Search results
Found 12997 matches for
A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape in >170,000 individuals of the GIANT Consortium
Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analyzed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
Digitally Enabled Care in Diverse Environments (DECIDE): protocol for a programme of rapid evaluation of technology-enabled remote monitoring in health and social care
Background There is considerable interest in technology-enabled remote monitoring in the UK. The aim is to respond to system pressures and improve access, experience and quality of care. There is an urgent need for process, outcome and impact evaluations of interventions at various stages of development and implementation to address evidence gaps around adoption, spread, sustainability and inequalities. Aim DECIDE (Digitally Enabled Care in Diverse Environments) is a centre for rapid evaluation of technology-enabled remote monitoring funded by the National Institute for Health and Care Research (2023 to 2026). It aims to support service users, service commissioners and providers of remote monitoring services, to enable high quality care. Example questions include: Is the technology-enabled remote monitoring innovation needed and, if so, for whom? How are technology-enabled care pathways implemented, and what are associated outcomes and impacts? What are the opportunities and challenges for sustainability, scale-up and spread? Methods A range of qualitative, quantitative and economic methods will be used. Exact methods and questions will be dependent on the focus, scope and scale of each evaluation. Evaluations will be informed by relevant theory, including the Non-Adoption, Abandonment and the challenges to Spread, Scale-up and Sustainability of technological innovation in health and care (NASSS) framework. A User Advisory Group and External Steering Committee, both with diverse voices, will help shape evaluation design, implementation and dissemination. Project-led dissemination will ensure timely sharing of insights and support impact. Conclusion Evaluations will advance understanding of when and for whom technology-enabled remote monitoring innovation is needed; how it works and how factors related to the intervention, implementation process and wider context influence adoption; associated outcomes and impacts, whether and how these tackle inequalities; and potential challenges to scale and spread. We aim to inform decision-making by policymakers, commissioners, providers, patients/service users and researchers.
Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Clinical characterisation and outcomes of human clade IIb mpox virus disease - a European multicentre observational cohort study (MOSAIC).
BACKGROUND: The global mpox outbreak which started in May 2022 was caused by a novel clade IIb variant of the mpox virus (MPXV). It differed from the traditional Western and Central Africa disease in transmission patterns and clinical presentation. METHODS: To address the need for detailed clinical and virologic data, we conducted an observational cohort study (MOSAIC) during May 2022-July 2023 in individuals with confirmed MPXV infection enrolled in six European Countries. Case-management decisions were left to the attending physician. Participants were monitored for up to six months for clinical signs/symptoms and clinical and virologic outcomes through hospital visits, phone interviews, and self-administered questionnaires. Outcomes included time-to-lesion resolution, clinical status, and virus clearance. RESULTS: The 518 participants not receiving any specific treatment ("untreated") were diagnosed a median 5 days from symptom onset; 90% were managed as outpatients. Lesions were mostly cutaneous (88%) as and peri-genital (74%). By Day 14 from the first PCR-positive sample, 39% had resolved lesions. Time-to 95% unculturable virus was longest in cutaneous lesions (52 days). A putative systemic antiviral was available for 57 participants, 44% as in-patients, 34% and 58% had resolved lesions by D14 from the first PCR-positive sample and from treatment start, respectively. Time-to 95% unculturable virus was 60 days in skin and oropharynx. No death or recrudescence occurred by Day 180. CONCLUSION: MOSAIC provides comprehensive insights into the clinical and virologic characteristics of mpox caused by the clade IIb variant. The study forms the basis of clinical characterisation for ongoing mpox outbreaks.
Ebola disease: bridging scientific discoveries and clinical application.
The west Africa Ebola disease epidemic (2014-16) marked a historic change of course for patient care during emerging infectious disease outbreaks. The epidemic response was a failure in many ways-a slow, cumbersome, and disjointed effort by a global architecture that was not fit for purpose for a rapidly spreading outbreak. In the most affected countries, health-care workers and other responders felt helpless-dealing with an overwhelming number of patients but with few, if any, tools at their disposal to provide high-quality care. These inadequacies, however, led to attention and innovation. The decade since then has seen remarkable achievements in clinical care for Ebola disease, including the approval of the first vaccines and treatments. In this paper, the first in a two-part Series, we reflect on this progress and provide expert summary of the modern landscape of Ebola disease, highlighting the priorities and ongoing activities aimed at further improving patient survival and wellbeing in the years ahead.
Improving clinical care of patients in Nipah outbreaks: moving beyond 'compassionate use'.
The 2024 Nipah outbreak in Kerala, India-its fifth in six years-and the recurring annual outbreaks in Bangladesh underscore the persistent threat posed by the Nipah virus (NiV) in the region. With a high mortality rate, human-to-human transmission potential, and the widespread presence of Pteropus bats, the natural reservoir, NiV remains a significant epidemic threat. Despite being a WHO priority pathogen, there has been no systematic effort to improve patient care for NiVD, leading to consistently poor outcomes. Current care relies on supportive measures and the 'compassionate use' of unapproved drugs like ribavirin and remdesivir. Drugs used 'off-label' during outbreaks can become the 'standard of care' without robust evidence of their safety or efficacy, complicating the testing of new therapies and perpetuating uncertainty about their true effectiveness. To improve NiVD care, we propose four key strategies: 1) Enhance early case detection, 2) optimize supportive care to improve outcomes and create a standard for future trials, 3) adopt a syndromic approach centered on encephalitis, and 4) explore innovative trial designs tailored to low case numbers as an alternative to 'compassionate use'. By integrating these strategies, healthcare systems in NiV-endemic regions will be better equipped to manage both current and future outbreaks.
Higher dose corticosteroids in hospitalised COVID-19 patients requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial.
BACKGROUND: Low dose corticosteroids (e.g., 6 mg dexamethasone) have been shown to reduce mortality for hypoxic COVID-19 patients. We have previously reported that higher dose corticosteroids cause harm in patients with clinical hypoxia but not receiving ventilatory support (the combination of non-invasive mechanical ventilation, including high-flow nasal oxygen, continuous positive airway pressure and bilevel positive airway pressure ventilation, and invasive mechanical ventilation or extra-corporeal membrane oxygenation), but the balance of efficacy and safety in patients receiving ventilatory support is uncertain. METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) assessed multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients receiving ventilatory support were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. Recruitment closed on 31 March 2024 when funding for the trial ended. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FINDINGS: Between 25 May 2021 and 9 January 2024, 477 COVID-19 patients receiving ventilatory support were randomly allocated to receive usual care plus higher dose corticosteroids vs. usual care alone (of whom 99% received corticosteroids during the follow-up period). Of those randomised, 221 (46%) were in Asia, 245 (51%) in the UK and 11 (2%) in Africa. 143 (30%) had diabetes mellitus. Overall, 86 (35%) of 246 patients allocated to higher dose corticosteroids vs. 86 (37%) of 231 patients allocated to usual care died within 28 days (rate ratio [RR] 0.87; 95% CI 0.64-1.18; p = 0.37). There was no significant difference in the proportion of patients discharged from hospital alive within 28 days (128 [52%] in the higher dose corticosteroids group vs. 120 [52%] in the usual care group; RR 1.04, 0.81-1.33]; p = 0.78). Among those not on invasive mechanical ventilation at baseline, there was no clear reduction in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (76 [37%] of 206 vs. 93 [45%] of 205; RR 0.79 [95% CI 0.63-1.00]; p = 0.05). INTERPRETATION: In patients hospitalised for COVID-19 receiving ventilatory support, we found no evidence that higher dose corticosteroids reduced the risk of death compared to usual care, which included low dose corticosteroids. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute for Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).
When health data go dark: the importance of the DHS Program and imagining its future.
BACKGROUND: The suspension and/or termination of many programmes funded through the United States Agency for International Development (USAID) by the new US administration has severe short- and long-term negative impacts on the health of people worldwide. We draw attention to the termination of the Demographic and Health Surveys (DHS) Program, which includes nationally representative surveys of households, DHS, Malaria Indicator Surveys [MIS]) and health facilities (Service Provision Assessments [SPA]) in over 90 low- and middle-income countries. USAID co-funding and provision of technical support for these surveys has been shut down. MAIN BODY: The impact of these disruptions will reverberate across local, regional, national, and global levels and severely impact the ability to understand the levels and changes in population health outcomes and behaviours. We highlight three key impacts on (1) ongoing data collection and data processing activities; (2) future data collection and consequent lack of population-level health indicators; and (3) access to existing data and lack of support for its use. CONCLUSIONS: We call for immediate action on multiple fronts. In the short term, universal access to existing data and survey materials should be restored, and surveys which were planned or in progress should be completed. In the long term, this crisis should serve as a tipping point for transforming these vital surveys. We call on national governments, regional organisations, and international partners to develop sustainable alternatives that preserve the principles (standardised questionnaires, backward compatibility, open access data with rigorous documentation) which made the DHS Program an invaluable global health resource.
Putting health facilities on the map: a renewed call to create geolocated, comprehensive, updated, openly licensed dataset of health facilities in sub-Saharan African countries.
BACKGROUND: Healthcare service provision, planning, and management depend on the availability of a geolocated, up-to-date, comprehensive health facility database (HFDB) to adequately meet a population's healthcare needs. HFDBs are an integral component of national health system infrastructure forming the basis of efficient health service delivery, planning, surveillance, and ensuring equitable resource distribution, response to epidemics and outbreaks, as well as for research. Despite the value of HFDBs, their availability remains a challenge in sub-Saharan Africa (SSA). Many SSA countries face challenges in creating a HFDB; existing facility lists are incomplete, lack geographical coordinates, or contain outdated information on facility designation, service availability, or capacity. Even in countries with a HFDB, it is often not available open-access to health system stakeholders. Consequently, multiple national and subnational parallel efforts attempt to construct HFDBs, resulting in duplication and lack of governmental input, use, and validation. MAIN BODY: In this paper, we advocate for a harmonized SSA-wide HFDB. To achieve this, we elaborate on the steps required and challenges to overcome. We provide an overview of the minimum attributes of a HFDB and discuss past and current efforts to collate HFDBs at the country and regional (SSA) levels. We contend that a complete HFDB should include administrative units, geographic coordinates of facilities, attributes of service availability and capacity, facilities from both public and private sectors, be updated regularly, and be available to health system stakeholders through an open access policy. We provide historical and recent examples while looking at key issues and challenges, such as privacy, legitimacy, resources, and leadership, which must be considered to achieve such HFDBs. CONCLUSION: A harmonized HFDB for all SSA countries will facilitate efficient healthcare planning and service provision. A continental, cross-border effort will further support planning during natural disasters, conflicts, and migration. This is only achievable if there is a regional commitment from countries and health system stakeholders to open data sharing. This SSA-wide HFDB should be a government-led initiative with contributions from all stakeholders, ensuring no one is left behind in the pursuit of improved health service provision and universal health coverage.
Prevalence, clinical management, and outcomes of adults hospitalised with endemic arbovirus illness in southeast Europe (MERMAIDS-ARBO): a prospective observational study.
BACKGROUND: Arboviruses have expanded into new regions in Europe, yet data indicate gaps in disease notifications and a risk of further spread. We aimed to report on prevalence, clinical management, and outcomes of endemic arbovirus infections in southeast Europe. METHODS: In this prospective observational study (MERMAIDS-ARBO), we enrolled adults (age ≥18 years) hospitalised with an arbovirus-compatible disease syndrome within 21 days of symptom onset across 21 hospitals in seven countries in southeast Europe over four arbovirus seasons (May 1-Oct 31, during 2016-19). We obtained data from case report forms completed by site investigators on admission and discharge. Participants were excluded if they had non-infectious CNS disorders, symptoms of another confirmed cause, an identified focal source of infection, or symptoms caused by recurrence of a pre-existing condition. The primary outcome was the proportion of participants with confirmed or probable acute infections with West Nile virus (WNV), tick-borne encephalitis virus (TBEV), Crimean-Congo haemorrhagic fever virus (CCHFV), or Toscana virus (TOSV), per reference laboratory criteria. Secondary outcomes were the proportions of patients treated with antivirals, antibiotics, or corticosteroids; the proportion of patients requiring intensive care; hospital length of stay; and mortality. FINDINGS: Of 2896 adults screened for eligibility, 929 were recruited and 913 met protocol-defined eligibility criteria (median age 43·1 years [IQR 29·5-59·7]; 550 [60%] men, 361 [40%] women, and two [<1%] with missing data). 530 (58%) participants presented with suspected meningitis, encephalitis, or both, and 318 (35%) with fever plus myalgia, fever plus arthralgia, or both. 820 (90%) reported no international travel within 21 days before symptom onset. 727 (80%) were administered antibiotics, 379 (42%) corticosteroids, and 222 (24%) antivirals. The median length of hospital stay was 9 days (IQR 6-14), and 113 (12%) required intensive care. Of 847 participants with a reference laboratory sample who met full eligibility criteria for analysis, 110 (13%) were diagnosed with 114 confirmed or probable acute arbovirus infections (four had coinfections or cross-reactivity): one (<1%) with CCHFV, 16 (2%) with TBEV, 44 (5%) with TOSV, and 53 (6%) with WNV. There was one death (<1%) of an individual with WNV. Of the 110 participants, 49 (45%) had a local clinician-attributed arbovirus discharge diagnosis. INTERPRETATION: Our data highlight the need to strengthen arbovirus surveillance systems for the early detection of emerging and re-emerging outbreaks, including investments to increase awareness of arbovirus infections among clinicians, to improve access to specialist diagnostics, and to develop effective and accessible vaccines and treatments to protect populations and health systems in southeast Europe. FUNDING: European Commission and Versatile Emerging infectious disease Observatory. TRANSLATIONS: For the Greek, Albanian, Romanian, Bosnian, Serbian, and Croatian translation of the summary see Supplementary Materials section.
Multi-antigen serology and a diagnostic algorithm for the detection of arbovirus infections as novel tools for arbovirus preparedness in southeast Europe (MERMAIDS-ARBO): a prospective observational study.
BACKGROUND: Arboviruses are increasingly affecting Europe, partly due to the effects of climate change. This increase in range and impact emphasises the need to improve preparedness for emerging arboviral infections that often co-circulate and might have overlapping clinical syndromes. We aimed to strengthen surveillance networks for four clinically relevant arboviruses in southeast Europe. METHODS: This study reports an in-depth analysis of the MERMAIDS-ARBO prospective observational study in adults (ie, aged ≥18 years) hospitalised with an arbovirus-compatible disease syndrome in 21 hospitals in seven countries in southeast Europe over four arbovirus seasons (May 1-Oct 31, 2016-19) to obtain arbovirus prevalence outcomes. The main objectives of the MERMAIDS-ARBO study, describing the clinical management and outcomes of four arboviruses endemic to southeast Europe, including Crimean-Congo haemorrhagic fever virus (CCHFV), tick-borne encephalitis virus (TBEV), Toscana virus, and West Nile virus (WNV), are reported elsewhere. In this analysis, given the challenges associated with arbovirus diagnostics, we developed a diagnostic algorithm accounting for serology outcomes and sample timing to study arbovirus prevalence in southeast Europe. Serum samples were collected on days 0, 7, 28, and 60 after hospital admission and tested for anti-CCHFV IgG and IgM antibodies with ELISAs (confirmed with an indirect immunofluorescence test) and for IgG and IgM antibodies specific to TBEV, Toscana virus, and WNV with custom-printed protein microarrays (confirmed with virus neutralisation tests). All acute-phase samples were tested by PCR for all four viruses. Descriptive analyses were performed for virus-reactive cases by geography and year, and possible factors (eg, age, sex, and insect bites) associated with virus reactivity were assessed. FINDINGS: Of 2896 individuals screened, 913 were eligible for inclusion, of whom 863 (514 men, 332 women, and 17 unknown) had samples sent to the study reference laboratories and were included in molecular and serological analyses. Some individuals had insufficient clinical data to be included in the clinical analysis, but met the eligibility criteria for and were included here. Serum sampling was incomplete (eg, samples missing from one or more timepoints or no data on time since symptom onset) for 602 (70%) patients, and the timing of collection was often heterogeneous after symptom onset up to 40 days (average median delay of 5-6 days across all timepoints), affecting the ability to diagnose arbovirus infection by serology. By use of an interpretation table incorporating timing and completeness of sampling, one (<1%) participant had a confirmed recent infection with CCHFV, ten (1%) with TBEV, 40 (5%) with Toscana virus, and 52 (6%) with WNV. Most acute confirmed infections of Toscana virus were found in Albania (25 [63%] of 40), whereas WNV was primarily identified in Romania (36 [69%] of 52). Albania also had the highest overall Toscana virus seropositivity (168 [60%] of 282), mainly explained by patients confirmed to be exposed or previously exposed (104 [62%] of 168). Patients without antibodies to WNV or Toscana virus were significantly younger than patients with antibodies (mean difference -8·48 years [95% CI -12·31 to -4·64] for WNV, and -6·97 years [-9·59 to -4·35] for Toscana virus). We found higher odds of Toscana virus reactivity in men (odds ratio 1·56 [95% CI 1·15 to 2·11]; p=0·0055), WNV reactivity with mosquito bites versus no mosquito bites (2·47 [1·54 to 3·97]; p=0·0002), and TBEV reactivity with tick bites versus no tick bites (2·21 [1·19 to 4·11]; p=0·018). INTERPRETATION: This study shows that despite incomplete and heterogeneous data, differential diagnosis of suspected arbovirus infections is possible, and the diagnostic interpretation algorithm we propose could potentially be used to strengthen routine diagnostics in clinical settings in areas at risk for arboviral diseases. Our data highlight potential hotspots for arbovirus surveillance and risk factors associated with these particular arbovirus infections. FUNDING: European Commission and Versatile Emerging infectious disease Observatory. TRANSLATIONS: For the Greek, Albanian, Romanian, Bosnian, Serbian, and Croatian translation of the summary see Supplementary Materials section.
Distinct Requirements for CD4+ T Cell Help for Immune Responses Induced by mRNA and Adenovirus-Vector SARS-CoV-2 Vaccines.
CD4+ T cells have been established as central orchestrators of cellular and humoral immune responses to infection or vaccination. However, the need for CD4+ T cell help to generate primary CD8+ T cell responses is variable depending on the infectious agent or vaccine and yet consistently required for the recall of CD8+ T cell memory responses or antibody responses. Given the deployment of new vaccine platforms such as nucleoside-modified mRNA vaccines, we sought to elucidate the requirement for CD4+ T cell help in the induction of cellular and antibody responses to mRNA and adenovirus (Ad)-vectored vaccines against SARS-CoV-2. Using antibody-mediated depletion of CD4+ T cells in a mouse immunization model, we observed that CD4+ T cell help was dispensable for both primary and secondary CD8+ T cell responses to the BNT162b2 and mRNA-1273 mRNA vaccines but required for the AZD1222 Ad-vectored vaccine. Nonetheless, CD4+ T cell help was needed by both mRNA and Ad-vectored vaccine platforms for the generation of antibodies, demonstrating the centrality of CD4+ T cells in vaccine-induced protective immunity against SARS-CoV-2. Ultimately, this highlights the shared and distinct regulation of humoral and cellular responses induced by these vaccine platforms.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
Regulation of the cell surface expression of classical and non-classical MHC proteins by the human cytomegalovirus UL40 and rhesus cytomegalovirus Rh67 proteins.
UNLABELLED: The signal sequences of the human cytomegalovirus (CMV) UL40 protein and its rhesus CMV (RhCMV) counterpart, Rh67, contain a peptide (VMAPRT[L/V][F/I/L/V]L, VL9) that is presented by major histocompatibility complex (MHC) antigen E (MHC-E). The CMV VL9 peptides replace VL9 peptides derived from classical MHC (Ia) signal sequences, which are lost when CMV disrupts antigen processing and presentation and MHC Ia expression. This allows infected cells to maintain MHC-E surface expression and escape killing by Natural Killer cells. We demonstrate that processing of the Rh67 VL9 peptide mirrors that of UL40, despite the lack of sequence conservation between the two proteins. Processing of both VL9 peptides is dependent on cleavage of their signal sequences by the host protease signal peptide peptidase. As previously shown for UL40, up-regulation of MHC-E expression by Rh67 requires only its signal sequence, with sequences upstream of VL9 critical for conferring independence from TAP, the transporter associated with antigen processing. Our results also suggest that the mature UL40 and Rh67 proteins contribute to CMV immune evasion by decreasing surface expression of MHC Ia. Unexpectedly, while the Rh67 VL9 peptide is resistant to the effects of Rh67, UL40 can partially counteract the up-regulation of MHC-E expression mediated by its own VL9 peptide. This suggests differences in the mechanisms by which the two VL9 peptides up-regulate MHC-E, and further work will be required to determine if any such differences have implications for translating a RhCMV-vectored simian immunodeficiency virus (SIV) vaccine to HIV-1 using human CMV as a vector. IMPORTANCE: The protective immune response induced by a rhesus cytomegalovirus (RhCMV)-vectored simian immunodeficiency virus (SIV) vaccine in rhesus macaques depends on the presence of the viral Rh67 gene in the vaccine. The Rh67 protein contains a peptide that allows the RhCMV-infected cells to maintain expression of major histocompatibility complex (MHC) antigen E at the cell surface. We show that production of this peptide, referred to as "VL9," mirrors that of the equivalent peptide present in the human cytomegalovirus (CMV) protein UL40, despite the little sequence similarity between the two CMV proteins. We also show that the mature UL40 and Rh67 proteins, which have no previously described function, also contribute to CMV immune evasion by reducing cell surface expression of MHC proteins important for the immune system to detect infected cells. Despite these similarities, our work also reveals possible differences between Rh67 and UL40, and these may have implications for the use of human CMV as the vector for a potential HIV-1 vaccine.
Association of nucleoside reverse transcriptase inhibitors with adverse perinatal outcomes in pregnant women living with HIV: systematic review and meta-analysis.
BACKGROUND: The WHO recommends antiretroviral therapy (ART) containing two nucleoside reverse transcriptase inhibitors (NRTIs) as backbone. WHO recommends tenofovir disoproxil fumarate combined with lamivudine or emtricitabine as first line in pregnancy, and zidovudine, abacavir or tenofovir alafenamide, combined with lamivudine or emtricitabine, as alternatives. OBJECTIVES: This study aims to evaluate the risk of adverse perinatal outcomes in pregnant women living with HIV (WLHIV) receiving different NRTIs. METHODS: Data sources included Medline, CINAHL, Global Health, and Embase. STUDY ELIGIBILITY CRITERIA: Cohort studies. PARTICIPANTS: Pregnant WLHIV. INTERVENTIONS: ART regimens containing different NRTI drugs. ASSESSMENT OF RISK OF BIAS: Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation. METHODS OF DATA SYNTHESIS: Random-effects meta-analysis. RESULTS: In total, 22 cohort studies including 124,478 pregnant WLHIV met the eligibility criteria. ART containing tenofovir disoproxil fumarate was associated with lower risk of preterm birth (risk ratio, 0.89; 95% CI, 0.81-0.97), very preterm birth (0.58; 0.40-0.86), small for gestational age (0.76; 0.59-0.98), very small for gestational age (0.60; 0.48-0.73), stillbirth (0.49; 0.31-0.78), and neonatal death (0.61; 0.40-0.93), compared with ART not containing tenofovir disoproxil fumarate. ART containing zidovudine was associated with an increased risk of very preterm birth (1.59; 1.01-2.49), small for gestational age (1.33; 1.03-1.70), very small for gestational age (1.63; 1.25-2.13), stillbirth (2.23; 1.10-4.55), and neonatal death (1.65; 1.08-2.52), compared with ART not containing zidovudine. For ART regimens also containing either lamivudine or emtricitabine, zidovudine was associated with an increased risk of very preterm birth (1.62; 1.04-2.52), small for gestational age (1.52; 1.28-1.82), very small for gestational age (1.68; 1.36-2.06), stillbirth (2.19; 1.03-4.67), and neonatal death (1.65; 1.08-2.52), compared with ART containing tenofovir disoproxil fumarate. Abacavir was not associated with adverse perinatal outcomes. Tenofovir alafenamide was not associated with low birthweight compared with tenofovir disoproxil fumarate. CONCLUSIONS: Tenofovir disoproxil fumarate is associated with a lower risk of adverse perinatal outcomes, whereas zidovudine is associated with an increased risk of perinatal outcomes. Abacavir is not associated with adverse perinatal outcomes. Our findings support current WHO guidelines.
Perinatal outcomes among pregnant women with HIV initiating antiretroviral therapy preconception and antenatally.
OBJECTIVE: Increasingly, pregnant women with HIV (WHIV) initiate antiretroviral therapy (ART) before conception. We assessed the risk of adverse perinatal outcomes among pregnant WHIV initiating ART preconception or antenatally, compared with women without HIV or ART-naive WHIV. DESIGN: Systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE, CINAHL, and Global Health for studies published between 1 January 1980 and 14 July 2023. We assessed the association of preconception/antenatal ART initiation with preterm birth (PTB), very PTB (VPTB), spontaneous PTB (sPTB), low birthweight (LBW), very LBW (VLBW), small for gestational age (SGA), very SGA (VSGA), stillbirth and neonatal death (NND). Data were analysed using random effects meta-analyses. Quality assessments, subgroup and sensitivity analyses were conducted. PROSPERO registration: CRD42021248987. RESULTS: Thirty-one cohort studies were eligible, including 199 156 women in 19 countries. WHIV with preconception ART were associated with increased risk of PTB [risk ratio (RR) 1.55; 95% confidence interval (CI) 1.27-1.90], VPTB (RR 2.14, 95% CI 1.02-4.47), LBW (RR 2.19, 95% CI 1.32-3.63), VLBW (RR 3.34, 95% CI 1.08-10.35), SGA (RR 1.92, 95% CI 1.01-3.66), and VSGA (RR 2.79, 95% CI 1.04-7.47), compared with women without HIV. WHIV with antenatal ART were associated with increased risk of PTB (RR 1.35, 95% CI 1.15-1.58), LBW (RR 2.16, 95% CI 1.39-3.34), VLBW (RR 1.97, 95% CI 1.01-3.84), SGA (RR 1.77, 95% CI 1.10-2.84), and VSGA (RR 1.21, 95% CI 1.09-1.33), compared with women without HIV. Compared to ART-naive WHIV, WHIV with preconception or antenatal ART were associated with increased risk of SGA (preconception: RR 1.40, 95% CI 1.12-1.73; antenatal: RR 1.39, 95% CI 1.11-1.74) and VSGA (preconception: RR 2.44, 95% CI 1.63-3.66; antenatal: RR 2.24, 95% CI 1.48-3.40). CONCLUSION: Among WHIV, both preconception and antenatal initiation of ART are associated with increased risks of adverse perinatal outcomes, compared to women without HIV and ART-naive WHIV.