Publications by authors named "Paul Heath"

328 Publications

Incidental findings in UK healthy volunteers screened for a COVID-19 vaccine trial.

Clin Transl Sci 2021 Oct 20. Epub 2021 Oct 20.

University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.

The safety of novel therapeutics and vaccines are typically assessed in early phase clinical trials involving "healthy volunteers." Abnormalities in such individuals can be difficult to interpret and may indicate previously unrecognized medical conditions. The frequency of incidental findings (IFs) in healthy volunteers who attend for clinical trial screening is unclear. To assess this, we retrospectively analyzed data for 1838 "healthy volunteers" screened for enrolment in a UK multicenter, phase I/II severe acute respiratory syndrome-coronavirus 2 (SARS-COV-2) vaccine trial. Participants were predominantly White (89.7%, 1640/1828) with a median age of 34 years (interquartile range [IQR] = 27-44). There were 27.7% of participants (510/1838) who had at least one IF detected. The likelihood of identifying evidence of a potential, new blood-borne virus infection was low (1 in 238 participants) compared with identification of an elevated alanine transaminase (ALT; 1 in 17 participants). A large proportion of participants described social habits that could impact negatively on their health; 21% consumed alcohol in excess, 10% were current smokers, 11% described recreational drug use, and only 48% had body weight in the ideal range. Our data demonstrate that screening prior to enrollment in early phase clinical trials identifies a range of IFs, which should inform discussion during the consent process. Greater clarity is needed to ensure an appropriate balance is struck between early identification of medical problems and avoidance of exclusion of volunteers due to spurious or physiological abnormalities. Debate should inform the role of the trial physician in highlighting and advising about unhealthy social habits.
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http://dx.doi.org/10.1111/cts.13170DOI Listing
October 2021

SARS-CoV-2 Infection in an Adolescent With X-linked Agammaglobulinemia.

Pediatr Infect Dis J 2021 Sep 28. Epub 2021 Sep 28.

From the Paediatric Infectious Diseases; HIV; Paediatric Respiratory Medicine; and Paediatric Immunology, St George's University Hospitals NHS Foundation Trust, Tooting, London, United Kingdom.

We present a case of a 17-year-old boy with X-linked agammaglobulinemia who had mild disease when initially infected with SARS-CoV-2 but after recovering from acute infection developed fevers and a raised erythrocyte sedimentation rate that persisted for several weeks without any ongoing respiratory symptoms. Multiple nasopharyngeal swabs were found to be negative for SARS-CoV-2 during the febrile period, but typical changes of COVID-19 on high resolution CT chest scan led to the detection of SARS-CoV-2 on RT-PCR in a sample from a bronchoalveolar lavage. His fevers completely resolved after a 5-day course of remdesivir.
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http://dx.doi.org/10.1097/INF.0000000000003360DOI Listing
September 2021

Applicability of the GAIA Maternal and Neonatal Outcome Case Definitions for the Evaluation of Adverse Events Following Vaccination in Pregnancy in High-income Countries.

Pediatr Infect Dis J 2021 Sep 28. Epub 2021 Sep 28.

From the Department of Paediatric Infectious Diseases and Immunology, University Hospital Southampton, Southampton, United Kingdom; Julius Global Health, Universitair Medisch Centrum, Utrecht, The Netherlands; Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas; Department of Obstetrics and Gynecology, and Department of Global Health, Seattle, Washington; Faculty of Medicine and Institute for Life Sciences, University of Southampton and NIHR Southampton Clinical Research Facility, Southampton, United Kingdom; Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Infection and Immunity, Monash Children's Hospital, Monash Health, Department of Paediatrics, Monash University, Melbourne, Australia; Yale University School of Medicine, Department of Pediatrics, Section of Infectious Diseases and Global Health; Yale Institute of Global Health, New Haven, Connecticut; Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, University of Washington, Seattle, Washington; Vaccine Institute, St George's, University of London, London, United Kingdom; Division of Infectious Diseases, Global Health Center, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas; Department of Primary Care and Population Sciences, Aldermoor Health Centre, University of Southampton, United Kingdom; Monash Immunisation, Monash Health, Melbourne, Australia; Emory University School of Medicine, Department of Pediatrics, Division of Infectious Diseases, Atlanta, Georgia; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's University of London; Fetal Medicine Unit, St Georges University Hospitals NHS Trust, London, United Kingdom; University Medical Center Utrecht, Julius Center, Utrech, The Netherlands; and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: The Brighton Collaboration Global Alignment of Immunization Safety in Pregnancy (GAIA) project developed case definitions for the assessment of adverse events in mothers and infants following maternal immunization. This study evaluated the applicability of these definitions to data collected in routine clinical care and research trial records across 7 sites in high-resource settings.

Methods: Data collection forms were designed and used to retrospectively abstract the key elements of the GAIA definitions from records for 5 neonatal and 5 maternal outcomes, as well as gestational age. Level of diagnostic certainty was assessed by the data abstractor and an independent clinician, and then verified by Automated Brighton Case logic. The ability to assign a level of diagnostic certainty for each outcome and the positive predictive value (PPV) for their respective ICD-10 codes were evaluated.

Results: Data from 1248 case records were abstracted: 624 neonatal and 622 maternal. Neonatal outcomes were most likely to be assessable and assigned by the level of diagnostic certainty. PPV for preterm birth, low birth weight, small for gestational age and respiratory distress were all above 75%. Maternal outcomes for preeclampsia and fetal growth restriction showed PPV over 80%. However, microcephaly (neonatal outcome) and dysfunctional labor (maternal outcome) were often nonassessable, with low PPVs.

Conclusions: The applicability of GAIA case definitions to retrospectively ascertain and classify maternal and neonatal outcomes was variable among sites in high-resource settings. The implementation of the case definitions is largely dependent on the type and quality of documentation in clinical and research records in both high- and low-resource settings. While designed for use in the prospective evaluation of maternal vaccine safety, the GAIA case definitions would likely need to be specifically adapted for observational studies using alternative sources of data, linking various data sources and allowing flexibility in the ascertainment of the elements and levels of certainty of the case definition.
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http://dx.doi.org/10.1097/INF.0000000000003261DOI Listing
September 2021

Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function.

Eur J Neurosci 2021 Sep 18. Epub 2021 Sep 18.

Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK.

Oxidative DNA damage induces changes in the neuronal cell cycle and activates a DNA damage response (DDR) to promote repair, but these processes may be altered under a chronic oxidative environment, leading to the accumulation of unrepaired DNA damage and continued activation of a DDR. Failure to repair DNA damage can lead to apoptosis or senescence, which is characterized by a permanent cell cycle arrest. Increased oxidative stress and accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration, but the effects of persistent DNA damage in neurons are not well characterized. We developed a model of persistent oxidative DNA damage in immortalized post-mitotic neurons in vitro by exposing them to a sublethal concentration of hydrogen peroxide following a 'double stress' protocol and performed a detailed characterization of the neuronal transcriptome using microarray analysis. Persistent DNA damage significantly altered the expression of genes involved in cell cycle regulation, DDR and repair mechanisms, and mitochondrial function, suggesting an active DDR response to replication stress and alterations in mitochondrial electron transport chain. Quantitative polymerase chain reaction (qPCR) and functional validation experiments confirmed hyperactivation of mitochondrial Complex I in response to persistent DNA damage. These changes in response to persistent oxidative DNA damage may lead to further oxidative stress, contributing to neuronal dysfunction and ultimately neurodegeneration.
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http://dx.doi.org/10.1111/ejn.15466DOI Listing
September 2021

Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2.

Brain Commun 2021 29;3(3):fcab141. Epub 2021 Jun 29.

Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcab141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364666PMC
June 2021

Changing knowledge, attitudes and behaviours towards cytomegalovirus in pregnancy through film-based antenatal education: a feasibility randomised controlled trial of a digital educational intervention.

BMC Pregnancy Childbirth 2021 Aug 18;21(1):565. Epub 2021 Aug 18.

Paediatric Infectious Diseases Research Group, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.

Background: Congenital cytomegalovirus (CMV) is the most common congenital infection globally, however information about CMV is not routinely included in antenatal education in the United Kingdom. This feasibility study aimed to gather the essential data needed to design and power a large randomised controlled trial (RCT) to investigate the efficacy of a digital intervention in reducing the risk of CMV acquisition in pregnancy. In order to do this, we carried out a single-centre RCT, which explored the knowledge, attitudes and risk reduction behaviours in women in the intervention and treatment as usual groups, pre- and post-intervention.

Methods: CMV seronegative women living with a child less than four years old, receiving antenatal care at a single UK tertiary centre, were randomised to the digital intervention or 'treatment as usual' groups. Participants completed questionnaires before the digital intervention and after and at 34 gestational weeks, and responses within groups and between groups were compared using tailored randomisation tests. CMV serology was tested in the first trimester and at the end of pregnancy.

Results: Of the 878 women screened, 865 samples were analysed with 43% (n = 372) being CMV seronegative and therefore eligible to take part in the RCT; of these, 103 (27.7%) women were enrolled and 87 (84%) of these completed the study. Most participants (n = 66; 64%) were unfamiliar with CMV at enrolment, however at 34 gestational weeks, women in the intervention group (n = 51) were more knowledgeable about CMV compared to the treatment as usual group (n = 52) and reported engaging in activities that may increase the risk of CMV transmission less frequently. The digital intervention was highly acceptable to pregnant women. Overall, four participants seroconverted over the course of the study: two from each study group.

Conclusions: A large multi-centre RCT investigating the efficacy of a CMV digital intervention is feasible in the United Kingdom; this study has generated essential data upon which to power such a study. This single-centre feasibility RCT demonstrates that a digital educational intervention is associated with increase in knowledge about CMV and can result in behaviour change which may reduce the risk of CMV acquisition in pregnancy.

Trial Registration: Clinicaltrials.gov, NCT03511274 , Registered 27.04.18, http://www.Clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12884-021-03979-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375137PMC
August 2021

COVID-19 vaccination during pregnancy: coverage and safety.

Am J Obstet Gynecol 2021 Aug 10. Epub 2021 Aug 10.

Fetal Medicine Unit, St George's Hospital, St George's University of London, London, United Kingdom; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom. Electronic address:

Background: Concerns have been raised regarding a potential surge of COVID-19 in pregnancy, secondary to the rising numbers of COVID-19 in the community, easing of societal restrictions, and vaccine hesitancy. Although COVID-19 vaccination is now offered to all pregnant women in the United Kingdom; limited data exist on its uptake and safety.

Objective: This study aimed to investigate the uptake and safety of COVID-19 vaccination among pregnant women.

Study Design: This was a cohort study of pregnant women who gave birth at St George's University Hospitals National Health Service Foundation Trust, London, United Kingdom, between March 1, 2020, and July 4, 2021. The primary outcome was uptake of COVID-19 vaccination and its determinants. The secondary outcomes were perinatal safety outcomes. Data were collected on COVID-19 vaccination uptake, vaccination type, gestational age at vaccination, and maternal characteristics, including age, parity, ethnicity, index of multiple deprivation score, and comorbidities. Further data were collected on perinatal outcomes, including stillbirth (fetal death at ≥24 weeks' gestation), preterm birth, fetal and congenital abnormalities, and intrapartum complications. Pregnancy and neonatal outcomes of women who received the vaccine were compared with that of a matched cohort of women with balanced propensity scores. Effect magnitudes of vaccination on perinatal outcomes were reported as mean differences or odds ratios with 95% confidence intervals. Factors associated with antenatal vaccination were assessed with logistic regression analysis.

Results: Data were available for 1328 pregnant women of whom 140 received at least 1 dose of the COVID-19 vaccine before giving birth and 1188 women who did not; 85.7% of those vaccinated received their vaccine in the third trimester of pregnancy and 14.3% in the second trimester of pregnancy. Of those vaccinated, 127 (90.7%) received a messenger RNA vaccine and 13 (9.3%) a viral vector vaccine. There was evidence of reduced vaccine uptake in younger women (P=.001), women with high levels of deprivation (ie, fifth quintile of the index of multiple deprivation; P=.008), and women of Afro-Caribbean or Asian ethnicity compared with women of White ethnicity (P<.001). Women with prepregnancy diabetes mellitus had increased vaccine uptake (P=.008). In the multivariable model the fifth deprivation quintile (most deprived) (adjusted odds ratio, 0.10; 95% confidence interval, 0.02-0.10; P=.003) and Afro-Caribbean ethnicity (adjusted odds ratio, 0.27; 95% confidence interval, 0.06-0.85; P=.044) were significantly associated with lower antenatal vaccine uptake, whereas prepregnancy diabetes mellitus was significantly associated with higher antenatal vaccine uptake (adjusted odds ratio, 10.5; 95% confidence interval, 1.74-83.2; P=.014). In a propensity score-matched cohort, the rates of adverse pregnancy outcomes of 133 women who received at least 1 dose of the COVID-19 vaccine in pregnancy were similar to that of unvaccinated pregnant women (P>.05 for all): stillbirth (0.0% vs 0.2%), fetal abnormalities (2.2% vs 2.5%), postpartum hemorrhage (9.8% vs 9.0%), cesarean delivery (30.8% vs 34.1%), small for gestational age (12.0% vs 12.8%), maternal high-dependency unit or intensive care admission (6.0% vs 4.0%), or neonatal intensive care unit admission (5.3% vs 5.0%). Intrapartum pyrexia (3.7% vs 1.0%; P=.046) was significantly increased but the borderline statistical significance was lost after excluding women with antenatal COVID-19 infection (P=.079). Mixed-effects Cox regression showed that vaccination was not significantly associated with birth at <40 weeks' gestation (hazard ratio, 0.93; 95% confidence interval, 0.71-1.23; P=.624).

Conclusion: Of pregnant women eligible for COVID-19 vaccination, less than one-third accepted COVID-19 vaccination during pregnancy, and they experienced similar pregnancy outcomes with unvaccinated pregnant women. There was lower uptake among younger women, non-White ethnicity, and lower socioeconomic background. This study has contributed to the body of evidence that having COVID-19 vaccination in pregnancy does not alter perinatal outcomes. Clear communication to improve awareness among pregnant women and healthcare professionals on vaccine safety is needed, alongside strategies to address vaccine hesitancy. These strategies include postvaccination surveillance to gather further data on pregnancy outcomes, particularly after first-trimester vaccination, and long-term infant follow-up.
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http://dx.doi.org/10.1016/j.ajog.2021.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352848PMC
August 2021

SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.

Mol Neurodegener 2021 08 10;16(1):53. Epub 2021 Aug 10.

Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, 385 Glossop Road, Sheffield, S10 2HQ, UK.

Background: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question.

Methods: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes.

Results: Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits.

Conclusions: Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.
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http://dx.doi.org/10.1186/s13024-021-00475-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353793PMC
August 2021

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

Lancet 2021 09 6;398(10303):856-869. Epub 2021 Aug 6.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.

Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.

Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.

Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.

Funding: UK Vaccine Task Force and National Institute for Health Research.
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http://dx.doi.org/10.1016/S0140-6736(21)01694-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346248PMC
September 2021

Prevention strategies for congenital cytomegalovirus infection.

Curr Opin Infect Dis 2021 Oct;34(5):546-551

St George's Hospital, University of London.

Purpose Of Review: Cytomegalovirus (CMV) is the most common viral cause of congenital infection, occurring in approximately 1-2% of live births worldwide. Given our increasing knowledge of risk, advances in the identification of maternal infection, and the extremely limited options for the treatment of fetal infection, the prevention is a promising direction for research efforts. Recently, there have been several exciting studies assessing different ways of preventing congenital infection in the fetus and one in particular has focused on the use of valaciclovir.

Recent Findings: A recent study reported a 71% reduction in vertical transmission of CMV with the use of oral valaciclovir following maternal primary CMV infection early in pregnancy. The clinical impact of this study could be enormous and it has particular implications for considerations around maternal serological screening in the first trimester of pregnancy. Further research assessing behaviour modifications during early pregnancy could also provide evidence for an effective primary prevention technique.

Summary: Prevention of congenital CMV infection, whether primary, secondary or tertiary, is possible, however, there are barriers to its utilisation in a clinical setting. The main limitation is the requirement for early, effective and large-scale serological screening of mothers to detect asymptomatic primary infection.
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http://dx.doi.org/10.1097/QCO.0000000000000777DOI Listing
October 2021

IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer.

NPJ Breast Cancer 2021 Jul 21;7(1):95. Epub 2021 Jul 21.

Department of Oncology and Metabolism, Weston Park Cancer Centre, University of Sheffield, Sheffield, UK.

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.
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http://dx.doi.org/10.1038/s41523-021-00305-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295314PMC
July 2021

Antibiotic Susceptibility, Virulome, and Clinical Outcomes in European Infants with Bloodstream Infections Caused by Enterobacterales.

Antibiotics (Basel) 2021 Jun 11;10(6). Epub 2021 Jun 11.

Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.

Mortality in neonates with Gram-negative bloodstream infections has remained unacceptably high. Very few data are available on the impact of resistance profiles, virulence factors, appropriateness of empirical treatment and clinical characteristics on patients' mortality. A survival analysis to investigate 28-day mortality probability and predictors was performed including (I) infants <90 days (II) with an available Enterobacterales blood isolate with (III) clinical, treatment and 28-day outcome data. Eighty-seven patients were included. Overall, 299 virulence genes were identified among all the pathogens.   had significantly more virulence genes identified compared with other species. A strong positive correlation between the number of resistance and virulence genes carried by each isolate was found. The cumulative probability of death obtained by the Kaplan-Meier survival analysis was 19.5%. In the descriptive analysis, early age at onset, gestational age at onset, culture positive for and number of classes of virulence genes carried by each isolate were significantly associated with mortality. By Cox multivariate regression, none of the investigated variables was significant. This pilot study has demonstrated the feasibility of investigating the association between neonatal sepsis mortality and the causative Enterobacterales isolates virulome. This relationship needs further exploration in larger studies, ideally including host immunopathological response, in order to develop a tailor-made therapeutic strategy.
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http://dx.doi.org/10.3390/antibiotics10060706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230887PMC
June 2021

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

N Engl J Med 2021 09 30;385(13):1172-1183. Epub 2021 Jun 30.

From the Vaccine Institute, St. George's, University of London, and St. George's University Hospitals NHS Foundation Trust (P.T.H., E.P.G., C.C., A.S.F.R.), Chelsea, Westminster Hospital NHS Foundation Trust and Imperial College London (M.B.), the Institute for Global Health, University College London, and Royal Free London NHS Foundation Trust (F.B.), the Centre for Rheumatic Disease, Kings College London (J.G.), the Department of Infectious Diseases, Guy's and St. Thomas' NHS Foundation Trust, MRC Clinical Trials Unit at University College London (A.L.G.), and Renal Services, Epsom and St. Helier University Hospitals NHS Trust (P.A.S.), London, Stockport NHS Foundation Trust, Stepping Hill Hospital, Stockport (D.N.B.), Royal Cornwall Hospitals NHS Trust, Truro (D.B.), Centre for Clinical Infection, South Tees Hospitals NHS Foundation Trust, James Cook University Hospital, Middlesbrough (D.R.C.), Layton Medical Centre, Blackpool (R.C.), Lakeside Healthcare Research, Lakeside Surgeries, Corby (A. Heer), University Hospitals of Morecambe Bay NHS Foundation Trust, Kendal (A. Higham), Accelerated Enrollment Solutions, Synexus Hexham Dedicated Research Site, Hexham General Hospital, Hexham (S.I.), Accelerated Enrollment Solutions, Synexus Thames Valley Dedicated Research Site, Reading (A.J.), Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich (C.J., J.T.), Salford Royal NHS Foundation Trust, Northern Care Alliance, Salford (P.A.K.), Accelerated Enrollment Solutions, Synexus Midlands Dedicated Research Site, Birmingham (C.K.), Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast and Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast (D.F.M.), Accelerated Enrollment Solutions, Synexus Merseyside Dedicated Research Site, Liverpool (A.M.), Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, and Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford (A.M.M.), St. James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds (J.M.), the Adam Practice, Poole (P.M.), University Hospital Southampton NHS Foundation Trust, Southampton (P.M.), Accelerated Enrollment Solutions, Synexus Glasgow Dedicated Research Site (I.M.), and MRC-University of Glasgow Centre for Virus Research and Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde (E.C.T.), Glasgow, Accelerated Enrollment Solutions, Synexus Wales Dedicated Research Site, Cardiff (H.N.), the School of Medical Sciences, Bangor University, and Betsi Cadwaladr University Health Board, Bangor (O.O.), the Division of Epidemiology and Public Health, University of Nottingham, Nottingham (J.P.), Haywood Hospital, Midlands Partnership NHS Foundation Trust, Stafford (J.P.), Accelerated Enrollment Solutions, Synexus Lancashire Dedicated Research Site, Chorley (C.H.P.), the National Institute for Health Research Patient Recruitment Centre and Bradford Teaching Hospitals NHS Foundation Trust, Bradford (D.S.), Royal Devon and Exeter Hospital, Exeter (R.P.S.), East Suffolk, North Essex NHS Foundation Trust and University of Essex, Colchester (R.S.), Aberdeen Royal Infirmary, NHS Grampian, and Aging Clinical and Experimental Research Group, University of Aberdeen, Aberdeen (R.L.S.), and Accelerated Enrollment Solutions, Synexus Manchester Dedicated Research Site, Manchester (M.E.V.) - all in the United Kingdom; and Novavax, Gaithersburg, MD (G.A., I.C., F.D., G.G., J.R., A.R., K.S., S.T.).

Background: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.

Methods: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.

Results: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.

Conclusions: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).
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http://dx.doi.org/10.1056/NEJMoa2107659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262625PMC
September 2021

Invasive Group B Streptococcus Disease With Recurrence and in Multiples: Towards a Better Understanding of GBS Late-Onset Sepsis.

Front Immunol 2021 2;12:617925. Epub 2021 Jun 2.

Department of Neonatology, Vest Children's Hospital Datteln, University Witten-Herdecke, Witten-Herdecke, Germany.

Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation.
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http://dx.doi.org/10.3389/fimmu.2021.617925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208644PMC
August 2021

A phase IV, multi-centre, randomized clinical trial comparing two pertussis-containing vaccines in pregnant women in England and vaccine responses in their infants.

BMC Med 2021 06 8;19(1):138. Epub 2021 Jun 8.

Immunisation and Countermeasures, National Infection Service, Public Health England, London, UK.

Background: Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants' antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP-IPV in pregnancy (three pertussis antigens).

Methods: This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP-IPV (n = 77) or TdaP-IPV (n = 77) at 28-32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum.

Results: Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP-IPV (n = 67) or TdaP-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP-IPV- and TdaP-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56-0.90] and 0.78 [0.61-0.98], respectively); by 13 months of age, this difference was no longer observed.

Conclusion: Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP-IPV and TdaP-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy.

Trial Registration: ClinicalTrials.gov , NCT02145624 , registered 23 May 2014.
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http://dx.doi.org/10.1186/s12916-021-02005-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186138PMC
June 2021

Integrative molecular characterization of pediatric spinal ependymoma: the UK Children's Cancer and Leukaemia Group study.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab043. Epub 2021 Mar 8.

Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Pediatric spinal ependymomas (SP-EPNs) are rare primary central nervous system tumors with heterogeneous clinical course. Considering that ependymomas in children are biologically distinct from their adult counterparts, this study aimed to define the molecular landscape of SP-EPNs in children.

Methods: In this retrospective study, we have collected tumor samples from 27 SP-EPN patients younger than 18 years and carried out the histological review, DNA methylation, and gene expression profiling.

Results: Unsupervised analyses with methylation profiles revealed 2 subgroups where all grade I tumors ( = 11) were in Group 1, but the grade II/III tumors split into 2 groups ( = 7 in Group 1 and = 9 in Group 2). The Heidelberg classifier assigned Group 1 tumors as spinal myxopapillary ependymomas (SP-MPEs), 5 Group 2 tumors as SP-EPNs, and failed to classify 4 Group 2 tumors. Copy numbers derived from DNA methylation arrays revealed subgroup-specific genetic alterations and showed that SP-EPN tumors lack amplification. Gene expression profiling revealed distinct transcriptomic signatures, including overexpression of genes involved in oxidative phosphorylation in SP-MPEs that were validated by Western blot analysis. We discovered widespread decreases in DNA methylation at enhancer regions that are associated with the expression of oncogenic signaling pathways in SP-MPEs. Furthermore, transcription factor motifs for master regulators, including , , and , were significantly overrepresented in probes specific to distal regulatory regions in SP-MPEs.

Conclusion: Our findings show substantial heterogeneity in pediatric SP-EPN and uncover novel enhancers and transcriptional pathways specific to the SP-MPE subgroup, providing a foundation for future therapeutic strategies.
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http://dx.doi.org/10.1093/noajnl/vdab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134525PMC
March 2021

Listeria infection in young infants: results from a national surveillance study in the UK and Ireland.

Arch Dis Child 2021 May 13. Epub 2021 May 13.

Paediatric Infectious Disease Research Group, University of London Saint George's, London, UK.

Objectives: To describe the epidemiology, age at infection, clinical characteristics and outcome of listeria infection in young infants to inform management and empiric antibiotic choice in young infants.

Design: Prospective 2-year surveillance of infection in young infants detected through the British Paediatric Surveillance Unit 'orange card' system and triangulated with the public health laboratories.

Setting: National population study (England, Wales, Scotland and the Ireland) PATIENTS: All infants under 90 days with proven or probable invasive listeriosis MAIN OUTCOME MEASURES: Incidence, mortality, age of infection, clinical characteristics and outcome RESULTS: During a 2-year period (2017-2019), 27 cases of listeriosis in infants <90 days of age were reported. The incidence of listeriosis in this study was 1.8 per 100 000 live births with 7% mortality (2/27). Nearly all cases presented within the first 24 hours of life (26/27). The majority (20/27, 74%) were born preterm and 16/24 (67%) were born to women from ethnic minority backgrounds.

Conclusions: Invasive listeriosis in young infants in the UK and Ireland is rare and presents early in the neonatal period. National guidelines that recommend the use of amoxicillin as part of empiric regimes for sepsis and meningitis in infants over 1 month of age should be modified.
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http://dx.doi.org/10.1136/archdischild-2021-321602DOI Listing
May 2021

Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.

Vaccine 2021 06 4;39(24):3296-3303. Epub 2021 May 4.

Global Clinical and Epidemiology R&D, GSK, 1101 CL Amsterdam, Netherlands. Electronic address:

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015-2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barré syndrome and acute disseminated encephalomyelitis were secondary outcomes. A total of 107,231 children aged 1-18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0-6 after 239,505 doses, and 23 febrile seizures occurred in days 0-6, and 4 Kawasaki disease cases in days 1-28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02-2.02) for seizures and 1.72 (95%CI: 1.08-2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination. This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations. Trial registration: NA.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.065DOI Listing
June 2021

Commentary: Perinatal Coronavirus Disease 2019 and Maternal Vaccination: What More Do We Need to Know?

Pediatr Infect Dis J 2021 05;40(5):e193

Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.

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http://dx.doi.org/10.1097/INF.0000000000003125DOI Listing
May 2021

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial.

Lancet 2021 04 30;397(10282):1351-1362. Epub 2021 Mar 30.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant.

Methods: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages.

Interpretation: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.

Funding: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00628-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009612PMC
April 2021

Persistence of SARS-CoV-2 N-Antibody Response in Healthcare Workers, London, UK.

Emerg Infect Dis 2021 04 18;27(4):1155-1158. Epub 2021 Mar 18.

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for <12 weeks in 312 seropositive participants. This finding was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.
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http://dx.doi.org/10.3201/eid2704.204554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007325PMC
April 2021

Reliability of dried blood spot (DBS) cards in antibody measurement: A systematic review.

PLoS One 2021 15;16(3):e0248218. Epub 2021 Mar 15.

Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.

Background: Increasingly, vaccine efficacy studies are being recommended in low-and-middle-income countries (LMIC), yet often facilities are unavailable to take and store infant blood samples correctly. Dried blood spots (DBS), are useful for collecting blood from infants for diagnostic purposes, especially in low-income settings, as the amount of blood required is miniscule and no refrigeration is required. Little is known about their utility for antibody studies in children. This systematic review aims to investigate the correlation of antibody concentrations against infectious diseases in DBS in comparison to serum or plasma samples that might inform their use in vaccine clinical trials.

Methods And Findings: We searched MEDLINE, Embase and the Cochrane library for relevant studies between January 1990 to October 2020 with no language restriction, using PRISMA guidelines, investigating the correlation between antibody concentrations in DBS and serum or plasma samples, and the effect of storage temperature on DBS diagnostic performance. We included 40 studies in this systematic review. The antibody concentration in DBS and serum/plasma samples reported a good pooled correlation, (r2 = 0.86 (ranged 0.43 to 1.00)). Ten studies described a decline of antibody after 28 days at room temperature compared to optimal storage at -20°C, where antibodies were stable for up to 200 days. There were only five studies of anti-bacterial antibodies.

Conclusions: There is a good correlation between antibody concentrations in DBS and serum/plasma samples, supporting the wider use of DBS in vaccine and sero-epidemiological studies, but there is limited data on anti-bacterial antibodies. The correct storage of DBS is critical and may be a consideration for longer term storage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959368PMC
October 2021

Value of systematic genetic screening of patients with amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2021 May 14;92(5):510-518. Epub 2021 Feb 14.

Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK

Objective: The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.

Methods: We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.

Results: 21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).

Conclusions: Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
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http://dx.doi.org/10.1136/jnnp-2020-325014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053339PMC
May 2021

Comparison and optimisation of microRNA extraction from the plasma of healthy pregnant women.

Mol Med Rep 2021 04 12;23(4). Epub 2021 Feb 12.

Sheffield Institute of Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, UK.

Circulating microRNA (miRNA) biomarkers are implicated in the diagnosis, monitoring and prediction of various disease processes. Before embarking upon biomarker discovery, miRNA extraction techniques must first be optimised in the biofluid and population under study. Using plasma from a healthy pregnant woman, it was attempted to optimise and compare the performance of two commercially available miRNA extraction kits; Qiagen (miRNeasy Serum/Plasma) and Promega (Maxwell RSC miRNA from Tissue or Plasma or Serum). Sample miRNA content (concentration and percentage) was assessed using Agilent Bioanalyzer Small RNA chips and reverse transcription‑quantitative PCR (RT‑qPCR) using four constitutively expressed miRNAs (hsa‑miR‑222‑3p, hsa‑let‑7i‑3p, hsa‑miR‑148‑3p and hsa‑miR‑30e‑5p). Quality control spike‑ins monitored RNA extraction (UniSp2, 4 and 5) and cDNA synthesis (UniSp6, cel‑miR‑39‑3p) efficiency. Optimisation approaches included: i) Starting volume of plasma; the addition of ii) Proteinase K; iii) a RNA bacteriophage carrier (MS2); and iv) a glycogen carrier. The two kits exhibited equivalence in terms of miRNA recovery based on Bioanalyzer and RT‑qPCR ΔΔCq results. Optimisation attempts for both kits failed to improve upon miRNA content compared with standard methodology. Comparing the standard methodology, the Qiagen kit was more consistent (smaller variance of ΔCq values) compared with the Promega kit. The standard methodology of either kit would be suitable for the investigation of miRNA biomarkers in a healthy pregnant population.
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http://dx.doi.org/10.3892/mmr.2021.11897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893782PMC
April 2021

The Fifth International Neonatal and Maternal Immunization Symposium (INMIS 2019): Securing Protection for the Next Generation.

mSphere 2021 01 27;6(1). Epub 2021 Jan 27.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Despite significant progress in reaching some milestones of the United Nations Sustainable Development Goals, neonatal and early infant morbidity and mortality remain high, and maternal health remains suboptimal in many countries. Novel and improved preventative strategies with the potential to benefit pregnant women and their infants are needed, with maternal and neonatal immunization representing effective approaches. Experts from immunology, vaccinology, infectious diseases, clinicians, industry, public health, and vaccine-related social sciences convened at the 5th International Neonatal and Maternal Immunization Symposium (INMIS) in Vancouver, Canada, from 15 to 17 September 2019. We critically evaluated the lessons learned from recent clinical studies, presented cutting-edge scientific progress in maternal and neonatal immunology and vaccine development, and discussed maternal and neonatal immunization in the broader context of infectious disease epidemiology and public health. Focusing on practical aspects of research and implementation, we also discussed the safety, awareness, and perception of maternal immunization as an existing strategy to address the need to improve maternal and neonatal health worldwide. The symposium provided a comprehensive scientific and practical primer as well as an update for all those with an interest in maternal and neonatal infection, immunity, and vaccination. The summary presented here provides an update of the current status of progress in maternal and neonatal immunization.
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http://dx.doi.org/10.1128/mSphere.00862-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885317PMC
January 2021

Meningococcal carriage in periods of high and low invasive meningococcal disease incidence in the UK: comparison of UKMenCar1-4 cross-sectional survey results.

Lancet Infect Dis 2021 05 19;21(5):677-687. Epub 2021 Jan 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.

Background: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule.

Methods: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001).

Findings: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001).

Interpretation: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease.

Funding: Wellcome Trust, UK Department of Health, and National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(20)30842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064914PMC
May 2021

Detection of group B streptococcus colonisation in pregnant women: Comparison of two different culture methods and study of antimicrobial resistance patterns.

J Infect 2021 05 8;82(5):186-230. Epub 2021 Jan 8.

Paediatric Infectious Diseases Research Group and Vaccine Institute, Institute for Infection and Immunity, St George's, University of London (United Kingdom); Pathogen Immunity Group. Public Health England, Porton Down (United Kingdom); Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine, Uganda Research Unit (Uganda).

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http://dx.doi.org/10.1016/j.jinf.2021.01.001DOI Listing
May 2021

Profiling microRNAs in uncomplicated pregnancies: Serum vs. plasma.

Biomed Rep 2021 Feb 14;14(2):24. Epub 2020 Dec 14.

Sheffield Institute of Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, United Kingdom.

Blood-derived microRNAs (miRNAs/miRs) are ideal clinical biomarkers, as they can be relatively non-invasively extracted and are stable across a range of storage conditions. However, the concentration and profile of miRNAs differ between specific patient groups and starting media, which must be a key consideration before embarking upon uses for clinical applications. The optimum blood-derived starting media for biomarker discovery involving pregnant women with an uncomplicated pregnancy has not been determined. Paired serum and plasma samples were collected from 10 pregnant women with uncomplicated low-risk pregnancies at three time points: i) During the second trimester of pregnancy; ii) during the third trimester; and iii) 6 weeks post-partum. Sample miRNA content was assessed using an Agilent Bioanalyzer Small RNA chip and reverse transcription-quantitative (RT-q)PCR using four constitutively expressed miRNAs: hsa-miR-222-3p, hsa-miR-23a, hsa-miR-30e-5p and hsa-miR-451a. Quality control spike-ins measured RNA extraction (UniSp2) and cDNA extraction (cel-miR-39-3p) efficiency. MiRNA concentration and percentage were significantly higher in the serum vs. plasma samples based on data obtained from the Bioanalyzer; however, RT-qPCR failed to replicate these differences in the majority of comparisons using the ΔCq values of the four constitutively expressed miRNAs. Using the standard deviations of the ΔCq values, the consistency of serum and plasma in terms of miRNA expression levels were equivalent. Thus, clinicians and researchers should take into consideration that different miRNA quantification methods can yield contrasting results with regards to the starting media utilized. Based on the equivalent performance of serum and plasma assessed using RT-qPCR, which is less likely to be influenced by the coagulation process or degraded long RNAs, both starting media assessed in the present study are equally suitable for ongoing biomarker discovery studies involving healthy pregnant women at any gestational time point or immediately postpartum.
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http://dx.doi.org/10.3892/br.2020.1400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780752PMC
February 2021

Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain.

Acta Neuropathol Commun 2021 01 6;9(1). Epub 2021 Jan 6.

Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.

Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.
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http://dx.doi.org/10.1186/s40478-020-01109-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788898PMC
January 2021

Heterogeneity of cellular inflammatory responses in ageing white matter and relationship to Alzheimer's and small vessel disease pathologies.

Brain Pathol 2021 05 15;31(3):e12928. Epub 2021 Feb 15.

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.

White matter lesions (WML) are common in the ageing brain, often arising in a field effect of diffuse white matter abnormality. Although WML are associated with cerebral small vessel disease (SVD) and Alzheimer's disease (AD), their cause and pathogenesis remain unclear. The current study tested the hypothesis that different patterns of neuroinflammation are associated with SVD compared to AD neuropathology by assessing the immunoreactive profile of the microglial (CD68, IBA1 and MHC-II) and astrocyte (GFAP) markers in ageing parietal white matter (PARWM) obtained from the Cognitive Function and Ageing Study (CFAS), an ageing population-representative neuropathology cohort. Glial responses varied extensively across the PARWM with microglial markers significantly higher in the subventricular region compared to either the middle-zone (CD68 p = 0.028, IBA1 p < 0.001, MHC-II p < 0.001) or subcortical region (CD68 p = 0.002, IBA1 p < 0.001, MHC-II p < 0.001). Clasmatodendritic (CD) GFAP astrocytes significantly increased from the subcortical to the subventricular region (p < 0.001), whilst GFAP stellate astrocytes significantly decreased (p < 0.001). Cellular reactions could be grouped into two distinct patterns: an immune response associated with MHC-II/IBA1 expression and CD astrocytes; and a more innate response characterised by CD68 expression associated with WML. White matter neuroinflammation showed weak relationships to the measures of SVD, but not to the measures of AD neuropathology. In conclusion, glial responses vary extensively across the PARWM with diverse patterns of white matter neuroinflammation. Although these findings support a role for vascular factors in the pathogenesis of age-related white matter neuroinflammation, additional factors other than SVD and AD pathology may drive this. Understanding the heterogeneity in white matter neuroinflammation will be important for the therapeutic targeting of age-associated white matter damage.
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http://dx.doi.org/10.1111/bpa.12928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412112PMC
May 2021
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