Ward-based in situ simulation: lessons learnt from a UK District General Hospital.

INTRODUCTION: In situ simulation (ISS) enables multiprofessional healthcare teams to train for real emergencies in their own working environment and identify latent patient safety threats. This study aimed to determine ISS impact on teamwork, technical skill performance, healthcare staff perception and latent error identification during simulated medical emergencies. MATERIALS AND METHODS: Unannounced ISS sessions (n=14, n=75 staff members) using a high-fidelity mannequin were conducted in medical, paediatric and rehabilitation wards at Stepping Hill Hospital (Stockport National Health Service Foundation Trust, UK). Each session encompassed a 15 min simulation followed by a 15 min faculty-led debrief. RESULTS: The clinical team score revealed low overall teamwork performances during simulated medical emergencies (mean±SEM: 4.3±0.5). Linear regression analysis revealed that overall communication (r=0.9, p<0.001), decision-making (r=0.77, p<0.001) and overall situational awareness (r=0.73, p=0.003) were the strongest statistically significant predictors of overall teamwork performance. Neither the number of attending healthcare professionals, their professional background, age, gender, degree of clinical experience, level of resuscitation training or previous simulation experience statistically significantly impacted on overall teamwork performance. ISS positively impacted on healthcare staff confidence and clinical training. Identified safety threats included unknown location of intraosseous kits, poor/absent airway management, incomplete A-E assessments, inability to activate the major haemorrhage protocol, unknown location/dose of epinephrine for anaphylaxis management, delayed administration of epinephrine and delayed/absence of attachment of pads to the defibrillator as well as absence of accessing ALS algorithms, poor chest compressions and passive behaviour during simulated cardiac arrests. CONCLUSION: Poor demonstration of technical/non-technical skills mandate regular ISS interventions for healthcare professionals of all levels. ISS positively impacts on staff confidence and training and drives identification of latent errors enabling improvements in workplace systems and resources.

Injuries in Fatalities of Dismounted Blast: Identification of Four Mechanisms of Head and Spine Injury.

Blast is the most common injury mechanism in conflicts of this century due to the widespread use of explosives, confirmed by recent conflicts such as in Ukraine. Data from conflicts in the last century such as Northern Ireland, the Falklands, and Vietnam up to the present day show that between 16% and 21% of personnel suffered a traumatic brain injury. Typical features of fatal brain injury to those outside of a vehicle (hereafter referred to as dismounted) due to blast include the presence of hemorrhagic brain injury alongside skull fractures rather than isolated penetrating injuries more typical of traditional ballistic head injuries. The heterogeneity of dismounted blast has meant that analysis from databases is limited and therefore a detailed look at the radiological aspects of injury is needed to understand the mechanism and pathology of dismounted blast brain injury. The aim of this study was to identify the head and spinal injuries in fatalities due to dismounted blast. All UK military fatalities from dismounted blast who suffered a head injury from 2007-2013 in the Iraq and Afghanistan conflicts were identified retrospectively. Postmortem computerized tomography images (CTPMs) were interrogated for injuries to the head, neck, and spine. All injuries were documented and classified using a radiology brain injury classification (BIC) tool. Chi-squared (χ2) and Fisher's exact tests were used to investigate correlations between injuries, along with odds ratios for determining the direction of correlation. The correlations were clustered. There were 71 fatalities from dismounted blast with an associated head injury with a CTPM or initial CT available for analysis. The results showed the heterogeneity of injury from dismounted blast but also some potential identifiable injury constellations. These were: intracranial haemorrhage, intracranial deep haemorrhage, spinal injury, and facial injury. These identified injury patterns can now be investigated to consider injury mechanisms and so develop mitigation strategies or clinical treatments. Level of Evidence: Observational. Study type: cohort observational.

Osteoid osteoma presenting with scoliosis: successful resection with endoscopic excision.

A young male in his mid-teen years presented with severe back pain for 3 months and was subsequently diagnosed with osteoid osteoma in the left superior articular process of the L4 vertebra. Initial treatment with non-steroidal anti-inflammatory drugs provided temporary relief. Due to concerns about scoliosis progression along with unrelieved pain, a multidisciplinary team recommended endoscopic excision of the osteoid osteoma. The procedure resulted in complete pain relief and an improvement in the scoliosis curve from 22° of Cobb's angle to 12 degrees at the 8-month follow-up.

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Proteomic changes induced by longevity-promoting interventions in mice.

Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging.

Spinal phosphaturic mesenchymal tumors: a rare etiology causing tumor-induced osteomalacia-a review of experience at a UK tertiary referral center and literature review.

PURPOSE: This article aims to provide a comprehensive review of the management challenges associated with Spinal Phosphaturic Mesenchymal tumors (PMTs) and evaluates the surgical management outcomes for this rare entity linked to Tumor-induced osteolysis. The primary objective of this study is to enhance the familiarity of treating physicians with the clinical features, diagnosis, and treatment options for Spinal PMTs. METHODS: A retrospective analysis was conducted, reviewing electronic medical records of patients diagnosed with spinal PMTs at our hospital between January 2019 and December 2022. The data collected included demographic information, clinical presentation, radiological findings, surgical details, and follow-up outcomes. RESULTS: A total of three cases of Spinal PMTs causing Tumor-induced osteomalacia were identified. The diagnosis of Spinal PMTs presented challenges, with incidental detection often occurring during routine imaging. Surgical management was undertaken, resulting in successful symptom resolution and normalization of phosphate levels. The application of 68 Ga-DOTA-TATE PET/CT scans facilitated tumor localization, aiding in surgical planning. Spinal PMTs demonstrated a favorable response to surgical intervention. CONCLUSION: Spinal PMTs play a significant role in Tumor-induced osteolysis, warranting timely and accurate diagnosis. Although diagnosing Spinal PMTs presents challenges, surgical management has proven to yield favorable outcomes, effectively alleviating symptoms and restoring phosphate levels. A multidisciplinary approach and continued vigilance are essential in ensuring early diagnosis, effective treatment, and long-term monitoring for patients affected by spinal PMTs.

The impact of Longitudinal Integrated Foundation Training: preliminary experiences in the United Kingdom.

BACKGROUND: The United Kingdom health system is challenged with retaining doctors entering specialty training directly after their second foundation year. Improving doctors' training experience during the foundation programme may aid such retention. The Longitudinal Integrated Foundation Training (LIFT) pilot scheme aimed to provide a programme that improves the quality of their foundation training experience, advance patient-centred care and provide doctors with more experience in the primary care settings. METHODS: During this pilot study, three methods were employed to evaluate and compare doctors' experiences across their 2-year foundation training programme: Horus ePortfolio assessment of six domains for good medical practice analysed using a T-test, online survey assessments analysed using a 2-tailed chi-square test, and focus group feedback sessions with thematic analysis. RESULTS: Doctors completing LIFT (n = 47) scored a higher but non-significant mean score on all six domains for good medical practice versus doctors completing traditional foundation training (n = 94). By the end of foundation training, 100% of LIFT doctors rated their understanding of how primary and secondary care work together as high versus 78.7% of traditional doctors (p < 0.05). Improvements in wellbeing were observed among LIFT doctors, along with a reduction in the proportion of doctors considering leaving medical training. A significantly greater number of LIFT doctors versus traditional doctors rated their compassion for patients as high (100% versus 86.8%; p < 0.05), intended to become general practitioners (23.1% versus 13.5%; p < 0.05) and rated the extent to which they felt well informed and able to consider a general practice career rather than a hospital career as high (91.7% versus 72.3%, respectively; p < 0.05). Some LIFT doctors felt they had reduced exposure to secondary care, received less on-call experience and considered working a half-day to be problematic; challenges ameliorated by the end of the 2-year foundation programme. CONCLUSION: The LIFT programme enhanced the quality of foundation training and improved doctors' experiences and competencies, generating valuable insights for the future of education and healthcare delivery. Applying the principles of LIFT to foundation training helps doctors to be more compassionate and patient-centred, leading to enhanced individualised patient care.

Borrelia PeptideAtlas: A proteome resource of common Borrelia burgdorferi isolates for Lyme research.

Lyme disease, caused by an infection with the spirochete Borrelia burgdorferi, is the most common vector-borne disease in North America. B. burgdorferi strains harbor extensive genomic and proteomic variability and further comparison is key to understanding the spirochetes infectivity and biological impacts of identified sequence variants. To achieve this goal, both transcript and mass spectrometry (MS)-based proteomics was applied to assemble peptide datasets of laboratory strains B31, MM1, B31-ML23, infective isolates B31-5A4, B31-A3, and 297, and other public datasets, to provide a publicly available Borrelia PeptideAtlas http://www.peptideatlas.org/builds/borrelia/. Included is information on total proteome, secretome, and membrane proteome of these B. burgdorferi strains. Proteomic data collected from 35 different experiment datasets, with a total of 855 mass spectrometry runs, identified 76,936 distinct peptides at a 0.1% peptide false-discovery-rate, which map to 1,221 canonical proteins (924 core canonical and 297 noncore canonical) and covers 86% of the total base B31 proteome. The diverse proteomic information from multiple isolates with credible data presented by the Borrelia PeptideAtlas can be useful to pinpoint potential protein targets which are common to infective isolates and may be key in the infection process.

Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers.

Aging manifests as progressive deteriorations in homeostasis, requiring systems-level perspectives to investigate the gradual molecular dysregulation of underlying biological processes. Here, we report systemic changes in the molecular regulation of biological processes under multiple lifespan-extending interventions. Differential Rank Conservation (DIRAC) analyses of mouse liver proteomics and transcriptomics data show that mechanistically distinct lifespan-extending interventions (acarbose, 17α-estradiol, rapamycin, and calorie restriction) generally tighten the regulation of biological modules. These tightening patterns are similar across the interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response. Differences in DIRAC patterns between proteins and transcripts highlight specific modules which may be tightened via augmented cap-independent translation. Moreover, the systemic shifts in fatty acid metabolism are supported through integrated analysis of liver transcriptomics data with a mouse genome-scale metabolic model. Our findings highlight the power of systems-level approaches for identifying and characterizing the biological processes involved in aging and longevity.

Vacuum Insulated Probe Heated Electrospray Ionization Source Enhances Microflow Rate Chromatography Signals in the Bruker timsTOF Mass Spectrometer.

By far the largest contribution to ion detectability in liquid chromatography-driven mass spectrometry-based proteomics is the efficient generation of peptide molecular ions by the electrospray source. To maximize the transfer of peptides from the liquid to gaseous phase and allow molecular ions to enter the mass spectrometer at microspray flow rates, an efficient electrospray process is required. Here we describe the superior performance of newly design vacuum insulated probe heated electrospray ionization (VIP-HESI) source coupled to a Bruker timsTOF PRO mass spectrometer operated in microspray mode. VIP-HESI significantly improves chromatography signals in comparison to electrospray ionization (ESI) and nanospray ionization using the captivespray (CS) source and provides increased protein detection with higher quantitative precision, enhancing reproducibility of sample injection amounts. Protein quantitation of human K562 lymphoblast samples displayed excellent chromatographic retention time reproducibility (<10% coefficient of variation (CV)) with no signal degradation over extended periods of time, and a mouse plasma proteome analysis identified 12% more plasma protein groups allowing large-scale analysis to proceed with confidence (1,267 proteins at 0.4% CV). We show that the Slice-PASEF VIP-HESI mode is sensitive in identifying low amounts of peptide without losing quantitative precision. We demonstrate that VIP-HESI coupled with microflow rate chromatography achieves a higher depth of coverage and run-to-run reproducibility for a broad range of proteomic applications. Data and spectral libraries are available via ProteomeXchange (PXD040497).

The imaging of cervical spondylotic myeloradiculopathy.

This review provides a detailed description of the imaging features of cervical spondylotic myelopathy and radiculopathy, with a focus on MRI. Where relevant, we will outline grading systems of vertebral central canal and foraminal stenosis. Whilst post-operative appearances of the cervical spine are outside the scope of this paper, we will touch on imaging features recognised as predictors of clinical outcome and neurological recovery. This paper will serve as a reference for both radiologists and clinicians involved in the care of patients with cervical spondylotic myeloradiculopathy.

Persistence of immune responses after heterologous and homologous third COVID-19 vaccine dose schedules in the UK: eight-month analyses of the COV-BOOST trial.

BACKGROUND: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms. METHODS: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation. RESULTS: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms. CONCLUSIONS: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.

Vacuum Insulated Probe Heated ElectroSpray Ionization source (VIP-HESI) enhances micro flow rate chromatography signals in the Bruker timsTOF mass spectrometer.

By far the largest contribution to ion detectability in liquid chromatography-driven mass spectrometry-based proteomics is the efficient generation of peptide ions by the electrospray source. To maximize the transfer of peptides from liquid to a gaseous phase to allow molecular ions to enter the mass spectrometer at micro-spray flow rates, an efficient electrospray process is required. Here we describe superior performance of new Vacuum-Insulated-Probe-Heated-ElectroSpray-Ionization source (VIP-HESI) coupled with micro-spray flow rate chromatography and Bruker timsTOF PRO mass spectrometer. VIP-HESI significantly improves chromatography signals in comparison to nano-spray ionization using the CaptiveSpray source and provides increased protein detection with higher quantitative precision, enhancing reproducibility of sample injection amounts. Protein quantitation of human K562 lymphoblast samples displayed excellent chromatographic retention time reproducibility (<10% coefficient-of-variation (CV)) with no signal degradation over extended periods of time, and a mouse plasma proteome analysis identified 12% more plasma protein groups allowing large-scale analysis to proceed with confidence (1,267 proteins at 0.4% CV). We show that Slice-PASEF mode with VIP-HESI setup is sensitive in identifying low amounts of peptide without losing quantitative precision. We demonstrate that VIP-HESI coupled with micro-flow-rate chromatography achieves higher depth of coverage and run-to-run reproducibility for a broad range of proteomic applications.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

Injuries in Underbody Blast Fatalities: Identification of Five Distinct Mechanisms of Head Injury.

Previous research has shown that injuries to the head and neck were prevalent in 73% of all mounted fatalities of underbody blast. The mechanisms that cause such injuries to the central nervous system (CNS) are not yet known. The aim of this study was to identify the head and spinal injuries in fatalities due to underbody blast (UBB) and then develop hypotheses on the causative mechanisms. All U.K. military fatalities from UBB with an associated head injury that occurred during 2007-2013 in the Iraq and Afghanistan conflicts were identified retrospectively. Computed tomography post-mortems (CTPMs) were interrogated for injuries to the head, neck, and spine. All injuries were documented and classified using a radiology classification. Pearson's chi-square and Fisher's exact tests were used to show a relationship between variables and form a hypothesis for injury mechanisms. There were 50 fatalities from UBB with an associated head injury. Of these, 46 had complete CTPMs available for analysis. Chi-square and Fisher's exact tests showed a relationship between lateral ventricle blood and injuries to the abdomen and thorax. Five partially overlapping injury constellations were identified: 1.multiple-level spinal injury with skull fracture and brainstem injury, 2.peri-mesencephalic hemorrhage, 3.spinal and brainstem injury, 4.parenchymal contusions with injury to C0-C1, and 5.an "eggshell" pattern of fractures from direct impact. These injury constellations can now be used to propose injury mechanisms to develop mitigation strategies or clinical treatments.

Emerging Gambling Problems and Suggested Interventions: A Systematic Review of Empirical Research.

The goal of the present systematic review is to identify emerging gambling problems and the harm minimization strategies proposed to address them. Our interdisciplinary research team conducted this systematic literature review in 5 nations between which there is significant gambling research exchange. A keyword search of the Scopus and Web of Science databases followed by filtering using inclusion criteria identified 1292 empirical gambling studies from peer-reviewed journals. The data obtained from the articles were analyzed using the content analysis technique. We then used a unique approach to identify relationships between harm minimization strategies and gambling problems. The findings reveal that the most frequently reported gambling problems are related to young gamblers, online gambling, electronic gaming machines, and children and adolescents (underage gamblers). Harm minimization strategies to address these included creating educational and awareness programs, further restrictions on gambling advertising, developing an intervention mechanism for online gambling, and remote gambling-related help (i.e., online counseling, online treatment).

Impact of meningococcal ACWY conjugate vaccines on pharyngeal carriage in adolescents: evidence for herd protection from the UK MenACWY programme.

OBJECTIVE: Serogroup W and Y invasive meningococcal disease increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) invasive meningococcal disease, the UK replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, the vaccine coverage in the eligible school cohorts aged 14 to 19 years was 84%. We assessed the impact of the MenACWY vaccination programme on meningococcal carriage. METHODS: An observational study of culture-defined oropharyngeal meningococcal carriage prevalence before and after the start of the MenACWY vaccination programme in UK school students, aged 15 to 19 years, using two cross-sectional studies: 2014 to 2015 "UKMenCar4" and 2018 "Be on the TEAM" (ISRCTN75858406). RESULTS: A total of 10 625 participants preimplementation and 13 438 postimplementation were included. Carriage of genogroups C, W, and Y (combined) decreased from 2.03 to 0.71% (OR 0.34 [95% CI 0.27-0.44], p < 0.001). Carriage of genogroup B meningococci did not change (1.26% vs 1.23% [95% CI 0.77-1.22], p = 0.80) and genogroup C remained rare (n = 7/10 625 vs 17/13 438, p = 0.135). The proportion of serogroup positive isolates (i.e. those expressing capsule) decreased for genogroup W by 53.8% (95% CI -5.0 - 79.8, p = 0.016) and for genogroup Y by 30.1% (95% CI 8.946·3, p = 0.0025). DISCUSSION: The UK MenACWY vaccination programme reduced carriage acquisition of genogroup and serogroup Y and W meningococci and sustained low levels of genogroup C carriage. These data support the use of quadrivalent MenACWY conjugate vaccine for indirect (herd) protection.

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 (anti-spike 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. FUNDING: UK Vaccine Task Force and National Institute for Health Research.