Microbiology & Immunology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 67
  • Item
    No Preview Available
    Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections
    Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Reynaldi, A ; Cromer, D ; Tan, CW ; Wang, L-F ; Wines, BD ; Hogarth, PM ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (AMER SOC CLINICAL INVESTIGATION INC, 2023-09-22)
    Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19-recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19-recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19-uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
  • Item
    No Preview Available
    Durable reprogramming of neutralizing antibody responses following Omicron breakthrough infection
    Lee, WS ; Tan, H-X ; Reynaldi, A ; Esterbauer, R ; Koutsakos, M ; Nguyen, J ; Amarasena, T ; Kent, HE ; Aggarwal, A ; Turville, SG ; Taiaroa, G ; Kinsella, P ; Liew, KC ; Tran, T ; Williamson, DA ; Cromer, D ; Davenport, MP ; Kent, SJ ; Juno, JA ; Khoury, DS ; Wheatley, AK (AMER ASSOC ADVANCEMENT SCIENCE, 2023-07)
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated individuals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following Omicron BA.1 or BA.2 breakthrough infection, with longitudinal sampling up to 8 months after infection. Both BA.1 and BA.2 infections robustly boosted neutralization activity against the infecting strain while expanding breadth against BA.4, although neutralization activity was substantially reduced for the more recent XBB and BQ.1.1 strains. Cross-reactive memory B cells against both ancestral and Omicron spike were predominantly expanded by infection, with limited recruitment of de novo Omicron-specific B cells or antibodies. Modeling of neutralization titers predicts that protection from symptomatic reinfection against antigenically similar strains will be durable but is undermined by new emerging strains with further neutralization escape.
  • Item
    No Preview Available
    Mucosal antibody responses following Vaxzevria vaccination
    Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Tan, CW ; Wang, L-F ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (WILEY, 2023-11)
    Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination (Vaxzevria) only weakly induces nasal IgG and IgA responses, unless vaccinees have been previously infected. However, little is known about how Vaxzevria vaccination impacts the ability of mucosal antibodies to induce Fc responses, particularly against SARS-CoV-2 variants of concern (VoCs). Here, we profiled paired mucosal (saliva, tears) and plasma antibodies from COVID-19 vaccinated only vaccinees (uninfected, vaccinated) and COVID-19 recovered vaccinees (COVID-19 recovered, vaccinated) who both received Vaxzevria vaccines. SARS-CoV-2 ancestral-specific IgG antibodies capable of engaging FcγR3a were significantly higher in the mucosal samples of COVID-19 recovered Vaxzevria vaccinees in comparison with vaccinated only vaccinees. However, when IgG and FcγR3a engaging antibodies were tested against a panel of SARS-CoV-2 VoCs, the responses were ancestral-centric with weaker recognition of Omicron strains observed. In contrast, salivary IgA, but not plasma IgA, from Vaxzevria vaccinees displayed broad cross-reactivity across all SARS-CoV-2 VoCs tested. Our data highlight that while intramuscular Vaxzevria vaccination can enhance mucosal antibodies responses in COVID-19 recovered vaccinees, restrictions by ancestral-centric bias may have implications for COVID-19 protection. However, highly cross-reactive mucosal IgA could be key in addressing these gaps in mucosal immunity and may be an important focus of future SARS-CoV-2 vaccine development.
  • Item
    No Preview Available
    Antibody Fc-binding profiles and ACE2 affinity to SARS-CoV-2 RBD variants
    Haycroft, ER ; Davis, SK ; Ramanathan, P ; Lopez, E ; Purcell, RA ; Tan, LL ; Pymm, P ; Wines, BD ; Hogarth, PM ; Wheatley, AK ; Juno, JA ; Redmond, SJ ; Gherardin, NA ; Godfrey, DI ; Tham, W-H ; Selva, KJ ; Kent, SJ ; Chung, AW (SPRINGER, 2023-08)
    Emerging SARS-CoV-2 variants, notably Omicron, continue to remain a formidable challenge to worldwide public health. The SARS-CoV-2 receptor-binding domain (RBD) is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. Here, we comprehensively investigated the impact of RBD mutations, including 5 variants of concern (VOC) or interest-including Omicron (BA.2)-and 33 common point mutations, both on IgG recognition and ACE2-binding inhibition, as well as FcγRIIa- and FcγRIIIa-binding antibodies, in plasma from two-dose BNT162b2-vaccine recipients and mild-COVID-19 convalescent subjects obtained during the first wave using a custom-designed bead-based 39-plex array. IgG-recognition and FcγR-binding antibodies were decreased against the RBD of Beta and Omicron, as well as point mutation G446S, found in several Omicron sub-variants as compared to wild type. Notably, while there was a profound decrease in ACE2 inhibition against Omicron, FcγR-binding antibodies were less affected, suggesting that Fc functional antibody responses may be better retained against the RBD of Omicron in comparison to neutralization. Furthermore, while measurement of RBD-ACE2-binding affinity via biolayer interferometry showed that all VOC RBDs have enhanced affinity to human ACE2, we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695) has reduced affinity to VOCs, while K26R (rs4646116) and S19P (rs73635825) have increased binding kinetics to the RBD of VOCs, potentially affecting virus-host interaction and, thereby, host susceptibility. Collectively, our findings provide in-depth coverage of the impact of RBD mutations on key facets of host-virus interactions.
  • Item
    No Preview Available
    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.
  • Item
    Thumbnail Image
    Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles
    Tan, H-X ; Juno, JA ; Esterbauer, R ; Kelly, HG ; Wragg, KM ; Konstandopoulos, P ; Alcantara, S ; Alvarado, C ; Jones, R ; Starkey, G ; Wang, BZ ; Yoshino, O ; Tiang, T ; Grayson, ML ; Opdam, H ; D'Costa, R ; Vago, A ; Mackay, LK ; Gordon, CL ; Masopust, D ; Groom, JR ; Kent, SJ ; Wheatley, AK (AMER ASSOC ADVANCEMENT SCIENCE, 2022-01)
    Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (BRM) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza-specific BRM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)- and nucleoprotein (NP)-specific lung BRM. We found that CCR6 facilitates increased recruitment and/or retention of BRM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning BRM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that BRM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.
  • Item
    No Preview Available
    Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection
    Phetsouphanh, C ; Darley, D ; Wilson, DB ; Howe, A ; Munier, CML ; Patel, SK ; Juno, JA ; Burrell, LM ; Kent, SJ ; Dore, GJ ; Kelleher, AD ; Matthews, G (NATURE PORTFOLIO, 2022-02)
    A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
  • Item
    No Preview Available
    Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?
    Kent, SJ ; Khoury, DS ; Reynold, A ; Juno, JA ; Wheatley, AK ; Stadler, E ; Wherry, EJ ; Triccas, J ; Sasson, SC ; Cromer, D ; Davenport, MP (NATURE PORTFOLIO, 2022-06)
    The rapid development of multiple vaccines providing strong protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a major achievement. There is now compelling evidence for the role of neutralizing antibodies in protective immunity. T cells may play a role in resolution of primary SARS-CoV-2 infection, and there is a widely expressed view that T cell-mediated immunity also plays an important role in vaccine-mediated protection. Here we discuss the role of vaccine-induced T cells in two distinct stages of infection: firstly, in protection from acquisition of symptomatic SARS-CoV-2 infection following exposure; secondly, if infection does occur, the potential for T cells to reduce the risk of developing severe COVID-19. We describe several lines of evidence that argue against a direct impact of vaccine-induced memory T cells in preventing symptomatic SARS-CoV-2 infection. However, the contribution of T cell immunity in reducing the severity of infection, particularly in infection with SARS-CoV-2 variants, remains to be determined. A detailed understanding of the role of T cells in COVID-19 is critical for next-generation vaccine design and development. Here we discuss the challenges in determining a causal relationship between vaccine-induced T cell immunity and protection from COVID-19 and propose an approach to gather the necessary evidence to clarify any role for vaccine-induced T cell memory in protection from severe COVID-19.
  • Item
    No Preview Available
    Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities
    Zhang, W ; Kedzierski, L ; Chua, BY ; Mayo, M ; Lonzi, C ; Rigas, V ; Middleton, BF ; McQuilten, HA ; Rowntree, LC ; Allen, LF ; Purcell, RA ; Tan, H-X ; Petersen, J ; Chaurasia, P ; Mordant, F ; Pogorelyy, MV ; Minervina, AA ; Crawford, JC ; Perkins, GB ; Zhang, E ; Gras, S ; Clemens, EB ; Juno, JA ; Audsley, J ; Khoury, DS ; Holmes, NE ; Thevarajan, I ; Subbarao, K ; Krammer, F ; Cheng, AC ; Davenport, MP ; Grubor-Bauk, B ; Coates, PT ; Christensen, B ; Thomas, PG ; Wheatley, AK ; Kent, SJ ; Rossjohn, J ; Chung, AW ; Boffa, J ; Miller, A ; Lynar, S ; Nelson, J ; Nguyen, THO ; Davies, J ; Kedzierska, K (NATURE PORTFOLIO, 2023-06)
    High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.
  • Item
    No Preview Available
    Establishment and recall of SARS-CoV-2 spike epitope-specific CD4+ T cell memory
    Wragg, KM ; Lee, WS ; Koutsakos, M ; Tan, H-X ; Amarasena, T ; Reynaldi, A ; Gare, G ; Konstandopoulos, P ; Field, KR ; Esterbauer, R ; Kent, HE ; Davenport, MP ; Wheatley, AK ; Kent, SJ ; Juno, JA (NATURE PORTFOLIO, 2022-05)
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4+ T cell responses to the spike protein, including circulating follicular helper T (cTFH) cells that correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S751 tetramer to track spike-specific CD4+ T cells, we show that primary infection or vaccination induces robust S751-specific CXCR5- and cTFH cell memory responses. Secondary exposure induced recall of CD4+ T cells with a transitory CXCR3+ phenotype, and drove expansion of cTFH cells transiently expressing ICOS, CD38 and PD-1. In both contexts, cells exhibited a restricted T cell antigen receptor repertoire, including a highly public clonotype and considerable clonotypic overlap between CXCR5- and cTFH populations. Following a third vaccine dose, the rapid re-expansion of spike-specific CD4+ T cells contrasted with the comparatively delayed increase in antibody titers. Overall, we demonstrate that stable pools of cTFH and memory CD4+ T cells established by infection and/or vaccination are efficiently recalled upon antigen reexposure and may contribute to long-term protection against SARS-CoV-2.