Targeted lentiviral vectors pseudotyped with the Tupaia paramyxovirus glycoproteins

Lentiviral vectors (LVs) are vectors of choice for many gene therapy applications since they mediate long term gene expression and can transduce dividing and non-dividing cells. Recently, efficient targeting of LVs pseudotyped with the measles virus (MV) glycoproteins has been reported. However, MV antibodies in patients might limit the clinical use of these vectors. Thus, aim of this study was the development of targeted LVs pseudotyped with the glycoproteins of Tupaia paramyxovirus (TPMV). Since this animal paramyxovirus does not infect humans, no TPMV antibodies in patients are expected. For efficient incorporation in LVs, the TPMV glycoproteins, the hemagglutinin (H) and fusion (F) protein, were modified by truncation of their cytoplasmic tails. Targeting was achieved by displaying a single-chain antibody against the B cell surface marker CD20 on the H protein. The modified proteins were biochemically characterized and tested for their functionality. Unexpectedly, it was observed that an additional proteolytic cleavage of the F protein occurs during activation, resulting in the fragments F1a, F1b and F2. The newly identified fragment F1a was detected in virions and in supernatant of transfected cells. The F1a/F1b cleavage site was mapped and a cysteine protease was identified as likely activating protease. The data indicate that F protein processing is more complex than expected. After characterization, the modified TPMV glycoproteins were screened in all combinations for their ability to form functional pseudotyped LVs. Most efficient pseudotype formation was achieved with CT truncations of 80 amino acids (aa) for H (HΔ80αCD20) and 32 aa for F (FΔ32) (titers ~ 106 t.u./ml). The resulting vectors selectively transduced CD20-positive cells in a mixed cell population. Furthermore, they mediated efficient gene transfer into activated and quiescent primary human B cells. Neutralization assays showed that TPMV-pseudotyped vectors were not neutralized by human sera containing MV antibodies. In conclusion, it was demonstrated that targeted LVs pseudotyped with TPMV glycoproteins can be generated and escape neutralization by MV antibodies. Remarkably, the vectors are able to efficiently transduce even quiescent B cells. Hence, they might be a valuable vector choice when systemic application of targeted lentiviral vectors in humans is required

Neural activity in the human anterior thalamus during natural vision

In natural vision humans and other primates explore environment by active sensing, using saccadic eye movements to relocate the fovea and sample different bits of information multiple times per second. Saccades induce a phase reset of ongoing neuronal oscillations in primary and higher-order visual cortices and in the medial temporal lobe. As a result, neuron ensembles are shifted to a common state at the time visual input propagates through the system (i.e., just after fixation). The extent of the brain’s circuitry that is modulated by saccades is not yet known. Here, we evaluate the possibility that saccadic phase reset impacts the anterior nuclei of the thalamus (ANT). Using recordings in the human thalamus of three surgical patients during natural vision, we found that saccades and visual stimulus onset both modulate neural activity, but with distinct field potential morphologies. Specifically, we found that fixation-locked field potentials had a component that preceded saccade onset. It was followed by an early negativity around 50 ms after fixation onset which is significantly faster than any response to visual stimulus presentation. The timing of these events suggests that the ANT is predictively modulated before the saccadic eye movement. We also found oscillatory phase concentration, peaking at 3–4 Hz, coincident with suppression of Broadband High-frequency Activity (BHA; 80–180 Hz), both locked to fixation onset supporting the idea that neural oscillations in these nuclei are reorganized to a low excitability state right after fixation onset. These findings show that during real-world natural visual exploration neural dynamics in the human ANT is influenced by visual and oculomotor events, which supports the idea that ANT, apart from their contribution to episodic memory, also play a role in natural vision

multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021

Funding Information: This project received funding from the European Centre for Disease Prevention and Control (ECDC) under the contract ECD.11486. Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101003673. Publisher Copyright: © 2022 European Centre for Disease Prevention and Control (ECDC). All rights reserved.Introduction: In July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe. Aim: Using a multicentre test-negative study, we measured COVID-19 vaccine effectiveness (VE) against symptomatic infection. Methods: Individuals with COVID-19 or acute respiratory symptoms at primary care/community level in 10 European countries were tested for SARS-CoV-2. We measured complete primary course overall VE by vaccine brand and by time since vaccination. Results: Overall VE was 74% (95% CI: 69-79), 76% (95% CI: 71-80), 63% (95% CI: 48-75) and 63% (95% CI: 16-83) among those aged 30-44, 45-59, 60-74 and ≥ 75 years, respectively. VE among those aged 30-59 years was 78% (95% CI: 75-81), 66% (95% CI: 58-73), 91% (95% CI: 87-94) and 52% (95% CI: 40-61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among people 60 years and older was 67% (95% CI: 52-77), 65% (95% CI: 48-76) and 83% (95% CI: 64-92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30-59 years was 87% (95% CI: 83-89) at 14-29 days and 65% (95% CI: 56-71%) at ≥ 90 days between vaccination and onset of symptoms. Conclusions: VE against symptomatic infection with the SARS-CoV-2 Delta variant varied among brands, ranging from 52% to 91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% at 90 days or more between vaccination and onset.publishersversionpublishe

Vaccine effectiveness against symptomatic SARS-CoV-2 infection in adults aged 65 years and older in primary care: I-MOVE-COVID-19 project, Europe, December 2020 to May 2021

I-MOVE-COVID-19 primary care study team (in addition to authors above): Nick Andrews, Jamie Lopez Bernal, Heather Whitaker, Caroline Guerrisi, Titouan Launay, Shirley Masse, Sylvie van der Werf, Vincent Enouf, John Cuddihy, Adele McKenna, Michael Joyce, Cillian de Gascun, Joanne Moran, Ana Miqueleiz, Ana Navascués, Camino Trobajo-Sanmartín, Carmen Ezpeleta, Paula López Moreno, Javier Gorricho, Eva Ardanaz, Fernando Baigorria, Aurelio Barricarte, Enrique de la Cruz, Nerea Egüés, Manuel García Cenoz, Marcela Guevara, Conchi Moreno-Iribas, Carmen Sayón, Verónica Gomez, Baltazar Nunes, Rita Roquete, Adriana Silva, Aryse Melo, Inês Costa, Nuno Verdasca, Patrícia Conde, Diogo FP Marques, Anna Molesworth, Leanne Quinn, Miranda Leyton, Selin Campbell, Janine Thoulass, Jim McMenamin, Ana Martínez Mateo, Luca Basile, Daniel Castrillejo, Carmen Quiñones Rubio, Concepción Delgado-Sanz, Jesús Oliva.The I-MOVE-COVID-19 network collates epidemiological and clinical information on patients with coronavirus disease (COVID-19), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virological characterisation in 11 European countries [1]. One component of I-MOVE-COVID-19 is the multicentre vaccine effectiveness (VE) study at primary care/outpatient level in nine European study sites in eight countries. We measured overall and product-specific COVID-19 VE against symptomatic SARS-CoV-2 infection among those aged 65 years and older. We also measured VE by time since vaccination.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101003673.info:eu-repo/semantics/publishedVersio

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe