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Cell May 2023Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We...
Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8 T cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared with conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for 3 months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.
Topics: Animals; Humans; Mice; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Endosomal Sorting Complexes Required for Transport; mRNA Vaccines; RNA, Messenger; SARS-CoV-2
PubMed: 37146611
DOI: 10.1016/j.cell.2023.04.024 -
Nature Reviews. Microbiology Mar 2023The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused substantial global morbidity and deaths, leading governments to turn to... (Review)
Review
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused substantial global morbidity and deaths, leading governments to turn to non-pharmaceutical interventions to slow down the spread of infection and lessen the burden on health care systems. These policies have evolved over the course of the COVID-19 pandemic, including after the availability of COVID-19 vaccines, with regional and country-level differences in their ongoing use. The COVID-19 pandemic has been associated with changes in respiratory virus infections worldwide, which have differed between virus types. Reductions in respiratory virus infections, including by influenza virus and respiratory syncytial virus, were most notable at the onset of the COVID-19 pandemic and continued in varying degrees through subsequent waves of SARS-CoV-2 infections. The decreases in community infection burden have resulted in reduced hospitalizations and deaths associated with non-SARS-CoV-2 respiratory infections. Respiratory virus evolution relies on the maintaining of a diverse genetic pool, but evidence of genetic bottlenecking brought on by case reduction during the COVID-19 pandemic has resulted in reduced genetic diversity of some respiratory viruses, including influenza virus. By describing the differences in these changes between viral species across different geographies over the course of the COVID-19 pandemic, we may better understand the complex factors involved in community co-circulation of respiratory viruses.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Vaccines; Pandemics; Viruses
PubMed: 36253478
DOI: 10.1038/s41579-022-00807-9 -
Circulation Research Apr 2021A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection... (Review)
Review
A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.
Topics: Angiotensin-Converting Enzyme 2; Biomarkers; COVID-19; Cardiomyopathies; Cardiovascular Diseases; Gene Expression; Humans; Immune System; Myocardium; Myocytes, Cardiac; Neuropilin-1; Platelet Activation; RNA, Messenger; Renin-Angiotensin System; Return to Sport; Risk Factors; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Troponin; Ventricular Remodeling; Virus Attachment; Virus Internalization
PubMed: 33856918
DOI: 10.1161/CIRCRESAHA.121.317997 -
Nature Reviews. Neurology Jan 2021Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent,... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a devastating CNS infection caused by JC virus (JCV), a polyomavirus that commonly establishes persistent, asymptomatic infection in the general population. Emerging evidence that PML can be ameliorated with novel immunotherapeutic approaches calls for reassessment of PML pathophysiology and clinical course. PML results from JCV reactivation in the setting of impaired cellular immunity, and no antiviral therapies are available, so survival depends on reversal of the underlying immunosuppression. Antiretroviral therapies greatly reduce the risk of HIV-related PML, but many modern treatments for cancers, organ transplantation and chronic inflammatory disease cause immunosuppression that can be difficult to reverse. These treatments - most notably natalizumab for multiple sclerosis - have led to a surge of iatrogenic PML. The spectrum of presentations of JCV-related disease has evolved over time and may challenge current diagnostic criteria. Immunotherapeutic interventions, such as use of checkpoint inhibitors and adoptive T cell transfer, have shown promise but caution is needed in the management of immune reconstitution inflammatory syndrome, an exuberant immune response that can contribute to morbidity and death. Many people who survive PML are left with neurological sequelae and some with persistent, low-level viral replication in the CNS. As the number of people who survive PML increases, this lack of viral clearance could create challenges in the subsequent management of some underlying diseases.
Topics: Adoptive Transfer; Humans; Immune Checkpoint Inhibitors; JC Virus; Leukoencephalopathy, Progressive Multifocal; T-Lymphocytes
PubMed: 33219338
DOI: 10.1038/s41582-020-00427-y -
Influenza and Other Respiratory Viruses Feb 2023Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year.... (Review)
Review
Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year. Despite the risk RSV poses to young children, older adults, and individuals with comorbidities or suppressed immunity, there is limited understanding of RSV symptom presentation across these at-risk groups, and there is no vaccine for RSV. We conducted two systematic literature reviews (SLRs) of studies that document signs and symptoms (S&S) of RSV in (1) children aged ≤5 years and (2) immunocompromised adolescents and adults, and adults at high risk for severe RSV due to age or comorbidities. Symptom duration and hospital length of stay (LOS) were explored. Electronic database searches were performed following PRISMA guidelines. Studies captured RSV S&S across community and hospital settings. Clinicians and caregivers reported ( = 25 studies) nasal discharge/congestion, cough, shortness of breath, feeding abnormalities, and fever in ≥40% of children across studies and settings. Median hospital stays for children ranged from 2 days in the United States to 7.5 days in China. High-risk adults with RSV ( = 6 studies) commonly (≥40% of adults) reported cough, sputum, dyspnea, and fever/feverishness. Median length of hospital stay in adults ranged from 6 to 15 days across studies. Caregivers and clinicians reported similar RSV S&S in young children, including upper and lower respiratory and systemic symptoms. In high-risk and immunocompromised adults, the most frequent (in multiple publications) and commonly reported RSV S&S were primarily LRTI symptoms. RSV symptoms could last for weeks and are variable based on geography.
Topics: Child; Humans; Infant; Child, Preschool; Aged; Adolescent; Respiratory Syncytial Virus Infections; Cough; Respiratory Syncytial Virus, Human; Hospitalization; Respiratory Tract Infections
PubMed: 36824394
DOI: 10.1111/irv.13100 -
Computational and Structural... 2020The increasing application of single-cell RNA sequencing (scRNA-seq) technology in life science and biomedical research has significantly increased our understanding of... (Review)
Review
The increasing application of single-cell RNA sequencing (scRNA-seq) technology in life science and biomedical research has significantly increased our understanding of the cellular heterogeneities in immunology, oncology and developmental biology. This review will summarize the development of various scRNA-seq technologies; primarily discussing the application of scRNA-seq on infectious diseases, and exploring the current development, challenges, and potential applications of scRNA-seq technology in the future.
PubMed: 33106757
DOI: 10.1016/j.csbj.2020.10.016 -
Annals of Neurology Dec 2021Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in... (Review)
Review
Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti-JCV immune responses, and include T-cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865-873.
Topics: Adoptive Transfer; Humans; Immune Checkpoint Inhibitors; Leukoencephalopathy, Progressive Multifocal; Prognosis; Treatment Outcome
PubMed: 34405435
DOI: 10.1002/ana.26198 -
Cell Jan 2021The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome....
The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.
Topics: A549 Cells; Animals; Biosynthetic Pathways; COVID-19; Cell Line; Chlorocebus aethiops; Cholesterol; Cluster Analysis; Clustered Regularly Interspaced Short Palindromic Repeats; Common Cold; Coronavirus; Coronavirus Infections; Gene Knockout Techniques; Genome-Wide Association Study; Host-Pathogen Interactions; Humans; Mice; Phosphatidylinositols; SARS-CoV-2; Vero Cells; Virus Internalization; Virus Replication
PubMed: 33333024
DOI: 10.1016/j.cell.2020.12.004 -
Annals of Neurology Feb 2023Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML).
OBJECTIVE
Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML).
METHODS
We conducted a multicenter survey compiling retrospective data from 79 PML patients, including 38 published cases and 41 unpublished cases, who received immune checkpoint inhibitors as add-on to standard of care. One-year follow-up data were analyzed to determine clinical outcomes and safety profile. Logistic regression was used to identify variables associated with 1-year survival.
RESULTS
Predisposing conditions included hematological malignancy (n = 38, 48.1%), primary immunodeficiency (n = 14, 17.7%), human immunodeficiency virus/acquired immunodeficiency syndrome (n = 12, 15.2%), inflammatory disease (n = 8, 10.1%), neoplasm (n = 5, 6.3%), and transplantation (n = 2, 2.5%). Pembrolizumab was most commonly used (n = 53, 67.1%). One-year survival was 51.9% (41/79). PML-immune reconstitution inflammatory syndrome (IRIS) was reported in 15 of 79 patients (19%). Pretreatment expression of programmed cell death-1 on circulating T cells did not differ between survivors and nonsurvivors. Development of contrast enhancement on follow-up magnetic resonance imaging at least once during follow-up (OR = 3.16, 95% confidence interval = 1.20-8.72, p = 0.02) was associated with 1-year survival. Cerebrospinal fluid JC polyomavirus DNA load decreased significantly by 1-month follow-up in survivors compared to nonsurvivors (p < 0.0001). Thirty-two adverse events occurred among 24 of 79 patients (30.4%), and led to treatment discontinuation in 7 of 24 patients (29.1%).
INTERPRETATION
In this noncontrolled retrospective study of patients with PML who were treated with immune checkpoint inhibitors, mortality remains high. Development of inflammatory features or overt PML-IRIS was commonly observed. This study highlights that use of immune checkpoint inhibitors should be strictly personalized toward characteristics of the individual PML patient. ANN NEUROL 2023;93:257-270.
Topics: Humans; Leukoencephalopathy, Progressive Multifocal; Immune Checkpoint Inhibitors; Retrospective Studies; JC Virus; Immune Reconstitution Inflammatory Syndrome
PubMed: 36151879
DOI: 10.1002/ana.26512 -
Multiple Sclerosis and Related Disorders Sep 2022Natalizumab is a humanized monoclonal antibody used for treatment of highly active relapsing-remitting multiple sclerosis (MS). With more than 15 years of post-marketing... (Review)
Review
BACKGROUND
Natalizumab is a humanized monoclonal antibody used for treatment of highly active relapsing-remitting multiple sclerosis (MS). With more than 15 years of post-marketing experience with natalizumab in Canada, several real-world studies have shown the long-term efficacy and safety of natalizumab. In addition, risk stratification/mitigation strategies for progressive leukoencephalopathy (PML), an adverse effect associated with natalizumab based on the John Cunningham virus (JCV) index; treatment duration beyond 24 months; and prior exposure to immunosuppressant drugs have been developed.
METHODS
A group of neurologists from various MS clinics across Canada met in September 2021 to update the 2015 Canadian practice recommendations for the use of natalizumab in persons with MS (PwMS).
RESULTS
The recommendations focused on the long-term efficacy and safety data from real-world studies, patient selection according to JCV index criteria, risk management strategies for PML (including extended interval dosing), and options for switching to currently available disease-modifying therapies for MS.
CONCLUSIONS
The recommendations of clinical neurologists seek to optimize the management of PwMS who may benefit from treatment with natalizumab.
Topics: Canada; Humans; Immunologic Factors; JC Virus; Leukoencephalopathy, Progressive Multifocal; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab
PubMed: 35810718
DOI: 10.1016/j.msard.2022.103995