Microbiology & Immunology - Research Publications

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    Broad spectrum SARS-CoV-2-specific immunity in hospitalized First Nations peoples recovering from COVID-19
    Zhang, W ; Clemens, EB ; Kedzierski, L ; Chua, BY ; Mayo, M ; Lonzi, C ; Hinchcliff, A ; Rigas, V ; Middleton, BF ; Binks, P ; Rowntree, LC ; Allen, LF ; Tan, H-X ; Petersen, J ; Chaurasia, P ; Krammer, F ; Wheatley, AK ; Kent, SJ ; Rossjohn, J ; Miller, A ; Lynar, S ; Nelson, J ; Nguyen, THO ; Davies, J ; Kedzierska, K (WILEY, 2023-11)
    Indigenous peoples globally are at increased risk of COVID-19-associated morbidity and mortality. However, data that describe immune responses to SARS-CoV-2 infection in Indigenous populations are lacking. We evaluated immune responses in Australian First Nations peoples hospitalized with COVID-19. Our work comprehensively mapped out inflammatory, humoral and adaptive immune responses following SARS-CoV-2 infection. Patients were recruited early following the lifting of strict public health measures in the Northern Territory, Australia, between November 2021 and May 2022. Australian First Nations peoples recovering from COVID-19 showed increased levels of MCP-1 and IL-8 cytokines, IgG-antibodies against Delta-RBD and memory SARS-CoV-2-specific T cell responses prior to hospital discharge in comparison with hospital admission, with resolution of hyperactivated HLA-DR+ CD38+ T cells. SARS-CoV-2 infection elicited coordinated ASC, Tfh and CD8+ T cell responses in concert with CD4+ T cell responses. Delta and Omicron RBD-IgG, as well as Ancestral N-IgG antibodies, strongly correlated with Ancestral RBD-IgG antibodies and Spike-specific memory B cells. We provide evidence of broad and robust immune responses following SARS-CoV-2 infection in Indigenous peoples, resembling those of non-Indigenous COVID-19 hospitalized patients.
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    Breakthrough COVID-19 is mild in vaccinated patients with hematological malignancy receiving tixagevimab-cilgavimab as pre-exposure prophylaxis
    Hall, VG ; Lim, C ; Saunders, NR ; Klimevski, E ; Nguyen, THO ; Kedzierski, L ; Seymour, JF ; Wadhwa, V ; Thursky, KA ; Yong, MK ; Kedzierska, K ; Slavin, MA ; Teh, BW (TAYLOR & FRANCIS LTD, 2023-09)
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    Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan
    van de Sandt, CE ; Nguyen, THO ; Gherardin, NA ; Crawford, JC ; Samir, J ; Minervina, AA ; Pogorelyy, MV ; Rizzetto, S ; Szeto, C ; Kaur, J ; Ranson, N ; Sonda, S ; Harper, A ; Redmond, SJ ; McQuilten, HA ; Menon, T ; Sant, S ; Jia, X ; Pedrina, K ; Karapanagiotidis, T ; Cain, N ; Nicholson, S ; Chen, Z ; Lim, R ; Clemens, EB ; Eltahla, A ; La Gruta, NL ; Crowe, J ; Lappas, M ; Rossjohn, J ; Godfrey, DI ; Thomas, PG ; Gras, S ; Flanagan, KL ; Luciani, F ; Kedzierska, K (NATURE PORTFOLIO, 2023-11)
    CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158-66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections.
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    CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity
    Gressier, E ; Schulte-Schrepping, J ; Petrov, L ; Brumhard, S ; Stubbemann, P ; Hiller, A ; Obermayer, B ; Spitzer, J ; Kostevc, T ; Whitney, PG ; Bachem, A ; Odainic, A ; van de Sandt, C ; Nguyen, THO ; Ashhurst, T ; Wilson, K ; Oates, CVL ; Gearing, LJ ; Meischel, T ; Hochheiser, K ; Greyer, M ; Clarke, M ; Kreutzenbeck, M ; Gabriel, SS ; Kastenmueller, W ; Kurts, C ; Londrigan, SL ; Kallies, A ; Kedzierska, K ; Hertzog, PJ ; Latz, E ; Chen, Y-CE ; Radford, KJ ; Chopin, M ; Schroeder, J ; Kurth, F ; Gebhardt, T ; Sander, LE ; Sawitzki, B ; Schultze, JL ; Schmidt, SV ; Bedoui, S (NATURE PORTFOLIO, 2023-06)
    Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.
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    Long-term safety and immunogenicity of an MF59- adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2 in adults aged 18-55 years or >56 years: 12-month results from a randomised, double-blind, placebo-controlled, phase 1 trial
    Chappell, KJ ; Mordant, FL ; Amarilla, AA ; Modhiran, N ; Liang, B ; Li, Z ; Wijesundara, DK ; Lackenby, JA ; Grif, P ; Bennet, JK ; Hensen, L ; Zhang, W ; Nguyen, THO ; Tran, MH ; Tapley, P ; Barnes, J ; Reading, PC ; Kedzierska, K ; Ranasinghe, C ; Subbarao, K ; Watterson, D ; Young, PR ; Munro, TP (ELSEVIER, 2023-11)
    BACKGROUND: We previously demonstrated the safety and immunogenicity of an MF59-adjuvanted COVID-19 vaccine based on the SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp using HIV-1 glycoprotein 41 sequences. Here, we describe 12-month results in adults aged 18-55 years and ≥56 years. METHODS: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020-December 2021; ClinicalTrials.govNCT04495933; active, not recruiting). Healthy adults (Part 1: 18-55 years; Part 2: ≥56 years) received two doses of placebo, 5 μg, 15 μg, or 45 μg vaccine, or one 45 μg dose of vaccine followed by placebo (Part 1 only), 28 days apart (n = 216; 24 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to day 394 (12 months after second dose). Effects of subsequent COVID-19 vaccination on humoral responses were examined. FINDINGS: All two-dose vaccine regimens were well tolerated and elicited strong antigen-specific and neutralising humoral responses, and CD4+ T-cell responses, by day 43 in younger and older adults, although cellular responses were lower in older adults. Humoral responses waned by day 209 but were boosted in those receiving authorised vaccines. Neutralising activity against Delta and Omicron variants was present but lower than against the Wuhan strain. Cross-reactivity in HIV diagnostic tests declined over time but remained detectable in most participants. INTERPRETATION: The SARS-CoV-2 molecular clamp vaccine is well tolerated and evokes robust immune responses in adults of all ages. Although the HIV glycoprotein 41-based molecular clamp is not being progressed, the clamp concept represents a viable platform for vaccine development. FUNDING: This study was funded by the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government.
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    Robust immunity to influenza vaccination in haematopoietic stem cell transplant recipients following reconstitution of humoral and adaptive immunity
    Zhang, W ; Rowntree, LC ; Muttucumaru, R ; Damelang, T ; Aban, M ; Hurt, AC ; Auladell, M ; Esterbauer, R ; Wines, B ; Hogarth, M ; Turner, SJ ; Wheatley, AK ; Kent, SJ ; Patil, S ; Avery, S ; Morrissey, O ; Chung, AW ; Koutsakos, M ; Nguyen, THO ; Cheng, AC ; Kotsimbos, TC ; Kedzierska, K (WILEY, 2023)
    OBJECTIVES: Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients. METHODS: We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls. RESULTS: Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21loCD27+ influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains. CONCLUSIONS: Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups.
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    Dual TCR-α Expression on Mucosal-Associated Invariant T Cells as a Potential Confounder of TCR Interpretation
    Suliman, S ; Kjer-Nielsen, L ; Iwany, SK ; Tamara, KL ; Loh, L ; Grzelak, L ; Kedzierska, K ; Ocampo, TA ; Corbett, AJ ; McCluskey, J ; Rossjohn, J ; Leon, SR ; Calderon, R ; Lecca-Garcia, L ; Murray, MB ; Moody, DB ; Van Rhijn, I (AMER ASSOC IMMUNOLOGISTS, 2022-03-15)
    Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant TCRα-chain that uses T cell receptor α-variable 1-2 (TRAV1-2) joined to TRAJ33/20/12 and recognizes metabolites from bacterial riboflavin synthesis bound to the Ag-presenting molecule MHC class I related (MR1). Our attempts to identify alternative MR1-presented Ags led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered Ag specificity likely alters affinity for the most potent known Ag, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), we performed bulk TCRα- and TCRβ-chain sequencing and single-cell-based paired TCR sequencing on T cells that bound the MR1-5-OP-RU tetramer with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Although we initially interpreted these as diverse MR1-restricted TCRs, single-cell TCR sequencing revealed that cells expressing atypical TCRα-chains also coexpressed an invariant MAIT TCRα-chain. Transfection of each non-TRAV1-2 TCRα-chain with the TCRβ-chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα-chain expression in human T cells and competition for the endogenous β-chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and noncanonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of Ag specificity.
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    Cutting Edge: High-Dose Live Attenuated Influenza Vaccines Elicit Pulmonary Tissue-Resident Memory CD8+ T Cells in the Face of Pre-Existing Humoral Immunity
    Zheng, MZM ; Fritzlar, S ; Wang, Z ; Tan, TK ; Kedzierska, K ; Townsend, A ; Reading, PC ; Wakim, LM (AMER ASSOC IMMUNOLOGISTS, 2022-11-15)
    In this study, we investigated how pre-existing Ab immunity to influenza virus established from prior immunizations affects the development of CD8+ T cell responses evoked after vaccination with a live attenuated vaccine. Using a mouse model and a panel of live attenuated influenza virus vaccine candidates (cold adapted and single cycle), we show that pre-existing influenza-specific Abs directed against the vaccine backbone attenuate the size and quality of the vaccine-induced CD8+ T cell response. Importantly, we show that increasing the vaccine dose can overcome this impediment, resulting in improved vaccine-induced circulating and tissue-resident memory CD8+ T cell responses, which were protective against heterologous influenza challenge. Thus, the reduced size and quality of the T cell response elicited by a live attenuated influenza virus vaccine imparted by the influenza-specific Ab landscape of the vaccinee can be overcome by increasing vaccine dose.
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    Cutting Edge: SARS-CoV-2 Infection Induces Robust Germinal Center Activity in the Human Tonsil
    Tan, H-X ; Wragg, KM ; Kelly, HG ; Esterbauer, R ; Dixon, BJ ; Lau, JSY ; Flanagan, KL ; van de Sandt, CE ; Kedzierska, K ; McMahon, JH ; Wheatley, AK ; Juno, JA ; Kent, SJ (AMER ASSOC IMMUNOLOGISTS, 2022-05-15)
    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 >3 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 samples 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.
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    Robust SARS-CoV-2 antibody and T cell immunity following three COVID-19 vaccine doses in inflammatory bowel disease patients receiving anti-TNF or alternative treatments
    Zhang, E ; Nguyen, THO ; Allen, LF ; Kedzierski, L ; Rowntree, LC ; Chang, SY ; Zhang, W ; Habel, JR ; Foo, IJ ; Menon, T ; Mitchell, J ; Leong, RW ; Bond, K ; Williamson, DA ; Kedzierka, K ; Christensen, B (BMJ PUBLISHING GROUP, 2024-03-07)