COVID-19
Abstract
The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, interferon-armed SARS-CoV-2 fusion protein vaccine with IM priming and intranasal (IN) boost sequential immunization. Our study showed that this sequential vaccination strategy of the IM+IN significantly enhances both upper respiratory and systemic antiviral immunity in a mouse model, characterized by the rapid increase in systemic and mucosal T and B cell responses, particularly the mucosal IgA antibody response. The IN boost triggered a swift secondary immune response, rapidly inducing antigen-specific IgA+ B cells. Further BCR-seq analysis indicated that these IgA+ B cells primarily arise through direct class switching from pre-existing IgG+ B cells in draining lymph nodes. Notably, our clinical studies reveal that the IN boost after IM vaccination elicited a robust systemic IgA antibody response in humans, as measured in serum. Thus, our cytokine-armed protein vaccine presents a promising strategy for inducing rapid and potent mucosal protection against respiratory viral infections.
Authors
Yifan Lin, Xuejiao Liao, Xuezhi Cao, Zhaoyong Zhang, Xiuye Wang, Xiaomeng He, Huiping Liao, Bin Ju, Furong Qi, Hairong Xu, Zhenhua Ren, Yanqun Wang, Zhenxiang Hu, Jiaming Yang, Yang-Xin Fu, Jincun Zhao, Zheng Zhang, Hua Peng
Abstract
Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade can be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.
Authors
Jian Zheng, Hima Dhakal, Enya Qing, Rejeena Shrestha, Anne E. Geller, Samantha M. Morrissey, Divyasha Saxena, Xiaoling Hu, Hong Li, Haiyan Li, Kevin Wilhelmsen, Linder H. Wendt, Klaus Klumpp, Patrick S. Hume, William J. Janssen, Rachel Brody, Kenneth E. Palmer, Silvia M. Uriarte, Patrick P. Ten Eyck, David K. Meyerholz, Michael L. Merchant, Kenneth McLeish, Tom Gallagher, Jiapeng Huang, Jun Yan, Stanley Perlman
Abstract
Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin–like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.
Authors
Wenyan Ren, Weiqi Hong, Jingyun Yang, Jun Zou, Li Chen, Yanan Zhou, Hong Lei, Aqu Alu, Haiying Que, Yanqiu Gong, Zhenfei Bi, Cai He, Minyang Fu, Dandan Peng, Yun Yang, Wenhai Yu, Cong Tang, Qing Huang, Mengli Yang, Bai Li, Jingmei Li, Junbin Wang, Xuelei Ma, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Zhenling Wang, Guowen Jia, Zhaoming Su, Bin Shao, Hanpei Miao, Johnson Yiu-Nam Lau, Yuquan Wei, Kang Zhang, Lunzhi Dai, Shuaiyao Lu, Xiawei Wei
Abstract
BACKGROUND. There is uncertainty around the timing of booster vaccination against COVID-19 in highly vaccinated populations during the present endemic phase of COVID-19. Studies focused on primary vaccination have previously suggested improved immunity after delaying immunisation. METHODS. We conducted a randomised controlled trial (Nov 2022 – Aug 2023) and assigned 52 fully vaccinated adults to an immediate or a 3-month delayed bivalent Spikevax mRNA booster vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), with saliva and plasma samples collected following each visit. RESULTS. The rise in neutralising antibody responses to ancestral and Omicron strains were almost identical between the immediate and delayed vaccination arms. Analyses of plasma and salivary antibody responses (IgG, IgA), plasma antibody-dependent phagocytic activity, and the decay kinetics of antibody responses were similar between the 2 arms. Symptomatic and asymptomatic SARS-CoV-2 infection occurred in 49% (21/49) participants over the median 11.5 months of follow up and were also similar between the 2 arms. CONCLUSIONS. Our data suggests no benefit from delaying COVID-19 mRNA booster vaccination in pre-immune populations during the present endemic phase of COVID-19 TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry number 12622000411741. FUNDING. National Health and Medical Research Council, Australia, Program Grant App1149990 and Medical Research Future Fund App2005544.
Authors
Wen Shi Lee, Jennifer Audsley, Mai-Chi Trieu, Arnold Reynaldi, L. Carissa Aurelia, Palak H. Mehta, Joanne Patterson, Helen E. Kent, Julie Nguyen, Thakshila Amarasena, Robyn Esterbauer, Ebene R. Haycroft, Pradhipa Ramanathan, Miles P. Davenport, Timothy E. Schlub, Joseph Sasadeusz, Adam K. Wheatley, Amy W. Chung, Jennifer A. Juno, Kevin J. Selva, Stephen J. Kent
Abstract
BACKGROUND Patients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODS We performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTS Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSION Our longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATION ClinicalTrials.gov NCT04378777.FUNDING NIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
Authors
Jeremy P. Gygi, Cole Maguire, Ravi K. Patel, Pramod Shinde, Anna Konstorum, Casey P. Shannon, Leqi Xu, Annmarie Hoch, Naresh Doni Jayavelu, Elias K. Haddad, IMPACC Network, Elaine F. Reed, Monica Kraft, Grace A. McComsey, Jordan P. Metcalf, Al Ozonoff, Denise Esserman, Charles B. Cairns, Nadine Rouphael, Steven E. Bosinger, Seunghee Kim-Schulze, Florian Krammer, Lindsey B. Rosen, Harm van Bakel, Michael Wilson, Walter L. Eckalbar, Holden T. Maecker, Charles R. Langelier, Hanno Steen, Matthew C. Altman, Ruth R. Montgomery, Ofer Levy, Esther Melamed, Bali Pulendran, Joann Diray-Arce, Kinga K. Smolen, Gabriela K. Fragiadakis, Patrice M. Becker, Rafick P. Sekaly, Lauren I.R. Ehrlich, Slim Fourati, Bjoern Peters, Steven H. Kleinstein, Leying Guan
Abstract
SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributed to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.
Authors
Mengfei Chen, Andrew Pekosz, Jason S. Villano, Wenjuan Shen, Ruifeng Zhou, Heather Kulaga, Zhexuan Li, Amy Smith, Asiana Gurung, Sarah E. Beck, Kenneth W. Witwer, Joseph L. Mankowski, Murugappan Ramanathan Jr., Nicholas R. Rowan, Andrew P. Lane
Abstract
Authors
Fang Yun Lim, Soo-Young Kim, Karisma N. Kulkarni, Rachel L. Blazevic, Louise E. Kimball, Hannah G. Lea, Amanda J. Haack, Maia S. Gower, Terry Stevens-Ayers, Lea M. Starita, Michael Boeckh, Ollivier Hyrien, Joshua T. Schiffer, Ashleigh B. Theberge, Alpana Waghmare
Abstract
Authors
Ruangang Pan, David K. Meyerholz, Stanley Perlman
Abstract
Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in severely ill patients and the pathophysiology of disease is thought to be immune-mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens, often promoting inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and non-human primates. Using a mouse model of MC-deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed, through detection of MC-specific proteases, including chymase, levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
Authors
Janessa Yan Jun Tan, Danielle E. Anderson, Abhay P.S. Rathore, Aled O'Neill, Chinmay Kumar Mantri, Wilfried A.A. Saron, Cheryl Q.E. Lee, Wern Cui Chu, Adrian E.Z. Kang, Randy Foo, Shirin Kalimuddin, Jenny G. Low, Lena Ho, Paul Tambyah, Thomas W. Burke, Christopher W. Woods, Kuan Rong Chan, Joern Karhausen, Ashley L. St. John
Abstract
Authors
Natalie E. Stevens, Feargal J. Ryan, Nicole L. Messina, Stephen J. Blake, Todd S. Norton, Susie Germano, Jane James, Georgina L. Eden, Yee C. Tee, Miriam A. Lynn, Rochelle Botten, Simone E. Barry, Nigel Curtis, David J. Lynn
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