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
Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI) preceded or coincided with increased general population COVID-19 mortality. Plasma samples from 2,250 blood donors who reported possible COVID-19 related PDI were tested for the presence of SARS-CoV-2 RNA. Detection of RNAemia peaked at 9-15% of PDI donors in late 2020 to early 2021 and fell to ~4% after implementation of widespread vaccination in the population. RNAemic donors were 1.2 to 1.4-fold more likely to report cough or shortness of breath and 1.8-fold more likely to report change in taste or smell compared to infected donors without detectable RNAemia. No infectious virus was detected in plasma from RNAemic donors; inoculation onto permissive cell lines showed <0.7-7 plaque forming units (PFU)/mL and into susceptible mice <100 PFU/mL in RNA positive plasma based on limits of detection in these models. These findings suggest that blood transfusions are highly unlikely to transmit SARS-CoV-2 infection.
Paula Saá, Rebecca V. Fink, Sonia Bakkour, Jing Jin, Graham Simmons, Marcus O. Muench, Hina Dawar, Clara Di Germanio, Alvin J. Hui, David J. Wright, David E. Krysztof, Steven H. Kleinman, Angela Cheung, Theresa Nester, Debra A. Kessler, Rebecca L. Townsend, Bryan R. Spencer, Hany Kamel, Jacquelyn M. Vannoy, Honey Dave, Michael P. Busch, Susan L. Stramer, Mars Stone, Rachael P. Jackman, Philip J. Norris
BACKGROUND. Patients undergoing immune-modifying therapies demonstrate a reduced humoral response after COVID-19 vaccination, but we lack a proper evaluation of the impact of such therapies on vaccine-induced T cell responses. METHODS. We longitudinally characterized humoral and Spike-specific T cell responses in inflammatory bowel disease (IBD) patients who are on antimetabolite therapy (azathioprine or methotrexate), TNF inhibitors and/or other biologic treatment (anti-integrin or anti-p40) for up to 6 months after completing two-dose COVID-19 mRNA vaccination. RESULTS. We demonstrated that a Spike-specific T cell response is not only induced in treated IBD patients at levels similar to healthy individuals, but also sustained at higher magnitude for up to 6 months after vaccination, particularly in those treated with TNF inhibitor therapy. Furthermore, the Spike-specific T cell response in these patients is mainly preserved against mutations present in SARS-CoV-2 B.1.1.529 (Omicron) and characterized by a Th1/IL-10 cytokine profile. CONCLUSION. Despite the humoral response defects, patients under immune-modifying therapies demonstrated a favorable profile of vaccine-induced T cell responses that might still provide a layer of COVID-19 protection. FUNDING. This study was funded by the National Centre for Infectious Diseases NCID Catalyst Grant (FY2021ES) and the National Research Fund Competitive Research Programme (NRF-CRP25-2020-0003). The funders played no role in the design, conduct, or reporting of this study.
Martin Qui, Nina Le Bert, Webber Pak Wo Chan, Malcolm Tan, Shou Kit Hang, Smrithi Hariharaputran, Jean Xiang Ying Sim, Jenny Guek Hong Low, Weiling Ng, Wei Yee Wan, Tiing Leong Ang, Antonio Bertoletti, Ennaliza Salazar
BACKGROUND. Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy (CPT), remains to be fully elucidated. METHODS. Here, we conducted a proof-of-principle study of CPT based on a phase I trial in thirty hospitalized COVID-19 patients with a median interval between the onset of symptoms and the first transfusion of 9 days (IQR, 7-11.8 days). A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. RESULTS. In the context of this trial CPT was safe as evidenced by the absence of transfusion related adverse events and a low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (p= 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio (HR)= 3.0 [95% confidence interval (CI) 1.1;8.1], p= 0.026). The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their pre-transfusion endogenous neutralization status recipients benefitted from plasma therapy with high neutralizing antibodies (HR= 3.5 [95% CI 1.1;11], p= 0.034). CONCLUSION. In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response and more broadly point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04869072 FUNDING. This study was funded via an “Innovation-Pool” project by the University Hospital Zurich, the “Swiss Red Cross “Glückskette” Corona Funding”, Pandemiefonds of the UZH Foundation and the Clinical Research Priority Program ‘Comprehensive Genomic Pathogen Detection’ of the University of Zurich.
Maddalena Marconato, Irene A. Abela, Anthony Hauser, Magdalena Schwarzmüller, Rheliana Katzensteiner, Dominique L. Braun, Selina Epp, Annette Audigé, Jacqueline Weber, Peter Rusert, Emèry Schindler, Chloé Pasin, Emily West, Jürg Böni, Verena Kufner, Michael Huber, Maryam Zaheri, Stefan Schmutz, Beat M. Frey, Roger D. Kouyos, Huldrych F. Günthard, Markus G. Manz, Alexandra Trkola
BACKGROUND. The Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase 1/2 trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing Sarbecovirus conserved Th and CTL epitopes on the nucleocapsid (N), membrane (M) and spike (S2) proteins. METHODS. We conducted a phase-1 primary 2-dose (28-day apart) trial of 10-, 30-, or 100-μg UB-612 in sixty healthy young adults aged 20-55 years, and fifty of them were boosted with 100-μg of UB-612 ~7-9 months post-2nd dose. A separate placebo-controlled and randomized phase-2 study was conducted with two doses of 100-μg UB-612 (n = 3,875, aged 18-85 years). We evaluated interim safety and immunogenicity of the phase-1 until 14 days post-3rd (booster) dose and of the phase-2 until 28 days post-2nd dose. RESULTS. No vaccine-related serious adverse events (SAE) were recorded. The most common solicited AEs were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were: long-lasting viral-neutralizing antibodies and broad T-cell immunity against SARS-CoV2 Variants of Concern (VoCs) including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron variants. CONCLUSION. UB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B- and broad T-cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines. TRIAL REGISTRATION. Clinical Trials.gov: NCT04545749, NCT04773067 and NCT04967742. FUNDING. United Biomedical Inc., Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.
Chang Yi Wang, Kao-Pin Hwang, Hui-Kai Kuo, Wen-Jiun Peng, Yea-Huei Shen, Be-Sheng Kuo, Juin-Hua Huang, Hope Liu, Yu-Hsin Ho, Feng Lin, Shuang Ding, Zhi Liu, Huan-Ting Wu, Ching-Tai Huang, Yuarn-Jang Lee, Ming-Che Liu, Yi-Ching Yang, Po-Liang Lu, Hung-Chin Tsai, Chen-Hsiang Lee, Zhi-Yuan Shi, Chun-Eng Liu, Chun-Hsing Liao, Feng-Yee Chang, Hsiang-Cheng Cheng, Fu-Der Wang, Kuo-Liang Hou, Jennifer Cheng, Min-Sheng Wang, Ya-Ting Yang, Han-Chen Chiu, Ming-Han Jiang, Hao-Yu Shih, Hsuan-Yu Shen, Po-Yen Chang, Yu-Rou Lan, Chi-Tian Chen, Yi-Ling Lin, Jian-Jong Liang, Chun-Che Liao, Yu-Chi Chou, Mary Kate Morris, Carl V. Hanson, Farshad Guirakhoo, Michael Hellerstein, Hui Jing Yu, Chwan-Chuen King, Tracy Kemp, D. Gray Heppner, Thomas P. Monath
Replication of SARS-CoV-2 in human population is defined by distributions of mutants that are present at different frequencies within the infected host, and can be detected by ultra-deep sequencing techniques. In this study, we have examined the SARS-CoV-2 mutant spectra of amplicons from the spike (S)-coding region of five nasopharyngeal isolates derived from vaccine-breakthrough patients. Interestingly, all patients became infected with the Alpha variant but amino acid substitutions that correspond to the Delta Plus, Iota and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from vaccine-breakthrough patients revealed a rich reservoir of mutant types, and may also inform of tolerated substitutions that can be represented in epidemiological dominant variants.
Brenda Martínez-González, Lucía Vázquez-Sirvent, María E. Soria, Pablo Mínguez, Llanos Salar-Vidal, Carlos García-Crespo, Isabel Gallego, Ana Ávila, Carlos Llorens, Beatriz Soriano, Ricardo Ramos-Ruiz, Jaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruiz-Hornillos, Concepción Pérez-Jorge, Esteban Domingo, Celia Perales
Eddie C.Y. Wang, Ceri A. Fielding, Richard J. Stanton
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