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Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050.
BACKGROUND: Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts. METHODS: We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen-drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level. FINDINGS: In 2021, we estimated 4·71 million (95% UI 4·23-5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00-1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000-372 000] and 57 200 attributable deaths [34 100-80 300] in 1990, to 550 000 associated deaths [500 000-600 000] and 130 000 attributable deaths [113 000-146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000-834 000) in 1990, to 1·03 million associated deaths (909 000-1·16 million) in 2021, and from 127 000 attributable deaths (82 100-171 000) in 1990, to 216 000 (168 000-264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56-2·26) deaths attributable to AMR and 8·22 million (6·85-9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2-69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5-89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (-6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8-102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08-13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths. INTERPRETATION: This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050. FUNDING: UK Department of Health and Social Care's Fleming Fund using UK aid, and the Wellcome Trust.
Meningococcal Vaccines Directed at Capsular Group B
Neisseria meningitidis group B (MenB) remains a global cause of meningitis and sepsis-especially in infants, young children, and adolescents, and of acute and prolonged meningococcal outbreaks. The protein antigens used in the MenB vaccines are novel and have distinct immunogenic properties different from those associated with the capsular polysaccharide-based vaccines. Two vaccines directed at MenB are in widespread use. MenB-FHbp contains two recombinant Factor H binding protein (FHbp) lipoprotein molecules, one from each major subfamily. MenB-4C contains a subfamily B FHbp sequence variant and three additional components- Neisseria Adhesin A (NadA), Neisseria Heparin binding antigen (NHba), and outer membrane vesicles (OMVs) containing as a dominant antigen the porin protein (PorA) serosubtype P1.4. Both vaccines elicit human serum bactericidal activity (SBA) against many but not all (and sometimes different) group B strains and against some non-group B strains. Vaccine effectiveness of ≥75% has been seen in infants and in the control of outbreaks. MenB-4C or MenB-FHbp are associated with higher rates of local and systemic reactions than with other commonly administered vaccines but prelicensure and post licensure studies have not detected an excess of serious adverse events related to either vaccine. Unlike the meningococcal polysaccharide-protein conjugate vaccines the MenB vaccines have shown no significant effect on meningococcal carriage. For individuals that remain at high risk, boosters should be administered at 1 year after primary series completion, then every 2-3 years thereafter. Next generation MenB vaccines in development combine the MenB protein antigens with the quadrivalent polysaccharide-protein conjugate vaccines.
Meningococcal Capsular Group A, C, W, and Y Conjugate Vaccines
Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a deadly illness that can progress rapidly. The case fatality rate is 10%-15%, and many survivors have long term sequelae such as hearing loss, cognitive deficits, or amputations due to necrosis of the extremities. Meningococcal disease is found globally but the incidence and most common capsular groups (types) vary widely among world regions. In the past 15 years, huge advances have been made in new meningococcal vaccines, which are having a striking impact on the global epidemiology of meningococcal disease. This chapter provides a comprehensive review of serogroup A, C, W, and Y meningococcal disease and vaccines. The chapter includes discussion of the clinical presentation and complications of meningococcal disease; meningococcal bacteriology and molecular epidemiology; disease pathogenesis, transmission, diagnosis, treatment, and prophylaxis; and global epidemiology, including risk factors for both disease and asymptomatic carriage. The discussion of meningococcal conjugate vaccines includes a detailed review of meningococcal conjugate vaccine development, immunogenicity, effectiveness, impact on asymptomatic carriage, safety, recommendations for use, and public health impact.
Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment.
Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.
Immune responses to typhoid conjugate vaccine in a two dose schedule among Nepalese children <2 years of age.
BACKGROUND: Previously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. METHODS: Infants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FINDINGS: Fifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p
Safety and immunogenicity of an acellular pertussis vaccine containing genetically detoxified pertussis toxin administered to pregnant women living with and without HIV and their newborns (WoMANPOWER): a randomised controlled trial in Uganda.
BACKGROUND: Immunisation in pregnancy against pertussis can reduce severe disease in infancy. There are few data on the safety and immunogenicity of vaccines given to pregnant women living with HIV and their infants. We aimed to describe the safety and immunogenicity of a tetanus-diphtheria-acellular pertussis (TdaP) vaccine containing genetically detoxified pertussis toxin given to pregnant women living with HIV and the effect of the vaccine on infant whole-cell pertussis vaccine responses. METHODS: We conducted an observer-blind, randomised, phase 2, multicentre, non-inferiority trial evaluating safety and immunogenicity of a vaccine containing genetically detoxified acellular pertussis in pregnant women living with HIV in Uganda. Women aged at least 18 years between 16 weeks and 26 weeks of gestation were randomly assigned to receive the tetanus-diphtheria (Td) vaccine or TdaP vaccine. Stratified block randomisation using blocks of four with a 1:1:1:1 ratio stratified by participant HIV status was used to distribute participants into equal groups (50 participants per group for a total of 200 participants). The intervention was a 0·5 mL single intramuscular dose of TdaP vaccine. Td or TdaP vaccination was randomly assigned to different clinic days using randomisation software. Primary immunogenicity endpoints were anti-pertussis toxin and anti-filamentous haemagglutinin IgG concentrations in infants at delivery and 18 weeks following three doses of a whole-cell pertussis containing vaccine. This study is registered at ClinicalTrials.gov, NCT04589312. FINDINGS: Between Oct 28, 2020, and May 21, 2021, 438 pregnant women were screened and 181 were randomly assigned: 90 to TdaP vaccine (40 HIV-positive participants and 50 HIV-negative participants) and 91 to Td vaccine (41 HIV-positive participants and 50 HIV-negative participants). All participants received Td, and 4 weeks later, 177 received either Td or TdaP. 32 serious adverse events occurred, none related to the study vaccine. At delivery, anti-pertussis toxin IgG concentrations for TdaP versus Td were superior in infants who were HIV-exposed but uninfected (geometric mean ratio 9·61, 95% CI 5·21-17·74) and HIV-unexposed infants (21·6, 11·2-41·7). In infants at 18 weeks, anti-pertussis toxin IgG concentrations for TdaP versus Td-vaccinated mothers were significantly lower for both infants who were HIV-exposed but uninfected (0·19, 0·09-0·43) and infants who were not HIV-exposed (0·17, 0·08-0·33). Serum bactericidal antibody generation following whole-cell pertussis vaccination in infants was not affected. INTERPRETATION: TdaP was safe and immunogenic in pregnant women living with HIV and their infants. TdaP provided superior anti-pertussis toxin IgG concentrations at delivery. Following routine vaccination with whole-cell pertussis vaccine, infants born to women receiving the TdaP vaccine had lower anti-pertussis toxin IgG concentrations than infants born to women receiving Td. In the absence of a correlate of protection against pertussis disease, the clinical significance of this finding is unclear. FUNDING: Medical Research Council Joint Clinical Trials, Canadian Institutes of Health Research, and British Columbia Children's Hospital Research Institute.
The discriminatory power of the t cell receptor
T cells use their T cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (pMHC) antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities and use it to measure the discriminatory power of the TCR and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as KD ∼ 1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.
Successful incorporation of a genetic risk prediction research platform into routine newborn screening
ABSTRACTAn increasing number of diseases can be offered treatments that are transformative if administered in a timely manner. However, many of these diseases are currently not included in the newborn screening programs because they lack sensitive and specific metabolic biomarkers, and detection of children at increased risk relies on genetic methods. Type 1 diabetes (T1D) constitutes a potential example of such disease.Between April 2018 and November 2020, over 15500 babies were enrolled into ‘INGR1D’ (Investigating Genetic Risk for T1D), a research study to identify newborns with an increased genetic risk of T1D. This project, performed as part of a T1D primary prevention study (the Primary Oral Insulin Trial, POInT), has helped to pioneer the integration of genetic screening into the NHS Newborn Blood Spot Screening Programme (NBSSP) for consenting mothers, without affecting the screening pathway. The use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population based genetic studies in the newborn.This project builds on the UK’s role as a world leader in genomic medicine, e.g. through its inception and completion of the 100 000 Genomes Project, and its subsequent ambition to map 5 million further genomes over the next 5 years.Our aim is therefore to describe the methodology used by INGR1D as a way to demonstrate how a successful research and clinical trial tool can be integrated into a national screening programme, with the potential for the tool to be developed to incorporate multiple diseases with genetic markers without altering the screening pathway.
Single Dose Administration, And The Influence Of The Timing Of The Booster Dose On Immunogenicity and Efficacy Of ChAdOx1 nCoV-19 (AZD1222) Vaccine
Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, MHRA, with a regimen of two standard doses given with an interval of between 4 and 12 weeks. The planned rollout 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 phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and phase I/II clinical trials in the UK and South Africa, against symptomatic disease caused by SARS-CoV-2. The data cut-off date for these analyses was 7th December 2020. The accumulated cases of COVID-19 disease at this cut-off date exceeds the number required for a pre-specified final analysis, which is also presented. As previously described, individuals over 18 years of age were randomised 1:1 to receive two standard doses (SD) of ChAdOx1 nCoV-19 (5x1010 viral particles) or a control vaccine/saline placebo. In the UK trial efficacy cohort a subset of participants received a lower dose (LD, 2.2x1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. All cases with a nucleic acid amplification test (NAAT) were adjudicated for inclusion in the analysis, by a blinded independent endpoint review committee. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Findings: 17,177 baseline seronegative trial participants were eligible for inclusion in the efficacy analysis, 8948 in the UK, 6753 in Brazil and 1476 in South Africa, with 619 documented NAAT +ve infections of which 332 met the primary endpoint of symptomatic infection >14 days post dose 2.The primary analysis of overall vaccine efficacy >14 days after the second dose including LD/SD and SD/SD groups, based on the prespecified criteria was 66.7% (57.4%, 74.0%). There were no hospitalisations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control group.Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and modelled 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 day (GMR 0.66, 95% CI 0.59, 0.74).In the SD/SD group, after the second dose, efficacy was higher with a longer prime-boost interval: VE 82.4% 95%CI 62.7%, 91.7% at 12+ weeks, compared with VE 54.9%, 95%CI 32.7%, 69.7% at <6 weeks. These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 2.19 (2.12, 2.26) in those who were 18-55 years of age.Interpretation: ChAdOx1 nCoV-19 vaccination programmes aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.Trial Registration: Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Funding: UKRI, NIHR, CEPI, 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 Astra Zeneca.Conflict of Interest: Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19. SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine. TL is named as aninventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project. PMF is a consultant to Vaccitech. AJP is Chair of UK Dept.Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO’sSAGE. AJP and SNF are NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO. AVSH reports personal feesfrom Vaccitech, outside the submitted work and has a patent on ChAdOx1 licensed to Vaccitech, and may benefit from royalty income to the University of Oxford from sales of this vaccine by AstraZeneca and sublicensees. MS reports grants from NIHR, non-financial support fromAstraZeneca, during the conduct of the study; grants from Janssen, grants fromGlaxoSmithKline, grants from Medimmune, grants from Novavax, grants and non-financialsupport from Pfizer, grants from MCM, outside the submitted work. CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work. SNF reports grants from Janssen and Valneva, outside the submitted work. ADD reports grants and personal fees from AstraZeneca, outside of the submitted work. In addition, ADD has a patent manufacturingprocess for ChAdOx vectors with royalties paid to AstraZeneca, and a patent ChAdOx2 vector with royalties paid to AstraZeneca. The other authors declare no competing interests.