Biology subjects

de Wilde, A.

Publications and source records attributed to de Wilde, A..

3 recordsLinked to original sources

bioRxiv2022

Immunogenicity of an Ad26-based SARS-CoV-2 Omicron Vaccine in Naïve Mice and SARS-CoV-2 Spike Pre-immune Hamsters

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant sparked concern due to its fast spread and the unprecedented number of mutations in the spike protein that enables it to partially evade spike-based COVID-19 vaccine-induced humoral immunity. In anticipation of a potential need for an Omicron spike-based vaccine, we generated an Ad26 vector encoding an Omicron (BA.1) spike protein (Ad26.COV2.S.529). Ad26.COV2.S.529 encodes for a prefusion stabilized spike protein, similar to the current COVID-19 vaccine Ad26.COV2.S encoding the Wuhan-Hu-1 spike protein. We verified that spike expression by Ad26.COV2.S.529 was comparable to Ad26.COV2.S. Immunogenicity of Ad26.COV2.S.529 was then evaluated in naive mice and SARS-CoV-2 Wuhan-Hu-1 spike pre-immunized hamsters. In naive mice, Ad26.COV2.S.529 elicited robust neutralizing antibodies against SARS-CoV-2 Omicron (BA.1) but not to SARS-CoV-2 Delta (B.1.617.2), while the opposite was observed for Ad26.COV2.S. In pre-immune hamsters, Ad26.COV2.S.529 vaccination resulted in robust increases in neutralizing antibody titers against both SARS-CoV-2 Omicron (BA.1) and Delta (B.1.617.2), while Ad26.COV2.S vaccination only increased neutralizing antibody titers against the Delta variant. Our data imply that Ad26.COV2.S.529 can both expand and boost a Wuhan-Hu-1 spike-primed humoral immune response to protect against distant SARS-CoV-2 variants.

immunology↗

bioRxiv2020

Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic -ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the -ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus.

biochemistry↗

bioRxiv2019

PET and CSF amyloid-β status are differently predicted by patient features: Information from discordant cases

BackgroundAmyloid-{beta} PET and CSF A{beta}42 yield discordant results in 10-20% of patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic and imaging features for amyloid-positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-{beta} status based on PET or CSF, or whether this differs by disease stage.\n\nMethodsWe included 768 patients (subjective cognitive decline (SCD, n=194), mild cognitive impairment (MCI, n=127), dementia (AD and non-AD, n=447) with amyloid-{beta} PET and CSF A{beta}42 measurement within one year. 97(13%) patients had discordant PET/CSF amyloid-{beta} status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature, and (ii) the patient feature adjusted for the status of the other amyloid modality.\n\nResultsAPOE4, CSF tau and p-tau had highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR=1.02[1.01-1.04], pFDR=0.03), MCI (OR=1.05[1.02-1.07], pFDR<0.01) and dementia (OR=1.04[1.03-1.05], pFDR<0.001), but not for CSF-amyloid. APOE4 (OR=3.07[1.33-7.07], punc<0.01) was associated with CSF-amyloid in SCD, while it was only predictive for PET-amyloid in MCI (OR=9.44[2.93,30.39], pFDR<0.01). Worse MMSE scores (OR=1.21[1.03-1.41], punc=0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR=1.17[1.05-1.31], pFDR=0.02) only predicted PET positivity in dementia.\n\nConclusionAmyloid status based on either PET or CSF was predicted by different patient features and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggests that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology. These findings can influence the choice between amyloid biomarkers in future studies or trials.

neuroscience↗