ORCID Profile
0000-0002-5593-9387
Current Organisations
University of Milano-Bicocca
,
University of Melbourne
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Functional Materials | Synthesis of Materials | Nanotechnology | Nanobiotechnology |
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Technology
Publisher: Public Library of Science (PLoS)
Date: 17-03-2020
Publisher: Rockefeller University Press
Date: 23-12-2016
DOI: 10.1084/JEM.20160789
Abstract: Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool. In this study, we show that an environmental sensor, the aryl hydrocarbon receptor (AhR) is highly induced upon B cell activation and serves a critical role in regulating activation-induced cell fate outcomes. We find that AhR negatively regulates class-switch recombination ex vivo by altering activation-induced cytidine deaminase expression. We further demonstrate that AhR suppresses class switching in vivo after influenza virus infection and immunization with model antigens. In addition, by regulating Blimp-1 expression via Bach2, AhR represses differentiation of B cells into plasmablasts ex vivo and antibody-secreting plasma cells in vivo. These experiments suggest that AhR serves as a molecular rheostat in B cells to brake the effector response, possibly to facilitate optimal recall responses. Thus, AhR might represent a novel molecular target for manipulation of B cell responses during vaccination.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
Publisher: Wiley
Date: 14-03-2019
Abstract: Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs-one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)-is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2022
Publisher: Springer Science and Business Media LLC
Date: 13-07-2020
Publisher: Springer Science and Business Media LLC
Date: 09-02-2006
Publisher: Informa UK Limited
Date: 15-07-2015
DOI: 10.1586/14760584.2015.1068125
Abstract: Influenza inflicts significant global mortality and morbidity that can be combated by effective immunization. However, the protective efficacy of current vaccines is limited by both the significant antigenic ersity of the viral hemagglutinin protein and the capacity for rapid antigenic change. This necessitates global influenza surveillance efforts, frequent vaccine reformulation and annual readministration. There is, therefore, tremendous interest in the development of novel strategies to elicit broad and durable protection against both seasonal and pandemic infection. This review presents an overview of candidate universal influenza vaccines designed to elicit cross-protective antibody responses to hemagglutinin. In particular, we focus on the potential impact that widespread pre-existing influenza immunity may play upon the design, testing and deployment of universal influenza vaccines.
Publisher: Copernicus GmbH
Date: 25-08-2021
DOI: 10.5194/ESSD-13-4067-2021
Abstract: Abstract. The science guiding the EUREC4A c aign and its measurements is presented. EUREC4A comprised roughly 5 weeks of measurements in the downstream winter trades of the North Atlantic – eastward and southeastward of Barbados. Through its ability to characterize processes operating across a wide range of scales, EUREC4A marked a turning point in our ability to observationally study factors influencing clouds in the trades, how they will respond to warming, and their link to other components of the earth system, such as upper-ocean processes or the life cycle of particulate matter. This characterization was made possible by thousands (2500) of sondes distributed to measure circulations on meso- (200 km) and larger (500 km) scales, roughly 400 h of flight time by four heavily instrumented research aircraft four global-class research vessels an advanced ground-based cloud observatory scores of autonomous observing platforms operating in the upper ocean (nearly 10 000 profiles), lower atmosphere (continuous profiling), and along the air–sea interface a network of water stable isotopologue measurements targeted tasking of satellite remote sensing and modeling with a new generation of weather and climate models. In addition to providing an outline of the novel measurements and their composition into a unified and coordinated c aign, the six distinct scientific facets that EUREC4A explored – from North Brazil Current rings to turbulence-induced clustering of cloud droplets and its influence on warm-rain formation – are presented along with an overview of EUREC4A's outreach activities, environmental impact, and guidelines for scientific practice. Track data for all platforms are standardized and accessible at 0.25326/165 (Stevens, 2021), and a film documenting the c aign is provided as a video supplement.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1038/MI.2017.89
Abstract: Tissue-resident memory (T
Publisher: Informa UK Limited
Date: 03-04-2017
Publisher: Public Library of Science (PLoS)
Date: 15-03-2017
Publisher: Elsevier BV
Date: 10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2021
DOI: 10.1101/2021.03.09.21252641
Abstract: Both previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Publisher: American Society for Microbiology
Date: 05-2018
DOI: 10.1128/JVI.01970-17
Abstract: Pandemic live attenuated influenza vaccines (pLAIV) prime subjects for a robust neutralizing antibody response upon subsequent administration of a pandemic inactivated subunit vaccine (pISV). However, a difference was not detected in H5-specific memory B cells in the peripheral blood between pLAIV-primed and unprimed subjects prior to pISV boost. To investigate the mechanism underlying pLAIV priming, we vaccinated groups of 12 African green monkeys (AGMs) with H5N1 pISV or pLAIV alone or H5N1 pLAIV followed by pISV and examined immunity systemically and in local draining lymph nodes (LN). The AGM model recapitulated the serologic observations from clinical studies. Interestingly, H5N1 pLAIV induced robust germinal center B cell responses in the mediastinal LN (MLN). Subsequent boosting with H5N1 pISV drove increases in H5-specific B cells in the axillary LN, spleen, and circulation in H5N1 pLAIV-primed animals. Thus, H5N1 pLAIV primes localized B cell responses in the MLN that are recalled systemically following pISV boost. These data provide mechanistic insights for the generation of robust humoral responses via prime-boost vaccination. IMPORTANCE We have previously shown that pandemic live attenuated influenza vaccines (pLAIV) prime for a rapid and robust antibody response on subsequent administration of inactivated subunit vaccine (pISV). This is observed even in in iduals who had undetectable antibody (Ab) responses following the initial vaccination. To define the mechanistic basis of pLAIV priming, we turned to a nonhuman primate model and performed a detailed analysis of B cell responses in systemic and local lymphoid tissues following prime-boost vaccination with pLAIV and pISV. We show that the nonhuman primate model recapitulates the serologic observations from clinical studies. Further, we found that pLAIVs induced robust germinal center B cell responses in the mediastinal lymph node. Subsequent boosting with pISV in pLAIV-primed animals resulted in detection of B cells in the axillary lymph nodes, spleen, and peripheral blood. We demonstrate that intranasally administered pLAIV elicits a highly localized germinal center B cell response in the mediastinal lymph node that is rapidly recalled following pISV boost into germinal center reactions at numerous distant immune sites.
Publisher: Wiley
Date: 31-10-2022
DOI: 10.1111/IMCB.12596
Abstract: A recently published article has confirmed that a novel immunization method of sustained and escalating antigen delivery augments the magnitude, quality and durability of humoral immune responses.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41591-021-01377-8
Abstract: Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1038/S41467-021-21444-5
Abstract: The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with in idual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4 + and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG + memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2018
DOI: 10.1038/S41591-018-0315-0
Abstract: In the version of this article originally published, data were incorrectly ascribed to monoclonal antibody CIS34 because of a labeling error. The data were generated with monoclonal antibody CIS04. Full details can be found in the correction notice.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2020
Publisher: Informa UK Limited
Date: 14-02-2019
DOI: 10.1080/14760584.2019.1578216
Abstract: Immunization has been a remarkably successful public health intervention however, new approaches to vaccine design are essential to counter existing and emerging infectious diseases which have defied traditional vaccination efforts to date. Nanoparticles (ordered structures with dimensions in the range of 1-1000 nm) have great potential to supplement traditional vaccines based upon pathogen subunits, or killed or attenuated microorganisms, as exemplified by the successful licensure of virus-like particle vaccines for human papillomavirus and hepatitis B. However, the immunological mechanisms that underpin the potent immunity of nanoparticle vaccines are poorly defined. Here, we review the immunity of nanoparticle immunization. The display of antigen in a repetitive, ordered array mimics the surface of a pathogen, as does their nanoscale size. These properties facilitate enhanced innate immune activation, improved drainage and retention in lymph nodes, stronger engagement with B cell receptors, and augmented T cell help in driving B cell activation. In the near future, increasingly complex nanoparticle vaccines displaying multiple antigens and/or co-delivered adjuvants will reach clinical trials. An improved mechanistic understanding of nanoparticle vaccination will ultimately facilitate the rational design of improved vaccines for human health.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.VACCINE.2009.08.016
Abstract: We developed highly expressing clade B and AE DNA and envelope protein (Env) vaccines for evaluation in mice and macaques as DNA prime rotein boost regimens. High levels of Env-specific antibodies were induced in mice, albeit with limited neutralizing activity in vitro. A combined clade B and AE regimen induced high titer Env-specific antibody in two pigtail macaques that neutralized several strains of HIV-1. However, upon mucosal challenge with SHIV(SF162P3) no protection from infection was observed. Although the vaccines tested provide a platform for inducing robust humoral immunity, further refinements to broaden coverage against ergent strains and induce mucosal immunity are needed.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.VACCINE.2013.02.064
Abstract: Sindbis replicon-based vaccine vectors are designed to combine the immunostimulatory properties of replicating viruses with the superior safety profile of non-replicating systems. In this study we performed a detailed assessment of Sindbis (SIN) replicon vectors expressing HIV-1 envelope protein (Env) for the induction of cell-mediated and humoral immune responses in a small animal model. SIN-derived virus-like particles (VLP) elicited Env-specific antibody responses that were detectable after boosting with recombinant Env protein. This priming effect could be mediated by replicon activity alone but may be enhanced by Env attached to the surface of VLP, offering a potential advantage for this mode of replicon delivery for Env based vaccination strategies. In contrast, the Env-specific CTL responses that were elicited by SIN-VLP were entirely dependent on replicon activity. SIN-VLP priming induced more durable humoral responses than immunization with protein only. This is important from a vaccine perspective, given the intrinsic tendency of Env to induce short-lived antibody responses in the context of vaccination or infection. These results indicate that further efforts to enhance the magnitude and durability of the HIV-1 Env-specific immune responses generated by Sindbis vectors, either alone or as part of prime-boost regimens, are justified.
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: American Society for Microbiology
Date: 08-2012
DOI: 10.1128/AAC.00453-12
Abstract: Bovine colostrum (first milk) contains very high concentrations of IgG, and on average 1 kg (500 g/liter) of IgG can be harvested from each immunized cow immediately after calving. We used a modified vaccination strategy together with established production systems from the dairy food industry for the large-scale manufacture of broadly neutralizing HIV-1 IgG. This approach provides a low-cost mucosal HIV preventive agent potentially suitable for a topical microbicide. Four cows were vaccinated pre- and/or postconception with recombinant HIV-1 gp140 envelope (Env) oligomers of clade B or A, B, and C. Colostrum and purified colostrum IgG were assessed for cross-clade binding and neutralization against a panel of 27 Env-pseudotyped reporter viruses. Vaccination elicited high anti-gp140 IgG titers in serum and colostrum with reciprocal endpoint titers of up to 1 × 10 5 . While nonimmune colostrum showed some intrinsic neutralizing activity, colostrum from 2 cows receiving a longer-duration vaccination regimen demonstrated broad HIV-1-neutralizing activity. Colostrum-purified polyclonal IgG retained gp140 reactivity and neutralization activity and blocked the binding of the b12 monoclonal antibody to gp140, showing specificity for the CD4 binding site. Colostrum-derived anti-HIV antibodies offer a cost-effective option for preparing the substantial quantities of broadly neutralizing antibodies that would be needed in a low-cost topical combination HIV-1 microbicide.
Publisher: Springer Science and Business Media LLC
Date: 08-2011
Abstract: This study evaluates the immunogenicity of the HIV envelope protein (env) in mice presented either attached to γ-retroviral virus-like-particles (VLPs), associated with cell-derived microsomes or as solubilized recombinant protein (gp160). The magnitude and polyfunctionality of the cellular immune response was enhanced when delivering HIV env in the VLP or microsome form compared to recombinant gp160. Humoral responses measured by antibody titres were comparable across the groups and low levels of antibody neutralization were observed. Lastly, we identified stronger IgG2a class switching in the two particle-delivered antigen vaccinations modalities compared to recombinant gp160.
Publisher: Wiley
Date: 24-02-2023
Abstract: Employing monoclonal antibodies to target vaccine antigens to different immune cells within lymph nodes where adaptive immunity is initiated can provide a mechanism to fine‐tune the magnitude or the quality of immune responses. However, studying the effects of different targeting antibodies head‐to‐head is challenging due to the lack of a feasible method that allows rapid screening of multiple antibodies for their impact on immunogenicity. Here self‐assembling ferritin nanoparticles are prepared that co‐display vaccine antigens and the Fc‐binding domain of Staphylococcal protein A, allowing rapid attachment of soluble antibodies to the nanoparticle surface. Using this tunable system, ten antibodies targeting different immune cell subsets are screened, with targeting to Clec9a associated with higher serum antibody titers after immunization. Immune cell targeting using ferritin nanoparticles with anti‐Clec9a antibodies drives concentrated deposition of antigens within germinal centers, boosting germinal center formation and robust antibody responses. However, the capacity to augment humoral immunity is antigen‐dependent, with significant boosting observed for prototypic ovalbumin immunogens but reduced effectiveness with the SARS‐CoV‐2 RBD. This work provides a rapid platform for screening targeting antibodies, which will accelerate mechanistic insights into optimal delivery strategies for nanoparticle‐based vaccines to maximize protective immunity.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2021
Publisher: Springer Science and Business Media LLC
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 09-09-2020
DOI: 10.1038/S41564-020-00789-5
Abstract: Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.
Publisher: Public Library of Science (PLoS)
Date: 25-03-2011
Publisher: Springer Science and Business Media LLC
Date: 21-03-2022
DOI: 10.1038/S41590-022-01175-5
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4
Publisher: Public Library of Science (PLoS)
Date: 29-05-2020
Publisher: American Society for Clinical Investigation
Date: 22-09-2023
Publisher: Public Library of Science (PLoS)
Date: 30-01-2014
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.VACCINE.2017.09.062
Abstract: Globally the most commonly utilised immunisation against influenza is the trivalent inactivated influenza vaccine (TIV) derived from an A/H1N1, an A/H3N2 and aB type influenza virus. Vaccine effectiveness of TIV varies year to year, depending on how well antigenically matched the strains in the vaccine are compared to circulating strains [1,2]. Moreover, vaccine effectiveness can vary within certain subpopulations such as HIV-positive, young children and the elderly. Decreased vaccine effectiveness in the elderly is associated with impaired Ab production, as measured by standard hemagglutination inhibition (HAI) assays. We investigated the level of Antibody Dependent Phagocytosis (ADP)-mediating Abs induced by the 2008-TIV in healthy Australian adults aged over and under 60years to determine if this immune function was also reduced in the elderly. We utilised an ADP assay that measures the uptake of IgG-opsonised HA-coated fluorescent microspheres by a monocytic cell line. We also measured HA-specific Abs that are close enough to bind to dimeric FcγRIIa ectodomains in an ELISA-based assay. Furthermore, we compared the extent of cross-reactive recognition of erse influenza strains by ADP-mediating Abs found in pre- and post-vaccination sera in both of these groups. We found that young adults and older adults mounted similar ADP activity against HAs contained in the 2008-TIV, despite older adults have diminished HI responses. The level of cross-reactive antibodies against other HAs was limited in both groups. We conclude that seasonal influenza vaccination elicits limited cross-reactive ADP to HA in both young and older adults. New influenza vaccination strategies that elicit cross-reactive and polyfunctional antibodies are needed.
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: American Society for Microbiology
Date: 15-04-2014
DOI: 10.1128/JVI.03422-13
Abstract: An understanding of the antigen-specific B-cell response to the influenza virus hemagglutinin (HA) is critical to the development of universal influenza vaccines, but it has not been possible to examine these cells directly because HA binds to sialic acid (SA) on most cell types. Here, we use structure-based modification of HA to isolate HA-specific B cells by flow cytometry and characterize the features of HA stem antibodies (Abs) required for their development. Incorporation of a previously described mutation (Y98F) to the receptor binding site (RBS) causes HA to bind only those B cells that express HA-specific Abs, but it does not bind nonspecifically to B cells, and this mutation has no effect on the binding of broadly neutralizing Abs to the RBS. To test the specificity of the Y98F mutation, we first demonstrated that previously described HA nanoparticles mediate hemagglutination and then determined that the Y98F mutation eliminates this activity. Cloning of immunoglobulin genes from HA-specific B cells isolated from a single human subject demonstrates that vaccination with H5N1 influenza virus can elicit B cells expressing stem monoclonal Abs (MAbs). Although these MAbs originated mostly from the IGHV1-69 germ line, a reasonable proportion derived from other genes. Analysis of stem Abs provides insight into the maturation pathways of IGVH1-69-derived stem Abs. Furthermore, this analysis shows that multiple non-IGHV1-69 stem Abs with a similar neutralizing breadth develop after vaccination in humans, suggesting that the HA stem response can be elicited in in iduals with non-stem-reactive IGHV1-69 alleles. IMPORTANCE Universal influenza vaccines would improve immune protection against infection and facilitate vaccine manufacturing and distribution. Flu vaccines stimulate B cells in the blood to produce antibodies that neutralize the virus. These antibodies target a protein on the surface of the virus called HA. Flu vaccines must be reformulated annually, because these antibodies are mostly specific to the viral strains used in the vaccine. But humans can produce broadly neutralizing antibodies. We sought to isolate B cells whose genes encode influenza virus antibodies from a patient vaccinated for avian influenza. To do so, we modified HA so it would bind only the desired cells. Sequencing the antibody genes of cells marked by this probe proved that the patient produced broadly neutralizing antibodies in response to the vaccine. Many sequences obtained had not been observed before. There are more ways to generate broadly neutralizing antibodies for influenza virus than previously thought.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2021
DOI: 10.1038/S41467-021-21665-8
Abstract: SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-02-2020
Abstract: In contrast to the well-studied αβ T cells, which recognize peptide antigens presented by major histocompatibility complex (MHC) and MHC-like molecules, how γδ T cells recognize antigens remains largely a mystery. One major class of γδ T cells, designated Vγ9Vδ2 + , is activated by small, phosphorylated nonpeptide antigens, or phosphoantigens, produced by microbes and cancer cells. Rigau et al. found that these cells needed the combination of two immunoglobulin superfamily members, butyrophilin 2A1 (BTN2A1) and BTN3A1, on their cell surface to recognize these phosphoantigens. BTN2A1 directly binds the Vγ9 + domain of the T cell receptor (TCR), whereas a second ligand, potentially BTN3A1, binds the Vδ2 and γ-chain regions on the opposite side of the TCR. A better understanding of this unexpected form of T cell antigen recognition should inform and enhance future γδ T cell–mediated immunotherapies. Science , this issue p. eaay5516
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: Elsevier BV
Date: 11-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 23-04-2021
Abstract: Neutralizing antibodies are important for immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as therapeutics for the prevention and treatment of COVID-19. We identified high-affinity nanobodies against SARS-CoV-2 receptor-binding domain and found that nanobody cocktails consisting of two noncompeting nanobodies were able to block ACE2 engagement with RBD variants present in human populations and potently neutralize both wild-type SARS-CoV-2 and the N501Y D614G variant at low concentrations. Prophylactic administration of nanobody cocktails reduced viral loads in mice infected with the N501Y D614G SARS-CoV-2 virus, showing that nanobody cocktails are useful as prophylactic agents against SARS-CoV-2.
Publisher: Oxford University Press (OUP)
Date: 13-01-2010
DOI: 10.1093/NAR/GKP1224
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
DOI: 10.1038/NM.4512
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: Mary Ann Liebert Inc
Date: 10-2014
Publisher: Research Square Platform LLC
Date: 19-10-2021
DOI: 10.21203/RS.3.RS-957030/V1
Abstract: CD4+ T cells play a critical role in the immune response to viral infection. SARS-CoV-2 infection and vaccination elicit strong CD4+ T cell responses to the viral spike protein, including circulating T follicular helper (cTFH) cells that correlate with the development of neutralising antibodies. Here we use a novel HLA-DRB1*15:01/S751 tetramer to precisely track spike-specific CD4+ T cells following recovery from mild/moderate COVID-19, or after vaccination with spike-encoding vaccines. SARS-CoV-2 infection induces robust S751-specific responses with both CXCR5- and cTFH phenotypes that are maintained for at least 12 months in a stable, CXCR3-biased, central memory pool. Vaccination of immunologically naïve subjects similarly drives expansion of S751-specific T cells with a highly restricted TCR repertoire comprised of both public and private clonotypes. Vaccination of convalescent in iduals drives recall of CD4+ T cell clones established during infection, which are shared between the CXCR5- and cTFH compartments. This recall response is evident 5 days after antigen exposure and includes a population of spike-specific cTFH that persist in the periphery after losing expression of PD-1. Overall this study demonstrates the generation of a stable pool of cTFH and memory CD4+ T cells that can be recalled upon spike antigen re-exposure, which may play an important role in long-term protection against SARS-CoV-2 infection.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/SREP36298
Abstract: Activation of immune cells (but not B cells) with lectins is widely known. We used the structurally defined interaction between influenza hemagglutinin (HA) and its cell surface receptor sialic acid (SA) to identify a B cell receptor (BCR) activation modality that proceeded through non-cognate interactions with antigen. Using a new approach to reconstitute antigen-receptor interactions in a human reporter B cell line, we found that sequence-defined BCRs from the human germline repertoire could be triggered by both complementarity to influenza HA and a separate mode of signaling that relied on multivalent ligation of BCR sialyl-oligosaccharide. The latter suggested a new mechanism for priming naïve B cell responses and manifested as the induction of SA-dependent pan-activation by peripheral blood B cells. BCR crosslinking in the absence of complementarity is a superantigen effect induced by some microbial products to subvert production of antigen-specific immune responses. B cell superantigen activity through affinity for BCR carbohydrate is discussed.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.COVIRO.2016.12.002
Abstract: Antibodies are a key defence against influenza infection and disease, but neutralizing antibodies are often strain-specific and of limited utility against ergent or pandemic viruses. There is now considerable evidence that influenza-specific antibodies with Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can assist in the clearance of influenza infection in vitro and in animal models. Further, ADCC-mediating antibodies that recognize a broad array of influenza strains are common in humans, likely as a result of being regularly exposed to influenza infections. The concept that influenza-specific ADCC can assist in the partial control of influenza infections in humans is gaining momentum. This review examines the utility of influenza-specific ADCC antibodies.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2017
DOI: 10.1038/NI.3680
Publisher: Elsevier BV
Date: 07-2016
Publisher: Elsevier BV
Date: 07-2023
Publisher: American Society for Clinical Investigation
Date: 23-08-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2017
DOI: 10.1126/SCIIMMUNOL.AAN2676
Abstract: Broadly protective antibodies are preferentially induced upon vaccination with a group 2 immunogen.
Publisher: American Chemical Society (ACS)
Date: 11-01-2017
Abstract: Despite the immense public health successes of immunization over the past century, effective vaccines are still lacking for globally important pathogens such as human immunodeficiency virus, malaria, and tuberculosis. Exciting recent advances in immunology and biotechnology over the past few decades have facilitated a shift from empirical to rational vaccine design, opening possibilities for improved vaccines. Some of the most important advancements include (i) the purification of subunit antigens with high safety profiles, (ii) the identification of innate pattern recognition receptors (PRRs) and cognate agonists responsible for inducing immune responses, and (iii) developments in nano- and microparticle fabrication and characterization techniques. Advances in particle engineering now allow highly tunable physicochemical properties of particle-based vaccines, including composition, size, shape, surface characteristics, and degradability. Enhanced collaborative efforts between researchers in immunology and materials science are expected to rise to next-generation vaccines. This process will be significantly aided by a greater understanding of the immunological principles guiding vaccine antigenicity, immunogenicity, and efficacy. With specific emphasis on PRR-targeted adjuvants and particle physicochemical properties, this review aims to provide an overview of the current literature to guide and focus rational particle-based vaccine design efforts.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2023
DOI: 10.1038/S41590-023-01508-Y
Abstract: 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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-08-2230
DOI: 10.1126/SCIIMMUNOL.ABF5314
Abstract: 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 (B RM ) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza - specific B RM 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 B RM . We found that CCR6 facilitates increased recruitment and/or retention of B RM 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 B RM 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 B RM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.
Publisher: Oxford University Press (OUP)
Date: 03-11-2022
Abstract: Vaccination remains the most effective mechanism to reduce the impact of COVID-19. Induction of neutralizing antibodies is a strong correlate of protection from infection and severe disease. An understanding of the cellular events that underpin the generation of effective neutralizing antibodies is therefore key to the development of efficacious vaccines that target emerging variants of concern. Analysis of the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and vaccination has identified circulating T follicular helper cells (cTFH) as a robust correlate of the neutralizing antibody response. Here, we discuss the analysis of cTFH cells and their lymphoid counterparts in human humoral immune responses during COVID-19, and in response to vaccination with SARS-CoV-2 spike. We discuss the phenotypic heterogeneity of cTFH cells and the utility of cTFH subsets as informative biomarkers for development of humoral immunity. We posit that the analysis of the most effective cTFH will be critical to inducing durable immunity to new variants of SARS-CoV-2.
Publisher: Research Square Platform LLC
Date: 09-03-2022
DOI: 10.21203/RS.3.RS-1390960/V1
Abstract: Influenza viruses circulate globally, causing seasonal influenza outbreaks. Although antibody-inducing vaccines are the most effective way to combat seasonal infections, current vaccines can have poor efficacy, especially in children and immunocompromised in iduals. We investigated the immunogenicity and efficacy of monovalent and quadrivalent formulations of the whole virus particle vaccine (WPV) in comparison to the commonly used split vaccines (SVs) in a non-human primate model. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV formulations consistently induced a stronger neutralizing antibody response against vaccine-matched virus strains, while reactogenicity was minimal. In contrast to the modest responses in SV-vaccinated animals, responses in WPV-primed animals were further increased by boosting with either formulation. Using a 28-parameter multiplex bead array to define key antibody features, we found that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV elevated IgG responses against A/H1N1 haemagglutinin (HA) and HA-Stem after each vaccine dose. Higher IgA responses to A/H1N1-HA were also induced after each WPV dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. WPV-enhanced antibody responses were associated with higher frequencies of HA-reactive B-cells and IFN-γ-producing CD4 + T-cell responses. Our data suggest that robust antibody responses require WPV to be given as a priming dose but do not depend on the vaccine type used for the second dose. In contrast, antibody responses are not as prominent when SV is given first. Our findings support vaccination regimens using WPV, which may be particularly beneficial for priming immunologically-naïve in iduals, such as the young and immunocompromised, and also advantageous in the event of a pandemic outbreak.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2019
Publisher: Wiley
Date: 03-10-2019
DOI: 10.1111/IRV.12687
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: The American Association of Immunologists
Date: 15-07-2015
Abstract: Because of significant viral ersity, vaccines that elicit durable and broad protection against influenza have been elusive. Recent research has focused on the potential of highly conserved regions of the viral hemagglutinin (HA) as targets for broadly neutralizing Ab responses. Abs that bind the highly conserved stem or stalk of HA can be elicited by vaccination in humans and animal models and neutralize erse influenza strains. However, the frequency and phenotype of HA stem–specific B cells in vivo remain unclear. In this article, we characterize HA stem–specific B cell responses following H5N1 vaccination and describe the re-expansion of a pre-existing population of memory B cells specific for stem epitopes. This population uses primarily, but not exclusively, IGHV1-69–based Igs for HA recognition. However, within some subjects, allelic polymorphism at the ighv1-69 locus can limit IGHV1-69 immunodominance and may reduce circulating frequencies of stem-reactive B cells in vivo. The accurate definition of allelic selection, recombination requirements, and ontogeny of neutralizing Ab responses to influenza will aid rational influenza vaccine design.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2023
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated in iduals 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 s ling 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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-02-2018
DOI: 10.1126/SCITRANSLMED.AAN8405
Abstract: Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T
Publisher: Cold Spring Harbor Laboratory
Date: 15-09-2022
DOI: 10.1101/2022.09.14.508046
Abstract: The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc .
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2023
DOI: 10.1101/2023.03.28.23287848
Abstract: 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 (convalescent, vaccinated) and in iduals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19 recovered vaccinees displayed improved antibody neutralizing activity, FcγR engagement and IgA compared to 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. IgG, but not IgA, responses to breakthrough COVID-19 variants were d ened and narrowed by increased pre-existing vaccine-induced immunity to the ancestral strain. Salivary antibodies delayed initiation of boosting following breakthrough COVID-19 infection, especially Omicron BA.2, however, rose rapidly thereafter. Our data highlight how pre-existing immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
Publisher: Cold Spring Harbor Laboratory
Date: 13-08-2021
DOI: 10.1101/2021.08.11.21261876
Abstract: A number of SARS-CoV-2 variants of concern (VOC) have been identified that partially escape serum neutralisation activity elicited by current vaccines. Recent studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. Here we integrate published data on in vitro neutralisation and clinical protection to understand and predict vaccine efficacy against existing SARS-CoV-2 variants. We find that neutralising activity against the ancestral SARS-CoV-2 is highly predictive of neutralisation of the VOC, with all vaccines showing a similar drop in neutralisation to the variants. Neutralisation levels remain strongly correlated with protection from infection with SARS-CoV-2 VOC (r=0.81, p=0.0005). We apply an existing model relating in vitro neutralisation to protection (parameterised on data from ancestral virus infection) and find this remains predictive of vaccine efficacy against VOC once drops in neutralisation to the VOC are taken into account. Modelling of predicted vaccine efficacy against variants over time suggests that protection against symptomatic infection may drop below 50% within the first year after vaccination for some current vaccines. Boosting of previously infected in iduals with existing vaccines (which target ancestral virus) has been shown to significantly increase neutralising antibodies. Our modelling suggests that booster vaccination should enable high levels of immunity that prevent severe infection outcomes with the current SARS-CoV-2 VOC, at least in the medium term.
Publisher: American Society for Clinical Investigation
Date: 14-11-2019
Publisher: Springer Science and Business Media LLC
Date: 18-01-2019
DOI: 10.1038/S41467-018-08165-Y
Abstract: Influenza B viruses (IBV) drive a significant proportion of influenza-related hospitalisations yet are understudied compared to influenza A. Current vaccines target the head of the viral hemagglutinin (HA) which undergoes rapid mutation, significantly reducing vaccine effectiveness. Improved vaccines to control IBV are needed. Here we developed novel IBV HA probes to interrogate humoral responses to IBV in humans. A significant proportion of IBV HA-specific B cells recognise both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages in a distinct pattern of cross-reactivity. Monoclonal antibodies (mAbs) were reconstituted from IBV HA-specific B cells, including mAbs providing broad protection in murine models of lethal IBV infection. Protection was mediated by neutralising antibodies targeting the receptor binding domain, or via Fc-mediated functions of non-neutralising antibodies binding alternative epitopes including the IBV HA stem. This work defines antigenic cross-recognition between IBV lineages and provides guidance for the rational design of improved IBV vaccines for broad and durable protection.
Publisher: American Society for Clinical Investigation
Date: 10-04-2023
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: Springer Science and Business Media LLC
Date: 12-04-2019
DOI: 10.1038/S41590-019-0395-0
Abstract: In the version of this article initially published, the labels (50 Å) above the scale bars in Fig. 1b were incorrect. The correct size is 50 nm. The error has been corrected in the HTML and PDF versions of the article.
Publisher: American Society for Microbiology
Date: 26-02-2019
Abstract: Current influenza vaccines are primarily strain specific, requiring annual updates, and offer minimal protection against drifted seasonal or pandemic strains. The highly conserved stem region of hemagglutinin (HA) of group 2 influenza A virus subtypes is a promising target for vaccine elicitation of broad cross-group protection against ergent strains. We used structure-guided protein engineering employing multiple protein stabilization methods simultaneously to develop group 2 HA stem-based candidate influenza A virus immunogens displayed as trimers on self-assembling nanoparticles. Characterization of antigenicity, thermostability, and particle formation confirmed structural integrity. Group 2 HA stem antigen designs were identified that, when displayed on ferritin nanoparticles, activated B cells expressing inferred unmutated common ancestor (UCA) versions of human antibody lineages associated with cross-group-reactive, broadly neutralizing antibodies (bNAbs). Immunization of mice led to protection against a lethal homosubtypic influenza virus challenge. These candidate vaccines are now being manufactured for clinical evaluation.
Publisher: American Society for Clinical Investigation
Date: 02-06-2014
DOI: 10.1172/JCI74351
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-04-2019
DOI: 10.1126/SCIIMMUNOL.AAU2710
Abstract: Ad4-H5 vaccine induces prolonged increases in H5-specific B cell frequency, antibody affinity, and somatic hypermutation.
Publisher: American Society for Microbiology
Date: 09-2015
Abstract: Antibody (Ab) affinity maturation enables an in idual to maintain immunity to an increasing number of pathogens within the limits of a total Ig production threshold. A better understanding of this process is critical for designing vaccines that generate optimal Ab responses to pathogens. Our study describes a simple flow-cytometric method that enumerates virus-specific germinal center (GC) B cells as well as their AC 50 , a measure of Ab avidity, defined as the antigen concentration required to detect 50% of specific B cells. Using a model of mouse Ab responses to the influenza A virus hemagglutinin (IAV HA), we obtained data indicating that AC 50 decreases with time postinfection in an affinity maturation-dependent process. As proof of principle of the utility of the method, our data clearly show that relative to intranasal IAV infection, intramuscular immunization against inactivated IAV in adjuvant results in a diminished GC HA B cell response, with increased AC 50 correlating with an increased serum Ab off-rate. Enabling simultaneous interrogation of both GC HA B cell quantity and quality, this technique should facilitate study of affinity maturation and rational vaccine design. IMPORTANCE Though it was first described 50 years ago, little is known about how antibody affinity maturation contributes to immunity. This question is particularly relevant to developing more effective vaccines for influenza A virus (IAV) and other viruses that are difficult vaccine targets. Limitations in methods for characterizing antigen-specific B cells have impeded progress in characterizing the quality of immune responses to vaccine and natural immunogens. In this work, we describe a simple flow cytometry-based approach that measures both the number and affinity of IAV-binding germinal center B cells specific for the IAV HA, the major target of IAV-neutralizing antibodies. Using this method, we showed that the route and form of immunization significantly impacts the quality and quantity of B cell antibody responses. This method provides a relatively simple yet powerful tool for better understanding the contribution of affinity maturation to viral immunity.
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Chemical Society (ACS)
Date: 18-04-2019
Abstract: Upon exposure to human blood, nanoengineered particles interact with a multitude of plasma components, resulting in the formation of a biomolecular corona. This corona modulates downstream biological responses, including recognition by and association with human immune cells. Considerable research effort has been directed toward the design of materials that can demonstrate a low affinity for various proteins (low-fouling materials) and materials that can exhibit low association with human immune cells (stealth materials). An implicit assumption common to bio-nano research is that nanoengineered particles that are low-fouling will also exhibit stealth. Herein, we investigated the link between the low-fouling properties of a particle and its propensity for stealth in whole human blood. High-fouling mesoporous silica (MS) particles and low-fouling zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) particles were synthesized, and their interaction with blood components was assessed before and after precoating with serum albumin, immunoglobulin G, or complement protein C1q. We performed an in-depth proteomics characterization of the biomolecular corona that both identifies specific proteins and measures their relative abundance. This was compared with observations from a whole blood association assay that identified with which cell type each particle system associates. PMPC-based particles displayed reduced association both with cells and with serum proteins compared with MS-based particles. Furthermore, the enrichment of specific proteins within the biomolecular corona was found to correlate with association with specific cell types. This study demonstrates how the low-fouling properties of a material are indicative of its stealth with respect to immune cell association.
Publisher: American Society for Clinical Investigation
Date: 22-01-2019
DOI: 10.1172/JCI123366
Start Date: 05-2021
End Date: 05-2024
Amount: $676,622.00
Funder: Australian Research Council
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