ORCID Profile
0000-0002-4155-7433
Current Organisation
University of Melbourne at Peter Doherty Institute
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Cellular Immunology | Virology | Molecular Evolution | Immunology
Health Related to Ageing | Human Biological Preventatives (e.g. Vaccines) | Expanding Knowledge in the Biological Sciences |
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 2022
Publisher: The American Association of Immunologists
Date: 03-2020
Abstract: Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/effector memory-like profile that is sustained into older age. Whereas low-grade levels of plasma cytokine/chemokine were apparent in older donors (& y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older in iduals and an aged environment resulted in the reversal of the baseline effector molecule profile comparable with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced Escherichia coli–specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRαβ analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire ersity of virus-specific CD8+ T cells. These data suggest that MAIT cells in older in iduals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity.
Publisher: Research Square Platform LLC
Date: 28-07-2020
DOI: 10.21203/RS.3.RS-47021/V1
Abstract: Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have mild or asymptomatic infection, but the underlying immunological differences remain unclear. We describe clinical features, virology, longitudinal cellular and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who were repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children were similar to their parents at all timepoints. All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincided with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child had IgG antibody detected against the S1 protein and virus neutralising activity ranging from just detectable to robust titers. Using a systems serology approach, we show that all family members demonstrated higher levels of SARS-CoV-2-specific antibody features than healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological evidence of infection. This raises the possibility that despite chronic exposure, immunity in children prevents establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may therefore not identify exposed children, with implications for epidemiological and clinical studies across the life-span.
Publisher: American Society for Microbiology
Date: 15-11-2016
DOI: 10.1128/JVI.01633-16
Abstract: Due to antigenic drift of influenza viruses, seasonal influenza vaccines need to be updated annually. These vaccines are based on predictions of strains likely to circulate in the next season. However, vaccine efficacy is greatly reduced in the case of a mismatch between circulating and vaccine strains. Furthermore, novel antigenically distinct influenza viruses are introduced into the human population from animal reservoirs occasionally and may cause pandemic outbreaks. To d en the impact of seasonal and pandemic influenza, vaccines that induce broadly protective and long-lasting immunity are preferred. Because influenza virus-specific CD8 + T cells are directed mainly against relatively conserved internal proteins, like nucleoprotein (NP), they are highly cross-reactive and afford protection against infection with antigenically distinct influenza virus strains, so-called heterosubtypic immunity. Here, we used modified vaccinia virus Ankara (MVA) as a vaccine vector for the induction of influenza virus NP-specific CD8 + T cells. To optimize the induction of CD8 + T cell responses, we made several modifications to NP, aiming at retaining the protein in the cytosol or targeting it to the proteasome. We hypothesized that these strategies would increase antigen processing and presentation and thus improve the induction of CD8 + T cell responses. We showed that NP with increased degradation rates improved CD8 + T cell activation in vitro if the amount of antigen was limited or if CD8 + T cells were of low functional avidity. However, after immunization of C57BL/6 mice, no differences were detected between modified NP and wild-type NP (NPwt), since NPwt already induced optimal CD8 + T cell responses. IMPORTANCE Due to the continuous antigenic drift of seasonal influenza viruses and the threat of a novel pandemic, there is a great need for the development of novel influenza vaccines that offer broadly protective immunity against multiple subtypes. CD8 + T cells can provide immunity against multiple subtypes of influenza viruses by the recognition of relatively conserved internal antigens. In this study, we aimed at optimizing the CD8 + T cell response to influenza A virus by making modifications to influenza A virus nucleoprotein (NP) expressed from the modified vaccinia virus Ankara (MVA) vaccine vector. These modifications resulted in increased antigen degradation, thereby producing elevated levels of peptides that can be presented on major histocompatibility complex (MHC) class I molecules to CD8 + T cells. Although we were unable to increase the NP-specific immune response in the mouse strain used, this approach may have benefits for vaccine development using less-immunogenic proteins.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2021
DOI: 10.1038/S41467-021-23212-X
Abstract: Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8 + T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous in iduals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8 + T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2 550–558 -specific CD8 + T cells being cross-reactive between IAV and IBV. Memory CD8 + T cells towards these specificities are present in blood (CD27 + CD45RA − phenotype) and tissues (CD103 + CD69 + phenotype) of healthy in iduals, and effector CD27 − CD45RA − PD-1 + CD38 + CD8 + T cells in IAV/IBV patients. Our data show influenza-specific CD8 + T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8 + T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
Publisher: eLife Sciences Publications, Ltd
Date: 28-06-2022
Publisher: American Thoracic Society
Date: 11-2017
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1258
Publisher: Public Library of Science (PLoS)
Date: 04-08-2020
Publisher: Springer Science and Business Media LLC
Date: 11-11-2020
DOI: 10.1038/S41467-020-19545-8
Abstract: Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2017
DOI: 10.1038/S41598-017-08719-Y
Abstract: Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro , ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA-GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies.
Publisher: MDPI AG
Date: 26-03-2018
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3701261
Publisher: The American Association of Immunologists
Date: 15-05-2022
Abstract: Understanding the generation of immunity to SARS-CoV-2 in lymphoid tissues draining the site of infection has implications for immunity to SARS-CoV-2. We performed tonsil biopsies under local anesthesia in 19 subjects who had recovered from SARS-CoV-2 infection 24–225 d previously. The biopsies yielded & million cells for flow cytometric analysis in 17 subjects. Total and SARS-CoV-2 spike-specific germinal center B cells, and T follicular helper cells, were readily detectable in human tonsils early after SARS-CoV-2 infection, as assessed by flow cytometry. Responses were higher in s les within 2 mo of infection but still detectable in some subjects out to 7 mo following infection. We conclude the tonsils are a secondary lymphoid organ that develop germinal center responses to SARS-CoV-2 infection and could play a role in the long-term development of immunity.
Publisher: Springer Science and Business Media LLC
Date: 06-12-2019
DOI: 10.1038/S41467-019-13346-4
Abstract: Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8 + T cells to mount robust responses. We elucidate the HLA-A*68:01 + CD8 + T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% in iduals have immunodominant A68/NP 145 + CD8 + T cell responses. Dissecting A68/NP 145 + CD8 + T cells in low vs. medium/high responders reveals that high responding donors have A68/NP 145 + CD8 + memory T cells with clonally expanded TCRαβs, while low-responders display A68/NP 145 + CD8 + T cells with predominantly naïve phenotypes and non-expanded TCRαβs. Single-cell index sorting and TCRαβ analyses link expansion of A68/NP 145 + CD8 + T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8 + T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8 + T cell compartments in HLA-A*68:01-expressing in iduals for establishment of pre-existing protective memory T cell pools.
Publisher: American Society for Microbiology
Date: 06-2018
DOI: 10.1128/JVI.00232-18
Abstract: Influenza virus-specific CD8 + T lymphocytes (CTLs) contribute to clearance of influenza virus infections and reduce disease severity. Variation at amino acid residues located in or outside CTL epitopes has been shown to affect viral recognition by virus-specific CTLs. In the present study, we investigated the effect of naturally occurring variation at residues outside the conserved immunodominant and HLA*0201-restricted M1 58-66 epitope, located in the influenza virus M1 protein, on the extent of virus replication in the presence of CTLs specific for the epitope. To this end, we used isogenic viruses with an M1 gene segment derived from either an avian or a human influenza virus, HLA-transgenic human epithelial cells, human T cell clones specific for the M1 58-66 epitope or a control epitope, and a novel, purposely developed in vitro system to coculture influenza virus-infected cells with T cells. We found that the M gene segment of a human influenza A/H3N2 virus afforded the virus the capacity to replicate better in the presence of M1 58-66 -specific CTLs than the M gene segment of avian viruses. These findings are in concordance with previously observed differential CTL activation, caused by variation at extra-epitopic residues, and may reflect an immune adaptation strategy of human influenza viruses that allows them to cope with potent CTL immunity to the M1 58-66 epitope in HLA-A*0201-positive in iduals, resulting in increased virus replication and shedding and possibly increasing disease severity. IMPORTANCE Influenza viruses are among the leading causes of acute respiratory tract infections. CD8 + T lymphocytes display a high degree of cross-reactivity with influenza A viruses of various subtypes and are considered an important correlate of protection. Unraveling viral immune evasion strategies and identifying signs of immune adaptation are important for defining the role of CD8 + T lymphocytes in affording protection more accurately. Improving our insight into the interaction between influenza viruses and virus-specific CD8 + T lymphocyte immunity may help to advance our understanding of influenza virus epidemiology, aid in risk assessment of potentially pandemic influenza virus strains, and benefit the design of vaccines that induce more broadly protective immunity.
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3751796
Publisher: Research Square Platform LLC
Date: 04-10-2021
DOI: 10.21203/RS.3.RS-745648/V1
Abstract: Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4 + and CD8 + T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.
Publisher: Informa UK Limited
Date: 21-07-2017
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.VACCINE.2014.08.003
Abstract: Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8(+) T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.
Publisher: American Society for Microbiology
Date: 15-01-2016
DOI: 10.1128/JVI.02439-15
Abstract: Natural influenza A virus infections elicit both virus-specific antibody and CD4 + and CD8 + T cell responses. Influenza A virus-specific CD8 + cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M1 58–66 ) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M1 58–66 epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8 + T cell recognition of the M1 58–66 epitope. These data indicate that human influenza A viruses can impair recognition by M1 58–66 -specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 in iduals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses. IMPORTANCE Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8 + cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes, mutations occur that allow influenza A viruses to evade recognition by CTLs. However, the immunodominant HLA-A*0201-restricted M1 58–66 epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M1 58–66 epitope that influence the recognition of the epitope. These results provide novel insights into the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 15-05-2023
Publisher: Springer Science and Business Media LLC
Date: 20-06-2011
Abstract: One reason why subunit protein and DNA vaccines are often less immunogenic than live-attenuated and whole-inactivated virus vaccines is that they lack the co-stimulatory signals provided by various components of the more complex vaccines. The HIV-1 envelope glycoprotein complex (Env) is no exception to this rule. Other factors that limit the induction of neutralizing antibodies against HIV-1 lie in the structure and instability of Env. We have previously stabilized soluble trimeric mimics of Env by introducing a disulfide bond between gp120 and gp41 and adding a trimer stabilizing mutation in gp41 (SOSIP.R6 gp140). We further stabilized the SOSIP.R6 gp140 using a GCN4-based isoleucine zipper motif, creating SOSIP.R6-IZ gp140. In order to target SOSIP.R6-IZ to immune cells, including dendritic cells, while at the same time activating these cells, we fused SOSIP.R6-IZ to the active domain of CD40 ligand (CD40L), which may serve as a ' cis -adjuvant'. The Env component of the SOSIP.R6-IZ-CD40L fusion construct bound to CD4 and neutralizing antibodies, while the CD40L moiety interacted with CD40. Furthermore, the chimeric molecule was able to signal efficiently through CD40 and induce maturation of human dendritic cells. Dendritic cells secreted IL-6, IL-10 and IL-12 in response to stimulation by SOSIP.R6-IZ-CD40L and were able to activate naïve T cells. Chimeric HIV-1 gp140 - CD40L trimers can target and activate dendritic cells. Targeting and activating immune cells using CD40L and other ' cis -adjuvants' may improve subunit protein vaccine immunogenicity for HIV-1 and other infectious diseases.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-09-2020
Abstract: As the recall of CD8 + T cell memory promotes rapid recovery in, for ex le, influenza, we investigated circulating SARS-CoV-2−specific CD8 + T cells from COVID-19 patients. For two HLA-A*02:01 SARS-CoV-2−specific CD8 + T cell epitopes, we found that, while ex vivo frequencies of responding T cells were approximately fivefold higher than for pre−COVID-19 s les, they were ∼10-fold lower than for influenza or EBV-specific memory CD8 + T cells. Additionally, SARS-CoV-2−specific CD8 + T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes. Might this unexpectedly low prevalence of classical effector memory T cells be a negative consequence of the infectious process that could be avoided by prior priming with an appropriately constituted vaccine?
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
DOI: 10.1038/S41598-018-24820-2
Abstract: The replication-deficient orthopoxvirus modified vaccinia virus Ankara (MVA) is a promising vaccine vector against various pathogens and has an excellent safety record. However, pre-existing vector-specific immunity is frequently suggested to be a drawback of MVA-based vaccines. To address this issue, mice were vaccinated with MVA-based influenza vaccines in the presence or absence of orthopoxvirus-specific immunity. Importantly, protective efficacy of an MVA-based influenza vaccine against a homologous challenge was not impaired in the presence of orthopoxvirus-specific pre-existing immunity. Nonetheless, orthopoxvirus-specific pre-existing immunity reduced the induction of antigen-specific antibodies under specific conditions and completely prevented induction of antigen-specific T cell responses by rMVA-based vaccination. Notably, antibodies induced by vaccinia virus vaccination, both in mice and humans, were not capable of neutralizing MVA. Thus, when using rMVA-based vaccines it is important to consider the main correlate of protection induced by the vaccine, the vaccine dose and the orthopoxvirus immune status of vaccine recipients.
Publisher: Oxford University Press (OUP)
Date: 12-04-2018
Publisher: Springer Science and Business Media LLC
Date: 25-09-2023
Publisher: Proceedings of the National Academy of Sciences
Date: 04-10-2021
Abstract: Indigenous populations worldwide are highly susceptible to influenza virus infections. Vaccination with inactivated virus is highly recommended to protect Indigenous populations, including Indigenous Australians. There is no study to date that assessed immune responses induced by the inactivated seasonal influenza vaccine in the Indigenous population. Vaccine recommendations are thus based on data generated for non-Indigenous populations and might not be representative for Indigenous people. We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of cT FH 1 cells at the acute response strongly correlating with total change of antibody vaccine titers induced by vaccination. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and subsequent complications.
Publisher: Microbiology Society
Date: 08-2015
DOI: 10.1099/VIR.0.000156
Publisher: MDPI AG
Date: 03-09-2012
DOI: 10.3390/V4091438
Publisher: Springer Science and Business Media LLC
Date: 09-07-2020
DOI: 10.1038/S41467-020-17441-9
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Future Medicine Ltd
Date: 09-2015
DOI: 10.2217/FMB.15.65
Abstract: In contrast to influenza A viruses, which have been investigated extensively, influenza B viruses have attracted relatively little attention. However, influenza B viruses are an important cause of morbidity and mortality in the human population and full understanding of their biological and epidemiological properties is imperative to better control this important pathogen. However, some of its characteristics are still elusive and warrant investigation. Here, we review evolution, epidemiology, pathogenesis and immunity and identify gaps in our knowledge of influenza B viruses. The ergence of two antigenically distinct influenza B viruses is highlighted. The co-circulation of viruses of these two lineages necessitated the development of quadrivalent influenza vaccines, which is discussed in addition to possibilities to develop universal vaccination strategies.
Publisher: Frontiers Media SA
Date: 08-10-2018
Publisher: Springer Science and Business Media LLC
Date: 05-06-2020
DOI: 10.1038/S41467-020-16633-7
Abstract: Virtual memory T (T VM ) cells are antigen-naïve CD8 + T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (T MEM ) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of T VM cells and their altered functionality with age, here we investigate T VM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of T VM , but not T MEM , cells and it increases with age in both subsets. The elevated SRC observed in aged mouse T VM cells and human CD8 + T cells from older in iduals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of T VM , but not T MEM , cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8 + T cells.
Publisher: eLife Sciences Publications, Ltd
Date: 15-07-2022
DOI: 10.7554/ELIFE.77969
Abstract: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood s les upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. OCR-treated MS patients exhibit a preserved recall response of CD8 + T central memory cells following first vaccination compared to HCs and a similar CD4 + circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4 + and CD8 + T cells. Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8 + T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-05-2022
DOI: 10.1212/NXI.0000000000001178
Abstract: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod. This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2–specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated. In ocrelizumab-treated patients (N = 24), IFN-γ–producing SARS-CoV-2–specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2–specific T cells were detected after second (N = 12) and third (N = 9) vaccinations. In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2020
Publisher: American Society for Microbiology
Date: 02-2014
DOI: 10.1128/JVI.02843-13
Abstract: In February 2013, zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of the virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8 + T cells (cytotoxic T lymphocytes [CTLs]) elicited during seasonal influenza A virus infections. These virus-specific CD8 + T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2 and H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8 + T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8 + T cells to H7N9 variants of known influenza A virus epitopes and H7N9 virus-infected cells was determined by their gamma interferon (IFN-γ) response and lytic activity. It was concluded that, apart from recognition of in idual H7N9 variant epitopes, CD8 + T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8 + T cells may afford some protection against infection with the new virus.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 06-04-2015
Publisher: Springer Science and Business Media LLC
Date: 16-03-2020
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41467-021-23018-X
Abstract: How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal s les from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 + or CD4 + T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Publisher: Oxford University Press (OUP)
Date: 12-01-2015
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1038/S41467-021-22236-7
Abstract: The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such ergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children ( n = 89), adults ( n = 98), elderly ( n = 57), and COVID-19 patients ( n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy in iduals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy in iduals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1423
Abstract: High‐magnitude CD8 + T cell responses are associated with mild COVID‐19 disease however, the underlying characteristics that define CD8 + T cell‐mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope‐specific CD8 + T cells remain largely unexplored and are essential for the development of next‐generation broad‐protective vaccines. This study identified a broad spectrum of conserved SARS‐CoV‐2 CD8 + T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS‐CoV‐2 infection. CD8 + T cells from 51 convalescent COVID‐19 donors were analysed for their ability to recognise 133 predicted and previously described SARS‐CoV‐2‐derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in‐depth ex vivo profiling of CD8 + T cell responses at quantitative and phenotypic levels. A comprehensive panel of 49 mostly conserved SARS‐CoV‐2‐specific CD8 + T cell epitopes, including five newly identified low‐magnitude epitopes, was established. We confirmed the immunodominance of HLA‐A*01:01/ORF1ab 1637–1646 and B*07:02/N 105–113 and identified B*35:01/N 325–333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N 361–369 and A*02:01/S 269–277 , depended on the donors' HLA‐I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID‐19 donors. SARS‐CoV‐2 infection induces a predominant CD8 + T memory response directed against a broad spectrum of conserved SARS‐CoV‐2 epitopes, which likely contributes to long‐term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross‐reactive immune response, which could aid future vaccine strategies.
Publisher: MDPI AG
Date: 10-11-2020
DOI: 10.20944/PREPRINTS202011.0316.V1
Abstract: The study experimentally investigated a novel approach for producing hydrogen from methane cracking in dielectric barrier discharge catalytic plasma reactor using a nanocatalyst. Plasma-catalytic methane (CH4) cracking was undertaken in a dielectric barrier discharge (DBD) catalytic plasma reactor using Ni/MgAl2O4. The Ni/MgAl2O4 was synthesised through co-precipitation followed customised hydrothermal method. The physicochemical properties of the catalyst were examined using X-ray diffraction (XRD), scanning electron microscopy - energy dispersive X-ray spectrometry (SEM-EDX) and thermogravimetric analysis (TGA). The Ni/MgAl2O4 shows a porous structure spinel MgAl2O4 and thermal stability. In the catalytic-plasma methane cracking, the Ni/MgAl2O4 shows 80% of the maximum conversion of CH4 with H2 selectivity 75%. Furthermore, the stability of the catalyst was encouraging 16 hours with CH4 conversion above 75%, and the selectivity of H2 was above 70%. This is attributed to the synergistic effect of the catalyst and plasma. The plasma-catalytic CH4 cracking is a promising technology for the simultaneous H2 and carbon nanotubes (CNTs) production for energy storage applications.
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3781631
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
Location: Australia
Start Date: Start date not available
End Date: End date not available
Funder: European Commission
View Funded ActivityStart Date: 2022
End Date: 12-2024
Amount: $438,712.00
Funder: Australian Research Council
View Funded Activity