1,720,971 research outputs found
Investigation of alternative seasonal influenza vaccination strategies to improve humoral and cellular immune responses among older adults
No full textOlder adults (≥65 years) contribute to the majority of influenza-related mortality and are prioritized for annual influenza vaccination. However, vaccine effectiveness in this age group is low and rapidly wanes within months. Currently, there are multiple seasonal inactivated influenza vaccine (IIV) options for older adults, but the regimen that invokes maximum protective capacity is unclear.
This study describes two randomized clinical trials (RCT), RETAIN and PIVOT, exploring the use of alternative vaccination strategies among older adults to maximize protective potential of currently available IIVs in a setting with perennial and/or semi-annual influenza seasonality. Through probing a wide array of immune correlates of protection, the magnitude, quality, and longevity of vaccine-elicited humoral and cellular responses is explored.
RETAIN is a longitudinal 5-year RCT investigating vaccine immunogenicity between once- versus twice-annual vaccination with the standard dose IIV among older adults aged 70-79 years in Hong Kong. RETAIN spans 10 semi-annual (6-monthly) influenza seasons and results from the first 3 seasons (2016/17, 2017 and 2017/18) are described. Twice-annual vaccination conferred short-term improved HAI and HA-specific IgG antibody quantity and antibody avidity during the 2017 southern hemisphere season against a novel vaccine H1 component but did not offer protective advantage against an unchanged H3 component compared to once-annual vaccination. Repeat vaccination led to a progressive decline in HAI responses, whilst ADCC and ADCP responses were not negatively impacted. Twice-annual vaccination also reduced long-term polyfunctional T cell quality, whilst T cell quality was improved by once-annual vaccination regardless of an additional mid-year dose. Therefore, occasional twice-annual vaccination strategies may be beneficial when a drifted seasonal virus emerges mid-year or when vaccine mismatch occurs, but otherwise confers no added immunogenicity.
PIVOT is a longitudinal 4-year RCT among older adults (65-82 years) in Hong Kong, investigating vaccine immunogenicity between standard dose IIV (S-IIV) versus three “enhanced” IIVs (eIIV): MF59-adjuvanted (A-eIIV), high dose HA (H-eIIV) and recombinant-HA (R-eIIV). This study spans 4 annual influenza seasons and results from years 1-3 (2017/18 to 2019/20) are described. In year 1, subjects were randomized to receive one of four vaccines, and were re-randomized in year 2 to generate combination vaccination strategies. Vaccination with eIIVs consistently conferred higher H3 HA-specific IgG quantity, ADCC and ADCP activity across 3 years. Following year 2 vaccination, improved IgG antibody longevity up to one year was observed for sequential eIIV (both repeated and alternating) regimens only. Across 3 years, only repeated A-eIIV receipt consistently enriched antibody avidity and cross-reactivity towards drifted H3 strains. Overall, sequential annual vaccination with enhanced vaccines should be prioritized for older adults to prolong year-round improve overall quality of response.
By encompassing a broad array of immune parameters, this study explores various strategies to maximize protective potential of existing seasonal IIVs available to older adults. These findings are also important for providing a benchmark for desirable immune responses needed for an effective next-generation influenza vaccine among older adults.published_or_final_versionPublic HealthDoctoralDoctor of Philosoph
The expression, function and potential mechanism of long non-coding RNA in the context of influenza virus infection
No full textInfluenza virus leads to contagious respiratory-related diseases, posing threats to public health.
The molecular interplay between viruses and host cells determines the progression of influenza
virus infection. Robust cellular reactions are triggered during influenza virus infection to
activate and synthesize antiviral molecules that target influenza virus replication in multiple
stages; meanwhile, host molecules can also be exploited to facilitate virus infection. As a
deeper understanding of virus-host interaction has been gained during recent years, diverse
types of novel molecules that play a crucial role in influenza virus infection have been
discovered. Long non-coding RNAs (lncRNAs) is a class of RNA transcripts that is encoded
from non-coding genes with limited protein-coding capacity, showing its significance in
influenza virus infection. However, the understanding of lncRNAs in influenza virus infection
remains preliminary.
This study revealed the profile landscape of lncRNAs and identified lncRNAs candidates that
are universally differentially expressed in influenza virus infection. Moreover, the study
unveiled Interferon Sensitive Response Element (ISRE)-dependent lncRNAs, lncRNAs
carrying ISRE-like motifs in the promoter region, may act as a vital regulator in influenza
virus-induced immune responses. To study the biological effect of lncRNAs, two lncRNA
candidates were investigated in detail. USP30-AS1 was identified as a universally differentially
expressed ISRE-dependent lncRNA in influenza virus infection. Knocking out of USP30-AS1
enhanced influenza virus replication via promoting viral protein synthesis without affecting
viral RNA transcription and replication. The activation of USP30-AS1 was JAK-STAT
signaling pathway dependent and USP30-AS1 was engaged in the regulation of inflammatory
response. Loss of USP30-AS1 switches a balanced immune response into acute inflammatory
reaction. Furthermore, BCAR4 was identified as another highly universally differentially
expressed lncRNA that carries out its biological activity through an immune-independent
manner during influenza virus infection. Deletion of BCAR4 inhibited influenza virus
replication via suppressing viral RNA transcription and replication, as well as subsequent viral
protein synthesis. The activation of BCAR4 was achieved through a potential promoter-enhancer
interaction in response to influenza virus infection and was associated with impeded
spliceosomes function.
This study reveals the profile signatures of lncRNAs in influenza virus infection and identifies
novel ISRE-dependent lncRNAs, providing more information and laying a solid foundation for
further studies. Elaborate study in USP30-AS1 reveals that influenza virus infection triggers
immune effectors, as well as immune regulators, which plays an equally critical role to
maintain a fine-tuned immune response. Moreover, the study of USP30-AS1 provides an
possible explanation for tissue damage caused by HPAIs induced acute inflammatory response,
implying USP30-AS1 may serve as a potential therapeutic target for attenuating severe
inflammation induced by HPAIs infection. The study of BCAR4 gains key clues that influenza
virus may trigger BCAR4-dependent emergency splicing working mode in cells by inducing
cell stresses and that this BCAR4-dependent splicing machinery is required for influenza virus
replication. The study also indicates that USP30-AS1 and BCAR4 is universally triggered under
different biological processes during influenza virus infection and highlights that the potential
value of USP30-AS1 and BCAR4 for prospective clinical application.published_or_final_versionPublic HealthDoctoralDoctor of Philosoph
Investigation of T cell immune pressure on the influenza virus genome within a universal vaccination model
No full textImproved vaccination strategies are needed against influenza which affects millions of people annually and causes a substantial health burden in many countries. Current strategies are vulnerable to seasonal adaptations caused by mutations within the influenza genome which are generated in response to selection pressure and offer little to no protection against newly emerging pandemic influenza strains. Next generation vaccines aim to provide universal protection against current circulating viruses and future arising variants. Universal vaccination can be achieved through multiple approaches, but a prevailing theory is augmenting T cell responses to leverage T cell recognition of conserved viral epitopes of influenza viruses. While T cells are essential for viral clearance and reducing severity during influenza infection, they can also exert increased immunological pressure which can lead to viral variants which adapt to circumvent the immune response. The capacity of T cell-activating vaccines to inadvertently cause viral escape mutants is one of the biggest questions still facing next generation vaccine design.
This study characterises mutational rates of the influenza genome and immunological responses to a next generation vaccine, Wyeth/IL-15/5Flu within a mouse challenge model. It was observed that this universal vaccine candidate leads to an increased incidence and frequency of significant mutations across multiple influenza genes when compared to mock vaccinated or seasonal inactivated influenza vaccines. However, the nature of these mutations appears to be stochastic, as few variants arose directly within T cell epitope regions. No high frequency T cell escape mutants were identified during this study, but potentially beneficial mutations were seen to arise in non-epitope regions after Wyeth/IL-15/5Flu vaccination, such as in polymerase genes and HA glycosylation positions. T cell depletion of Wyeth/IL-15/5Flu vaccinated mice reduced the incidence of significant mutations and the overall mutational frequency across multiple genes, indicating that this increased mutational rate is T cell mediated. This suggests that universal influenza vaccination may provide an increased opportunity for adaptations to arise within the influenza genome. This study also further characterised effects of mild immunopathology of increased weight loss associated with universal vaccination. Wyeth/IL-15/5Flu vaccination skewed the response to an inflammatory Th1 response compared to an anti-inflammatory Th2 response upon phylogenic HA group 2 influenza virus challenge. It is possible this occurred due to a mismatch between humoral group 1 HA phylogeny influenza-specific vaccine immunity and heterosubtypic cellular immunity during group 2 influenza infection.
This study provides a novel examination of the effects of next generation T cell-activating vaccines on the influenza genome and host responses. This project used an interdisciplinary approach combining both next generation sequencing techniques and immunological approaches to determine the impact of universal vaccination against the influenza genome. These findings can help inform future vaccine design and aid in the generation of improved influenza vaccination strategies.published_or_final_versionPublic HealthDoctoralDoctor of Philosoph
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Universal influenza vaccines are futile when benchmarked against seasonal influenza vaccines
No full textDispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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