Publications by authors named "Anthony Cunningham"

202 Publications

Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial.

Lupus Sci Med 2021 May;8(1)

Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA

Introduction: Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.

Methods: Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.

Discussion And Dissemination: Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.

Trial Registration Number: ClinicalTrials.gov Registry (NCT04358302).
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http://dx.doi.org/10.1136/lupus-2021-000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108689PMC
May 2021

Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways.

PLoS Pathog 2021 Apr 27;17(4):e1009536. Epub 2021 Apr 27.

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, Australia.

Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro, inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived MNPs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal MNPs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting.
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http://dx.doi.org/10.1371/journal.ppat.1009536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104422PMC
April 2021

Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype.

PLoS Pathog 2021 Apr 19;17(4):e1009522. Epub 2021 Apr 19.

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia.

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.
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http://dx.doi.org/10.1371/journal.ppat.1009522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084337PMC
April 2021

Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells.

Nat Commun 2021 04 12;12(1):2147. Epub 2021 Apr 12.

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14CD1c monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).
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http://dx.doi.org/10.1038/s41467-021-22375-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042121PMC
April 2021

The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection.

Viruses 2021 02 25;13(3). Epub 2021 Feb 25.

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has recently been increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.
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http://dx.doi.org/10.3390/v13030359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996247PMC
February 2021

Vaccines for older adults.

BMJ 2021 02 22;372:n188. Epub 2021 Feb 22.

Departments of Pediatrics and Medicine, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, Colorado, USA.

The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants-as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine-or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.
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http://dx.doi.org/10.1136/bmj.n188DOI Listing
February 2021

The adjuvanted recombinant zoster vaccine is efficacious and safe in Asian adults ≥ 50 years of age: a sub-cohort analysis of the ZOE-50 and ZOE-70 randomized trials.

Hum Vaccin Immunother 2021 Jul 19;17(7):2050-2057. Epub 2021 Feb 19.

GSK, Rockville, MD, USA.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy (VE) against herpes zoster (HZ) in adults ≥50 years of age (YOA). This post-hoc analysis assessed the VE against HZ and postherpetic neuralgia (PHN), in participants from Asian study sites enrolled in ZOE-50/70. Reactogenicity and safety were also assessed. Participants ≥50 YOA were randomized 1:1 to receive 2 doses of either RZV or placebo, 2 months apart. VE was evaluated for a median follow-up of 4 years post-vaccination overall and by age in the ZOE-50 Asian population ≥50 YOA and in the pooled ZOE-50/70 Asian population ≥70 YOA. Of the 2,729 participants included in the ZOE-50 Asian population ≥50 YOA, 3 RZV and 66 placebo recipients reported a confirmed HZ episode. Overall VE was 95.6% (95% confidence interval [CI]: 86.4-99.1) against HZ and 100% (95% CI: 35.44-100) against PHN. In the pooled ZOE-50/70 Asian population ≥70 YOA, 4 RZV and 75 placebo recipients out of the 2,723 participants reported a confirmed HZ episode. Overall VE was 94.7% (95% CI: 85.9-98.6) against HZ and 89.8% (95% CI: 28.39-99.77) against PHN. Pain and myalgia were the most frequent solicited local and general adverse events, respectively, in both populations. No safety concern was identified during the study periods. RZV is highly efficacious against HZ and PHN and has an acceptable safety profile in Asian populations ≥50 YOA, similar to what was observed in the general ZOE-50/70 populations.: is a trademark owned by or licensed to the GSK group of companies.
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http://dx.doi.org/10.1080/21645515.2020.1859321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189096PMC
July 2021

Identification of SARS-CoV-2 Nucleocapsid and Spike T-Cell Epitopes for Assessing T-Cell Immunity.

J Virol 2021 02 24;95(6). Epub 2021 Feb 24.

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia.

Developing optimal T-cell response assays to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is critical for measuring the duration of immunity to this disease and assessing the efficacy of vaccine candidates. These assays need to target conserved regions of SARS-CoV-2 global variants and avoid cross-reactivity to seasonal human coronaviruses. To contribute to this effort, we employed an immunoinformatics analysis pipeline to identify immunogenic peptides resulting from conserved and highly networked regions with topological importance from the SARS-CoV-2 nucleocapsid and spike proteins. A total of 57 highly networked T-cell epitopes that are conserved across geographic viral variants were identified from these viral proteins, with a binding potential to diverse HLA alleles and 80 to 100% global population coverage. Importantly, 18 of these T-cell epitope derived peptides had limited homology to seasonal human coronaviruses making them promising candidates for SARS-CoV-2-specific T-cell immunity assays. Moreover, two of the NC-derived peptides elicited effector/polyfunctional responses of CD8 T cells derived from SARS-CoV-2 convalescent patients. The development of specific and validated immunologic tools is critical for understanding the level and duration of the cellular response induced by SARS-CoV-2 infection and/or vaccines against this novel coronavirus disease. To contribute to this effort, we employed an immunoinformatics analysis pipeline to define 57 SARS-CoV-2 immunogenic peptides within topologically important regions of the nucleocapsid (NC) and spike (S) proteins that will be effective for detecting cellular immune responses in 80 to 100% of the global population. Our immunoinformatics analysis revealed that 18 of these peptides had limited homology to circulating seasonal human coronaviruses and therefore are promising candidates for distinguishing SARS-CoV-2-specific immune responses from pre-existing coronavirus immunity. Importantly, CD8 T cells derived from SARS-CoV-2 survivors exhibited polyfunctional effector responses to two novel NC-derived peptides identified as HLA-binders. These studies provide a proof of concept that our immunoinformatics analysis pipeline identifies novel immunogens which can elicit polyfunctional SARS-CoV-2-specific T-cell responses.
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http://dx.doi.org/10.1128/JVI.02002-20DOI Listing
February 2021

Recombinant Zoster Vaccine Is Efficacious and Safe in Frail Individuals.

J Am Geriatr Soc 2021 Mar 16;69(3):744-752. Epub 2020 Nov 16.

Division of Geriatric Medicine, Department of Medicine, Dalhousie University, Halifax, Canada.

Background/objectives: Frail participants are often under-represented in randomized trials, raising questions about outcomes of interventions in real-world settings. Frailty is strongly associated with vulnerability to illness and adverse health outcomes. We studied the impact of frailty on recombinant zoster vaccine (RZV) clinical outcomes.

Design/setting: Data from two previously conducted phase III randomized trials of RZV were pooled. These two parent trials were conducted concurrently at the same study sites using the same methods.

Participants/intervention: In the two parent studies, participants aged ≥50 years (ZOE-50 study) and ≥70 years (ZOE-70 study), respectively, were randomized 1:1 to receive two doses of RZV or placebo.

Measurements: In the current ZOE-Frailty study (NCT03563183), a frailty index was created using previously validated methods. Clinical outcomes assessed by frailty status included vaccine efficacy, immunogenicity, reactogenicity, and safety.

Results: Of 29,305 participants from the pooled ZOE-50 and ZOE-70 total vaccinated cohort, 92% were included in this study. Mean age was 68.8 years; 58.1% were women; 45.6% were pre-frail and 11.3% frail. The percentage of frail participants increased with age from 5.7% aged 50-59 years to 22.7% aged ≥80 years. RZV vaccine efficacy against herpes zoster was >90% for all frailty subgroups (non-frail: 95.8% (95% confidence interval = 91.6-98.2), pre-frail: 90.4% (84.4-94.4), frail: 90.2% (75.4-97.0)). The RZV group demonstrated robust anti-gE antibody and gE-specific CD4 responses, with mean concentrations remaining above pre-vaccination levels at least 3 years post-dose two, in all frailty subgroups. In the RZV group, the percentage of participants reporting solicited adverse events tended to decrease with increasing frailty.

Conclusion: The relatively nonrestrictive inclusion/exclusion criteria in the parent ZOE studies resulted in a range of participants that included frail and pre-frail older adults. RZV significantly reduced the risk of herpes zoster across all frailty subgroups.
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http://dx.doi.org/10.1111/jgs.16917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984267PMC
March 2021

Blue genome: chromosome-scale genome reveals the evolutionary and molecular basis of indigo biosynthesis in Strobilanthes cusia.

Plant J 2020 11 28;104(4):864-879. Epub 2020 Oct 28.

Key Laboratory for Forest Resources Conservation and Utilization in the Southwest Mountains of China, Ministry of Education, Southwest Forestry University, Kunming, 650224, China.

Natural plant dyes have been developed and used across many traditional societies worldwide. The blue pigment indigo has seen widespread usage across South America, Egypt, Europe, India and China for thousands of years, mainly extracted from indigo-rich plants. The utilization and genetic engineering of indigo in industries and ethnobotanical studies on the effects of cultural selection on plant domestication are limited due to lack of relevant genetic and genomic information of dye plants. Strobilanthes cusia (Acanthaceae) is a typical indigo-rich plant important to diverse ethnic cultures in many regions of Asia. Here we present a chromosome-scale genome for S. cusia with a genome size of approximately 865 Mb. About 79% of the sequences were identified as repetitive sequences and 32 148 protein-coding genes were annotated. Metabolic analysis showed that the main indigoid pigments (indican, indigo and indirubin) were mainly synthesized in the leaves and stems of S. cusia. Transcriptomic analysis revealed that the expression level of genes encoding metabolic enzymes such as monooxygenase, uridine diphosphate-glycosyltransferase and β-glucosidase were significantly changed in leaves and stems compared with root tissues, implying their participation in indigo biosynthesis. We found that several gene families involved in indigo biosynthesis had undergone an expansion in number, with functional differentiation likely facilitating indigo biosynthesis in S. cusia. This study provides insight into the physiological and molecular bases of indigo biosynthesis, as well as providing genomic data that provide the basis for further study of S. cusia cultivation by Asia's traditional textile producers.
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http://dx.doi.org/10.1111/tpj.14992DOI Listing
November 2020

AFid: a tool for automated identification and exclusion of autofluorescent objects from microscopy images.

Bioinformatics 2021 05;37(4):559-567

School of Medicine, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia.

Motivation: Autofluorescence is a long-standing problem that has hindered the analysis of images of tissues acquired by fluorescence microscopy. Current approaches to mitigate autofluorescence in tissue are lab-based and involve either chemical treatment of sections or specialized instrumentation and software to 'unmix' autofluorescent signals. Importantly, these approaches are pre-emptive and there are currently no methods to deal with autofluorescence in acquired fluorescence microscopy images.

Results: To address this, we developed Autofluorescence Identifier (AFid). AFid identifies autofluorescent pixels as discrete objects in multi-channel images post-acquisition. These objects can then be tagged for exclusion from downstream analysis. We validated AFid using images of FFPE human colorectal tissue stained for common immune markers. Further, we demonstrate its utility for image analysis where its implementation allows the accurate measurement of HIV-Dendritic cell interactions in a colorectal explant model of HIV transmission. Therefore, AFid represents a major leap forward in the extraction of useful data from images plagued by autofluorescence by offering an approach that is easily incorporated into existing workflows and that can be used with various samples, staining panels and image acquisition methods. We have implemented AFid in ImageJ, Matlab and R to accommodate the diverse image analysis community.

Availability And Implementation: AFid software is available at https://ellispatrick.github.io/AFid.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa780DOI Listing
May 2021

Herpes Simplex Virus Type 1 Interactions with the Interferon System.

Int J Mol Sci 2020 Jul 21;21(14). Epub 2020 Jul 21.

Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead NSW 2145, Australia.

The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host.
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http://dx.doi.org/10.3390/ijms21145150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404291PMC
July 2020

Early impact of the Australian national shingles vaccination program with the herpes zoster live attenuated vaccine.

Hum Vaccin Immunother 2020 12 18;16(12):3081-3089. Epub 2020 May 18.

Faculty of Medicine and Health, The Westmead Institute for Medical Research , Westmead, Australia.

Herpes zoster (shingles) is a painful condition resulting from reactivation of latent varicella zoster virus (VZV). The Australian National Shingles Vaccination Program (commenced November 2016) provides free herpes zoster vaccination for eligible adults aged 70 years, with a 5-year catch-up program (until October 2021) for adults aged 71-79 years. Patterns and impact of the program were evaluated by analysis of vaccine distribution and delivery data and specific antiviral prescription data from the Pharmaceutical Benefits Scheme. During the first 2 years, uptake of funded live attenuated shingles vaccine ZOSTAVAX® (Zoster Virus Vaccine Live; ZVL) was high across the ongoing and catch-up programs. Before program implementation (2006-2016), herpes zoster coded antiviral prescription rates increased by 2.2% per year (95% CI: 1.5, 2.9) in the 70-79 years age group. In the two years since program launch, herpes zoster antiviral prescription rates declined substantially in this age group, by an average of 13.6% per year (95% CI: 1.5, 24.2). These results indicate that the National Shingles Vaccination Program has been highly successful in vaccinating a considerable proportion of Australian adults aged 70-79 years against herpes zoster and suggest that vaccine uptake was associated with decreased incidence of herpes zoster.
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http://dx.doi.org/10.1080/21645515.2020.1754702DOI Listing
December 2020

Post hoc analysis of reactogenicity trends between dose 1 and dose 2 of the adjuvanted recombinant zoster vaccine in two parallel randomized trials.

Hum Vaccin Immunother 2020 11 29;16(11):2628-2633. Epub 2020 Apr 29.

The Westmead Institute for Medical Research, University of Sydney , Sydney, Australia.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age. Solicited adverse events (AEs) were collected for 7 days post-each dose in a study sub-cohort. The incidence of reported solicited AEs was higher for RZV compared to placebo recipients. Since reactogenicity may contribute to a person's willingness to be vaccinated, knowing about expected reactogenicity might help keep high compliance with the second dose. This post hoc analysis assessed the intensity of solicited AEs post-dose 2 reported to the same event's intensity post-dose 1. Intensity was graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees who did not experience a specific AE post-dose 1, 72.6-91.7% did not experience the same event after dose 2. Although the frequency of grade 3 AEs post-dose 2 was the highest in participants reporting the same AEs at grade 3 post-dose 1, 65.8-89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the same AEs at lower intensity post-dose 2. These data can help inform health-care professionals about the frequency and intensity of AEs post-dose 2 with respect to post-dose 1.
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http://dx.doi.org/10.1080/21645515.2020.1741312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733973PMC
November 2020

Erratum: Scientists' Warning on Climate Change and Medicinal Plants.

Planta Med 2020 Jan 6;86(1):e1. Epub 2020 Feb 6.

Naturalis Biodiversity Center, Leiden, The Netherlands; Biosystematics Group, Wageningen University, The Netherlands.

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http://dx.doi.org/10.1055/a-1113-1659DOI Listing
January 2020

Mass Cytometry Imaging for the Study of Human Diseases-Applications and Data Analysis Strategies.

Front Immunol 2019 14;10:2657. Epub 2019 Nov 14.

The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia.

High parameter imaging is an important tool in the life sciences for both discovery and healthcare applications. Imaging Mass Cytometry (IMC) and Multiplexed Ion Beam Imaging (MIBI) are two relatively recent technologies which enable clinical samples to be simultaneously analyzed for up to 40 parameters at subcellular resolution. Importantly, these "Mass Cytometry Imaging" (MCI) modalities are being rapidly adopted for studies of the immune system in both health and disease. In this review we discuss, first, the various applications of MCI to date. Second, due to the inherent challenge of analyzing high parameter spatial data, we discuss the various approaches that have been employed for the processing and analysis of data from MCI experiments.
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http://dx.doi.org/10.3389/fimmu.2019.02657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868098PMC
November 2020

Clarification regarding the statement of the association between the recombinant zoster vaccine (RZV) and gout flares.

Ann Rheum Dis 2019 Dec 2. Epub 2019 Dec 2.

Centre for Virus Research, The Westmead Institute for Medical Research, University of Sydney, Australia, Westmead, New South Wales, Australia.

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http://dx.doi.org/10.1136/annrheumdis-2019-216639DOI Listing
December 2019

Scientists' Warning on Climate Change and Medicinal Plants.

Planta Med 2020 Jan 15;86(1):10-18. Epub 2019 Nov 15.

Naturalis Biodiversity Center, Leiden, The Netherlands; Biosystematics Group, Wageningen University, The Netherlands.

The recent publication of a World Scientists' Warning to Humanity highlighted the fact that climate change, absent strenuous mitigation or adaptation efforts, will have profound negative effects for humanity and other species, affecting numerous aspects of life. In this paper, we call attention to one of these aspects, the effects of climate change on medicinal plants. These plants provide many benefits for human health, particularly in communities where Western medicine is unavailable. As for other species, their populations may be threatened by changing temperature and precipitation regimes, disruption of commensal relationships, and increases in pests and pathogens, combined with anthropogenic habitat fragmentation that impedes migration. Additionally, medicinal species are often harvested unsustainably, and this combination of pressures may push many populations to extinction. A second issue is that some species may respond to increased environmental stresses not only with declines in biomass production but with changes in chemical content, potentially affecting quality or even safety of medicinal products. We therefore recommend actions including conservation and local cultivation of valued plants, sustainability training for harvesters and certification of commercial material, preservation of traditional knowledge, and programs to monitor raw material quality in addition to, of course, efforts to mitigate climate change.
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http://dx.doi.org/10.1055/a-1041-3406DOI Listing
January 2020

The Use of Microfluidic Neuronal Devices to Study the Anterograde Axonal Transport of Herpes Simplex Virus-1.

Methods Mol Biol 2020 ;2060:409-418

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Understanding how herpes simplex virus-1 (HSV-1) interacts with different parts of the neuron is fundamental in understanding the mechanisms behind HSV-1 transport during primary and recurrent infections. In this chapter, we describe a unique neuronal culture system that is capable of compartmentalizing neuronal cell bodies from their axons to study the transport of HSV-1 along axons. The ability to separate neuronal cell bodies and axons provides a unique model to investigate the mechanisms used by HSV-1 for viral transport, assembly, and exit from different parts of the neuron.
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http://dx.doi.org/10.1007/978-1-4939-9814-2_25DOI Listing
December 2020

Transmission Immunoelectron Microscopy of Herpes Simplex Virus-1-Infected Dorsal Root Ganglia Neurons Sectioned in Growth Plane.

Methods Mol Biol 2020 ;2060:355-364

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Transmission immunoelectron microscopy allows for the ultrastructural detection and localization of herpes simplex virus-1 (HSV-1) particles and viral proteins within the infected cell and their relation to the cell cytoskeleton, cellular proteins, vesicles, membranes, and organelles. For the successful application of immunoelectron microscopy, preservation of cell ultrastructure and of epitope antigenicity is essential during sample preparation. This chapter describes the use of chemical fixation followed by rapid cooling of HSV-1 infected sensory neurons in the presence of sucrose as a cryoprotectant to achieve optimal preservation of cell morphology and the use of freeze substitution and resin polymerization at low temperatures for preservation of protein antigenicity. In order to examine HSV-1 infection in the specialized compartments of the neurons (cell body, axons, and growth cones), neurons cultured on plastic coverslips are flat embedded prior to resin polymerization. Overall, this method allows for the ultrathin sectioning and immunogold labeling of the neurons and their axons in growth plane.
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http://dx.doi.org/10.1007/978-1-4939-9814-2_21DOI Listing
December 2020

Preparation of Herpes Simplex Virus-Infected Primary Neurons for Transmission Electron Microscopy.

Methods Mol Biol 2020 ;2060:343-354

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Transmission electron microscopy (TEM) provides the resolution necessary to identify both viruses and subcellular components of cells infected with many types of viruses, including herpes simplex virus. Recognized as a powerful tool in both diagnostic and research-based virology laboratories, TEM has made possible the identification of new viruses and has contributed to the elucidation of virus life cycle and virus-host cell interaction.While there are many sample preparation techniques for TEM, conventional processing using chemical fixation and resin embedding remains a useful technique, available in virtually all EM laboratories, for studying virus/cell ultrastructure. In this chapter, we describe the preparation of herpes simplex virus infected primary neurons, grown on plastic coverslips, to allow for sectioning of neurons and axons in their growth plane. This technique allows for TEM examination of cell bodies, axons, growth cones and varicosities, providing powerful insights into virus-cell interaction.
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http://dx.doi.org/10.1007/978-1-4939-9814-2_20DOI Listing
December 2020

Vaccines for Herpes Simplex: Recent Progress Driven by Viral and Adjuvant Immunology.

Methods Mol Biol 2020 ;2060:31-56

Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.

Herpes simplex viruses (HSV) types 1 and 2 are ubiquitous. They both cause genital herpes, occasionally severe disease in the immunocompromised, and facilitate much HIV acquisition globally. Despite more than 60 years of research, there is no licensed prophylactic HSV vaccine and some doubt as to whether this can be achieved. Nevertheless, a previous HSV vaccine candidate did have partial success in preventing genital herpes and HSV acquisition and another immunotherapeutic candidate reduced viral shedding and recurrent lesions, inspiring further research. However, the entry pathway of HSV into the anogenital mucosa and the subsequent cascade of immune responses need further elucidation so that these responses could be mimicked or improved by a vaccine, to prevent viral entry and colonization of the neuronal ganglia. For an effective novel vaccine against genital herpes the choice of antigen and adjuvant may be critical. The incorporation of adjuvants of the vaccine candidates in the past, may account for their partial efficacy. It is likely that they can be improved by understanding the mechanisms of immune responses elicited by different adjuvants and comparing these to natural immune responses. Here we review the history of vaccines for HSV, those in development and compare them to successful vaccines for chicken pox or herpes zoster. We also review what is known of the natural immune control of herpes lesions, via interacting innate immunity and CD4 and CD8 T cells and the lessons they provide for development of new, more effective vaccines.
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http://dx.doi.org/10.1007/978-1-4939-9814-2_2DOI Listing
December 2020

Manipulation of Mononuclear Phagocytes by HIV: Implications for Early Transmission Events.

Front Immunol 2019 24;10:2263. Epub 2019 Sep 24.

School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.

Mononuclear phagocytes are antigen presenting cells that play a key role in linking the innate and adaptive immune systems. In tissue, these consist of Langerhans cells, dendritic cells and macrophages, all of which express the key HIV entry receptors CD4 and CCR5 making them directly infectible with HIV. Mononuclear phagocytes are the first cells of the immune system to interact with invading pathogens such as HIV. Each cell type expresses a specific repertoire of pathogen binding receptors which triggers pathogen uptake and the release of innate immune cytokines. Langerhans cells and dendritic cells migrate to lymph nodes and present antigens to CD4 T cells, whereas macrophages remain tissue resident. Here we review how HIV-1 manipulates these cells by blocking their ability to produce innate immune cytokines and taking advantage of their antigen presenting cell function in order to gain transport to its primary target cells, CD4 T cells.
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http://dx.doi.org/10.3389/fimmu.2019.02263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768965PMC
October 2020

Persistence of a T Cell Infiltrate in Human Ganglia Years After Herpes Zoster and During Post-herpetic Neuralgia.

Front Microbiol 2019 11;10:2117. Epub 2019 Sep 11.

Discipline of Infectious Diseases and Immunology, The University of Sydney, Sydney, NSW, Australia.

Varicella-zoster virus (VZV) is a human herpesvirus which causes varicella (chicken pox) during primary infection, establishes latency in sensory ganglia, and can reactivate from this site to cause herpes zoster (HZ) (shingles). A major complication of HZ is a severe and often debilitating pain called post-herpetic neuralgia (PHN) which persists long after the resolution of the HZ-associated rash. The underlying cause of PHN is not known, although it has been postulated that it may be a consequence of immune cell mediated damage. However, the nature of virus-immune cell interactions within ganglia during PHN is unknown. We obtained rare formalin fixed paraffin embedded sections cut from surgically excised ganglia from a PHN-affected patient years following HZ rash resolution. VZV DNA was readily detected by qPCR and regions of immune infiltration were detected by hematoxylin and eosin staining. Immunostaining using a range of antibodies against immune cell subsets revealed an immune cell response comprising of CD4 and CD8 T cells and CD20 B cells. This study explores the immune cell repertoire present in ganglia during PHN and provides evidence for an ongoing immune cell inflammation years after HZ.
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http://dx.doi.org/10.3389/fmicb.2019.02117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749866PMC
September 2019

Efficacy of the adjuvanted recombinant zoster vaccine (RZV) by sex, geographic region, and geographic ancestry/ethnicity: A post-hoc analysis of the ZOE-50 and ZOE-70 randomized trials.

Vaccine 2019 10 16;37(43):6262-6267. Epub 2019 Sep 16.

GSK, 14200 Shady Grove Road, Rockville, MD 20850, USA. Electronic address:

Background: Herpes zoster (HZ) risk appears to vary by sex and geographic ancestry/ethnicity.

Methods: In 2 randomized clinical trials, participants received 2 doses of adjuvanted recombinant zoster vaccine (RZV) or placebo intramuscularly, 2 months apart. In this post-hoc analysis, we investigate efficacy of RZV against HZ and postherpetic neuralgia (PHN) by sex, geographic region, and geographic ancestry/ethnicity in ≥50-year-olds (ZOE-50: NCT01165177) and ≥70-year-olds (pooled data from ZOE-50 and ZOE-70: NCT01165229).

Results: Vaccine efficacy against HZ or PHN was similar in women and men. Across geographic regions, efficacy against HZ ranged between 95.7 and 97.2% in ≥50-year-olds, and between 87.3% and 95.1% in ≥70-year-olds; efficacy against PHN ranged between 86.8 and 100% in ≥70-year-olds. Across ancestral/ethnic groups, efficacy ranged between 88.1 and 100% against HZ and between 65.9 and 100% against PHN in ≥70-year-olds.

Conclusions: While the ZOE-50/70 studies were not powered or pre-designed for these post-hoc analyses, RZV appears efficacious against HZ and PHN irrespective of sex, region, or geographic ancestry/ethnicity.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.028DOI Listing
October 2019

Island blues: indigenous knowledge of indigo-yielding plant species used by Hainan Miao and Li dyers on Hainan Island, China.

J Ethnobiol Ethnomed 2019 Jul 3;15(1):31. Epub 2019 Jul 3.

Department of Economic Plants and Biotechnology, Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, 132# Lanhei Road, Kunming, 650201, China.

Background: Historically, indigo-yielding plant species were important cash crops from Central Asia to the southern United States and Central America. Indigo-dyed textiles were widely traded along the legendary Silk Road that linked China to Europe. Today, due to the labor-intensive nature of indigo extraction at the household level, lifestyle changes and the widespread availability of commercially produced indigo paste, traditional indigo extraction methods have declined in villages. Yet Li textile weavers on Hainan Island are internationally recognized as producers of indigo-dyed textile using warp ikat techniques. In contrast, Hainan Miao weavers produce indigo-dyed textiles using batik (wax resist) techniques. The aim of this study was to document the indigenous knowledge on indigo-yielding plant species used by both Hainan Miao and Li people on Hainan Island, China.

Method: Ethnic uses were documented during three field surveys, through a questionnaire survey of 193 respondents, comprising 144 Hainan Miao and 49 Li traditional dyers. Mention index (QI), Availability index (AI), and Preference ranking (PR) of each indigo-yielding plant species were calculated to screen out plant resources with potential development value.

Results: Five indigo-yielding plant species (from four plant families and four genera) were historically used by Hainan Miao and Li dyers. However, just four species are still in use. Strobilanthes cusia was the main indigo source for Hainan Miao dyers. Li dyers also commonly use Indigofera species (I. tinctoria and I. suffruticosa) for indigo extraction. Wrightia laevis is less commonly used as a contemporary indigo source. Indigo extraction by steeping in water to which lime is added to increase the pH is sharing by the five indigo-yielding plant species. Strobilanthes cusia had the highest QI, AI and PR values in Hainan Miao villages. Indigofera tinctoria had the highest QI and AI values, but Indigofera suffruticosa was preferred by Li dyers.

Conclusion: In the process of modernization and urbanization, some Hainan Miao and Li dyers retain the traditional indigo extraction methods. We found that Strobilanthes cusia and Indigofera tinctoria have the most potential for sustainable indigo production in the future. Furthermore, this study documents the details of extraction method from Wrightia laevis for the first time and the use of Ricinus communis seeds in that process. As one of the last places globally where Wrightia laevis is still used for indigo production, the may also be a nice market among textile collectors and museums that keeps the tradition of Wrightia laevis production and use for indigo extraction alive.
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http://dx.doi.org/10.1186/s13002-019-0314-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609400PMC
July 2019

Identification of HIV transmitting CD11c human epidermal dendritic cells.

Nat Commun 2019 06 21;10(1):2759. Epub 2019 Jun 21.

Centre for Virus Research, The Westmead Institute for Medical Research, 176 Hawkesbury Road, Westmead, New South Wales, 2145, Australia.

Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33 cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.
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http://dx.doi.org/10.1038/s41467-019-10697-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588576PMC
June 2019

Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant zoster vaccine: a pooled post-hoc analysis of two parallel randomized trials.

Hum Vaccin Immunother 2019 28;15(12):2865-2872. Epub 2019 Jun 28.

The Westmead Institute for Medical Research, Westmead, University of Sydney, Sydney, NSW, Australia.

In two pivotal efficacy studies (ZOE-50; ZOE-70), the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster (HZ).Adults aged ≥50 or ≥70 years (ZOE-50 [NCT01165177]; ZOE-70 [NCT01165229]) were randomized to receive 2 doses of RZV or placebo 2 months apart. Vaccine efficacy and safety were evaluated post-hoc in the pooled (ZOE-50/70) population according to the number and type of selected medical conditions present at enrollment.At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4-97.1) in participants with respiratory disorders to 97.0% (95%CI: 82.3-99.9) in those with coronary heart disease. Moreover, efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant.As indicated by the similarity of the point estimates, this post-hoc analysis suggests that RZV efficacy remains high in all selected medical conditions, as well as with increasing number of medical conditions. No safety concern was identified by the type or number of medical conditions present at enrollment.
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http://dx.doi.org/10.1080/21645515.2019.1627818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930113PMC
May 2020

Understanding the immunology of Shingrix, a recombinant glycoprotein E adjuvanted herpes zoster vaccine.

Curr Opin Immunol 2019 08 17;59:42-48. Epub 2019 Apr 17.

Departments of Pedatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States. Electronic address:

Herpes zoster is common in older and immune suppressed persons due to diminished VZV-specific cellular immunity. A recombinant herpes zoster vaccine (RZV) consisting of a single VZV glycoprotein and an adjuvant system stimulates robust and persistent VZV-specific antibody and CD4+ T cell responses in these high-risk populations. VZV-specific immune responses induced by RZV, including the generation of polyfunctional T cells, are driven by the synergistic actions of the components of the vaccine adjuvant system. RZV provides unprecedented protection against herpes zoster in older adults regardless of age at vaccination and is efficacious in immune suppressed populations. Adjuvanted subunit antigens may represent a general strategy for vaccines in the elderly and other individuals typically considered immunologically resistant to vaccination.
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http://dx.doi.org/10.1016/j.coi.2019.02.009DOI Listing
August 2019

Mechanisms of Immune Control of Mucosal HSV Infection: A Guide to Rational Vaccine Design.

Front Immunol 2019 6;10:373. Epub 2019 Mar 6.

Centre for Virus Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.

Herpes Simplex Virus (HSV) is a highly prevalent sexually transmitted infection that aside from causing cold sores and genital lesions, causes complications in the immunocompromised and has facilitated a large proportion of HIV acquisition globally. Despite decades of research, there is no prophylactic HSV vaccine ready for use in humans, leaving many questioning whether a prophylactic vaccine is an achievable goal. A previous HSV vaccine trial did have partial success in decreasing acquisition of HSV2-promising evidence that vaccines can prevent acquisition. However, there is still an incomplete understanding of the immune response pathways elicited by HSV after initial mucosal infection and how best to replicate these responses with a vaccine, such that acquisition and colonization of the dorsal root ganglia could be prevented. Another factor to consider in the rational design of an HSV vaccine is adjuvant choice. Understanding the immune responses elicited by different adjuvants and whether lasting humoral and cell-mediated responses are induced is important, especially when studies of past trial vaccines found that a sufficiently protective cell-mediated response was lacking. In this review, we discuss what is known of the immune control involved in initial herpes lesions and reactivation, including the importance of CD4 and CD8 T cells, and the interplay between innate and adaptive immunity in response to primary infection, specifically focusing on the viral relay involved. Additionally, a summary of previous and current vaccine trials, including the components used, immune responses elicited and the feasibility of prophylactic vaccines looking forward, will also be discussed.
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http://dx.doi.org/10.3389/fimmu.2019.00373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414784PMC
September 2020