Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Phase analysis and microwave dielectric properties of BaO-Nd 2 O 3 -5TiO 2 composite ceramics using variable size TiO 2 reagents

There are significant inconsistencies in published literature surrounding the phase analysis and physical properties of ceramics with the nominal composition BaO-Nd2O3-5TiO2 (BNT125). A careful phase analysis investigation of BNT125 ceramics using variable size TiO2 reagents was therefore undertaken using XRD, FESEM and EPMA with corresponding dielectric properties characterised over 2-3 GHz. Three distinct phases were consistently formed: Ba6-3xNd8+2xTi18O54 (x ∼ 0.67), Ba2Ti9O20 and TiO2. The use of nano-scale TiO2 reagents significantly reduced porosity and improved the dielectric properties of the composite ceramics, while markedly reducing processing times. Structural and crystal chemical indications as to the origin of this system's physical properties are discussed, with these results providing new insights into optimisation paths for microwave dielectric materials of this type

Phase Relations in Ba6−3xLn8+2xTi18O54 (Ln = Nd & Sm) Electroceramics

A careful, systematic investigation of Ba6−3xLn8+2xTi18O54 (BLnTss) ceramics has been performed in order to understand the relationship between composition, microstructure evolution, and microwave dielectric properties. In this paper, we report the effects of composition, morphology, and sintering time on the phase relations and properties of BLnTss (Ln = Nd, Nd/Sm, Sm) ceramics. The microwave dielectric properties of the materials are reported in addition to phase characterisation and structural analysis via X-ray diffraction and field emission scanning electron microscopy coupled with energy dispersive X-ray spectroscopy. BLnTss, x=0.33, ceramics with high Sm content are found to experience a severe degradation of Qf and changes in τcf trending, associated with the onset of globular and needle-like grain morphology and a Ba-Ti rich phase. x=0.67 ceramics with high Nd content are found to exhibit a secondary phase (Nd2Ti2O7) upon prolonged sintering which resulted in beneficial changes to Qf and τcf without affecting εr. Two BLnTss ceramics compositions with near-zero τcf were successfully synthesised with high Qf and εr values

Chessboard/diamond nanostructures and the A-site deficient, Li 1/2-3x Nd 1/2+x TiO 3 , defect perovskite solid solution

The crystal chemical origin of nanoscale chessboard/diamond ordering in perovskite-related solid solutions of composition Li0.5-3xNd 0.5+xTiO3 (LNT, x ∼ 0.02-0.12) is investigated. Experimental and simulated scanning transmission electron microscopy (S

Chessboard/Diamond Nanostructures and the <i>A</i>‑site Deficient, Li_{1/2–3<i>x</i>} Nd_1/2+<i>x</i>TiO₃, Defect Perovskite Solid Solution

The crystal chemical origin of nanoscale chessboard/diamond ordering in perovskite-related solid solutions of composition Li_{0.5–3<i>x</i>}Nd_0.5+<i>x</i>TiO₃ (LNT, <i>x</i> ∼ 0.02–0.12) is investigated. Experimental and simulated scanning transmission electron microscopy (STEM) images are found to be consistent with the compositional modulation model proposed by previous authors. However, these earlier models do not satisfactorily explain other features observed in high-resolution STEM and TEM images, such as the two-dimensional {100} lattice fringes with the same periodicity, √2<i>a</i>_p × √2<i>a</i>_p, as the local LNT unit cell viewed along the [001] direction (where <i>a</i>_p is the parent perovskite unit cell parameter). Based on bond valence sum calculations, we propose a new set of crystal structures for LNT in which Li ions are primarily bonded to only two O ions, and order one-dimensionally with √2<i>a</i>_p periodicity. Bright-field STEM image simulations performed for this new model reproduced the experimentally observed √2<i>a</i>_p lattice fringes, thus strongly suggesting that the finer features of the high-resolution (S)­TEM images are the result of Li ion ordering and associated local structural relaxation. In this new model, the LNT chessboard supercell then results from the ordered combinations of two sublattices: the Li ion sublattice and its translational variants on the one hand, and the Nd_0.5TiO₃ sublattice and its oxygen octahedral tilt twin variants on the other. Dielectric measurements indicate the presence of long-lived polar clusters that are easily activated under an applied electric field. This suggests that these clusters consist of spatially correlated Li ions

Electron-pinned defect-dipoles for high-performance colossal permittivity materials

The immense potential of colossal permittivity (CP) materials for use in modern microelectronics as well as for high-energy-density storage applications has propelled much recent research and development. Despite the discovery of several new classes of C