Publications
75 results found
Flasche S, Jit M, Rodríguez-Barraquer I, et al., 2016, The long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study, Plos Medicine, Vol: 13, ISSN: 1549-1676
BACKGROUND: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. METHODS AND FINDINGS: The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%-25% (all simulations: -3%-34%) and in high-transmission settings (SP9 ≥ 70%) by 13%-25% (all simulations: 10%- 34%). These endemicity levels are represen
Ferguson NM, Rodriguez-Barraquer I, Dorigatti I, et al., 2016, Benefits and risks of the Sanofi-Pasteur dengue vaccine: Modeling optimal deployment, Science, Vol: 353, Pages: 1033-1036, ISSN: 0036-8075
The first approved dengue vaccine has now been licensed in six countries. We propose that this live attenuated vaccine acts like a silent natural infection in priming or boosting host immunity. A transmission dynamic model incorporating this hypothesis fits recent clinical trial data well and predicts that vaccine effectiveness depends strongly on the age group vaccinated and local transmission intensity. Vaccination in low-transmission settings may increase the incidence of more severe “secondary-like” infection and, thus, the numbers hospitalized for dengue. In moderate transmission settings, we predict positive impacts overall but increased risks of hospitalization with dengue disease for individuals who are vaccinated when seronegative. However, in high-transmission settings, vaccination benefits both the whole population and seronegative recipients. Our analysis can help inform policy-makers evaluating this and other candidate dengue vaccines.
Cook LBM, Melamed A, Demontis MA, et al., 2016, Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients, Retrovirology, Vol: 13, ISSN: 1742-4690
BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) infects an estimated 10 million persons globally with transmission resulting in lifelong infection. Disease, linked to high proviral load, occurs in a minority. In established infection HTLV-1 replicates through infectious spread and clonal expansion of infected lymphocytes. Little is known about acute HTLV-1 infection. The kinetics of early HTLV-1 infection, following transplantation-acquired infection in three recipients from one HTLV-1 infected donor, is reported. The recipients were treated with two HTLV-1 enzyme inhibitors 3 weeks post exposure following the detection of HTLV-1 provirus at low level in each recipient. HTLV-1 infection was serially monitored by serology, quantification of proviral load and HTLV-1 2LTR DNA circles and by HTLV-1 unique integration site analysis.ResultsHTLV-1 antibodies were first detected 16–39 days post-transplantation. HTLV-1 provirus was detected by PCR on day 16–23 and increased by 2–3 log by day 38–45 with a peak proviral doubling time of 1.4 days, after which steady state was reached. The rapid proviral load expansion was associated with high frequency of HTLV-1 2LTR DNA circles. The number of HTLV-1 unique integration sites was high compared with established HTLV-1 infection. Clonal expansion of infected cells was detected as early as day 37 with high initial oligoclonality index, consistent with early mitotic proliferation.ConclusionsIn recipients infected through organ transplantation HTLV-1 disseminated rapidly despite early anti-HTLV-1 treatment. Proviral load set point was reached within 6 weeks. Seroconversion was not delayed. Unique integration site analysis and HTLV-1 2LTR DNA circles indicated early clonal expansion and high rate of infectious spread.
Bangham CRM, Melamed A, Laydon D, et al., 2015, HTLV-1 drives vigorous clonal expansion of infected CD8 + T cells in natural infection, Retrovirology, Vol: 12, ISSN: 1742-4690
BackgroundHuman T-lymphotropic Virus Type I (HTLV-1) is a retrovirus that persistently infects 5–10 million individuals worldwide and causes disabling or fatal inflammatory and malignant diseases. The majority of the HTLV-1 proviral load is found in CD4 + T cells, and the phenotype of adult T cell leukemia (ATL) is typically CD4 + . HTLV-1 also infects CD8 + cells in vivo, but the relative abundance and clonal composition of the two infected subpopulations have not been studied. We used a high-throughput DNA sequencing protocol to map and quantify HTLV-1 proviral integration sites in separated populations of CD4 + cells, CD8 + cells and unsorted peripheral blood mononuclear cells from 12 HTLV-1-infected individuals.ResultsWe show that the infected CD8 + cells constitute a median of 5 % of the HTLV-1 proviral load. However, HTLV-1-infected CD8 + clones undergo much greater oligoclonal proliferation than the infected CD4 + clones in infected individuals, regardless of disease manifestation. The CD8 + clones are over-represented among the most abundant clones in the blood and are redetected even after several years.ConclusionsWe conclude that although they make up only 5 % of the proviral load, the HTLV-1-infected CD8 + T-cells make a major impact on the clonal composition of HTLV-1-infected cells in the blood. The greater degree of oligoclonal expansion observed in the infected CD8 + T cells, contrasts with the CD4 + phenotype of ATL; cases of CD8 + adult T-cell leukaemia/lymphoma are rare. This work is consistent with growing evidence that oligoclonal expansion of HTLV-1-infected cells is not sufficient for malignant transformation.
Laydon DJ, Sunkara V, Bangham CRM, et al., 2015, Estimating rates of de novo infection and mitotic replication in HTLV-1 persistence: de novo infection continues after early infection, RETROVIROLOGY, Vol: 12, ISSN: 1742-4690
Asquith RE, Laydon D, Bangham C, 2015, Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 370, ISSN: 1471-2970
A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens. However, direct measurement of total TCR diversity is impossible. The diversity is high and the frequency distribution of individual TCRs is heavily skewed; the diversity therefore cannot be captured in a blood sample. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. This is analogous to the ‘unseen species problem’ in ecology. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.
Ploubidis GB, Benova L, Grundy E, et al., 2014, Lifelong Socio Economic Position and biomarkers of later life health: Testing the contribution of competing hypotheses, SOCIAL SCIENCE & MEDICINE, Vol: 119, Pages: 258-265, ISSN: 0277-9536
- Author Web Link
- Cite
- Citations: 28
Niederer HA, Laydon DJ, Melamed A, et al., 2014, HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP, Virology Journal, Vol: 11, ISSN: 1743-422X
Background: HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by aunique proviral integration site in the host genome. The proviral load is strongly correlated with odds of theinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence thatasymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency ofHLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shownthat specific features of the host genome flanking the proviral integration site favour clone survival and spontaneousexpression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies werenot designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients.Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs andHAM/TSP patients, and between individuals with strong or weak HBZ presentation.Methods: We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLAclass I alleles predicted to bind HBZ peptides were classified ‘strong’ HBZ binders; the remainder were classified ‘weakbinders’.Results: The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes andin areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integrationsites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespectiveof HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weakHBZ binders.Conclusion: Clonal abundance is correl
Cook LB, Melamed A, Niederer H, et al., 2014, The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia/lymphoma, Blood, Vol: 123, Pages: 3925-3931, ISSN: 0006-4971
Adult T-cell leukemia/lymphoma (ATL) occurs in ∼5% of human T-lymphotropic virus type 1 (HTLV-1)–infected individuals and is conventionally thought to be a monoclonal disease in which a single HTLV-1+ T-cell clone progressively outcompetes others and undergoes malignant transformation. Here, using a sensitive high-throughput method, we quantified clonality in 197 ATL cases, identified genomic characteristics of the proviral integration sites in malignant and nonmalignant clones, and investigated the proviral features (genomic structure and 5′ long terminal repeat methylation) that determine its capacity to express the HTLV-1 oncoprotein Tax. Of the dominant, presumed malignant clones, 91% contained a single provirus. The genomic characteristics of the integration sites in the ATL clones resembled those of the frequent low-abundance clones (present in both ATL cases and carriers) and not those of the intermediate-abundance clones observed in 24% of ATL cases, suggesting that oligoclonal proliferation per se does not cause malignant transformation. Gene ontology analysis revealed an association in 6% of cases between ATL and integration near host genes in 3 functional categories, including genes previously implicated in hematologic malignancies. In all cases of HTLV-1 infection, regardless of ATL, there was evidence of preferential survival of the provirus in vivo in acrocentric chromosomes (13, 14, 15, 21, and 22).
Laydon DJ, Melamed A, Sim A, et al., 2014, Quantification of HTLV-1 Clonality and TCR Diversity, PLOS COMPUTATIONAL BIOLOGY, Vol: 10
- Author Web Link
- Open Access Link
- Cite
- Citations: 53
Melamed A, Witkover AD, Laydon DJ, et al., 2014, Clonality of HTLV-2 in natural infection, PLoS Pathogens, Vol: 10, Pages: 1-9, ISSN: 1553-7366
Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.
Bangham C, Cook L, Laydon D, et al., 2013, Clonality, latency and integration of HTLV-1 in vivo, RETROVIROLOGY, Vol: 10, Pages: S3-S3, ISSN: 1742-4690
Gillet NA, Cook L, Laydon DJ, et al., 2013, Strongyloidiasis and Infective Dermatitis Alter Human T Lymphotropic Virus-1 Clonality <i>in vivo</i>, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7374
- Author Web Link
- Open Access Link
- Cite
- Citations: 52
Melamed A, Laydon DJ, Gillet NA, et al., 2013, Genome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7366
- Author Web Link
- Open Access Link
- Cite
- Citations: 76
Hodson A, Laydon DJ, Bain BJ, et al., 2013, Pre-morbid human T-lymphotropic virus type I proviral load, rather than percentage of abnormal lymphocytes, is associated with an increased risk of aggressive adult T-cell leukemia/lymphoma, HAEMATOLOGICA, Vol: 98, Pages: 385-388, ISSN: 0390-6078
- Author Web Link
- Cite
- Citations: 17
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.