A single dose of SAAVI MVA-C reboosts rhesus macaques after more than 3 years post DNA-MVA prime-boost vaccination

We have previously reported induction of robust immune responses in rhesus macaques following a prime boost immunization with candidate HIV-1 vaccines, SAAVI DNA-C (DNA) and SAAVI MVA-C (MVA). These vaccines are already in clinical evaluation. In the current study, we investigated whether re-boosting these animals with a single MVA inoculation after more than 3 years was sufficient to restore previous magnitudes of HIV-specific immune responses

A prime-boost immunization with rBCG expressing HIV-1 Gag, RT and gp120 and SAAVI MVA-C elicits immune responses in blood and MALT of rhesus macaques

CG pantothenate auxtroph (ΔpanCD) is safer to use as a live vaccine vector than wild-type BCG. We constructed 3 recombinant BCGΔpanCD candidate vaccines expressing HIV-1 subtype C Gag, RT and Env (gp120). The current study investigated immune responses in rhesus macaques following a prime with a mixture of these rBCG vaccines and a boost with SAAVI MVA-C (MVA)

P19-53 LB. Priming with recombinant BCG expressing HIV-1 Gag or RT and boosting with recombinant MVA induces an effective immune response in mice

Mycobacterium bovis BCG (BCG) has a number of characteristics that give it great potential to act as a vehicle for the delivery of recombinant vaccines. However, its success depends on overcoming the challenges of poor antigen expression levels and genetic instability. Our studies using an optimized mycobacterial shuttle vector which utilizes the Mycobacterium tuberculosis mtrA promoter, induced upon infection of macrophages, and the M. tuberculosis 19 kDa signal sequence may overcome these issues. We have used this system to generate a recombinant BCG (rBCG) expressing HIV-1 subtype C full length Gag or reverse transcriptase (RT)

Bayesian adaptive designs for multi-arm trials: an orthopaedic case study

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The data used in this study were generated as part of the CAST study. Requests to share individual, de-identified participant data, aggregated data, data dictionaries, and other study documents from this study should be sent to the CAST Chief Investigator (SEL). Data sharing requests will be assessed on their individual merits. The FACTS files used to simulate the Bayesian adaptive designs are publicly available at https://github.com/egryan90/Bayesian-adaptive-designs-for-CAST-study-Ryan-et-al.-2019Background: Bayesian adaptive designs can be more efficient than traditional methods for multi‐arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi‐arm phase III clinical trials and assess potential benefits that these designs offer. Methods: We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These incorporated response adaptive randomisation, arm dropping, and early stopping for efficacy or futility. We studied the Bayesian designs’ operating characteristics via simulation. We then virtually re‐executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. Results: We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original design’s target sample size. The virtual executions 2 showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. Conclusions: Using CAST as an example, this case study showed how Bayesian adaptive designs can be constructed for phase III multi‐arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to betterperforming arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Medical Research Council (MRC)National Co‐ordinating Centre for Health Technology AssessmentNational Institute of Health Researc

Bayesian adaptive designs for multi-arm trials: an orthopaedic case study

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The data used in this study were generated as part of the CAST study. Requests to share individual, de-identified participant data, aggregated data, data dictionaries, and other study documents from this study should be sent to the CAST Chief Investigator (SEL). Data sharing requests will be assessed on their individual merits. The FACTS files used to simulate the Bayesian adaptive designs are publicly available at https://github.com/egryan90/Bayesian-adaptive-designs-for-CAST-study-Ryan-et-al.-2019Background: Bayesian adaptive designs can be more efficient than traditional methods for multi‐arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi‐arm phase III clinical trials and assess potential benefits that these designs offer. Methods: We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These incorporated response adaptive randomisation, arm dropping, and early stopping for efficacy or futility. We studied the Bayesian designs’ operating characteristics via simulation. We then virtually re‐executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. Results: We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original design’s target sample size. The virtual executions 2 showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. Conclusions: Using CAST as an example, this case study showed how Bayesian adaptive designs can be constructed for phase III multi‐arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to betterperforming arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Medical Research Council (MRC)National Co‐ordinating Centre for Health Technology AssessmentNational Institute of Health Researc

Homeostasis of metabolites in Escherichia coli on transition from anaerobic to aerobic conditions and the transient secretion of pyruvate

We have developed a method for rapid quenching of samples taken from chemostat cultures of Escherichia coli that gives reproducible and reliable measurements of extracellular and intracellular metabolites by 1H NMR and have applied it to study the major central metabolites during the transition from anaerobic to aerobic growth. Almost all metabolites showed a gradual change after perturbation with air, consistent with immediate inhibition of pyruvate formate-lyase, dilution of overflow metabolites and induction of aerobic enzymes. Surprisingly, although pyruvate showed almost no change in intracellular concentration, the extracellular concentration transiently increased. The absence of intracellular accumulation of pyruvate suggested that one or more glycolytic enzymes might relocate to the cell membrane. To test this hypothesis, chromosomal pyruvate kinase (pykF) was modified to express either PykF-green fluorescent protein or PykF-FLAG fusion proteins. Measurements showed that PykF-FLAG relocates to the cell membrane within 5 min of aeration and then slowly returns to the cytoplasm, suggesting that on aeration, PykF associates with the membrane to facilitate secretion of pyruvate to maintain constant intracellular levels

Comprehensive Geriatric Assessment on an Acute Medical Unit: a Qualitative Study of Older People’s and Informal Carer’s Perspectives of the Care and Treatment Received

Objective: This qualitative study was imbedded in a randomized controlled trial evaluating the addition of geriatricians to usual care to enable the comprehensive geriatric assessment process with older patients on acute medical units. The qualitative study explored the perspectives of intervention participants on their care and treatment.Design: A constructivist study incorporating semi-structured interviews that were conducted in patients’ homes within six weeks of discharge from the acute medical unit. These interviews were recorded, transcribed, and analysed using thematic analysis.Setting: An acute medical unit in the United Kingdom.Participants: Older patients (n = 18) and their informal carers (n = 6) discharged directly home from an acute medical unit, who had been in the intervention group of the randomized controlled trial.Results: Three core themes were constructed: (1) perceived lack of treatment on the acute medical unit; (2) nebulous grasp of the role of the geriatrician; and (3) on-going health and activities of daily living needs postdischarge. These needs impacted upon the informal carers, who either took over, or helped the patients to complete their activities of daily living. Despite the help received with activities of daily living, a lot of the patients voiced a desire to complete these activities themselves.Conclusions:The participants perceived they were just monitored and observed on the acute medical unit, rather than receiving active treatment, and spoke of on-going unresolved health and activity of daily living needs following discharge, despite receiving the additional intervention of a geriatrician

Limited polymorphism in Plasmodium falciparum ookinete surface antigen, von Willebrand factor A domain-related protein from clinical isolates

BACKGROUND: As malaria becomes increasingly drug resistant and more costly to treat, there is increasing urgency to develop effective vaccines. In comparison to other stages of the malaria lifecycle, sexual stage antigens are under less immune selection pressure and hence are likely to have limited antigenic diversity. METHODS: Clinical isolates from a wide range of geographical regions were collected. Direct sequencing of PCR products was then used to determine the extent of polymorphisms for the novel Plasmodium falciparum sexual stage antigen von Willebrand Factor A domain-related Protein (PfWARP). These isolates were also used to confirm the extent of diversity of sexual stage antigen Pfs28. RESULTS: PfWARP was shown to have non-synonymous substitutions at 3 positions and Pfs28 was confirmed to have a single non-synonymous substitution as previously described. CONCLUSION: This study demonstrates the limited antigenic diversity of two prospective P. falciparum sexual stage antigens, PfWARP and Pfs28. This provides further encouragement for the proceeding with vaccine trials based on these antigens