scholarly journals Emergence of multiple SARS-CoV-2 antibody escape variants in an immunocompromised host undergoing convalescent plasma treatment

2021 ◽  
Author(s):  
Liang Chen ◽  
Michael C Zody ◽  
Jose R Mediavilla ◽  
Marcus H Cunningham ◽  
Kaelea Composto ◽  
...  
Keyword(s):  
Mutation Frequency ◽  
Immune Escape ◽  
Immunocompromised Host ◽  
Tracheal Aspirate ◽  
Immunosuppressed Patient ◽  
Plasma Therapy ◽  
In Vitro Susceptibility ◽  
S Protein ◽  
Tracheal Aspirates

SARS-CoV-2 Variants of Concerns (VOC), e.g., B.1.351 (20H/501Y.V2) and P1 (20J/501Y.V3), harboring N-terminal domain (NTD) or the receptor-binding domain (RBD) (e.g., E484K) mutations, exhibit reduced in vitro susceptibility to convalescent serum, commercial antibody cocktails, and vaccine neutralization, and have been associated with reinfection. The accumulation of these mutations could be the consequence of intra-host viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on tacrolimus, steroids and convalescent plasma therapy, and identify the emergence of multiple NTD and RBD mutations associated with reduced antibody neutralization as early as three weeks after infection. SARS-CoV-2 genomes from the first swab (Day 0) and three tracheal aspirates (Day 7, 21 and 27) were compared at the sequence level. We identified five different S protein mutations at the NTD or RBD regions from the second tracheal aspirate sample (21 Day). The S:Q493R substitution and S:243-244LA deletion had ~70% frequency, while ORF1a:A138T, S:141-144LGVY deletion, S:E484K and S:Q493K substitutions demonstrated ~30%, ~30%, ~20% and ~10% mutation frequency, respectively. However, the third tracheal aspirate sample collected one week later (Day 27) was predominated by the haplotype of ORF1a:A138T, S:141-144LGVY deletion and S:E484K (> 95% mutation frequency). Notably, S protein deletions (141-144LGVY and 243-244LA deletions in NTD region) and substitutions (Q493K/R and E484K in the RBD region) previously showed reduced susceptibly to monoclonal antibody or convalescent plasma. The observation supports the hypothesis that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune-escape mutants.

scholarly journals Characterization and antimicrobial susceptibility of coagulase-negative staphylococci isolated from clinical samples

2018 ◽  
Vol 10 (04) ◽  
pp. 414-419 ◽  
Author(s):  
Prapti Bora ◽  
Priya Datta ◽  
Varsha Gupta ◽  
Lipika Singhal ◽  
Jagdish Chander
Keyword(s):  
Antibiotic Susceptibility ◽  
Tracheal Aspirate ◽  
Polymyxin B ◽  
Common Species ◽  
Diffusion Method ◽  
Clinical Samples ◽  
Coagulase Negative Staphylococci ◽  
Disk Diffusion Method ◽  
In Vitro Susceptibility

ABSTRACT PURPOSE: This study has been done to speciate coagulase-negative staphylococci (CoNS) and also study their antibiotic susceptibility pattern isolated from clinical samples. MATERIALS AND METHODS: A total of 120 consecutive CoNS were isolated from various clinical samples such as blood, pus, wound swab, drain fluid, tracheal aspirate, peritoneal fluid, and pleural fluid over a period of 6 months. CoNS were identified by characteristic growth on media such as Blood agar and MacConkey agar. Speciation and identification were done by a range of biochemical testing such as PYR broth hydrolysis, novobiocin resistance, polymyxin B sensitivity, and then by matrix-assisted laser desorption ionization-time of flight. Antibiotic susceptibility of the isolates was done by Kirby-Bauer disk diffusion method as per CLSI 2017 guidelines. RESULTS: Among the 120 isolates, the most common species was Staphylococcus epidermidis (56.67%) followed by Staphylococcus haemolyticus (21.67%), Staphylococcus lugdunensis (11.67%), Staphylococcus caprae (5%), Staphylococcus cohnii (3.33%), and finally Staphylococcus vitulinus (1.67%). Good in vitro susceptibility was noted toward linezolid (100%), vancomycin (100%), teicoplanin (100%), and doxycycline (80.2%). The antibiotics to which resistance was seen were penicillin (96.5%), ciprofloxacin (57.1%), and oxacillin (45.5%). MR CoNS in our study ranged from 50% to 68.67%. CONCLUSION: Antibiotic resistance in CoNS is increasing toward penicillin, ciprofloxacin, and oxacillin as found in our study. The antibiotics such as vancomycin, teicoplanin, linezolid, and doxycycline which showed good in vitro susceptibility, therefore, should be kept as reserve drugs and used judiciously.

scholarly journals Comparison of the in Vitro Susceptibility of Rodent Isolates of Pseudomonas Aeruginosa and Pasteurella Pneumotropica to Enrofloxacin

2007 ◽  
Vol 19 (5) ◽  
pp. 557-560 ◽  
Author(s):  
Hiraku Sasaki ◽  
Eiichi Kawamoto ◽  
Satoshi Kunita ◽  
Ken-ichi Yagami
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mutation Frequency ◽  
Laboratory Mice ◽  
In Vitro Susceptibility ◽  
Minimum Inhibitory Concentrations

The objectives of this study were to determine and compare the in vitro enrofloxacin susceptibility of 94 Pseudomonas aeruginosa isolates obtained from enrofloxacin-treated and untreated mice and that of 40 Pasteurella pneumotropica strains and also to assess the efficacy and effects of enrofloxacin treatment of laboratory mice. The minimum inhibitory concentrations (MICs) of enrofloxacin against all the Ps. aeruginosa isolates were in the range of 1 to 4 μg/ml, whereas those against all the P. pneumotropica strains were less than 0.5 μg/ml. The mutation frequency in 54% of the Ps. aeruginosa isolates on treatment with enrofloxacin ranged from 10−6 to 10−8; however, none of the P. pneumotropica strains could grow on medium containing more than 3 μg/ml enrofloxacin. Comparison of in vitro enrofloxacin susceptibilities suggested that enrofloxacin was effective for eliminating P. pneumotropica but not for eliminating Ps. aeruginosa for which the MIC of enrofloxacin was more than 1 μg/ml. These results indicated that the enrofloxacin susceptibility of P. pneumotropica was higher than that of Ps. aeruginosa, and that the enrofloxacin treatment might not affect the susceptibility of Ps. aeruginosa.

scholarly journals Efficacy of ancestral receptor-binding domain, S1 and trimeric spike protein vaccines against SARS-CoV-2 variants B.1.1.7, B.1.351, and B.1.617.1

2021 ◽  
Author(s):  
Yong Yang ◽  
Jinkai Zang ◽  
Shiqi Xu ◽  
Xueyang Zhang ◽  
Sule Yuan ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Immune Escape ◽  
Neutralizing Antibody ◽  
Prototype Strain ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Antibody Titers ◽  
Continued Use

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current SARS-CoV-2 vaccines are based on spike (S) protein, S1 subunit, or receptor-binding domain (RBD) of prototype strain. Emergence of several novel SARS-CoV-2 variants has raised concern about potential immune escape. In this study, we performed an immunogenicity comparison of ancestral RBD, S1, and S ectodomain trimer (S-trimer) antigens and tested the efficacy of these prototype vaccines against the circulating variants, especially B.1.617 that has been linked to India's current COVID-19 surge. We found that RBD and S-trimer proteins could induce significantly higher neutralizing antibody titers than S1 protein. For the three vaccines, the neutralizing titers decreased over time, but still remained high for at least five months after immunization. Importantly, the three prototype vaccines were still effective in neutralizing the variants of concern, although B.1.351 and B.1.617.1 lineages showed varying degrees of reduction in neutralization by the immune sera. The vaccines-induced sera were shown to block receptor binding and inhibit S protein-mediated membrane fusion. In addition, the immune sera did not promote antibody-dependent enhancement (ADE) in vitro. Our work provides valuable information for development of SARS-CoV-2 subunit vaccines and also supports the continued use of ancestral RBD or S-based vaccines to fight the COVID-19 epidemic.

scholarly journals 146. antifungal Susceptibility Patterns of candida Parapsilosis Bloodstream Isolates in the US, 2008–2018

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S203-S203
Author(s):  
Brenda L Tesini ◽  
Meghan Lyman ◽  
Brendan R Jackson ◽  
Anita Gellert ◽  
William Schaffner ◽  
...  
Keyword(s):  
Candida Species ◽  
Regional Variation ◽  
Antifungal Susceptibility ◽  
Bloodstream Infections ◽  
Emerging Infections ◽  
In Vitro Susceptibility ◽  
Fluconazole Resistance ◽  
The Us ◽  
Susceptibility Patterns

Abstract Background Multidrug resistant Candida is an increasing concern. C. parapsilosis in particular has decreased in vitro susceptibility to echinocandins. As a result, fluconazole had been favored for C. parapsilosis treatment. However, there is growing concern about increasing azole resistance among Candida species. We report on antifungal susceptibility patterns of C. parapsilosis in the US from 2008 through 2018. Methods Active, population-based surveillance for candidemia through the Centers for Disease Control and Prevention’s (CDC) Emerging Infections Program was conducted between 2008–2018, eventually encompassing 9 states (GA, MD,OR, TN, NY, CA, CO, MN, NM). Each incident isolate was sent to the CDC for species confirmation and antifungal susceptibility testing (AFST). Frequency of resistance was calculated and stratified by year and state using SAS 9.4 Results Of the 8,704 incident candidemia isolates identified, 1,471 (15%) were C. parapsilosis; the third most common species after C. albicans and C. glabrata. AFST results were available for 1,340 C. parapsilosis isolates. No resistance was detected to caspofungin (MIC50 0.25) or micafungin (MIC50 1.00) with only one (< 1%) isolate resistant to anidulafungin (MIC50 1.00). In contrast, 84 (6.3%) isolates were resistant to fluconazole and another 44 (3.3%) isolates had dose-dependent susceptibility to fluconazole (MIC50 1.00). Fluconazole resistance increased sharply from an average of 4% during 2008–2014 to a peak of 14% in 2016 with a subsequent decline to 6% in 2018 (see figure). Regional variation is also observed with fluconazole resistance ranging from 0% (CO, MN, NM) to 42% (NY) of isolates by site. Conclusion The recent marked increase in fluconazole resistance among C. parapsilosis highlights this pathogen as an emerging drug resistant pathogen of concern and the need for ongoing antifungal resistance surveillance among Candida species. Our data support the empiric use of echinocandins for C. parapsilosis bloodstream infections and underscore the need to obtain AFST prior to fluconazole treatment. Furthermore, regional variation in fluconazole resistance emphasizes the importance of understanding local Candida susceptibility patterns. Disclosures Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)

scholarly journals Clinical and immunological effects of mRNA vaccines in malignant diseases

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Annkristin Heine ◽  
Stefan Juranek ◽  
Peter Brossart
Keyword(s):  
Immune Responses ◽  
Messenger Rna ◽  
Immune Escape ◽  
Special Focus ◽  
Potential Efficacy ◽  
Protective Antibodies ◽  
Technological Developments ◽  
Broad Variety ◽  
Antigen Loss

AbstractIn vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.

scholarly journals Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

2021 ◽  
Vol 9 (2) ◽  
pp. 320
Author(s):  
Wilmer Alcazar ◽  
Sami Alakurtti ◽  
Maritza Padrón-Nieves ◽  
Maija Liisa Tuononen ◽  
Noris Rodríguez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Leishmania Amazonensis ◽  
Superoxide Production ◽  
In Vitro Susceptibility ◽  
Intracellular Parasites ◽  
Betulin Derivatives

Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

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