Showing papers by "Fred Hutchinson Cancer Research Center published in 2021"
TL;DR: Weighted-nearest neighbor analysis as mentioned in this paper is an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities.
3,369 citations
Brigham and Women's Hospital1, Baylor College of Medicine2, Emory University3, University of Maryland, Baltimore4, Saint Louis University5, University of Illinois at Chicago6, George Washington University7, University of California, San Diego8, Vanderbilt University9, Fred Hutchinson Cancer Research Center10
TL;DR: The mRNA-1273 vaccine as discussed by the authors is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.
Abstract: Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
2,721 citations
TL;DR: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death, in an international, randomized, double-blind, placebo-controlled, phase 3 trial.
Abstract: Background The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-...
1,760 citations
TL;DR: In this article, the authors map how convalescent plasma antibodies are impacted by all mutations to the spike's receptor-binding domain (RBD), the main target of plasma neutralizing activity.
912 citations
TL;DR: A deep mutational scanning method is described to map how all amino-acid mutations in the RBD affect antibody binding, and this method is applied to 10 human monoclonal antibodies to enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.
830 citations
Daniel Taliun1, Daniel N. Harris2, Michael D. Kessler2, Jedidiah Carlson1 +202 more•Institutions (61)
TL;DR: The Trans-Omics for Precision Medicine (TOPMed) project as discussed by the authors aims to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases.
Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history
801 citations
TL;DR: In this article, the authors map how all mutations to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LYCoV016.
Abstract: Antibodies are a potential therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the risk of the virus evolving to escape them remains unclear. Here we map how all mutations to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. These complete maps uncover a single amino acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies, REGN10933 and REGN10987, targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2 and during in vitro viral escape selections. Finally, the maps reveal that mutations escaping the individual antibodies are already present in circulating SARS-CoV-2 strains. These complete escape maps enable interpretation of the consequences of mutations observed during viral surveillance.
620 citations
TL;DR: In this article, the authors evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated, and they found a robust correlation was seen between neutralizing titer and efficacy.
600 citations
TL;DR: In this article, the authors examined whether sera from recovered and naive donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants.
Abstract: Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naive donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold. Neutralization was due to antibodies targeting the receptor binding domain and was not boosted by a second immunization. Immunization of naive donors also elicited cross-neutralizing responses, but at lower titers. Our study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.
405 citations
05 Apr 2021
TL;DR: In this article, the authors map all the mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-coV555, and its cocktail combination with LY CoV016.
Abstract: Monoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for coronavirus disease 2019 (COVID-19). However, ongoing evolution of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can render monoclonal antibodies ineffective. Here, we completely map all of the mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escapes LY-CoV016). In addition, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to the antigenic evolution of SARS-CoV-2.
350 citations
Baylor College of Medicine1, Brigham and Women's Hospital2, University of Miami3, University of Pittsburgh4, Emory University5, University of Colorado Denver6, University of California, Los Angeles7, Fred Hutchinson Cancer Research Center8, University of Cincinnati9, Henry Ford Health System10, University of Maryland, College Park11
TL;DR: The mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-... as discussed by the authors ) in a phase 3, observer-blinded, placebo-controlled clinical trial.
Abstract: Background At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-...
Mayo Clinic1, Harvard University2, Roswell Park Cancer Institute3, University of California, Irvine4, University of Wisconsin–Milwaukee5, Rutgers University6, City of Hope National Medical Center7, Boston University8, University of Wisconsin-Madison9, American Cancer Society10, University of Southern California11, University of Oxford12, Stanford University13, Fred Hutchinson Cancer Research Center14, University of Washington15, National Institutes of Health16, Vanderbilt University17, Cornell University18, University of Utah19, University of Pennsylvania20
TL;DR: In this paper, population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and risk assessment.
Abstract: Background Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and...
Fred Hutchinson Cancer Research Center1, Washington University in St. Louis2, University of Washington3, Memorial Sloan Kettering Cancer Center4, Cornell University5, Rega Institute for Medical Research6, University of Cambridge7, Lawrence Berkeley National Laboratory8, University of Texas Southwestern Medical Center9, Howard Hughes Medical Institute10
TL;DR: In this paper, the authors comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD).
Abstract: An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse sarbecoviruses4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics. A survey of SARS-CoV-2 RBD antibodies identifies those with activity against diverse SARS-CoV-2 variants and SARS-related coronaviruses, highlighting epitopes and features to prioritize in antibody and vaccine development.
University of Groningen1, Erasmus University Rotterdam2, Katholieke Universiteit Leuven3, Chinese Academy of Sciences4, University of Surrey5, King's College London6, University of Toronto7, Avera Health8, Karolinska Institutet9, University of Copenhagen10, University of Greifswald11, University of Kiel12, Yeshiva University13, Sungkyunkwan University14, University of Tartu15, Weizmann Institute of Science16, Copenhagen University Hospital17, University of Texas Health Science Center at Houston18, University of Alabama at Birmingham19, Stockholm University20, University of Michigan21, VU University Amsterdam22, University of Oxford23, University of Bristol24, University of Amsterdam25, Maastricht University26, University of California, San Diego27, University of Eastern Finland28, National Institutes of Health29, University of California, Los Angeles30, Linköping University31, Harvard University32, Radboud University Nijmegen33, University of North Carolina at Chapel Hill34, Ewha Womans University35, Fred Hutchinson Cancer Research Center36, National Research Council37
TL;DR: In this article, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts) and found high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples.
Abstract: To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
Fred Hutchinson Cancer Research Center1, University of Washington2, Ottawa Hospital Research Institute3, Medical University of Vienna4, University of Chieti-Pescara5, University of Toronto6, Case Western Reserve University7, University of California, San Francisco8, University of British Columbia9, Provincial Health Services Authority10, McMaster University11, Cardiff University12, University of Minnesota13, American University of Beirut14, Cochrane Collaboration15
TL;DR: In this paper, the authors present evidence-based guidelines of the American Society of Hematology (ASH) to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.
TL;DR: A novel SARS-CoV-2 variant, 20E (EU1) that emerged in Spain in early summer, and subsequently spread across Europe is reported in this article.
Abstract: Following its emergence in late 2019, the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2 has been tracked via phylogenetic analysis of viral genome sequences in unprecedented detail3–5. While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, within Europe travel resumed in the summer of 2020. Here we report on a novel SARS-CoV-2 variant, 20E (EU1), that emerged in Spain in early summer, and subsequently spread across Europe. We find no evidence of increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate 20E (EU1) was introduced hundreds of times to European countries by summertime travelers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how a variant can rapidly become dominant even in absence of a substantial transmission advantage in favorable epidemiological settings. Genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes.
TL;DR: In this paper, the authors assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.
Abstract: Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
TL;DR: This article used a yeast display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures.
Abstract: Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.
Johns Hopkins University1, Vanderbilt University2, Mayo Clinic3, University of Wisconsin-Madison4, University of Colorado Boulder5, Duke University6, University of California, San Francisco7, City of Hope National Medical Center8, Harvard University9, University of Texas at Austin10, Fred Hutchinson Cancer Research Center11, Memorial Sloan Kettering Cancer Center12, University of South Florida13, Fox Chase Cancer Center14, Stanford University15, University of California, Los Angeles16, Brigham and Women's Hospital17, Case Western Reserve University18, University of Pennsylvania19, Northwestern University20, University of California, San Diego21, University of Michigan22, University of Texas Southwestern Medical Center23, Ohio State University24, Yale University25, University of Nebraska Medical Center26, University of Utah27, Roswell Park Cancer Institute28, National Comprehensive Cancer Network29
TL;DR: In this article, the authors discuss the challenges of SARS-CoV-2 infection in patients with a weakened immune system, including the potential implications regard to immunosuppression.
Abstract: SARS-CoV-2 and Immunosuppression In this article, the authors discuss the challenges of SARS-CoV-2 infection in patients with a weakened immune system, including the potential implications regardin...
20 Jul 2021
TL;DR: In this article, the authors evaluated 254 COVID-19 patients longitudinally up to 8 months and found durable broad-based immune responses to SARS-CoV-2 infection.
Abstract: Summary Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.
TL;DR: In this article, an age-stratified mathematical model paired with optimization algorithms was used to determine optimal vaccine allocation for four different metrics (deaths, symptomatic infections, and maximum non-ICU and ICU hospitalizations) under many scenarios.
Abstract: Vaccines, when available, will likely become our best tool to control the COVID-19 pandemic. Even in the most optimistic scenarios, vaccine shortages will likely occur. Using an age-stratified mathematical model paired with optimization algorithms, we determined optimal vaccine allocation for four different metrics (deaths, symptomatic infections, and maximum non-ICU and ICU hospitalizations) under many scenarios. We find that a vaccine with effectiveness ≥50% would be enough to substantially mitigate the ongoing pandemic, provided that a high percentage of the population is optimally vaccinated. When minimizing deaths, we find that for low vaccine effectiveness, irrespective of vaccination coverage, it is optimal to allocate vaccine to high-risk (older) age groups first. In contrast, for higher vaccine effectiveness, there is a switch to allocate vaccine to high-transmission (younger) age groups first for high vaccination coverage. While there are other societal and ethical considerations, this work can provide an evidence-based rationale for vaccine prioritization.
University of Minnesota1, Mayo Clinic2, Scripps Research Institute3, University of California, Riverside4, University of Pittsburgh5, University of Texas Health Science Center at Houston6, Fred Hutchinson Cancer Research Center7, University of Washington8, Ohio State University9, West Virginia University10
TL;DR: In this paper, the contribution of immune system ageing to organism ageing was defined by selectively deleting Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence.
Abstract: Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
St. Jude Children's Research Hospital1, Fred Hutchinson Cancer Research Center2, Center for International Blood and Marrow Transplant Research3, Medical College of Wisconsin4, University of Texas MD Anderson Cancer Center5, Cincinnati Children's Hospital Medical Center6, University of Washington7, Yale University8, Memorial Sloan Kettering Cancer Center9, Cornell University10, University of North Carolina at Chapel Hill11
TL;DR: In this paper, the authors describe the characteristics and outcomes of Haematopoietic stem-cell transplantation (HSCT) recipients after developing COVID-19.
University of California, Los Angeles1, Fred Hutchinson Cancer Research Center2, LSU Health Sciences Center New Orleans3, University of São Paulo4, Asociación Civil Impacta Salud y Educación5, Chiang Mai University6, Centers for Disease Control and Prevention7, University of Pennsylvania8, St. Jude Children's Research Hospital9, University of North Carolina at Chapel Hill10, University of Cape Town11, University of Alabama at Birmingham12, Rutgers University13, Cornell University14, Johns Hopkins University15, Anschutz Medical Campus16, Harvard University17, University of Miami18, National Institutes of Health19
TL;DR: In this paper, safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
Abstract: Background Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preve...
Northwestern University1, Stanford University2, Johns Hopkins University3, Duke University4, University of Pennsylvania5, Fred Hutchinson Cancer Research Center6, Harvard University7, Mayo Clinic8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, Memorial Sloan Kettering Cancer Center11, Fox Chase Cancer Center12, Washington University in St. Louis13, Roswell Park Cancer Institute14, University of Wisconsin-Madison15, University of California, San Diego16, Case Western Reserve University17, Vanderbilt University18, University of South Florida19, University of California, Los Angeles20, University of Tennessee Health Science Center21, University of California, San Francisco22, Ohio State University23, University of Michigan24, University of Nebraska Medical Center25, University of Utah26, National Comprehensive Cancer Network27
TL;DR: The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease Recommendations for disease monitoring and treatment of recurrent disease are also included as mentioned in this paper.
Abstract: The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease Recommendations for disease monitoring and treatment of recurrent disease are also included The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer
TL;DR: BayesSpace is introduced, a fully Bayesian statistical method that uses the information from spatial neighborhoods for resolution enhancement of spatial transcriptomic data and for clustering analysis and shows that it improves identification of distinct intra-tissue transcriptional profiles from samples of the brain, melanoma, invasive ductal carcinoma and ovarian adenocarcinoma.
Abstract: Recent spatial gene expression technologies enable comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing analysis methods do not address the limited resolution of the technology or use the spatial information efficiently. Here, we introduce BayesSpace, a fully Bayesian statistical method that uses the information from spatial neighborhoods for resolution enhancement of spatial transcriptomic data and for clustering analysis. We benchmark BayesSpace against current methods for spatial and non-spatial clustering and show that it improves identification of distinct intra-tissue transcriptional profiles from samples of the brain, melanoma, invasive ductal carcinoma and ovarian adenocarcinoma. Using immunohistochemistry and an in silico dataset constructed from scRNA-seq data, we show that BayesSpace resolves tissue structure that is not detectable at the original resolution and identifies transcriptional heterogeneity inaccessible to histological analysis. Our results illustrate BayesSpace's utility in facilitating the discovery of biological insights from spatial transcriptomic datasets.
University of Washington1, University of Texas Southwestern Medical Center2, Harvard University3, Wayne State University4, Cornell University5, Laboratory of Molecular Biology6, Memorial Sloan Kettering Cancer Center7, Kettering University8, Fred Hutchinson Cancer Research Center9, Columbia University10, University of Würzburg11, St. Jude Children's Research Hospital12
TL;DR: The structures of many eukaryotic protein complexes are unknown, and there are likely many protein-protein interactions not yet identified as mentioned in this paper, but these structures play critical roles in biology.
Abstract: Protein-protein interactions play critical roles in biology, but the structures of many eukaryotic protein complexes are unknown, and there are likely many interactions not yet identified. We take ...
Fred Hutchinson Cancer Research Center1, University of North Carolina at Chapel Hill2, Emory University3, College of Health Sciences, Bahrain4, Asociación Civil Impacta Salud y Educación5, University of Pennsylvania6, Columbia University7, Harvard University8, Brigham and Women's Hospital9, Johns Hopkins University School of Medicine10
TL;DR: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV- 1 isolates provided proof-of-concept that bnAb prophylaxis can be effective.
Abstract: Background Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. Methods We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. Results Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 Conclusions VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).
Stanford University1, National Institutes of Health2, Mayo Clinic3, Harvard University4, University of Western Ontario5, Baylor College of Medicine6, University of Oxford7, Genentech8, University of Cambridge9, Johns Hopkins University10, Fred Hutchinson Cancer Research Center11, University of California, Irvine12, National Institute for Health Research13, European Bioinformatics Institute14, University of North Carolina at Chapel Hill15, Centers for Disease Control and Prevention16, Emory University17, Kaiser Permanente18
TL;DR: The Polygenic Risk Score Reporting Standards (PRS-RS) as discussed by the authors is a comprehensive reporting framework that defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications.
Abstract: Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.