Microbiology & Immunology - Research Publications
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ItemNo Preview AvailableCutting Edge: SARS-CoV-2 Infection Induces Robust Germinal Center Activity in the Human Tonsil(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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ItemLung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles(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.
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ItemNo Preview AvailableDisentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?(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.
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ItemNo Preview AvailableEstablishment and recall of SARS-CoV-2 spike epitope-specific CD4+ T cell memory(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.
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ItemNo Preview AvailableImmunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection(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.
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ItemHeterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma(WILEY, 2022)OBJECTIVES: Following infection with SARS-CoV-2, virus-specific antibodies are generated, which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. By comparison, other antibody isotypes including IgA have been poorly characterised. METHODS: Here, we characterised plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. RESULTS: Convalescent plasma IgA from > 60% of the cohort had the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated ACE2 inhibition than matched IgG when tested at equivalent concentrations. Plasma IgA and IgG from this cohort broadly recognised similar RBD epitopes and had similar capacities to inhibit ACE2 from binding to 22 of the 23 prevalent RBD mutations assessed. However, plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison with plasma IgG. CONCLUSION: Overall, convalescent plasma IgA contributed to the neutralising antibody response of wild-type SARS-CoV-2 RBD and various RBD mutations. However, this response displayed large heterogeneity and was less potent than IgG.
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ItemThe magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants(CELL PRESS, 2022-07-12)Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.
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ItemPhenotypic and functional characteristics of highly differentiated CD57+NKG2C+ NK cells in HIV-1-infected individuals(OXFORD UNIV PRESS, 2022-12-15)Natural killer (NK) cells are important anti-viral effector cells. The function and phenotype of the NK cells that constitute an individual's NK cell repertoire can be influenced by ongoing or previous viral infections. Indeed, infection with human cytomegalovirus (HCMV) drives the expansion of a highly differentiated NK cell population characterized by expression of CD57 and the activating NKG2C receptor. This NK cell population has also been noted to occur in HIV-1-infected individuals. We evaluated the NK cells of HIV-1-infected and HIV-1-uninfected individuals to determine the relative frequency of highly differentiated CD57+NKG2C+ NK cells and characterize these cells for their receptor expression and responsiveness to diverse stimuli. Highly differentiated CD57+NKG2C+ NK cells occurred at higher frequencies in HCMV-infected donors relative to HCMV-uninfected donors and were dramatically expanded in HIV-1/HCMV co-infected donors. The expanded CD57+NKG2C+ NK cell population in HIV-1-infected donors remained stable following antiretroviral therapy. CD57+NKG2C+ NK cells derived from HIV-1-infected individuals were robustly activated by antibody-dependent stimuli that contained anti-HIV-1 antibodies or therapeutic anti-CD20 antibody, and these NK cells mediated cytolysis through NKG2C. Lastly, CD57+NKG2C+ NK cells from HIV-1-infected donors were characterized by reduced expression of the inhibitory NKG2A receptor. The abundance of highly functional CD57+NKG2C+ NK cells in HIV-1-infected individuals raises the possibility that these NK cells could play a role in HIV-1 pathogenesis or serve as effector cells for therapeutic/cure strategies.
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ItemAt Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant(FRONTIERS MEDIA SA, 2022-05-17)Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.
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ItemAnti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine(AMER CHEMICAL SOC, 2022-08-23)Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle (LNP) mRNA vaccines for SARS-CoV-2 contain small amounts of PEG, but it is not known whether PEG antibodies are enhanced by vaccination and what their impact is on particle-immune cell interactions in human blood. We studied plasma from 130 adults receiving either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines or no SARS-CoV-2 vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was significantly boosted a mean of 13.1-fold (range 1.0-70.9) following mRNA-1273 vaccination and a mean of 1.78-fold (range 0.68-16.6) following BNT162b2 vaccination. Anti-PEG IgM increased 68.5-fold (range 0.9-377.1) and 2.64-fold (0.76-12.84) following mRNA-1273 and BNT162b2 vaccination, respectively. The rise in PEG-specific antibodies following mRNA-1273 vaccination was associated with a significant increase in the association of clinically relevant PEGylated LNPs with blood phagocytes ex vivo. PEG antibodies did not impact the SARS-CoV-2 specific neutralizing antibody response to vaccination. However, the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity following two doses of vaccination. We conclude that PEG-specific antibodies can be boosted by LNP mRNA vaccination and that the rise in PEG-specific antibodies is associated with systemic reactogenicity and an increase of PEG particle-leukocyte association in human blood. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA vaccines should be monitored. It may be useful to identify suitable alternatives to PEG for developing next-generation LNP vaccines to overcome PEG immunogenicity in the future.
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