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

Satellite tracking and stable isotope analysis highlight differential recruitment among foraging areas in green turtles

Identifying links between breeding and non-breeding sites in migratory animals is an important step in understanding their ecology. Recognising the relative importance of foraging areas and ascertaining site-specific levels of recruitment can provide fundamental and applied insights. Here, satellite telemetry and the stable isotope ratios (δ13C, δ15N and δ34S) of 230 green turtles Chelonia mydas from a regionally important rookery in northern Cyprus were employed to evaluate the relative importance of 4 foraging areas. A preliminary analysis of stable isotope ratios suggested that a major foraging area had been missed through satellite telemetry as a large proportion of turtles had isotope ratios that did not correspond to sites previously identified. Stable isotope ratios were then employed to select 5 turtles to be fitted with platform terminal transmitters in 2015. All 5 turtles were subsequently tracked to the same location, Lake Bardawil in Egypt. Serially collected tissue samples from 45 females, ranging over 2 to 4 breeding seasons, suggested that foraging site fidelity was very common, with 82% of females exhibiting extremely high temporal consistency in isotope ratios. Quantifying fidelity allowed an evaluation of foraging area - specific contributions to each breeding cohort over the past 2 decades and demonstrated that recruitment was unequal among sites, and dynamic over time, with Egypt now currently the major contributor to the nesting aggregation. This work demonstrates the utility of stable isotope analysis to elucidate the spatial ecology of cryptic taxa and illustrates how more robust baselines can be assembled against which to measure the success of future marine conservation initiatives

Detecting green shoots of recovery: the importance of long-term individual-based monitoring of marine turtles

Post-print version deposited in accordance with SHERPA RoMEO guidelines. The definitive version is available at http://onlinelibrary.wiley.com/doi/10.1111/acv.12128/fullPopulation monitoring is an essential part of evaluating the effectiveness of management interventions for conservation. Coastal breeding aggregations of marine vertebrate species that come ashore to pup or nest provide an opportunistic window of observation into otherwise widely dispersed populations. Green turtle (Chelonia mydas) nesting on the north and west coasts of northern Cyprus has been monitored consistently and exhaustively since 1993, with an intensive saturation tagging programme running at one key site for the same duration. This historically depleted nesting population is showing signs of recovery, possibly in response to nest protection approaching two decades, with increasing nest numbers and rising levels of recruitment. Strong correlation between year to year magnitude of nesting and the proportion of new breeders in the nesting cohort implies that recruitment of new individuals to the breeding population is an important driver of this recovery trend. Recent changes in fishing activities may be impacting the local juvenile neritic stage, however, which may hinder this potential recovery. Individuals returning to breed after 2 years laid fewer clutches than those returning after 3 or 4 years, demonstrating a trade-off between remigration interval and breeding output. Average clutch frequencies have remained stable around a median of three clutches a year per female despite the demographic shift towards new nesters, which typically lay fewer clutches in their first season. We show that where local fecundity has been adequately assessed, the use of average clutch frequencies can be a reliable method for deriving nester abundance from nest counts. Index sites where individual based monitoring is possible will be important in monitoring long-term climate driven changes in reproductive rates.European Social Fund, British Chelonia Group, North Cyprus British High Commission, North Cyprus British Residents Society, Erwin Warth Foundation, Friends of SPOT, Kuzey Kıbrıs Turkcell and MEDASSET UK

Satellite tracking and stable isotope analysis highlight differential recruitment among foraging areas in green turtles

Identifying links between breeding and non-breeding sites in migratory animals is an important step in understanding their ecology. Recognising the relative importance of foraging areas and ascertaining site-specific levels of recruitment can provide fundamental and applied insights. Here, satellite telemetry and the stable isotope ratios (δ13C, δ15N and δ34S) of 230 green turtles Chelonia mydas from a regionally important rookery in northern Cyprus were employed to evaluate the relative importance of 4 foraging areas. A preliminary analysis of stable isotope ratios suggested that a major foraging area had been missed through satellite telemetry as a large proportion of turtles had isotope ratios that did not correspond to sites previously identified. Stable isotope ratios were then employed to select 5 turtles to be fitted with platform terminal transmitters in 2015. All 5 turtles were subsequently tracked to the same location, Lake Bardawil in Egypt. Serially collected tissue samples from 45 females, ranging over 2 to 4 breeding seasons, suggested that foraging site fidelity was very common, with 82% of females exhibiting extremely high temporal consistency in isotope ratios. Quantifying fidelity allowed an evaluation of foraging area - specific contributions to each breeding cohort over the past 2 decades and demonstrated that recruitment was unequal among sites, and dynamic over time, with Egypt now currently the major contributor to the nesting aggregation. This work demonstrates the utility of stable isotope analysis to elucidate the spatial ecology of cryptic taxa and illustrates how more robust baselines can be assembled against which to measure the success of future marine conservation initiatives

Satellite tracking and stable isotope analysis highlight differential recruitment among foraging areas in green turtles

Identifying links between breeding and non-breeding sites in migratory animals is an important step in understanding their ecology. Recognising the relative importance of foraging areas and ascertaining site-specific levels of recruitment can provide fundamental and applied insights. Here, satellite telemetry and the stable isotope ratios (δ13C, δ15N and δ34S) of 230 green turtles Chelonia mydas from a regionally important rookery in northern Cyprus were employed to evaluate the relative importance of 4 foraging areas. A preliminary analysis of stable isotope ratios suggested that a major foraging area had been missed through satellite telemetry as a large proportion of turtles had isotope ratios that did not correspond to sites previously identified. Stable isotope ratios were then employed to select 5 turtles to be fitted with platform terminal transmitters in 2015. All 5 turtles were subsequently tracked to the same location, Lake Bardawil in Egypt. Serially collected tissue samples from 45 females, ranging over 2 to 4 breeding seasons, suggested that foraging site fidelity was very common, with 82% of females exhibiting extremely high temporal consistency in isotope ratios. Quantifying fidelity allowed an evaluation of foraging area - specific contributions to each breeding cohort over the past 2 decades and demonstrated that recruitment was unequal among sites, and dynamic over time, with Egypt now currently the major contributor to the nesting aggregation. This work demonstrates the utility of stable isotope analysis to elucidate the spatial ecology of cryptic taxa and illustrates how more robust baselines can be assembled against which to measure the success of future marine conservation initiatives

Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, and next-generation sequencing in cases and controls

BACKGROUND: Circulating biomarkers are urgently needed in hepatocellular carcinoma (HCC). The aims of this study were to determine the feasibility of detecting and isolating circulating tumor cells (CTCs) in HCC patients using enrichment for epithelial cell adhesion molecule (EpCAM) expression, to examine their prognostic value, and to explore CTC-based DNA sequencing in metastatic HCC patients compared to a control cohort with non-malignant liver diseases (NMLD). METHODS: Whole blood was obtained from patients with metastatic HCC or NMLD. CTCs were enumerated by CellSearch then purified by immunomagnetic EpCAM enrichment and fluorescence-activated cell sorting. Targeted ion semiconductor sequencing was performed on whole genome-amplified DNA from CTCs, tumor specimens, and peripheral blood mononuclear cells (PBMC) when available. RESULTS: Twenty HCC and 10 NMLD patients enrolled. CTCs ≥ 2/7.5 mL were detected in 7/20 (35%, 95% confidence interval: 12%, 60%) HCC and 0/9 eligible NMLD (p = 0.04). CTCs ≥ 1/7.5 mL was associated with alpha-fetoprotein ≥ 400 ng/mL (p = 0.008) and vascular invasion (p = 0.009). Sequencing of CTC DNA identified characteristic HCC mutations. The proportion with ≥ 100x coverage depth was lower in CTCs (43%) than tumor or PBMC (87%) (p < 0.025). Low frequency variants were higher in CTCs (p < 0.001). CONCLUSIONS: CTCs are detectable by EpCAM enrichment in metastatic HCC, without confounding false positive background from NMLD. CTC detection was associated with poor prognostic factors. Sequencing of CTC DNA identified known HCC mutations but more low-frequency variants and lower coverage depth than FFPE or PBMC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1195-z) contains supplementary material, which is available to authorized users