Clinical Medicine
Abstract
BACKGROUND. Maintaining durable immunity to vaccination represents a major challenge, but whether booster mRNA vaccination improves durability is unknown. METHODS. We measured antibody responses in 55 healthy adults who received a booster dose of Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster, we measured serum antibody titers, and memory B and T cell responses. RESULTS. The booster (3rd immunization) dose at 6 - 10 months increased the half-life of serum neutralizing antibody (nAb) titers to 76 days from 56 - 66 days after the primary two-dose vaccination. A second booster dose (4th immunization) a year after the primary vaccination increased the half-life further to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss in neutralization capacity against Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48, 71, and 66-fold drop in titers respectively, relative to the WA.1 strain). While only 45 – 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (3rd dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months. CONCLUSION. The durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.
Authors
Prabhu S Arunachalam, Lilin Lai, Hady Samaha, Yupeng Feng, Mengyun Hu, Harold Sai-yin Hui, Bushra Wali, Madison L. Ellis, Meredith E. Davis-Gardner, Christopher M. Huerta, Kareem Bechnak, Sarah Bechnak, Matthew Lee, Matthew B. Litvack, Cecilia Losada, Alba Grifoni, Alessandro Sette, Veronika I. Zarnitsyna, Nadine Rouphael, Mehul S. Suthar, Bali Pulendran
Abstract
BACKGROUND. Hepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of non-alcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL. METHODS. Forty consecutive non-diabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24-hr, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry. RESULTS. Within a subset of subjects, DNL was detectable after a 24-hr fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, NEFA, and ketones. Additionally, they sustained glycogenolysis and spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis. CONCLUSION. Metabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL. TRIAL REGISTRATION. Data obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease; ClinicalTrials.gov NCT02690792.
Authors
Xiaorong Fu, Justin A. Fletcher, Stanisław Deja, Melissa Inigo-Vollmer, Shawn C. Burgess, Jeffrey D. Browning
Abstract
BACKGROUND Mosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODS This double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara–vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTS Env-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2–4.2) for mosaic recipients, 1.6 (95% CI, 0.82–2.6) for CON-S recipients, and 1.1 (95% CI, 0.62–1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSION Priming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATION ClinicalTrials.gov NCT02296541.FUNDING US NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.
Authors
Kristen W. Cohen, Andrew Fiore-Gartland, Stephen R. Walsh, Karina Yusim, Nicole Frahm, Marnie L. Elizaga, Janine Maenza, Hyman Scott, Kenneth H. Mayer, Paul A. Goepfert, Srilatha Edupuganti, Giuseppe Pantaleo, Julia Hutter, Daryl E. Morris, Stephen C. De Rosa, Daniel E. Geraghty, Merlin L. Robb, Nelson L. Michael, Will Fischer, Elena E. Giorgi, Harman Malhi, Michael N. Pensiero, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Peter B. Gilbert, M. Juliana McElrath, Barton F. Haynes, Bette T. Korber, Lindsey R. Baden, the NIAID HVTN 106 Study Group
Abstract
BACKGROUND. The role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored. METHODS. In a prospective, observational, monocentric ORCHESTRA cohort study, conducted between March 2021 and November 2022, mild-to-moderately ill COVID-19 patients (n=204) receiving bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were longitudinally studied over 28 days for viral loads, de novo Spike mutations, mAb kinetics, seroneutralization against infecting variants of concern, and T-cell immunity. Additionally, a machine learning-based circulating immune-related (CIB) biomarker profile predictive of evasive Spike mutations was constructed and confirmed in an independent dataset (n=19) that included patients receiving sotrovimab or tixagevimab/cilgavimab. RESULTS. Patients treated with various mAbs developed evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Immunocompromised patients receiving mAb therapy not only continued to display significantly higher viral loads, but also showed higher likelihood of developing de novo Spike mutations. Development of escape mutants also strongly correlated with neutralizing capacity of the therapeutic mAbs and T-cell immunity, suggesting immune pressure as an important driver of escape mutations. Lastly, we showed that an anti-inflammatory and healing-promoting host milieu facilitates Spike mutations, where 4 CIBs identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy. CONCLUSIONS. Our data demonstrate that host-driven immune and non-immune responses are essential for development of mutant SARS-CoV-2. These data also support point-of-care decision-making in reducing the risk of mAb treatment failure and improving mitigation strategies for possible dissemination of escape SARS-CoV-2 mutants.
Authors
Akshita Gupta, Angelina Konnova, Mathias Smet, Matilda Berkell, Alessia Savoldi, Matteo Morra, Vincent Van averbeke, Fien H.R. De Winter, Denise Peserico, Elisa Danese, An Hotterbeekx, Elda Righi, Pasquale De Nardo, Evelina Tacconelli, Surbhi Malhotra-Kumar, Samir Kumar-Singh
Abstract
BACKGROUND. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable between subtypes and the expression profile of MCC tumors is unexplored. METHODS. Here we leveraged bulk and single-cell RNA sequencing of patient-derived tumor biopsies and cell lines to explore the underlying transcriptional diversity of MCC. RESULTS. Strikingly, MCC samples could be separated into transcriptional subtypes that were independent of MCPyV status. Instead, we observed an inverse correlation between a NE gene signature and the Hippo pathway transcription factors Yes1-associated transcriptional regulator (YAP1) and WW domain containing transcriptional regulator (WWTR1). This inverse correlation was present at the transcript and protein levels in the tumor biopsies as well as in established and patient-derived cell lines. Mechanistically, expression of YAP1 or WWTR1 in a MCPyV-positive MCC cell line induced cell-cycle arrest at least in part through TEAD-dependent transcriptional repression of MCPyV LT. CONCLUSION. These findings describe previously unrecognized heterogeneity in NE gene expression within MCC and support the model that YAP1/WWTR1 silencing is essential for the development of MCPyV-positive MCC. FUNDING. US Public Health Service grants R35CA232128, P01CA203655, and P30CA06516.
Authors
Thomas C. Frost, Ashley K. Gartin, Mofei Liu, Jingwei Cheng, Harita Dharaneeswaran, Derin B. Keskin, Catherine J. Wu, Anita Giobbie-Hurder, Manisha Thakuria, James A. DeCaprio
Abstract
BACKGROUND. Relatlimab+nivolumab (anti-LAG3+anti-PD1) has been approved by FDA as a 1st-line therapy in stage III/IV melanoma, but its detailed effect on the immune system is unknown. METHODS. We evaluated blood samples from 40 immunotherapy-naïve or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG3+anti-PD1 in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq) combined with other multiomics profiling. RESULTS. The highest LAG3 expression was noted in NK cells, regulatory T cells (Tregs), and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy resulting in an active phenotype. LAG3+ Tregs expanded but based on the transcriptome profile became metabolically silent during the treatment. Lastly, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained more cytotoxic and NK-like phenotype. CONCLUSION. Anti-LAG3+anti-PD1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01968109) FUNDING. Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland, and an investigator-initiated research grant from BMS.
Authors
Jani Huuhtanen, Henna H.E. Kasanen, Katriina Peltola, Tapio Lönnberg, Virpi Glumoff, Oscar Brück, Olli Dufva, Karita Peltonen, Johanna Vikkula, Emmi Jokinen, Mette Ilander, Moon Hee Lee, Siru Mäkelä, Marta Nyakas, Bin Li, Micaela Hernberg, Petri Bono, Harri Lähdesmäki, Anna Kreutzman, Satu Mustjoki
Abstract
BACKGROUND. The fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). T-helper (Th) cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th-cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized. METHODS. We used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls. RESULTS. We show that clonally expanded, high-avidity A. fumigatus-specific effector Th-cells develop in pwCF, which are absent in healthy donors. Individual patients were characterized by distinct Th1, Th2, or Th17 dominated responses that remained stable over years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th-cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2-cells that cross-recognize various filamentous fungi. CONCLUSION. Our data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2-cells as a potential risk factor for ABPA. FUNDING. This research was supported by grants from the German Research Foundation (DFG) under Germany’s Excellence Strategy - EXC 2167-390884018 “Precision Medicine in Chronic Inflammation”, EXC 2051-390713860 “Balance of the Microverse”; the Oskar Helene Heim Stiftung; the Christiane Herzog Stiftung, Stuttgart, Germany; the Mukoviszidose Institut gGmbH, Bonn, the research and development arm of the German Cystic Fibrosis Association Mukoviszidose e.V; the German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath, BMBF 03ZZ0838A+B.
Authors
Carsten Schwarz, Patience Eschenhagen, Henrijette Schmidt, Thordis Hohnstein, Christina Iwert, Claudia Grehn, Jobst Roehmel, Eva Steinke, Mirjam Stahl, Laura Lozza, Ekaterina Tikhonova, Elisa Rosati, Ulrik Stervbo, Nina Babel, Jochen G. Mainz, Hilmar Wisplinghoff, Frank Ebel, Lei-Jie Jia, Matthew G. Blango, Peter Hortschansky, Sascha Brunke, Bernhard Hube, Axel A. Brakhage, Olaf Kniemeyer, Alexander Scheffold, Petra Bacher
Abstract
BACKGROUND. To date, only limited data is available on the mechanisms of protection against colonization with Bordetella pertussis in humans. METHODS. In this study, the cellular responses to Bordetella pertussis challenge were monitored longitudinally using high-dimensional EuroFlow-based flow cytometry, allowing quantitative detection of >250 different immune cell subsets in the blood of 15 healthy donors. RESULTS. Participants who were protected against colonization showed different early cellular responses compared to colonized participants. Especially prominent for colonization-protected participants were the early expansion of (CD36-) non classical monocytes at day 1 (d1), Natural Killer cells (d3), follicular T helper cells (d1-d3) and plasma cells (d3). Plasma cell expansion at d3 correlated negatively with the CFU load at d7 and d9 post-challenge. Increased plasma cell maturation at d11-14 was found in participants with seroconversion. CONCLUSION. These early cellular immune responses following experimental infection can now be further characterized and potentially linked to an efficient mucosal immune response, preventing colonization. Ultimately, their presence may be used to evaluate whether new Bordetella pertussis vaccine candidates are protective against Bordetella pertussis colonization, e.g., by bacterial challenge post-vaccination. TRIAL REGISTRATION. NCT03751514. FUNDING. This study is part of the PERISCOPE Project, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115910. The flow cytometric studies were supported by the EuroFlow Consortium.
Authors
Annieck M. Diks, Hans de Graaf, Cristina Teodosio, Rick J. Groenland, Bas de Mooij, Muktar Ibrahim, Alison R. Hill, Robert C. Read, Jacques J.M. van Dongen, Magdalena A. Berkowska
Abstract
BACKGROUND. Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown. METHODS. We carried an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5’-Leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets. RESULTS. Clones carrying proviruses with 5’-Leader defects can cause persistent NSV up to ~103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor site (MSD) and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced non-infectious virions containing viral RNA but lacking Envelope. CONCLUSION. These findings show that proviruses with 5’-Leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5’-Leader can help understanding failure to completely suppress viremia. FUNDING. Office of the NIH Director and National Institute of Dental & Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases, NIH, to the PAVE, BEAT-HIV and DARE Martin Delaney collaboratories.
Authors
Jennifer A. White, Fengting Wu, Saif Yasin, Milica Moskovljevic, Joseph Varriale, Filippo Dragoni, Angelica Camilo Contreras, Jiayi Duan, Mei Y. Zheng, Ndeh F. Tadzong, Heer B. Patel, Jeanelle Mae C. Quiambao, Kyle Rhodehouse, Hao Zhang, Jun Lai, Subul A. Beg, Michael Delannoy, Christin Kilcrease, Christopher J. Hoffmann, Sébastien Poulin, Frédéric Chano, Cecile Tremblay, Jerald Cherian, Patricia Barditch-Crovo, Natasha Chida, Richard D. Moore, Michael F. Summers, Robert F. Siliciano, Janet D. Siliciano, Francesco R. Simonetti
Abstract
BACKGROUND. Assessing circadian rhythmicity from infrequently sampled data is challenging, however this type of data is often encountered when measuring circadian transcripts in hospitalised patients. METHODS. We present ClinCirc. This method combines two existing mathematical methods (Lomb-Scargle periodogram and cosinor) sequentially, and is designed to measure circadian oscillations from infrequently sampled clinical data. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. ClinCirc was then evaluated in 13 ICU patients as well as in a separate cohort of 29 kidney transplant recipients. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney transplant recipients. RESULTS. ClinCirc had comparable performance to existing methods for analysing simulated data or clock transcript expression of healthy volunteers. It had improved accuracy compared to the cosinor method in evaluating circadian parameters in PER2::luc cell lines. In ICU patients, it was the only method investigated to suggest that loss of circadian oscillations in the peripheral oscillator was associated with inflammation, a feature widely reported in animal models. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. This phase shift could explain why a significant complication of kidney transplantation (delayed graft dysfunction) oscillates according to the time-of-day kidney transplantation is performed. CONCLUSION. ClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalised patients. FUNDING. UKRI, NIHR, EPSRC, NIAA, Asthma+Lung UK, Kidneys for Life.
Authors
Peter S. Cunningham, Gareth B. Kitchen, Callum Jackson, Stavros Papachristos, Thomas Springthorpe, David van Dellen, Julie E. Gibbs, Timothy W. Felton, Anthony J. Wilson, Jonathan Bannard-Smith, Martin K. Rutter, Thomas House, Paul Dark, Titus Augustine, Ozgur E. Akman, Andrew L. Hazel, John F. Blaikley
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ISSN: 0021-9738 (print), 1558-8238 (online)