Microbiology & Immunology - Research Publications

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    Tear antibodies to SARS-CoV-2: implications for transmission
    Selva, K ; Davis, S ; Haycroft, E ; Lee, WS ; Lopez, E ; Reynaldi, A ; Davenport, M ; Kent, H ; Juno, J ; Chung, A ; Kent, S ( 2021)


    SARS-CoV-2 can be transmitted by aerosols and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS-CoV-2 in tears after infection or vaccination. We analysed SARS-CoV-2 specific IgG and IgA responses in human tears after either COVID-19 infection or vaccination.


    We recruited 16 subjects with COVID-19 infection an average of 7 months previously and 15 subjects before and 2 weeks after Comirnaty (Pfizer-BioNtech) vaccination. Plasma, saliva and basal tears were collected. Pre-pandemic plasma, saliva and basal tears from 11 individuals were included as healthy controls. Antibody responses to 5 SARS-CoV-2 antigens were measured via multiplex.


    IgG antibodies to Spike and Nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS-CoV-2 infection in comparison to uninfected controls. While RBD-specific antibodies were detected in plasma, minimal RBD-specific antibodies were detected in tears and saliva. In contrast, high levels of IgG antibodies to Spike and RBD, but not Nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS-CoV-2 antigens were detected in plasma following infection or vaccination, but were unchanged in tears and saliva.


    Both infection and vaccination induce SARS-CoV-2-specific IgG antibodies in tears. RBD-specific IgG antibodies in tears were induced by vaccination but were not present 7 months post-infection. This suggests neutralising antibodies may be low in the tears late following infection.
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    Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation
    Kedzierska, K ; Habel, J ; Chua, B ; Kedzierski, L ; Selva, K ; Damelang, T ; Haycroft, E ; Nguyen, T ; Koay, H-F ; Nicholson, S ; McQuilten, H ; Jia, X ; Allen, L ; Hensen, L ; Zhang, W ; de Sandt, CV ; Neil, J ; Amanat, F ; Krammer, F ; Wragg, K ; Juno, J ; Wheatley, A ; Tan, H-X ; Pell, G ; Audsley, J ; Thevarajan, I ; Denholm, J ; Subbarao, K ; Godfrey, D ; Cheng, A ; Tong, S ; Bond, K ; Williamson, D ; James, F ; Holmes, N ; Smibert, O ; Trubiona, J ; Gordon, C ; Chung, A ; Whitehead, C ; Kent, S ; Lappas, M ; Rowntree, L ( 2021)
    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.
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    Cross-reactive antibodies after SARS-CoV-2 infection and vaccination
    Grobben, M ; van der Straten, K ; Brouwer, PJM ; Brinkkemper, M ; Maisonnasse, P ; Dereuddre-Bosquet, N ; Burger, J ; Poniman, M ; Oomen, M ; Eggink, D ; Bijl, TPL ; van Willigen, HDG ; Wynberg, E ; Verkaik, B ; Figaroa, OJA ; de Vries, P ; Boertien, T ; Grand, RL ; de Jong, M ; Prins, M ; Chung, A ; de Bree, G ; Sanders, R ; van Gils, M ( 2021)
    Current SARS-CoV-2 vaccines are losing efficacy against emerging variants and may not protect against future novel coronavirus outbreaks, emphasizing the need for more broadly protective vaccines. To inform the development of a pan-coronavirus vaccine, we investigated the presence and specificity of cross-reactive antibodies against the spike (S) proteins of human coronaviruses (hCoV) after SARS-CoV-2 infection and vaccination. We found an 11 to 123-fold increase in antibodies binding to SARS-CoV and MERS-CoV as well as a 2 to 4-fold difference in antibodies binding to seasonal hCoVs in COVID-19 convalescent sera compared to pre-pandemic healthy donors, with the S2 subdomain of the S protein being the main target for cross-reactivity. In addition, we detected cross-reactive antibodies to all hCoV S proteins after SARS-CoV-2 S protein immunization in macaques, with higher responses for hCoV more closely related to SARS-CoV-2. These findings support the feasibility of and provide guidance for development of a pan-coronavirus vaccine.
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    Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay
    Lopez, E ; Haycroft, E ; Adair, A ; Mordant, F ; O’Neill, M ; Pymm, P ; Redmond, S ; Gherardin, N ; Wheatley, A ; Juno, J ; Selva, K ; Davis, S ; Harty, L ; Purcell, DFJ ; Subbarao, K ; Godfrey, D ; Kent, S ; Tham, W-H ; Chung, A ( 2021)


    The SARS-CoV-2 Receptor Binding Domain (RBD) is both the principal target of neutralizing antibodies, and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate that immune escape can occur through two mechanisms, antibodies that fail to recognize mutations, along with antibodies that have reduced inhibitory capacity due to enhanced variant RBD-ACE2 affinity. A competitive approach where antibodies simultaneously compete with ACE2 for binding to the RBD may therefore more accurately reflect the physiological dynamics of infection. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P and N501Y to the ACE2 receptor, and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research; informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.
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    Immune responses to SARS-CoV-2 in children of parents with symptomatic COVID-19
    Tosif, S ; Neeland, M ; Sutton, P ; Licciardi, P ; Sarkar, S ; Selva, K ; Do, LAH ; Donato, C ; Toh, ZQ ; Higgins, R ; de Sandt, CV ; Lemke, M ; Lee, C ; Shoffner, S ; Flanagan, K ; Arnold, K ; Mordant, F ; Mulholland, K ; Bines, J ; Dohle, K ; Pellicci, D ; Curtis, N ; McNab, S ; Steer, A ; Saffery, R ; Subbarao, K ; Chung, A ; Kedzierska, K ; Burgner, D ; Crawford, N ( 2020)
    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.
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    Decay of Fc-dependent antibody functions after mild to moderate COVID-19
    Lee, WS ; Selva, KJ ; Davis, S ; Wines, B ; Reynaldi, A ; Esterbauer, R ; Kelly, H ; Haycroft, E ; Tan, H-X ; Juno, J ; Wheatley, A ; Hogarth, M ; Cromer, D ; Davenport, M ; Chung, A ; Kent, S ( 2020)
    The capacity of antibodies to engage with innate and adaptive immune cells via the Fc region is important in preventing and controlling many infectious diseases, and is likely critical in SARS-CoV-2 infection. The evolution of such antibodies during convalescence from COVID-19 is largely unknown. We developed novel assays to measure Fc-dependent antibody functions against SARS-CoV-2 spike (S)-expressing cells in serial samples from a cohort of 53 subjects primarily with mild-moderate COVID-19, out to a maximum of 149 days post-infection. We found that S-specific antibodies capable of engaging dimeric FcγRIIa and FcγRIIIa decayed linearly over time. S-specific antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP) activity within plasma declined linearly as well, in line with the decay of S-specific IgG. Although there was significant decay in S-specific plasma ADCC and ADP activity, they remained readily detectable by all assays in 94% of our cohort at the last timepoint studied, in contrast with neutralisation activity which was only detectable in 70% of our cohort by the last timepoint. Our results suggest that Fc effector functions such as ADCC and ADP could contribute to the durability of SARS-CoV-2 immunity, particularly late in convalescence when neutralising antibodies have waned. Understanding the protective potential of antibody Fc effector functions is critical for defining the durability of immunity generated by infection or vaccination.
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    Distinct systems serology features in children, elderly and COVID patients
    Selva, K ; van de Sandt, C ; Lemke, M ; Lee, C ; Shoffner, S ; Chua, B ; Nguyen, THO ; Rowntree, L ; Hensen, L ; Koutsakos, M ; Wong, CY ; Jackson, D ; Flanagan, K ; Crowe, J ; Cheng, A ; Doolan, D ; Amanat, F ; Krammer, F ; Chappell, K ; Modhiran, N ; Watterson, D ; Young, P ; Wines, B ; Hogarth, M ; Esterbauer, R ; Kelly, H ; Tan, H-X ; Juno, J ; Wheatley, A ; Kent, S ; Arnold, K ; Kedzierska, K ; Chung, A ( 2020)
    SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such divergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy individuals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fcγ receptor binding, which accurately distinguished COVID-19 patients from healthy individuals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fcγ receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.