Background Humoral response against SARS-CoV-2 after two doses of BNT162b2 (Pfizer-BioNTech) has been proven less intense in maintenance dialysis patients as compared to healthy subjects, leading the French authorities to recommend a third injection in this population. Here, we investigated the response to the third injection in two cohorts of hemodialysis patients. Methods Data from two prospective observational cohorts were collected. In the first -“systematic”- cohort, patients from 2 hemodialysis centers (n = 66) received a 3rd injection of BNT162b2, regardless of the response after two injections. In the second -“conditional”- cohort, the injection was only prescribed to patients (n = 34) with no or low response to the previous two doses. In both cohorts, the 3rd dose was injected 1 to 2 months after the 2nd dose. Serology was performed after the 2nd and 3rd dose to assess anti-Spike IgG antibody titer. Results In the “systematic” cohort, anti-Spike IgG were found in 83.3% and 92.4% of patients after the 2nd and the 3rd dose of BNT162b2, respectively. In this cohort, 6/11 (54.5%) and 20/21 (95.2%) patients switched from non-responder to low-responder and from low-responder to high-responder, respectively. In low and high-responders to 2 doses, 50/55 (90.9%) at least doubled their anti-Spike IgG titer. Similar trends were observed in the “conditional” cohort. Conclusions In maintenance hemodialysis patients, humoral response against SARS-Cov-2 was boosted after a third dose of BNT162b2, allowing seroconversion in more than half of non-responders. These data may support an intensified vaccination protocol with a 3rd dose of BNT162b2 in dialysis patients.

A novel and efficient keteniminium-initiated cationic polycyclization is reported. This reaction, which only requires triflic acid or bistriflimide as promoters, affords a straightforward entry to polycyclic nitrogen heterocycles possessing up to three contiguous stereocenters and seven fused cycles. These complex, polycyclic molecules can be obtained in a single operation from readily available ynamides which were shown to be remarkable building blocks for multiple, consecutive cationic transformations.

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Apolipoprotein E (apoE) is a forefront actor in the transport of lipids and the maintenance of cholesterol homeostasis, and is also strongly implicated in Alzheimer’s disease. Upon lipid-binding apoE adopts a conformational state that mediates the receptor-induced internalization of lipoproteins. Due to its inherent structural dynamics and the presence of lipids, the structure of the biologically active apoE remains so far poorly described. To address this issue, we developed an innovative hybrid method combining experimental data with molecular modeling and dynamics to generate comprehensive models of the lipidated apoE4 isoform. Chemical cross-linking combined with mass spectrometry provided distance restraints, characterizing the three-dimensional organization of apoE4 molecules at the surface of lipidic nanoparticles. The ensemble of spatial restraints was then rationalized in an original molecular modeling approach to generate monomeric models of apoE4 that advocated the existence of two alternative conformations. These two models point towards an activation mechanism of apoE4 relying on a regulation of the accessibility of its receptor binding region. Further, molecular dynamics simulations of the dimerized and lipidated apoE4 monomeric conformations revealed an elongation of the apoE N-terminal domain, whereby helix 4 is rearranged, together with Arg172, into a proper orientation essential for lipoprotein receptor association. Overall, our results show how apoE4 adapts its conformation for the recognition of the low density lipoprotein receptor and we propose a novel mechanism of activation for apoE4 that is based on accessibility and remodeling of the receptor binding region.