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diff --git a/bussiness_understanding/main.tex b/bussiness_understanding/main.tex index c64fc0e..f01b002 100644 --- a/bussiness_understanding/main.tex +++ b/bussiness_understanding/main.tex @@ -24,9 +24,47 @@ A \gls{model} is a model. \item other papers \end{itemize} -\section{Influenza mortality papers} +\section{background} + +\cite{GuidanceIndustryClinical2007} +Influenza viruses are enveloped ribonucleic acid viruses belonging to the family of +Orthomyxoviridae and are divided into three distinct types on the basis of antigenic differences +of internal structural proteins (Ref. 2). Two influenza types, Type A and B, are responsible for +yearly epidemic outbreaks of respiratory illness in humans and are further classified based on the +structure of two major external glycoproteins, hemagglutinin (HA) and neuraminidase (NA). +Type B viruses, which are largely restricted to the human host, have a single HA and NA +subtype. In contrast, numerous HA and NA Type A influenza subtypes have been identified to +date. Type A strains infect a wide variety of avian and mammalian species. +Type A and B influenza variant strains emerge as a result of frequent antigenic change, +principally from mutations in the HA and NA glycoproteins. These variant strains may arise +through one of two mechanisms: selective point mutations in the viral genome (Refs. 3 and 4) or +from reassortment between two co-circulating strains (Refs. 5 and 6). +Since 1977, influenza A virus subtypes H1N1 and H3N2, and influenza B viruses have been in +global circulation in humans. The current U.S. licensed inactivated trivalent vaccines are +formulated to prevent influenza illness caused by these influenza viruses. Because of the +frequent emergence of new influenza variant strains, the antigenic composition of influenza +vaccines needs to be evaluated yearly, and the trivalent inactivated influenza vaccines are +reformulated almost every year. The immune response elicited by previous vaccination may not +be protective against new variants. +The Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on +Immunization Practices (ACIP) has expanded the recommendations for receipt of influenza +vaccination to include an increasing scope of at risk populations, currently including pregnant +women, persons 50 years of age and older, and children 6 to 59 months of age (Refs. 7, 8, and 9). + +Increased demand for influenza vaccines, including that resulting from the broader +recommendations, the withdrawal from the U.S. market by several influenza vaccine +manufacturers, and intermittent decreases in vaccine production due to manufacturing problems +have led to shortages or delays in the availability of influenza vaccine over the past several +seasons. These shortages highlight both the complexity of the production process and the need +to increase the availability of influenza vaccines from multiple manufacturers. Currently, even +with full production, manufacturing capacity would not produce enough seasonal influenza +vaccine to vaccinate all those for whom the vaccine is now recommended. Finally, the +availability of adequate supplies of licensed seasonal inactivated influenza vaccines from +multiple manufacturers will be of value in responding to the emergence of a new pandemic +influenza strain. + +\subsection{Influenza mortality papers} -\subsection{US mortality associated influenza abstract} \cite{thompsonMortalityAssociatedInfluenza2003} Context Influenza and respiratory syncytial virus (RSV) cause substantial morbidity and mortality. Statistical methods used to estimate deaths in the @@ -95,7 +133,6 @@ deliberations of the Advisory Committee on Immunization Practices (ACIP) regarding influenza vaccination recommendations3 guided our choice of age groups for these analyses. -\subsection{England influenza mortality} \cite{greenMortalityAttributableInfluenza2013} Very different influenza seasons have been observed from 2008/09-2011/12 in England and Wales, with the reported burden varying overall and by age group. @@ -126,7 +163,6 @@ preparatory work to establish a routine mortality monitoring system ahead of introduction of the UK universal childhood seasonal influenza vaccination programme in 2013/14. -\subsection{Global mortality paper} \cite{iulianoEstimatesGlobalSeasonal2018} Background Estimates of influenza-associated mortality are important for national and @@ -172,7 +208,7 @@ than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated. -\section{Vaccine success criteria} +\subsection{Vaccine success criteria} \cite{zhouHospitalizationsAssociatedInfluenza2012} Background. Age-specific comparisons of influenza and respiratory syncytial @@ -203,6 +239,197 @@ are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time. +\cite{GuidanceIndustryClinical2007} +something about the effectiveness of vaccines. + +\cite{dejongHaemagglutinationinhibitingAntibodyInfluenza2003} + +The results of the haemagglutination-inhibiting (HI) antibody test for +influenza virus antibody in human sera closely match those produced by virus +neutralization assays and are predictive of protection. On the basis of the +data derived from 12 publications concerning healthy adults, we estimated the +median HI titre protecting 50\% of the vaccinees against the virus concerned at +28. This finding supports the current policy requiring vaccines to induce serum +HI titres of > or = 40 to the vaccine viruses in the majority of the vaccinees. +Unfortunately similar studies are scanty for the elderly, the group most at +risk of influenza. There still remain many unsolved technical problems with the +HI assay and we recommend that these problems be studied and the virus +neutralization test as a predictor of resistance to influenza be assessed. +Although the studies on this issue often give conflicting results, they +generally show that HI antibody responses to influenza vaccination tend to +diminish with increasing age, when health is often compromized. Advanced age in +itself seems not to be an independent factor in this process. However, even in +completely healthy elderly individuals the response to vaccination with an +antigenically new virus may be strongly reduced compared with younger +vaccinees. + +\subsection{antibody response vaccine} +\cite{sridharCellularImmuneCorrelates2013} +The role of T cells in mediating heterosubtypic protection against natural +influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) +provided a unique natural experiment to determine whether crossreactive +cellular immunity limits symptomatic illness in antibody-naive individuals. We +followed 342 healthy adults through the UK pandemic waves and correlated the +responses of pre-existing T cells to the pH1N1 virus and conserved core protein +epitopes with clinical outcomes after incident pH1N1 infection. Higher +frequencies of pre-existing T cells to conserved CD8 epitopes were found in +individuals who developed less severe illness, with total symptom score having +the strongest inverse correlation with the frequency of interferon-g (IFN-g)+ +interleukin-2 (IL-2)− CD8+ T cells (r = −0.6, P = 0.004). Within this +functional CD8+IFN-g+IL-2− population, cells with the CD45RA+ chemokine (C-C) +receptor 7 (CCR7)− phenotype inversely correlated with symptom score and had +lung-homing and cytotoxic potential. In the absence of crossreactive +neutralizing antibodies, CD8+ T cells specific to conserved viral epitopes +correlated with crossprotection against symptomatic influenza. This protective +immune correlate could guide universal influenza vaccine development. + +\cite{bentebibelInductionICOSCXCR3} +The role of T cells in mediating heterosubtypic protection against natural +influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) +provided a unique natural experiment to determine whether crossreactive +cellular immunity limits symptomatic illness in antibody-naive individuals. We +followed 342 healthy adults through the UK pandemic waves and correlated the +responses of pre-existing T cells to the pH1N1 virus and conserved core protein +epitopes with clinical outcomes after incident pH1N1 infection. Higher +frequencies of pre-existing T cells to conserved CD8 epitopes were found in +individuals who developed less severe illness, with total symptom score having +the strongest inverse correlation with the frequency of interferon-g (IFN-g)+ +interleukin-2 (IL-2)− CD8+ T cells (r = −0.6, P = 0.004). Within this +functional CD8+IFN-g+IL-2− population, cells with the CD45RA+ chemokine (C-C) +receptor 7 (CCR7)− phenotype inversely correlated with symptom score and had +lung-homing and cytotoxic potential. In the absence of crossreactive +neutralizing antibodies, CD8+ T cells specific to conserved viral epitopes +correlated with crossprotection against symptomatic influenza. This protective +immune correlate could guide universal influenza vaccine development. + +\cite{trieuLongtermMaintenanceInfluenzaSpecific2017} +Background. Annual vaccination for healthcare workers and other high-risk +groups is the mainstay of the public health strategy to combat influenza. +Inactivated influenza vaccines confer protection by inducing neutralizing +antibodies efficiently against homologous and closely matched virus strains. In +the absence of neutralizing antibodies, cross-reactive T cells have been shown +to limit disease severity. However, animal studies and a study in +immunocompromised children suggested that repeated vaccination hampers CD8+ T +cells. Yet the impact of repeated annual influenza vaccination on both +cross-reactive CD4+ and CD8+ T cells has not been explored, particularly in +healthy adults. Methods. We assembled a unique cohort of healthcare workers +who received a single AS03-adjuvanted H1N1pdm09 vaccine in 2009 and +subsequently either repeated annual vaccination or no further vaccination +during 2010–2013. Blood samples were collected before the influenza season or +vaccination to assess antibody and T-cell responses. Results. Antibody titers +to H1N1pdm09 persisted above the protective level in both the repeated- and +single-vaccination groups. The interferon γ+ (IFN-γ+) and multifunctional CD4+ +T-cell responses were maintained in the repeated group but declined +significantly in the single-vaccination group. The IFN-γ+CD8+ T cells remained +stable in both groups. Conclusions. This study provides the immunological +evidence base for continuing annual influenza vaccination in adults. + +\subsection{Machine learning usage} + +\cite{furmanApoptosisOtherImmune2013} +Despite the importance of the immune system in many diseases, there are +currently no objective benchmarks of immunological health. In an effort to +identifying such markers, we used influenza vaccination in 30 young (20–30 +years) and 59 older subjects (60 to >89 years) as models for strong and weak +immune responses, respectively, and assayed their serological responses to +influenza strains as well as a wide variety of other parameters, including gene +expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset +phenotypes and in vitro cytokine stimulation. Using machine learning, we +identified nine variables that predict the antibody response with 84\% accuracy. +Two of these variables are involved in apoptosis, which positively associated +with the response to vaccination and was confirmed to be a contributor to +vaccine responsiveness in mice. The identification of these biomarkers provides +new insights into what immune features may be most important for immune health. + +\cite{sobolevAdjuvantedInfluenzaH1N1Vaccination2016} +Adjuvanted vaccines afford invaluable protection against disease, and the +molecular and cellular changes they induce offer direct insight into human +immunobiology. Here we show that within 24 h of receiving adjuvanted swine flu +vaccine, healthy individuals made expansive, complex molecular and cellular +responses that included overt lymphoid as well as myeloid contributions. +Unexpectedly, this early response was subtly but significantly different in +people older than ~35 years. Wide-ranging adverse clinical events can seriously +confound vaccine adoption, but whether there are immunological correlates of +these is unknown. Here we identify a molecular signature of adverse events +that was commonly associated with an existing B cell phenotype. Thus +immunophenotypic variation among healthy humans may be manifest in complex +pathophysiological responses. + +\cite{tsangGlobalAnalysesHuman2014} +A major goal of systems biology is the development of models that accurately +predict responses to perturbation. Constructing such models requires the +collection of dense measurements of system states, yet transformation of data +into predictive constructs remains a challenge. To begin to model human +immunity, we analyzed immune parameters in depth both at baseline and in +response to influenza vaccination. Peripheral blood mononuclear cell +transcriptomes, serum titers, cell subpopulation frequencies, and B cell +responses were assessed in 63 individuals before and after vaccination and were +used to develop a systematic framework to dissect inter- and intra-individual +variation and build predictive models of postvaccination antibody responses. +Strikingly, independent of age and pre-existing antibody titers, accurate +models could be constructed using pre-perturbation cell populations alone, +which were validated using independent baseline time points. Most of the +parameters contributing to prediction delineated temporally stable baseline +differences across individuals, raising the prospect of immune monitoring +before intervention. + +\subsection{Problems of previous studies} +\cite{chattopadhyaySinglecellTechnologiesMonitoring2014} +The complex heterogeneity of cells, and their interconnectedness with each +other, are major challenges to identifying clinically relevant measurements +that reflect the state and capability of the immune system. Highly multiplexed, +single-cell technologies may be critical for identifying correlates of disease +or immunological interventions as well as for elucidating the underlying +mechanisms of immunity. Here we review limitations of bulk measurements and +explore advances in single-cell technologies that overcome these problems by +expanding the depth and breadth of functional and phenotypic analysis in space +and time. The geometric increases in complexity of data make formidable hurdles +for exploring, analyzing and presenting results. We summarize recent approaches +to making such computations tractable and discuss challenges for integrating +heterogeneous data obtained using these single-cell technologies. + +\cite{galliEndOmicsHigh2019} +High-dimensional single-cell (HDcyto) technologies, such as mass cytometry +(CyTOF) and flow cytometry, are the key techniques that hold a great promise +for deciphering complex biological processes. During the last decade, we +witnessed an exponential increase of novel HDcyto technologies that are able to +deliver an in-depth profiling in different settings, such as various autoimmune +diseases and cancer. The concurrent advance of custom data-mining algorithms +has provided a rich substrate for the development of novel tools in +translational medicine research. HDcyto technologies have been successfully +used to investigate cellular cues driving pathophysiological conditions, and to +identify disease-specific signatures that may serve as diagnostic biomarkers or +therapeutic targets. These technologies now also offer the possibility to +describe a complete cellular environment, providing unanticipated insights into +human biology. In this review, we present an update on the current cutting-edge +HDcyto technologies and their applications, which are going to be fundamental +in providing further insights into human immunology and pathophysiology of +various diseases. Importantly, we further provide an overview of the main +algorithms currently available for data mining, together with the conceptual +workflow for high-dimensional cytometric data handling and analysis. Overall, +this review aims to be a handy overview for immunologists on how to design, +develop and read HDcyto data. + +\cite{simoniMassCytometryPowerful2018} +Advancement in methodologies for single cell analysis has historically been a +major driver of progress in immunology. Currently, high dimensional flow +cytometry, mass cytometry and various forms of single cell sequencing-based +analysis methods are being widely adopted to expose the staggering +heterogeneity of immune cells in many contexts. Here, we focus on mass +cytometry, a form of flow cytometry that allows for simultaneous interrogation +of more than 40 different marker molecules, including cytokines and +transcription factors, without the need for spectral compensation. We argue +that mass cytometry occupies an important niche within the landscape of +single-cell analysis platforms that enables the efficient and in-depth study of +diverse immune cell subsets with an ability to zoom-in on myeloid and lymphoid +compartments in various tissues in health and disease. We further discuss the +unique features of mass cytometry that are favorable for combining multiplex +peptide-MHC multimer technology and phenotypic characterization of antigen +specific T cells. By referring to recent studies revealing the complexities of +tumor immune infiltrates, we highlight the particular importance of this +technology for studying cancer in the context of cancer immunotherapy. Finally, +we provide thoughts on current technical limitations and how we imagine these +being overcome. \bibliographystyle{unsrt} \bibliography{../references.bib} |