Lorenza Bellusci, Hana Golding, Surender Khurana
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.
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
BACKGROUND. The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS. We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52). CONCLUSION. Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. TRIAL REGISTRATION. Long-term Impact of Infection with Novel Coronavirus (LIINC); NCT04362150 FUNDING. This work was supported by the National Institute of Allergy and Infectious Diseases NIH/NIAID 3R01AI141003-03S1 to TJ Henrich, R01AI158013 to M Gandhi and M Spinelli, K24AI145806 to P Hunt, and by the Zuckerberg San Francisco Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine. MJP is supported on K23 A137522 and received support from the UCSFBay Area Center for AIDS Research (P30-AI027763).
Michael J. Peluso, Tyler-Marie Deveau, Sadie E. Munter, Dylan M. Ryder, Amanda M. Buck, Gabriele Beck-Engeser, Fay Chan, Scott Lu, Sarah A. Goldberg, Rebecca Hoh, Viva Tai, Leonel Torres, Nikita S. Iyer, Monika Deswal, Lynn H. Ngo, Melissa Buitrago, Antonio E. Rodriguez, Jessica Y. Chen, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, Amelia N. Deitchman, Joanna Hellmuth, Matthew A. Spinelli, Matthew S. Durstenfeld, Priscilla Y. Hsue, John Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Timothy J. Henrich
BACKGROUND. Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP. METHODS. Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP-donors (n=113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTS. The median follow-up of patients was 396 days, the estimated 1-year survival was 78.7% in the CCP and 60.2% in the control group (p=0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared to the control group (91.5% versus 60.2%; p=0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase of neutralizing antibodies after vaccination between CCP and the control group. CONCLUSION. The trial demonstrated a trend towards better outcome in the CCP group without reaching statistical significance. A pre-defined subgroup analysis showed a significant better outcome (long-term survival; time to discharge from ICU and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared to the control group. A substantial long-term disease burden remains after severe COVID-19. TRIAL REGISTRATION. EudraCT number 2020-001310-38 FUNDING. Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802/ZMI1-2521COR802
Sixten Körper, Beate Grüner, Daniel Zickler, Thomas Wiesmann, Patrick Wuchter, Rainer Blasczyk, Kai Zacharowski, Peter Spieth, Torsten Tonn, Peter Rosenberger, Gregor Paul, Jan Pilch, Joachim Schwäble, Tamam Bakchoul, Thomas Thiele, Julian Knoerlein, Matthias M. Dollinger, Joerg Krebs, Martin Bentz, Victor M. Corman, Dzenan Kilalic, Gerlinde Schmidtke-Schrezenmeier, Philipp M. Lepper, Lucas Ernst, Hinnerk Wulf, Alexandra Ulrich, Manfred Weiss, Jan Kruse, Thomas Burkhardt, Rebecca Müller, Harald Klüter, Michael Schmidt, Bernd Jahrsdörfer, Ramin Lotfi, Markus Rojewski, Thomas Appl, Benjamin Mayer, Philipp Schnecko, Erhard Seifried, Hubert Schrezenmeier
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
Mehdi Benamar, Qian Chen, Janet Chou, Amélie M. Julé, Rafik Boudra, Paola Contini, Elena Crestani, Peggy S. Lai, Muyun Wang, Jason Fong, Shira Rockwitz, Pui Y. Lee, Tsz Man Fion Chan, Ekin Zeynep Altun, Eda Kepenekli, Elif Karakoc-Aydiner, Ahmet Ozen, Perran Boran, Fatih Aygun, Pınar Önal, Ayse Ayzit Kilinc Sakalli, Haluk Cokugras, Metin Yusuf Gelmez, Fatma B. Oktelik, Esin Cetin Aktas, Yuelin Zhong, Maria L. Taylor, Katherine Irby, Natasha B. Halasa, Elizabeth H. Mack, Sara Signa, Ignazia Prigione, Marco Gattorno, Nicola Cotugno, Donato Amodio, Raif S. Geha, Mary Beth Son, Jane W. Newburger, Pankaj B. Agrawal, Stefano Volpi, Paolo Palma, Ayca Kiykim, Adrienne Randolph, Gunnur Deniz, Safa Baris, Raffaele De Palma, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Lauren A. Henderson, Talal A. Chatila
BACKGROUND. Heterologous effects of vaccines are mediated by ‘trained immunity’ whereby myeloid cells are metabolically and epigenetically reprogrammed resulting in heightened responses to subsequent insults. Adenovirus vaccine vector has been reported to induce trained immunity in mice. Therefore, we sought to determine if the ChAdOx1 nCoV-19 vaccine (AZD1222), which uses an adenoviral vector, could induce trained immunity in vivo in humans. METHODS. Ten healthy volunteers donated blood on the day before receiving the ChAdOx1 nCoV-19 vaccine and on day 14, 56 and 90 post vaccination. Monocytes were purified from PBMC; cell phenotype was determined by flow cytometry, expression of metabolic enzymes were quantified by RT-qPCR and production of cytokines and chemokine in response to stimulation ex vivo were analyzed by multiplex ELISA. RESULTS. Monocyte frequency and count were increased in peripheral blood up to 3 months post vaccination compared with their own pre-vaccine control. Expression of HLA-DR, CD40 and CD80 was enhanced on monocytes for up to 3 months following vaccination. Moreover, monocytes had increased expression of glycolysis-associated enzymes 2 months post vaccination. Upon stimulation ex vivo with unrelated antigens, monocytes produced increased IL-1β, IL-6, IL-10, CXCL1, and MIP-1α, and decreased TNF, compared with pre-vaccine controls. Resting monocytes produced more IFN-γ, IL-18, and MCP-1 up to 3 months post vaccination compared with pre-vaccine controls. CONCLUSION. These data provide evidence for the induction of trained immunity following a single dose of the ChAdOx1 nCoV-19 vaccine. FUNDING. This work was funded by The Health Research Board (EIA-2019-010) and Science Foundation Ireland Strategic Partnership Programme (Proposal ID 20/SPP/3685).
Dearbhla M. Murphy, Donal J. Cox, Sarah A. Connolly, Eamon P Breen, Aenea A.I. Brugman, James J. Phelan, Joseph Keane, Sharee A. Basdeo
SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.
Guoli Shi, Abhilash I. Chiramel, Tiansheng Li, Kin Kui Lai, Adam D. Kenney, Ashley Zani, Adrian C Eddy, Saliha Majdoul, Lizhi Zhang, Tirhas Dempsey, Paul A. Beare, Swagata Kar, Jonathan W. Yewdell, Sonja M Best, Jacob S. Yount, Alex A. Compton
Susanne L. Linderman, Lilin Lai, Estefany L. Bocangel Gamarra, Max S.Y. Lau, Srilatha Edupuganti, Diya Surie, Mark W. Tenforde, James D. Chappell, Nicholas M. Mohr, Kevin W. Gibbs, Jay S. Steingrub, Matthew C. Exline, Nathan I. Shapiro, Anne E. Frosch, Nida Qadir, Meredith E. Davis-Gardner, M. Juliana McElrath, Adam S. Lauring, Mehul S. Suthar, Manish M. Patel, Wesley H. Self, Rafi Ahmed
The SARS-CoV-2 spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARSCoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific monoclonal antibody (mAb) exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated antibodydependent cellular cytotoxicity (ADCC) against infected cells. These findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based monoclonal antibody therapies to treat COVID-19.
Tanushree Dangi, Sarah Sanchez, Jacob Class, Michelle C. Richner, Lavanya Visvabharathy, Young Rock Chung, Kirsten Bentley, Richard J. Stanton, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster
Background We report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.Methods Adults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR–positive (RT-PCR–positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2–seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.Findings Data cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.Conclusion AZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registration ClinicalTrials.gov NCT04516746.Funding AstraZeneca; US government.
Magdalena E. Sobieszczyk, Jill Maaske, Ann R. Falsey, Stephanie Sproule, Merlin L. Robb, Robert W. Frenck Jr., Hong-Van Tieu, Kenneth H. Mayer, Lawrence Corey, Kathleen M. Neuzil, Tina Tong, Margaret Brewinski Isaacs, Holly Janes, Himanshu Bansal, Lindsay M. Edwards, Justin A. Green, Elizabeth J. Kelly, Kathryn Shoemaker, Therese Takas, Tom White, Prakash Bhuyan, Tonya Villafana, and Ian Hirsch, on behalf of the AstraZeneca AZD1222 Clinical Study Group
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