Enhancing anti-tumor immunity through local gene delivery to lymph nodes

Biodegradable polymer carriers offer attractive features for therapeutic cancer vaccines including delivery of multiple vaccine components, efficient internalization, and sustained release of adjuvants and tumor-associated antigens (TAAs). We previously demonstrated that local delivery of depots containing nucleic acid-based toll-liked receptor agonists (TLRas) to lymph nodes (LNs) potently enhances antigen-specific T cell immunity. Building on this work, we hypothesized that local LN delivery of microparticles loaded with TAA-encoding plasmid DNA (pDNA) and TLRas might drive strong local expression and presentation of antigen by LN-resident antigen presenting cells. These effects could help drive more potent and effective CD8+ T cell functions that slow or stop tumor growth.https://doi.org/10.1186/2051-1426-3-S2-P43

Molecular phylogenetics of subfamily Urgineoideae (Hyacinthaceae): Toward a coherent generic circumscription informed by molecular, morphological, and distributional data

The taxonomy and systematics of Urgineoideae (Hyacinthaceae) have been controversial in recent decades, with contrasting taxonomic treatments proposed based on preliminary and partial studies that have focused on morphology and/or solely plastid DNA sequence data. Some authors have recognized only two genera, with a very broadly conceived Drimia, while others have accepted several genera that, although better defined morphologically, were doubtfully monophyletic. Here, we present phylogenetic analyses involving four plastid DNA regions (trnL intron, trnL-F spacer, matK, and the trnCGCA-ycf6 intergenic region), a nuclear region (Agt1), and a selection of 40 morphological characters. Our study covers 293 samples and ca. 160 species of Urgineoideae (ca. 80% of its global diversity). Bayesian inference, maximum likelihood, and maximum parsimony analyses were performed to derive the phylogenetic patterns. The combination of data yielded phylogenetic trees with 31 well-defined clades or lineages, most corresponding to previously described genera, although some have required description or revised circumscription. As with other monocot families, a considerable degree of homoplasy was observed in morphological characters, especially in those groups with unspecialized flowers; nonetheless, consistent syndromes of traditional and novel characters are shown to support clade recognition at genus rank. The forthcoming revised classification of Urgineoideae is outlined here.This work was partly supported by H2020 Research and Innovation Staff Exchange Programme of the European Commission, project 645636: ‘Insect-plant relationships: insights into biodiversity and new applications’ (FlyHigh) and the complementary supporting funds UAUSTI17-03, ACIE17-01, UAUSTI2019-008 (University of Alicante, Spain)

New combinations in the tribe Urgineeae (Asparagaceae subfam. Scilloideae) with comments on contrasting taxonomic treatments

As part of a taxonomic revision of tribe Urgineeae, and informed by morphological and phylogenetic evidence obtained in the last decade, we present 17 new combinations in Austronea, Indurgia, Schizobasis, Tenicroa, Thuranthos, Urgineopsis, and Vera-duthiea. These are for taxa recently described in Drimia sensu latissimo or otherwise named during the past century. We include type information for all considered taxa and designate lectotypes for Drimia pauciflora, Urginea salmonea and U. sebirii. We discuss recent analytic and synthetic approaches to taxonomic arrangements for the Urgineeae and reinforce the support of an analytic treatment that recognises several genera characterised by distinct syndromes of morphological characters, biogeography and molecular evidence.This work was partly supported by H2020 Research and Innovation Staff Exchange Programme of the European Commission, project 645636: ‘Insect-plant relationships: insights into the biodiversity and new applications’ (FlyHigh), and the grants ACIE18-03 and UAUSTI18-02 from University of Alicante

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Feasibility of Wii Fit Training to Improve Clinical Measures of Balance in Older Adults

Background and purpose: Numerous interventions have been proposed to improve balance in older adults with varying degrees of success. A novel approach may be to use an off-the-shelf video game system utilizing real-time force feedback to train older adults. The purpose of this study is to investigate the feasibility of using Nintendo\u27s Wii Fit for training to improve clinical measures of balance in older adults and to retain the improvements after a period of time. Methods: Twelve healthy older adults (aged \u3e70 years) were randomly divided into two groups. The experimental group completed training using Nintendo\u27s Wii Fit game three times a week for 3 weeks while the control group continued with normal activities. Four clinical measures of balance were assessed before training, 1 week after training, and 1 month after training: Berg Balance Scale (BBS), Fullerton Advanced Balance (FAB) scale, Functional Reach (FR), and Timed Up and Go (TUG). Friedman two-way analysis of variance by ranks was conducted on the control and experimental group to determine if training using the Wii Balance Board with Wii Fit had an influence on clinical measures of balance. Results: Nine older adults completed the study (experimental group n = 4, control group n = 5). The experimental group significantly increased their BBS after training while the control group did not. There was no significant change for either group with FAB, FR, and TUG. Conclusion: Balance training with Nintendo\u27s Wii Fit may be a novel way for older adults to improve balance as measured by the BBS

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum

SARS-CoV-2 has undergone progressive change with variants conferring advantage rapidly becoming dominant lineages e.g. B.1.617. With apparent increased transmissibility variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the UK. Here we study the ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 and complement this with structural analyses of Fab/RBD complexes and map the antigenic space of current variants. Neutralization of both viruses is reduced when compared with ancestral Wuhan related strains but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2 suggesting that individuals previously infected by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insight for immunisation policy with future variant vaccines in non-immune populations