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Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individuals

Samanovic, Marie I; Cornelius, Amber R; Gray-Gaillard, Sophie L; Allen, Joseph Richard; Karmacharya, Trishala; Wilson, Jimmy P; Wesley Hyman, Sara; Tuen, Michael; Koralov, Sergei B; Mulligan, Mark J; Sedaghat Herati, Ramin
[Figure: see text].
PMID: 34874183
ISSN: 1946-6242
CID: 5086932

PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine

Herati, Ramin Sedaghat; Knorr, David A; Vella, Laura A; Silva, Luisa Victoria; Chilukuri, Lakshmi; Apostolidis, Sokratis A; Huang, Alexander C; Muselman, Alexander; Manne, Sasikanth; Kuthuru, Oliva; Staupe, Ryan P; Adamski, Sharon A; Kannan, Senthil; Kurupati, Raj K; Ertl, Hildegund C J; Wong, Jeffrey L; Bournazos, Stylianos; McGettigan, Suzanne; Schuchter, Lynn M; Kotecha, Ritesh R; Funt, Samuel A; Voss, Martin H; Motzer, Robert J; Lee, Chung-Han; Bajorin, Dean F; Mitchell, Tara C; Ravetch, Jeffrey V; Wherry, E John
Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.
PMID: 35902637
ISSN: 1529-2916
CID: 5276912

Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells

Herati, Ramin Sedaghat; Muselman, Alexander; Vella, Laura; Bengsch, Bertram; Parkhouse, Kaela; Del Alcazar, Daniel; Kotzin, Jonathan; Doyle, Susan A; Tebas, Pablo; Hensley, Scott E; Su, Laura F; Schmader, Kenneth E; Wherry, E John
T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38. This subset expressed more Bcl-6, c-Maf, and IL-21 than other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS+CD38+ cTfh at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated Activation Induced Marker (AIM) expression. Moreover, TCRB sequencing identified a clonal response in ICOS+CD38+ cTfh that correlated strongly with the increased circulating ICOS+CD38+ cTfh frequency and the circulating plasmablast response. In subjects who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS+CD38+ cTfh subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTfh after vaccination persisted in the ICOS-CD38- cTfh repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more-stable ICOS-CD38- cTfh subset. These data highlight the antigen-specificity, lineage relationships and memory properties of human cTfh responses to vaccination, providing new avenues for tracking and monitoring cTfh responses during infection and vaccination in humans.
PMID: 28620653
ISSN: 2470-9468
CID: 4050562

mRNA COVID-19 vaccine elicits potent adaptive immune response without the acute inflammation of SARS-CoV-2 infection

Ivanova, Ellie N.; Shwetar, Jasmine; Devlin, Joseph C.; Buus, Terkild B.; Gray-Gaillard, Sophie; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I.; Herrera, Alberto; Mimitou, Eleni P.; Zhang, Chenzhen; Karmacharya, Trishala; Desvignes, Ludovic; Ødum, Niels; Smibert, Peter; Ulrich, Robert J.; Mulligan, Mark J.; Koide, Shohei; Ruggles, Kelly V.; Herati, Ramin S.; Koralov, Sergei B.
SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.
ISSN: 2589-0042
CID: 5620862

Multimodal single-cell datasets characterize antigen-specific CD8+ T cells across SARS-CoV-2 vaccination and infection

Zhang, Bingjie; Upadhyay, Rabi; Hao, Yuhan; Samanovic, Marie I; Herati, Ramin S; Blair, John D; Axelrad, Jordan; Mulligan, Mark J; Littman, Dan R; Satija, Rahul
The immune response to SARS-CoV-2 antigen after infection or vaccination is defined by the durable production of antibodies and T cells. Population-based monitoring typically focuses on antibody titer, but there is a need for improved characterization and quantification of T cell responses. Here, we used multimodal sequencing technologies to perform a longitudinal analysis of circulating human leukocytes collected before and after immunization with the mRNA vaccine BNT162b2. Our data indicated distinct subpopulations of CD8+ T cells, which reliably appeared 28 days after prime vaccination. Using a suite of cross-modality integration tools, we defined their transcriptome, accessible chromatin landscape and immunophenotype, and we identified unique biomarkers within each modality. We further showed that this vaccine-induced population was SARS-CoV-2 antigen-specific and capable of rapid clonal expansion. Moreover, we identified these CD8+ T cell populations in scRNA-seq datasets from COVID-19 patients and found that their relative frequency and differentiation outcomes were predictive of subsequent clinical outcomes.
PMID: 37735591
ISSN: 1529-2916
CID: 5606242

Immune response, phenotyping and molecular graft surveillance in kidney transplant recipients following severe acute respiratory syndrome coronavirus 2 vaccination

Ali, Nicole M; Herati, Ramin S; Mehta, Sapna A; Leonard, Jeanette; Miles, Jake; Lonze, Bonnie E; DiMaggio, Charles; Tatapudi, Vasishta S; Stewart, Zoe A; Alnazari, Nasser; Neumann, Henry J; Thomas, Jeffrey; Cartiera, Katarzyna; Weldon, Elaina; Michael, Jennifer; Hickson, Christopher; Whiteson, Harris; Khalil, Karen; Stern, Jeffrey M; Allen, Joseph R; Tuen, Michael; Gray-Gaillard, Sophie L; Solis, Sabrina M; Samanovic, Marie I; Mulligan, Mark J; Montgomery, Robert A
BACKGROUND:Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS:We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS:Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS:SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.
PMID: 37707287
ISSN: 1399-3062
CID: 5593762

Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection

Ivanova, Ellie N; Devlin, Joseph C; Buus, Terkild B; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I; Herrera, Alberto; Zhang, Chenzhen; Desvignes, Ludovic; Odum, Niels; Ulrich, Robert; Mulligan, Mark J; Koide, Shohei; Ruggles, Kelly V; Herati, Ramin S; Koralov, Sergei B
Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.
PMID: 33907755
ISSN: n/a
CID: 4852132

Molecularly distinct memory CD4+ T cells are induced by SARS-CoV-2 infection and mRNA vaccination

Gray-Gaillard, Sophie L; Solis, Sabrina; Monteiro, Clarice; Chen, Han M; Ciabattoni, Grace; Samanovic, Marie I; Cornelius, Amber R; Williams, Tijaana; Geesey, Emilie; Rodriguez, Miguel; Ortigoza, Mila Brum; Ivanova, Ellie N; Koralov, Sergei B; Mulligan, Mark J; Herati, Ramin Sedaghat
UNLABELLED:Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs between these two contexts. Notable differences in humoral and cellular immune responses to primary mRNA vaccination were observed and associated with prior COVID-19 history, including in the establishment and recall of Spike-specific CD4+ T cells. It was unclear whether CD4+ T cell memory established by infection or mRNA vaccination as the first exposure to Spike was qualitatively similar. To assess whether the mechanism of initial memory T cell priming affected subsequent responses to Spike protein, 14 people who were receiving a third mRNA vaccination, referenced here as the booster, were stratified based on whether the first exposure to Spike protein was by viral infection or immunization (infection-primed or vaccine-primed). Using multimodal scRNA-seq of activation-induced marker (AIM)-reactive Spike-specific CD4+ T cells, we identified 220 differentially expressed genes between infection- and vaccine-primed patients at the post-booster time point. Infection-primed participants had greater expression of genes related to cytotoxicity and interferon signaling. Gene set enrichment analysis (GSEA) revealed enrichment for Interferon Alpha, Interferon Gamma, and Inflammatory response gene sets in Spike-specific CD4+ T cells from infection-primed individuals, whereas Spike-specific CD4+ T cells from vaccine-primed individuals had strong enrichment for proliferative pathways by GSEA. Finally, SARS-CoV-2 breakthrough infection in vaccine-primed participants resulted in subtle changes in the transcriptional landscape of Spike-specific memory CD4+ T cells relative to pre-breakthrough samples but did not recapitulate the transcriptional profile of infection-primed Spike-specific CD4+ T cells. Together, these data suggest that CD4+ T cell memory is durably imprinted by the inflammatory context of SARS-CoV-2 infection, which has implications for personalization of vaccination based on prior infection history. ONE SENTENCE SUMMARY/UNASSIGNED:SARS-CoV-2 infection and mRNA vaccination prime transcriptionally distinct CD4+ T cell memory landscapes which are sustained with subsequent doses of vaccine.
PMID: 36415470
ISSN: 2692-8205
CID: 5390872

High-throughput interrogation of immune responses using the Human Immune Profiling Pipeline

Wang, Guanning; Lyudovyk, Olga; Kim, Justin Y; Lin, Ya-Hui; Elhanati, Yuval; Mathew, Divij; Wherry, E John; Herati, Ramin S; Greenplate, Allison R; Greenbaum, Benjamin; Vardhana, Santosha A; Huang, Alexander C
The current abundance of immunotherapy clinical trials presents an opportunity to learn about the underlying mechanisms and pharmacodynamic effects of novel drugs on the human immune system. Here, we present a protocol to study how these immune responses impact clinical outcomes using large-scale high-throughput immune profiling of clinical cohorts. We describe the Human Immune Profiling Pipeline, which comprises an end-to-end solution from flow cytometry results to computational approaches and unsupervised patient clustering based on lymphocyte landscape. For complete details on the use and execution of this protocol, please refer to Lyudovyk et al. (2022).1.
PMID: 37159385
ISSN: 2666-1667
CID: 5509292

Human T follicular helper clones seed the germinal center-resident regulatory pool

Le Coz, Carole; Oldridge, Derek A; Herati, Ramin S; De Luna, Nina; Garifallou, James; Cruz Cabrera, Emylette; Belman, Jonathan P; Pueschl, Dana; Silva, Luisa V; Knox, Ainsley V C; Reid, Whitney; Yoon, Samuel; Zur, Karen B; Handler, Steven D; Hakonarson, Hakon; Wherry, E John; Gonzalez, Michael; Romberg, Neil
The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38+, germinal center-resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38- nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.
PMID: 37027481
ISSN: 2470-9468
CID: 5463922