020 The Author(s).)

Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a pneumococcal conjugate vaccine, Pnc1-TT, could affect the expression of tumor necrosis factor receptor (TNF-R) superfamily members, known to be involved in the initiation and maintenance of antibody responses; B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA) and their ligands, BAFF, and a proliferation inducing ligand (APRIL). Initially we assessed the maturation status of different B cell populations and their expression of BAFF-R and BCMA. Neonatal mice had dramatically fewer B cells than adult mice and the composition of different subsets within the B cell pool differed greatly. Proportionally newly formed B cells were most abundant, but they had diminished BAFF-R expression which could explain low proportions of marginal zone and follicular B cells observed. Limited BCMA expression was also detected in neonatal pre-plasmablasts/plasmablasts. LT-K63 enhanced vaccine-induced BAFF-R expression in splenic marginal zone, follicular and newly formed B cells, leading to increased plasmablast/plasma cells, and their enhanced expression of BCMA in spleen and bone marrow. Additionally, the induction of BAFF and APRIL expression occurred early in neonatal mice immunized with Pnc1-TT either with or without LT-K63. However, BAFF + and APRIL + cells in spleens were maintained at a higher level in mice that received the adjuvant. Furthermore, the early increase of APRIL + cells in bone marrow was more profound in mice immunized with vaccine and adjuvant. Finally, we assessed, for the first time in neonatal mice, accessory cells of the plasma cell niche in bone marrow and their secretion of APRIL. We found that LT-K63 enhanced the frequency and APRIL expression of eosinophils, macrophages, and megakaryocytes, which likely contributed to plasma cell survival, even though APRIL + cells showed a fast decline. All this was associated with enhanced, sustained vaccine-specific antibody-secreting cells in bone marrow and persisting vaccine-specific serum antibodies. Our study sheds light on the mechanisms behind the adjuvanticity of LT-K63 and identifies molecular pathways that should be triggered by vaccine adjuvants to induce sustained humoral immunity in early life., (Copyright © 2020 Aradottir Pind, Molina Estupiñan, Magnusdottir, Del Giudice, Jonsdottir and Bjarnarson.)

Polysaccharide-protein conjugates have been developed to overcome the T-independent response, hyporesponsiveness to repeated vaccination, and poor immunogenicity in infants of polysaccharides. To address the impact of polysaccharide length, typhoid conjugates made with short- and long-chain fractions of Vi polysaccharide with average sizes of 9.5, 22.8, 42.7, 82.0, and 165 kDa were compared. Long-chain-conjugated Vi (165 kDa) induced a response in both wild-type and T cell-deficient mice, suggesting that it maintains a T-independent response. In marked contrast, short-chain Vi (9.5 to 42.7 kDa) conjugates induced a response in wild-type mice but not in T cell-deficient mice, suggesting that the response is dependent on T cell help. Mechanistically, this was explained in neonatal mice, in which long-chain, but not short-chain, Vi conjugate induced late apoptosis of Vi-specific B cells in spleen and early depletion of Vi-specific B cells in bone marrow, resulting in hyporesponsiveness and lack of long-term persistence of Vi-specific IgG in serum and IgG + antibody-secreting cells in bone marrow. We conclude that while conjugation of long-chain Vi generates T-dependent antigens, the conjugates also retain T-independent properties, leading to detrimental effects on immune responses. The data reported here may explain some inconsistencies observed in clinical trials and help guide the design of effective conjugate vaccines., Competing Interests: Competing interest statement: This work was undertaken at the request of and was sponsored by GlaxoSmithKline Biologicals SA. F.M., F.N., R.D.B., F.S., M.C., C.G., I.P., L.B.M., G.D.G., and R.R. are employees of the GSK group of companies. M.A. received a PhD studentship from GSK and University of Birmingham. C.A.M. was employee of Novartis Vaccines Institute for Global Health (acquired by the GSK group of companies in March 2015) at the time of the study. A.S. was an employee of GSK group of companies when the study was performed. F.M., L.B.M., C.A.M., and A.S. are listed as inventors on patents related to this work owned by the GSK group of companies. GVGH (GSK Vaccines Institute for Global Health), an Institute with a nonprofit mission, has partnered with Biological E Ltd., a vaccine manufacture located in Hyderabad, India, for the development of a Typhoid Conjugate Vaccine, which received Indian marketing authorization in March 2020., (Copyright © 2020 the Author(s). Published by PNAS.)

Prevention of infectious diseases through immunisation of the growing ageing adult population is essential to improve healthy ageing. However, many licenced and recommended vaccines for this age group show signs of waning of the protective effect due to declining immune responses (immuno-senescence) and decreasing vaccine uptake. Today's major challenge is to improve vaccine effectiveness and uptake and to deploy efficient vaccination strategies for this age group. The Vaccines and InfecTious diseases in the Ageing popuLation (VITAL) project, with partners from 17 academic & research groups and public institutes as well as seven industry collaborators, aims to address this challenge. The ambition is to provide evidence-based knowledge to local decision makers. Using a holistic and multidisciplinary approach and novel analytical methods, VITAL will provide tools that allow the development of targeted immunisation programs for ageing adults in European countries. The project is based on four pillars focussing on the assessment of the burden of vaccine-preventable diseases in ageing adults, the dissection of the mechanisms underlying immuno-senescence, the analysis of the clinical and economic public health impact of vaccination strategies and the development of educational resources for healthcare professionals. By the end of the project, a clear, detailed, and integrated program should be available for implementing a consistent, affordable, and sustainable vaccination strategy for ageing adults with regular evaluations of its impact over time., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giuseppe Del Giudice and Baudouin Standaert are employees and shareholders of the GSK group of companies, Stephen Lockhart is an employee and shareholder of Pfizer, and Christine Luxemburger is an employee and shareholder of Sanofi., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Omics technologies have been widely applied in toxicology studies to investigate the effects of different substances on exposed biological systems. A classical toxicogenomic study consists in testing the effects of a compound at different dose levels and different time points. The main challenge consists in identifying the gene alteration patterns that are correlated to doses and time points. The majority of existing methods for toxicogenomics data analysis allow the study of the molecular alteration after the exposure (or treatment) at each time point individually. However, this kind of analysis cannot identify dynamic (time-dependent) events of dose responsiveness., Results: We propose TinderMIX, an approach that simultaneously models the effects of time and dose on the transcriptome to investigate the course of molecular alterations exerted in response to the exposure. Starting from gene log fold-change, TinderMIX fits different integrated time and dose models to each gene, selects the optimal one, and computes its time and dose effect map; then a user-selected threshold is applied to identify the responsive area on each map and verify whether the gene shows a dynamic (time-dependent) and dose-dependent response; eventually, responsive genes are labelled according to the integrated time and dose point of departure., Conclusions: To showcase the TinderMIX method, we analysed 2 drugs from the Open TG-GATEs dataset, namely, cyclosporin A and thioacetamide. We first identified the dynamic dose-dependent mechanism of action of each drug and compared them. Our analysis highlights that different time- and dose-integrated point of departure recapitulates the toxicity potential of the compounds as well as their dynamic dose-dependent mechanism of action., (© The Author(s) 2020. Published by Oxford University Press.)

Vaccine development has traditionally been driven by the need to prevent high numbers of childhood deaths due to infectious disease. With few exceptions, vaccines for adults are the same as vaccines for infants, although it has long been apparent that they become less effective as age increases. It is only in the last few years that concerted efforts have commenced to develop life-long vaccination strategies through into older age. Impressive progress has been made in the field of vaccine technologies which, when they will be applied to vaccination of older adults, could change the landscape for disease prevention in this age group. The recently licensed adjuvanted herpes zoster vaccine shows that immunosenescence need not be a barrier to highly effective vaccination, and that highly effective vaccines for older adults can be achieved with good vaccine design. One of the greatest public health challenges of the 21st century is ensuring the health and well-being of the aged. New or improved vaccines targeting pathogens with a high disease burden in older adults have the potential to major contributions to the longevity and productivity of the older aged population., (© 2020 S. Karger AG, Basel.)

As populations age globally, the health of older adults is looming larger on the agendas of public health bodies. In particular, the priority is to ensure that older adults remain healthy, independent, and engaged in their communities. In other words, ensuring that increasing life spans are matched by increasing "health spans," meaning years spent in good health. Chronic conditions such as cancer or respiratory and cardiovascular diseases account for the bulk of the disease burden in older adults, and the consensus is that these can best be tackled by effective primary prevention. However, given the diverse nature of older populations, whose prior health experiences can be complicated by multi-morbidity and poly-pharmacy, effective primary prevention can be challenging. One approach that is gaining momentum is what is called "precision" or P4 medicine. The acronym stands for "predictive, personalized, preventive, participatory" medicine, and is based on the premise that preventing disease is better than treating it. However, effective prevention requires the ability to predict disease risk for a given patient, the tailoring of treatment to their circumstances, and their consent for or participation in the offered treatment. A P4 approach may seem counter-intuitive, given that vaccination is generally considered a public health intervention. However, in this article, we discuss the application of P4 medicine as a complement to planning the vaccination of older individuals, with a special focus on the important role that vaccine-preventable infections play in the burden of non-communicable disease., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20-21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

Background: Despite the existence of efficacious vaccines, the burden of vaccine-preventable diseases remains high and the potential health benefits of paediatric, adolescent and adult vaccination are not being achieved due to suboptimal vaccine coverage rates. Based on emerging evidence that pharmacy-based vaccine interventions are feasible and effective, the European Interdisciplinary Council for Ageing (EICA) brought together stakeholders from the medical and pharmacy professions, the pharmaceutical industry, patient/ageing organisations and health authorities to consider the potential for pharmacy-based interventions to increase vaccine uptake. We report here the proceedings of this 3-day meeting held in March 2018 in San Servolo island, Venice, Italy, focussing firstly on examples from countries that have introduced pharmacy-based vaccination programmes, and secondly, listing the barriers and solutions proposed by the discussion groups., Conclusions: A range of barriers to vaccine uptake have been identified, affecting all target groups, and in various countries and healthcare settings. Ease of accessibility is a potentially modifiable determinant in vaccine uptake, and thus, improving the diversity of settings where vaccines can be provided to adults, for example by enabling community pharmacists to vaccinate, may increase the number of available opportunities for vaccination.

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56-81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination., (Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Inc. All rights reserved.)

Immaturity of the immune system contributes to poor vaccine responses in early life. Germinal center (GC) activation is limited due to poorly developed follicular dendritic cells (FDC), causing generation of few antibody-secreting cells (ASCs) with limited survival and transient antibody responses. Herein, we compared the potential of five adjuvants, namely LT-K63, mmCT, MF59, IC31, and alum to overcome limitations of the neonatal immune system and to enhance and prolong responses of neonatal mice to a pneumococcal conjugate vaccine Pnc1-TT. The adjuvants LT-K63, mmCT, MF59, and IC31 significantly enhanced GC formation and FDC maturation in neonatal mice when co-administered with Pnc1-TT. This enhanced GC induction correlated with significantly enhanced vaccine-specific ASCs by LT-K63, mmCT, and MF59 in spleen 14 days after immunization. Furthermore, mmCT, MF59, and IC31 prolonged the induction of vaccine-specific ASCs in spleen and increased their persistence in bone marrow up to 9 weeks after immunization, as previously shown for LT-K63. Accordingly, serum Abs persisted above protective levels against pneumococcal bacteremia and pneumonia. In contrast, alum only enhanced the primary induction of vaccine-specific IgG Abs, which was transient. Our comparative study demonstrated that, in contrast to alum, LT-K63, mmCT, MF59, and IC31 can overcome limitations of the neonatal immune system and enhance both induction and persistence of protective immune response when administered with Pnc1-TT. These adjuvants are promising candidates for early life vaccination., (Copyright © 2019 Aradottir Pind, Dubik, Thorsdottir, Meinke, Harandi, Holmgren, Del Giudice, Jonsdottir and Bjarnarson.)

Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting., Competing Interests: Competing interestsAll authors are employees of the GSK group of companies. A.D., G.D.G., B.L. and F.T.D.S. hold shares in the GSK group of companies. A.D. owns patents related to AS01 that are unrelated to the topic of this paper., (© The Author(s) 2019.)

Biomedical informatics has traditionally adopted a linear view of the informatics process (collect, store and analyse) in translational medicine (TM) studies; focusing primarily on the challenges in data integration and analysis. However, a data management challenge presents itself with the new lifecycle view of data emphasized by the recent calls for data re-use, long term data preservation, and data sharing. There is currently a lack of dedicated infrastructure focused on the 'manageability' of the data lifecycle in TM research between data collection and analysis. Current community efforts towards establishing a culture for open science prompt the creation of a data custodianship environment for management of TM data assets to support data reuse and reproducibility of research results. Here we present the development of a lifecycle-based methodology to create a metadata management framework based on community driven standards for standardisation, consolidation and integration of TM research data. Based on this framework, we also present the development of a new platform (PlatformTM) focused on managing the lifecycle for translational research data assets.

Systems vaccinology approaches have been used successfully to define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate or surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, as well as three agonists of Toll-like receptors (TLRs) with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus that of an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle, and the peripheral blood mononuclear cells (PBMCs)isolated from the circulating blood from 4 hr after injection and over the next week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers that are reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, and provide a way to select candidates with acceptable safety profiles., Competing Interests: PM, DC, YA, JM, JW, SK, DL, RS No competing interests declared, Rv, GD is an employee of the GSK group of companies. Reports ownership of shares and/or restricted shares in GSK, (© 2019, McKay et al.)

As the global population ages, there is concern about the effect of an increased proportion of older individuals on the economic sustainability of healthcare systems and the social effects of an older society. Health authorities and advocacy groups in countries at the forefront of this trend are now developing strategies to ameliorate the social and financial effects of an ageing population. There is broad agreement that for both society and for the individuals, it is important to ensure that increasing lifespans are matched with increased "healthspans" - the number of years spent in good health. There is also growing consensus that vaccination is one of the tools that can play an important role in improving adult health - though currently vaccination coverage is often poor. This review focuses on two issues that consistently appear to be associated with under-vaccination: the low awareness of risk (and potential consequences) for vaccine-preventable diseases and a poor understanding of the value of improved vaccination coverage for adults. We suggest that understanding of vaccination as a health-promoting activity, rather than a medical intervention designed to prevent the spread of a specific pathogen - is a crucial step to improve vaccination uptake among adults (see Supplementary video abstract ). Key messages As populations age globally, we are seeing an increasing burden of vaccine-preventable disease in adults. Adult vaccination against some common diseases has been shown to dramatically improve health and quality of life for older people. Despite the attested benefits, vaccination coverage is almost always poor in adults, even in countries where access is free at point of care. In this article, we discuss what appears to a neglected issue in adult vaccination, that of personal autonomy. We argue that adult vaccination will only be successful if it respects individual autonomy and that this requires treating the choice to vaccinate as a public health issue akin to smoking cessation, exercise and healthy diet.

Immunogens inducing antibodies against the stem of influenza virus hemagglutinin are promising candidates for the development of universal vaccines. In this issue of JEM , Kosik et al. (https://doi.org/10.1084/jem.20181624) report that inhibition of neuraminidase by anti-stem antibodies contributes to their broadly neutralizing activity., (© 2019 Rappuoli and Del Giudice.)

After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics. For example, they induce early activation (although at different levels) of innate immunity which then translates into higher antibody and cellular responses to the vaccine antigens. In addition, most of these adjuvants (e.g. MF59, AS03, AS04) clearly induce a wider breadth of adaptive responses able to confer protection against, for example, heterovariants of the influenza viruses (MF59, AS03) or against human papillomavirus strains not contained in the vaccine (AS04). Finally, the use of some of these adjuvants has contributed to significantly enhance the immune response and the efficacy and effectiveness of vaccines in the elderly who experience a waning of the immune responsiveness to infection and vaccination, as shown for MF59- or AS03-adjuvanted influenza vaccines and AS01-adjuvanted herpes zoster vaccine. These results, together with the track record of acceptable safety profiles of the adjuvanted vaccines, pave the way for the development of novel vaccines at the extremes of age and against infections with a high toll of morbidity and mortality. Here, we review the mechanisms associated with the performance of those adjuvanted vaccines in animal models and in humans through recent advances in systems vaccinology and biomarker discovery. We also provide some perspectives on remaining knowledge gaps but also on opportunities that could accelerate the development of new vaccines., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intramuscular immunisation with a vaccine composed of three recombinant Helicobacter pylori antigens-vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), and neutrophil-activating protein (NAP)-prevented infection in animal models and was well tolerated and highly immunogenic in healthy adults. We aimed to assess the efficacy of the vaccine in prevention of a H pylori infection after challenge with a CagA-positive strain (BCM 300) in healthy volunteers., Methods: In this randomised phase 1/2, observer-blind, placebo-controlled, single-centre study, healthy non-pregnant adults aged 18-40 years who were confirmed negative for H pylori infection were randomly assigned (3:4) to three intramuscular doses of either placebo or vaccine at 0, 1, and 2 months. Randomisation was via a computer-generated list with study numbers ensuring the correct ratio within a block size of seven. Participants were consecutively assigned in a double-blind manner to existing study numbers of the study protocol. Investigators and participants were blinded to allocation throughout the study. One month after the third immunisation, participants underwent challenge with a CagA-positive H pylori strain, which, for safety reasons, was initially administered in a subset of participants. The primary efficacy outcome was the efficacy of the vaccine as measured by the proportion of participants infected with H pylori 12 weeks after the challenge. At the end of the study, participants infected with H pylori were treated for 14 days with combination therapy consisting of a proton pump inhibitor and two antibiotics twice daily. Safety and immunogenicity were monitored at pre-established visits. This trial is registered with ClinicalTrials.gov, number NCT00736476, and is completed., Findings: 63 patients were randomly assigned, 27 to placebo and 36 to the vaccine. 34 participants (19 in the vaccinated group and 15 in the placebo group) underwent infectious challenge, all but one of whom experienced transient mild-to-moderate epigastric symptoms. 12 weeks after infectious challenge, six (32%) of 19 people in the vaccinated group and six (40%) of 15 people in the placebo group remained positive for H pylori. Eradication was successful in everyone who remained infected at 12 weeks. The geometric mean concentrations of antibodies specific to CagA (202 [95% CI 69-588] vs 4·73 [95% CI 1·41-16]; p=0·001), VacA (1469 [838-2577] vs 73 [39-138]; p=0·001), and NAP (208 [139-313] vs 8·01 [5·05-13]; p=0·001) were significantly higher in the vaccine group than in the placebo group 12 weeks after infectious challenge., Interpretation: Compared with placebo, the vaccine did not confer additional protection against H pylori infection after challenge with a CagA-positive strain, despite increased systemic humoral responses to key H pylori antigens. The finding of spontaneous clearance of H pylori infection in more than half the participants in the placebo group is remarkable and suggests important immune protection in the healthy adult population., Funding: Novartis Vaccine and Diagnostics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

During the height of the 2009 H1N1 swine-derived influenza pandemic, a clinical trial was conducted in which seven subjects were immunized using a monovalent, MF59®-adjuvanted vaccine, developed from an egg-passaged candidate vaccine virus (CVV), A/California/07/2009 X-181. Whole blood was collected prior to immunization and at 8, 22, and 202 days post-vaccination, and subjects' serological responses were evaluated. Here, we reconstruct and examine the longitudinal, influenza-specific circulating B cell repertoire of one subject in that study. Genotypic analysis of 390 total subject-derived antibodies (Abs) revealed a total of 29 germline genes in use among immunoglobulin heavy chain variable regions (IgHV), with the majority of those sequences isolated representing memory recall responses and two major lineages dominating the early response. In vitro phenotyping showed a diverse set of binding epitopes on the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), many of which are considered subdominant. Strong correlations were found between IgHV germline usage among non-related lineages and both binding epitope and neutralization breadth. Results here highlight the potential for Ab responses to be misdirected to egg-adaptive artifacts on CVVs while simultaneously stressing the ability to mount potent, broadly neutralizing responses to mostly novel antigens via recall of subdominant memory responses, as well as the need for evaluating alternative endpoint assays and anti-NA responses following clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Transurethral resection of bladder tumors (TURBTs) can be a challenging procedure, primarily due to limitations in tooltip dexterity, visualization, and lack of tissue depth information. A transurethral robotic system was developed to revolutionize TURBTs by addressing some of these limitations. The results of three pilot in vivo porcine studies using the novel robotic system are presented and potential improvements are proposed based on experimental observations., Materials and Methods: A transvesical endoscope with a mounted optically tracked camera was placed through the bladder of the swine under general anesthesia. Simulated bladder lesions were created by injecting HistoGel processing gel mixed with blue dye, transabdominally, into various locations in the bladder wall under endoscopic visualization. A 7-degree-of-freedom (DoF) robot was then used for transurethral resection/ablation of these simulated tumors. An independent 2-DoF distal laser arm (DLA) was deployed through the robot for laser ablation and was assisted by a manually controlled gripper for en bloc resection attempts., Results: Lesions were created and ablated using our novel endoscopic robot in the swine bladder. Full accessibility of the bladder, including the bladder neck and dome, was demonstrated without requiring bladder deflation or pubic compression. Simulated lesions were ablated using the holmium laser. En bloc resection was demonstrated using the DLA and a manual grasper., Conclusion: Feasibility of robot-assisted en bloc resection was demonstrated. Main challenges were lack of depth perception and visual occlusion induced by the transvesical endoscope. Recommendations are given to enhance robot-assisted TURBTs. Lessons learned through these pilot swine studies verify the feasibility of robot-assisted TURBTs while informing designers about critical aspects needed for future clinical deployment.

Life-long primary prevention interventions beginning and continuing throughout an individual's lifetime are increasingly seen as key to meeting the global healthcare challenges that accompany demographic changes - a concept referred to as "Healthy aging". In this perspective, vaccination is seen as part of a triad, together with healthy diet and exercise. Current adult vaccine coverage is lower than target vaccination rates in most developed countries, and so vaccine preventable diseases continue to present a substantial burden on health and healthcare resources, especially in older individuals. In part, this is due to lack of knowledge and understanding of the benefits of vaccination, inconsistent recommendations by providers and uncertainties about cost benefits. However, lower vaccine effectiveness in older adults plays a part, and new vaccines with novel characteristics to improve effectiveness in older adults are required. A life-course immunization approach to ensure optimal vaccine uptake across adults of all ages can be expected to reduce morbidity and mortality in later life. To achieve this, greater emphasis on public and healthcare provider education is necessary, based on appropriate economic analyses that demonstrate the overall value of vaccination. This article introduces the technical, economic, political and demographic issues that make establishing effective adult vaccination programs such a difficult, but pressing issue, and outlines some of the steps that are now being taken to address them. Key messages Life-long preventive activities that start and continue throughout life are essential, especially as the world's population is "getting older". This "Healthy aging" approach includes not only healthy diet and physical exercise; vaccination is critical in reducing some infectious diseases and their complications. Many adults, especially older adults (who have lower immunity than younger people) develop infections such as influenza and shingles that could potentially be prevented through vaccination. This review provides a perspective on the challenges in delivering a life-course immunization program. While some vaccines are less effective in older people, newer vaccines have been developed which provide stronger and longer protection in older patients than standard existing vaccines. However, the benefits of vaccination can only be realized if the vaccines are recommended and used. For that purpose, greater education of patients and their healthcare providers is necessary. Better knowledge of vaccines and making sure that all adults are up to date with all their recommended vaccines is an essential part of "Healthy aging". This should prevent not only vaccine-preventable diseases but also reduce the risk of complications in later life.