The Network aims to promote multi-disciplinary approaches to address challenging vaccine-related questions. This page contains a curated list of publications that highlight high-impact and collaborative approaches.
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Journal articleFrankel GM, Habibzay M, Crepin-Sevenou V, et al., 2015,
Tir-induced actin remodeling triggers expression of CXCL1 in enterocytes and neutrophil recruitment during Citrobacter rodentium infection
, Infection and Immunity, Vol: 83, Pages: 3342-3354, ISSN: 1098-5522The hallmarks of enteropathogenic Escherichia coli (EPEC) infection are formation of attaching and effacing (A/E) lesions on mucosal surfaces and actin-rich pedestals on cultured cells, both dependent on the type III secretion system effector Tir. Following translocation into cultured cells and clustering by intimin, Tir Y474 is phosphorylated leading to recruitment of Nck, activation of N-WASP and actin polymerization via the Arp2/3 complex. A secondary, weak, actin polymerization pathway is triggered via an NPY motif (Y454). Importantly, Y454 and Y474 play no role in A/E lesion formation on mucosal surfaces following infection with the EPEC-like mouse pathogen Citrobacter rodentium. In this study we investigated the roles of Tir segments located upstream of Y451 and downstream of Y471 in C. rodentium colonization and A/E lesion formation. We also tested the role Tir residues Y451 and Y471 play in host immune responses to C. rodentium infection. We found that deletion of amino acids 382-462 or 478-547 had no impact on the ability of Tir to mediate A/E lesion formation, although deletion of amino acids 478-547 affected Tir translocation. Examination of enterocytes isolated from infected mice revealed that a C. rodentium expressing Tir_Y451A/Y471A recruited significantly less neutrophils to the colon and triggered less colonic hyperplasia on day 14 post infection, compared to infection with the wild type strain. Consistently, enterocytes isolated from mice infected with C. rodentium expressing Tir_Y451A/Y471A expressed significantly less CXCL1. These result show that Tir-induced actin remodeling plays a direct role in modulation of immune responses to C. rodentium infection.
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Journal articleMessens W, Bolton D, Frankel G, et al., 2015,
Defining pathogenic verocytotoxin-producing <i>Escherichia coli</i> (VTEC) from cases of human infection in the European Union, 2007-2010
, EPIDEMIOLOGY AND INFECTION, Vol: 143, Pages: 1652-1661, ISSN: 0950-2688- Author Web Link
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- Citations: 22
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Journal articleHunter PJ, Shaw RK, Berger CN, et al., 2015,
Older leaves of lettuce (Lactuca spp.) support higher levels of Salmonella enterica ser. Senftenberg attachment and show greater variation between plant accessions than do younger leaves
, FEMS Microbiology Letters, Vol: 362, ISSN: 0378-1097Salmonella can bind to the leaves of salad crops including lettuce and survive for commercially relevant periods. Previous studies have shown that younger leaves are more susceptible to colonization than older leaves and that colonization levels are dependent on both the bacterial serovar and the lettuce cultivar. In this study, we investigated the ability of two Lactuca sativa cultivars (Saladin and Iceberg) and an accession of wild lettuce (L. serriola) to support attachment of Salmonella enterica serovar Senftenberg, to the first and fifth to sixth true leaves and the associations between cultivar-dependent variation in plant leaf surface characteristics and bacterial attachment. Attachment levels were higher on older leaves than on the younger ones and these differences were associated with leaf vein and stomatal densities, leaf surface hydrophobicity and leaf surface soluble protein concentrations. Vein density and leaf surface hydrophobicity were also associated with cultivar-specific differences in Salmonella attachment, although the latter was only observed in the older leaves and was also associated with level of epicuticular wax.
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Journal articleHabibi MS, Jozwik A, Makris S, et al., 2015,
Impaired antibody-mediated protection and defective IgA B cell memory in experimental infection of adults with respiratory syncytial virus
, American Journal of Respiratory and Critical Care Medicine, Vol: 191, ISSN: 1535-4970Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
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Journal articleSchreiber F, Kay S, Frankel G, et al., 2015,
The H<i>d</i>, H<i>j</i>, and H<i>z66</i> flagella variants of <i>Salmonella enterica</i> serovar Typhi modify host responses and cellular interactions
, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322- Author Web Link
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- Citations: 9
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Journal articleChiu C, Openshaw PJ, 2015,
Antiviral B cell and T cell immunity in the lungs
, NATURE IMMUNOLOGY, Vol: 16, Pages: 18-26, ISSN: 1529-2908- Author Web Link
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- Citations: 91
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Journal articleWhite MT, Bejon P, Olotu A, et al., 2014,
A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine
, BMC Medicine, Vol: 12, ISSN: 1741-7015Background: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titresto the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes ofclinical malaria.Methods: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity(anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes.We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.Results: Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001),pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001).Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095).Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and asecond slower decay over the next three to four years. Antibody titres were significantly associated with protection,with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections inchildren. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculationrate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S willavert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infantswhen co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations includean absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.Conclusions: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observedva
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Journal articleBlagborough AM, Churcher TS, Upton LM, et al., 2013,
Transmission-blocking interventions eliminate malaria from laboratory populations
, Nature Communications, Vol: 4, ISSN: 2041-1723Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field.
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Journal articleBejon P, White MT, Olotu A, et al., 2013,
Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data
, LANCET INFECTIOUS DISEASES, Vol: 13, Pages: 319-327, ISSN: 1473-3099- Author Web Link
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- Citations: 68
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