scholarly journals Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sebastian Weigang ◽  
Jonas Fuchs ◽  
Gert Zimmer ◽  
Daniel Schnepf ◽  
Lisa Kern ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Kidney Transplant Recipient ◽  
Immunosuppressive Treatment ◽  
Escape Variant ◽  
Persistent Infections ◽  
Infection Dynamics ◽  
Next Generation Sequencing Ngs ◽  
Host Evolution

AbstractThe origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient’s escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants.

scholarly journals Special considerations in generic substitution of immunosuppressive drugs in transplantation

2012 ◽  
Vol 153 (34) ◽  
pp. 1341-1349
Author(s):  
Ádám Remport ◽  
Dávid Dankó ◽  
Zsuzsa Gerlei ◽  
Krisztina Czebe ◽  
István Kiss
Keyword(s):  
Organ Transplantation ◽  
Generic Substitution ◽  
Kidney Transplant Recipient ◽  
Immunosuppressive Treatment ◽  
Solid Organ Transplantation ◽  
Immunosuppressive Drugs ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Published Evidence

Long-term success in solid organ transplantation strongly depends on the optimal use of maintenance immunosuppressive treatment. Cyclosporin and tacrolimus are the most frequently administered immunosuppressants and they are designed to narrow therapeutic index drugs. The substitution of the branded formulation by their generic counterparts may lead to economic benefit only if equivalent clinical outcomes can be achieved. There is no published evidence to date on the guarantee of their long-term therapeutic equivalence and cases of therapeutic failures have been reported due to inadvertent drug conversion. The disadvantageous clinical consequences of a non medical, mechanistic forced switch from the original to generic formulation of tacrolimus and the estimated loss of the payer’s presumed savings are presented in a kidney transplant recipient population. Special problems related to pediatric patients, drug interactions with concurrent medications and the burden of additional therapeutic drug monitoring and follow up visits are also discussed. The authors are convinced that the implementation of the European Society of Organ Transplantation guidelines on generic substitution may provide a safe way for patients and healthcare payers. Orv. Hetil., 2012, 153, 1341–1349.

scholarly journals Model-based inference of neutralizing antibody avidities against influenza virus

2020 ◽  
Author(s):  
Janina Linnik ◽  
Mohammedyaseen Syedbasha ◽  
Yvonne Hollenstein ◽  
Jörg Halter ◽  
Adrian Egli ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Immunosuppressive Treatment ◽  
Neutralizing Antibody ◽  
Biophysical Model ◽  
Hematopoietic Stem ◽  
Lower Baseline ◽  
2009 H1n1 ◽  
Experimental Effort

To assess the response to vaccination, quality (avidity) and quantity (concentration) of neutralizing antibodies are the most important parameters. Specifically, increase in avidity indicates germinal center (GC) formation, which is required for establishing long-term protection. For influenza, the classical hemagglutination inhibition (HI) assay, however, quantifies the combination of both and to separately determine avidity requires high experimental effort. Here, we present a biophysical model that infers avidities from measured HI titers and IgG concentrations. We applied our model to infer serum IgG avidities against influenza A/California/7/2009 (H1N1) in vaccinated hematopoietic stem cell transplantation patients (n= 43) and validated our results with independent avidity measurements. The model predicted that increased IgG concentrations mainly contribute to observed titer increases and that immunosuppressive treatment is associated with lower baseline avidities. Because the model requires only easy-to-establish measurements as inputs, we anticipate that it will help to disentangle causes for poor vaccination outcomes also in larger vaccine studies.

scholarly journals Molecular Epidemiology and Dynamics of Pseudomonas aeruginosa Populations in Lungs of Cystic Fibrosis Patients

2007 ◽  
Vol 75 (5) ◽  
pp. 2214-2224 ◽  
Author(s):  
Lars Jelsbak ◽  
Helle Krogh Johansen ◽  
Anne-Louise Frost ◽  
Regitze Thøgersen ◽  
Line E. Thomsen ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Opportunistic Pathogen ◽  
Infection Process ◽  
Fundamental Aspect ◽  
Chronic Infections ◽  
Persistent Infections ◽  
Infection Dynamics ◽  
Evolutionary Success

ABSTRACT The ability to establish lifelong persistent infections is a fundamental aspect of the interactions between many pathogenic microorganisms and their mammalian hosts. One example is chronic lung infections by the opportunistic pathogen Pseudomonas aeruginosa in cystic fibrosis (CF) patients. This infection process is associated with extensive genetic adaptation and microevolution of the infecting bacteria. Through investigations of P. aeruginosa populations and infection dynamics in a group of CF patients followed at the Danish CF Clinic in Copenhagen, we have identified two distinct and dominant clones that have evolved into highly successful colonizers of CF patient airways. A significant component of the evolutionary success of these two clones has been their efficient transmissibility among the CF patients. The two clones have been present and transmitted among different CF patients for more than 2 decades. Our data also suggest that the P. aeruginosa population structure in the CF patient airways has been influenced by competition between different clones and that the two dominant clones have been particularly competitive within the lungs, which may add to their overall establishment success. In contrast, we show that adaptive traits commonly associated with establishment of chronic P. aeruginosa infections of CF patients, such as transition to the mucoid phenotype and production of virulence factors, play minor roles in the ability of the two dominant clones to spread among patients and cause long-term chronic infections. These findings suggest that hitherto-unrecognized evolutionary pathways may be involved in the development of successful and persistent P. aeruginosa colonizers of CF patient lungs.

scholarly journals SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

2021 ◽  
Author(s):  
Evgeniia Alekseeva ◽  
Oksana Stanevich ◽  
Maria Sergeeva ◽  
Artem Fadeev ◽  
Kseniya Komissarova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Hla Class I Antigens ◽  
Cell Clones

Abstract Evolution of SARS-CoV-2 in immunocompromised hosts may result in novel variants with changed properties, but the mode of selection underlying this process remains unclear. While escape from humoral immunity certainly plays a role in intra-host evolution, escape from cellular immunity is poorly understood. Here, we report a case of long-term COVID-19 in an immunocompromised patient with non-Hodgkin’s lymphoma who received treatment with rituximab and lacked neutralizing antibodies. Over the 318 days of the disease, the SARS-CoV-2 genome gained a total of 40 changes, 34 of which were present by the end of the study period. Among the acquired mutations, 12 reduced or prevented binding of known immunogenic SARS-CoV-2 HLA class I antigens, suggesting that virus immunoediting is largely driven by cytotoxic CD8 T cell clones. The two changes with the strongest effect, nsp3:T504A and nsp3:T504P, were experimentally assessed in a cytotoxic assay of the patient's CD8 T cells. Both these changes were associated with immune escape, with a stronger effect observed for nsp3:T504P, the change which ultimately got fixed. Together, these results suggest that CD8 T cell escape may be an underappreciated contributor to SARS-CoV-2 evolution in humans.

Hashimoto encephalopathy

2013 ◽  
Vol 154 (33) ◽  
pp. 1312-1316 ◽  
Author(s):  
Gábor Pocsay ◽  
Andrea Gazdag ◽  
József Engelhardt ◽  
István Szaniszló ◽  
Zoltán Szolnoki ◽  
...  
Keyword(s):  
Psychiatric Symptoms ◽  
Immunosuppressive Treatment ◽  
Unknown Origin ◽  
Corticosteroid Treatment ◽  
Thyroid Peroxidase ◽  
Thyroid Autoantibodies ◽  
Thyroglobulin Antibodies ◽  
Hashimoto Encephalopathy ◽  
Generalized Seizures

The authors present a case report and review the literature on Hashimoto encephalopathy. The onset of the disease may be marked by focal and then progressively generalized seizures or other neurological symptoms, but a cognitive decline or various psychiatric symptoms may also emerge. High levels of anti-thyroid peroxidase antibodies and/or anti-thyroglobulin antibodies are present in the serum. Corticosteroid treatment usually results in an improvement of symptoms. The syndrome is frequently overlooked and, therefore, the authors strongly recommend testing serum thyroid autoantibodies in cases with encephalopathy of unknown origin independently on the presence of thyroid disease in the patient or family history. The importance of long-term immunosuppressive treatment should also be stressed. Orv. Hetil., 2013, 154, 1312–1316.

scholarly journals Long-term Persistence of Neutralizing Antibodies to SARS-CoV-2 Following Infection

2021 ◽  
Author(s):  
Juan P. Wisnivesky ◽  
Kimberly Stone ◽  
Emilia Bagiella ◽  
Molly Doernberg ◽  
Damodara Rao Mendu ◽  
...  
Keyword(s):  
Neutralizing Antibodies

scholarly journals Elicitation of Broadly Neutralizing Antibodies against B.1.1.7, B.1.351, and B.1.617.1 SARS-CoV-2 Variants by Three Prototype Strain-Derived Recombinant Protein Vaccines

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1421
Author(s):  
Yong Yang ◽  
Jinkai Zang ◽  
Shiqi Xu ◽  
Xueyang Zhang ◽  
Sule Yuan ◽  
...  
Keyword(s):  
Recombinant Protein ◽  
Neutralizing Antibodies ◽  
Wild Type Strain ◽  
Immune Escape ◽  
High Titer ◽  
Prototype Strain ◽  
Vaccine Antigen ◽  
Broadly Neutralizing Antibodies ◽  
Continued Use ◽  
Further Development

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most of the currently approved SARS-CoV-2 vaccines use the prototype strain-derived spike (S) protein or its receptor-binding domain (RBD) as the vaccine antigen. The emergence of several novel SARS-CoV-2 variants has raised concerns about potential immune escape. In this study, we performed an immunogenicity comparison of prototype strain-derived RBD, S1, and S ectodomain trimer (S-trimer) antigens and evaluated their induction of neutralizing antibodies against three circulating SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.617.1. We found that, at the same antigen dose, the RBD and S-trimer vaccines were more potent than the S1 vaccine in eliciting long-lasting, high-titer broadly neutralizing antibodies in mice. The RBD immune sera remained highly effective against the B.1.1.7, B.1.351, and B.1.617.1 variants despite the corresponding neutralizing titers decreasing by 1.2-, 2.8-, and 3.5-fold relative to that against the wild-type strain. Significantly, the S-trimer immune sera exhibited comparable neutralization potency (less than twofold variation in neutralizing GMTs) towards the prototype strain and all three variants tested. These findings provide valuable information for further development of recombinant protein-based SARS-CoV-2 vaccines and support the continued use of currently approved SARS-CoV-2 vaccines in the regions/countries where variant viruses circulate.

scholarly journals Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Liping Huang ◽  
Yiyi Zhang ◽  
Yanan Li ◽  
Fanling Meng ◽  
Hongyu Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Near Infrared ◽  
Immune Escape ◽  
Regulatory Protein ◽  
In Vivo Studies ◽  
Breast Cancer Patients ◽  
Thermally Responsive ◽  
Immunosuppressive Microenvironment

AbstractThe highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients. Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising, yet greatly challenging, to reverse postoperative immunosuppression. Here, an injectable hierarchical gel matrix, composed of dual lipid gel (DLG) layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios, was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy. The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide (GO) nanoparticles. GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages (TAMs) and promote an immunogenic tumor microenvironment. The inner layer, loaded with anti-CD47 antibody (aCD47), could maintain the gel state for a much longer time, enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory protein α (SIRPα) pathway for a long-term antitumor effect. In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape, thereby boosting the systemic immune responses.

scholarly journals COVID-19: Mechanisms of Vaccination and Immunity

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 404 ◽  
Author(s):  
Daniel E. Speiser ◽  
Martin F. Bachmann
Keyword(s):  
Immune Responses ◽  
Clinical Management ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Public Life ◽  
High Affinity ◽  
Vaccination Strategies ◽  
Detailed Evaluation ◽  
Pros And Cons

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

Following the infection dynamics of the tropical trematode Oligogonotylus mayae in its intermediate and definitive hosts for 13 years

2020 ◽  
Vol 94 ◽  
Author(s):  
A.L. May-Tec ◽  
N.A. Herrera-Castillo ◽  
V.M. Vidal-Martínez ◽  
M.L. Aguirre-Macedo
Keyword(s):  
Time Series ◽  
Cross Correlation ◽  
Southern Oscillation ◽  
Fish Host ◽  
Snail Host ◽  
Monthly Data ◽  
Infection Dynamics ◽  
Infection Parameters ◽  
Over Time

Abstract We present a time series of 13 years (2003–2016) of continuous monthly data on the prevalence and mean abundance of the trematode Oligogonotylus mayae for all the hosts involved in its life cycle. We aimed to determine whether annual (or longer than annual) environmental fluctuations affect these infection parameters of O. mayae in its intermediate snail host Pyrgophorus coronatus, and its second and definitive fish host Mayaheros urophthalmus from the Celestun tropical coastal lagoon, Yucatan, Mexico. Fourier time series analysis was used to identify infection peaks over time, and cross-correlation among environmental forcings and infection parameters. Our results suggest that the transmission of O. mayae in all its hosts was influenced by the annual patterns of temperature, salinity and rainfall. However, there was a biannual accumulation of metacercarial stages of O. mayae in M. urophthalmus, apparently associated with the temporal range of the El Niño-Southern Oscillation (five years) and the recovery of the trematode population after a devasting hurricane. Taking O. mayae as an example of what could be happening to other trematodes, it is becoming clear that environmental forcings acting at long-term temporal scales affect the population dynamics of these parasites.

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