Three-month follow-up of heterologous vs homologous third vaccination in kidney transplant recipients

ImportanceResponse to SARS-CoV-2 vaccines in kidney transplant recipients (KTR) is severely reduced. Heterologous 3rd vaccination combining mRNA and vector vaccines did not increase seroconversion at four weeks after vaccination but evolution of antibody levels beyond the first month remain unknown. ObjectiveTo assess changes in antibody response following a 3rd vaccination with mRNA or vector vaccine in KTR from month one to month three after vaccination. Design, Setting and ParticipantsThree-month follow-up (pre-specified secondary endpoint) of a single-center, single-blinded, 1:1 randomized, controlled trial on 3rd vaccination against SARS-CoV-2 in 201 KTR who did not develop SARS-CoV-2 spike protein antibodies following two doses of an mRNA vaccine. Intervention(s)mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as 3rd SARS-CoV-2 vaccine Main Outcomes and MeasuresMain outcome was seroconversion at the second follow-up between 60-120 days after the 3rd vaccination. Subsequently, higher cut-off levels associated with neutralizing capacity and protective immunity were applied (i.e. >15, >100, >141 and >264 BAU/mL). In addition, trajectories of antibody levels from month one to month three were analyzed. Finally, SARS-CoV-2 specific CD4 and CD8 T-cells at four weeks were compared among the 18 top responders in both groups. ResultsA total of 169 patients were available for the three-month follow-up. Overall, seroconversion at three months was similar between both groups (45% versus 50% for mRNA and vector group, respectively; OR=1.24, 95%CI=[0.65, 2.37], p=0.539). However, when applying higher cut-off levels, a significantly larger number of individual in the vector group reached antibody levels > 141 and > 264 BAU/mL at the three-month follow-up (141 BAU/mL: 4% vs. 15% OR=4.96, 95%CI=[1.29, 28.21], p=0.009 and 264 BAU/mL: 1% vs. 10% OR=8.75, 95%CI=[1.13, 396.17], p=0.018 for mRNA vs. vector vaccine group, respectively). In line, antibody levels in seroconverted patients further increased from month one to month three in the vector group while remaining unchanged in the mRNA group (median increase: mRNA= 1.35 U/mL and vector = 27.6 U/mL, p = 0.004). Of particular note, there was no difference in the CD4 and CD8 T-cell response between the mRNA and vector vaccine group at month one. Conclusions and RelevanceDespite a similar overall seroconversion rate at three months following 3rd vaccination in KTR, a heterologous 3rd booster vaccination with Ad26COVS1 resulted in significantly higher antibody levels in responders. Trial RegistrationEurdraCT: 2021-002927-39

First report of polymyxin B activity in Klebsiella pneumoniae biofilm.

Considering the clinical importance of biofilm in medical devices and chronic infections, this study aimed to investigate the action of polymyxin B on Klebsiella pneumoniae (K. pneumoniae) biofilm. The experiments were performed using a biofilm formation assay and the interaction of polysorbate 80 was explored. Both inhibition of biofilm formation and reduction of pre-formed biofilm occurred in a concentration-dependent manner with inhibition as high as 56 and 64%, and reduction of pre-formed biofilm as high as 70 and 66%, with and without polysorbate, respectively. The addition of polysorbate enhances the biofilm reduction, but more studies are needed to elucidate this mechanism. Our findings reveal, for the first time, polymyxin B as a potential agent for the treatment of K. pneumoniae biofilm, a current challenge for clinical practice.

Antimalarial activity of 4-metoxychalcones: docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate.

Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a-i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC50 = 2.06 µM) had the best selectivity index (9.0). All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79) and molecular weights (MWs) below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (-7.3 Kcal/mol). The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate.