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Roles and responsibilities of participants, researchers, and the media in the communication of vaccine trials: Experience from the United Kingdom's first COVID-19 vaccine trial.

BACKGROUND: The media have played an important part in presenting arguments for and against vaccination. The potential for the media to influence public attitudes to vaccines is becoming increasingly crucial to address. METHODS: To understand the differing roles and responsibilities in the communication of vaccine trials we draw insight from a retrospective study of 349 survey responses and 102 semi-structured interviews conducted in 2020 with participants in the United Kingdom's first-in-human clinical trial of the Oxford-AstraZeneca COVID-19 vaccine. RESULTS: We found that trial participants had mixed views as to whether their participation conferred responsibility to communicate more widely about their trial experiences. Some participants perceived themselves to have an altruistic obligation to communicate to the media about the trial, and others felt that those who did share their participation had 'attention-seeking' motives. When participants did speak out they preferred to do so anonymously. Frustration was also reported with sensationalised and false media stories. Social media was viewed as a means to accelerate misinformation or as a force for recruitment and public education about trials. Participants were pleased to see trial investigators and trial team playing prominent roles in the media and this instilled confidence in the vaccine and the trial. We discuss these evolving roles and responsibilities for trial communication, concentrating on the views of participants about experiences, opportunities, and risks. CONCLUSIONS: We argue that the pandemic has demonstrated the need for clinical trials to be made more transparent as a scientific practice that requires better public understanding and engagement. For high-profile vaccine trials we recommend; (1) explicit and comprehensive guidance aimed at all participants for interactions with the media; (2) prioritising having open and effectively expressed accounts of trial composition, processes, and participation; (3) offering support and a direct communication channel for journalists to report trials by utilising internal press officers to engage with journalists.

Implementation and adherence to regular asymptomatic testing in a COVID-19 vaccine trial.

BACKGROUND: For pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine's potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial. METHODS: COV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics. FINDINGS: 356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42·6-90·9), which translated to a 74·5% (IQR 50·9-78·8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers. INTERPRETATION: The COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, AstraZeneca.

The waning of maternal measles antibodies: a multi-country maternal-infant seroprevalence study.

OBJECTIVES: To assess geographical variation in maternal measles antibody levels from birth to nine months of age, to inform recommendations for the timing of first measles vaccine dose. METHODS: Stored infant serum samples from 11 countries taken at delivery and/or follow-up time points prior to measles vaccination (N=2,845) were tested for measles plaque reduction neutralisation (PRNT) and measles, mumps, and rubella immunoglobulin G at a central laboratory. Antibody decay in infants was modelled using linear mixed effects models with participant-level random intercepts and random slopes. Proportions of infants with antibody concentrations above the clinical protection threshold (0.12 IU/mL) were estimated at each age. RESULTS: At birth most (94%, 519/552) infants had PRNT ≥0.12 IU/mL, but geometric mean concentrations ranged 0.32 IU/mL (Guatemala) to 1.60 IU/mL (Pakistan). There was no geographical variation in decay rate of PRNT nor immunoglobulin G. Geometric mean PRNT fell below 0.12 IU/mL between ages 2.5 months (Guatemala) and 6.2 months (Pakistan). At age 6 months <50% of infants had PRNT ≥0.12 IU/mL in all countries except Pakistan. CONCLUSIONS: Reliance on maternal antibodies for protection until age 9 months or later leaves most infants with insufficient direct protection against measles infection between ages 6-9 months.

The use of controlled human infection models to identify correlates of protection for invasive Salmonella vaccines.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S. Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S. Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Respiratory viral detection in children hospitalized with pneumonia during periods of major population disruptions in Nepal, 2014-2018.

BACKGROUND: Respiratory viruses commonly cause pneumonia in children. We aimed to identify respiratory viral nucleic acids in the nasopharynx of children admitted with pneumonia from 2014 to 2018, a period including a major earthquake (April 2015), PCV10 introduction (August 2015), and a fuel shortage (October 2015 to March 2016). METHODS: Children 2 months to 14 years admitted to Patan Hospital between March 2014 and February 2018 with a clinical diagnosis of pneumonia had nasopharyngeal swabs collected and tested with a multiplex panel for the presence of genetic material from 23 respiratory pathogens. RESULTS: Of 1343 children with pneumonia, 974 (72.5%) had the nucleic acids of at least one respiratory virus in the nasopharynx. The median age of children with any viral genetic material detected was lower than those without (1.18, IQR: 0.59-2.39 years; versus 2.01 years, IQR: 0.81-4.34 years; p<0.001). Commonly detected viral nucleic acids included those of RSV (21.0%), rhino/enterovirus (30.8%), and parainfluenza (7.4%). The odds of detecting any respiratory viral genetic material in children with pneumonia increased by 1.88 (95% confidence interval: 1.15, 3.06) in the year after the earthquake, when there were several aftershocks and a fuel crisis, relative to other periods and accounting for other potential confounding factors. CONCLUSIONS: These findings highlight the importance of viral diagnostics in pediatric pneumonia and suggest that public health measures addressing environmental conditions during disasters might help reduce respiratory infections.

LISTEN: lived experiences of Long COVID: a social media analysis of mental health and supplement use

IntroductionLong COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), is a complex condition characterized by a wide range of persistent symptoms that can significantly impact an individual's quality of life and mental health. This study explores public perspectives on the mental health impact of Long COVID and the use of dietary supplements for recovery, drawing on social media content. It uniquely addresses how individuals with Long COVID discuss supplement use in the absence of public health recommendations.MethodsThe study employs the LISTEN method (“Collaborative and Digital Analysis of Big Qual Data in Time Sensitive Contexts”), an interdisciplinary approach that combines human insight and digital analysis software. Social media data related to Long COVID, mental health, and supplement use were collected using the Pulsar Platform. Data were analyzed using the free-text discourse analysis tool Infranodus and collaborative qualitative analysis methods.ResultsThe findings reveal key themes, including the impact of Long COVID on mental health, occupational health, and the use of food supplements. Analysis of attitudes toward supplement use highlights the prevalence of negative emotions and experiences among Long COVID patients. The study also identifies the need for evidence-based recommendations and patient education regarding supplement use.DiscussionThe findings contribute to a better understanding of the complex nature of Long COVID and inform the development of comprehensive, patient-centered care strategies addressing both physical and mental health needs.

Seroprevalence of Cytomegalovirus Among Pregnant Women at Kawempe National Referral Hospital, Uganda: A Cross-sectional Study.

BACKGROUND: Maternal primary cytomegalovirus (CMV) infection is associated with abortion and congenital anomalies. In Uganda, the burden of maternal CMV infection is not well studied. This study thus assessed the seroprevalence and factors associated with CMV infection among pregnant women at Kawempe National Referral Hospital in Kampala. This work forms a part of the PROGRESS study, an observational cohort study undertaken in Kampala, Uganda, between November 2018 and April 2021. METHODS: We conducted a cross-sectional study between September 2020 and January 2021 among the 639 pregnant women admitted to the labor ward at a government hospital. Sociodemographic, medical, obstetric, and socioeconomic data were collected. Blood samples from study participants were drawn and analyzed for the presence of CMV immunoglobulin G (IgG) and IgM using enzyme-linked immunosorbent assay-based quantitative assays. Further analysis of all IgM-positive samples was conducted using CMV IgG avidity assays. All infants had a nasal polymerase chain reaction (PCR) on the first day of life to investigate CMV positivity. Logistic regression was performed to determine the factors associated with CMV infection. RESULTS: Seroprevalence of CMV IgG among the 637 women was universal (100%), and that of CMV (IgM) was 5.8% (37/637). CMV (IgM) was associated with being low socioeconomic status (odds ratio, 3.44; 95% CI, 1.05-11.32; P = .04). Transmission risk was low, and no infant had a positive PCR for CMV at birth. CONCLUSIONS: Universally, by the time women in Kampala conceive, they will have been exposed to CMV. Women of lower socioeconomic status were more likely to have recent CMV infection than their more affluent counterparts, highlighting the need for screening guidelines in this setting.

The validity of test-negative design for assessment of typhoid conjugate vaccine protection: comparison of estimates by different study designs using data from a cluster-randomised controlled trial.

BACKGROUND: Typhoid fever remains a substantial public health challenge in low-income and middle-income countries. By 2023, typhoid conjugate vaccines (TCVs) had been introduced in six countries globally, with more than 50 million doses distributed. Now that TCVs are being deployed, there is a need for observational studies to assess vaccine effectiveness in the field. We aimed to evaluate the validity of different observational study designs in estimating vaccine protection. METHODS: We compared different observational and experimental study designs for assessing vaccine effectiveness by re-analysing data from the TyVAC Bangladesh trial, a participant-blinded and observer-blinded cluster-randomised controlled trial done in Mirpur, Dhaka, Bangladesh. 150 geographical clusters were randomly assigned (1:1) to receive either TCV or Japanese encephalitis vaccine. Eligible children aged 9 months to 15 years were offered a single dose of the vaccine randomly assigned to their cluster of residence, and baseline vaccination was done between April 15 and May 15, 2018. We compared estimates of vaccine effectiveness from the cluster-randomised controlled trial analysis-which assessed the risk of blood-culture-confirmed typhoid fever among recipients of TCV versus recipients of Japanese encephalitis vaccine-with estimates from cohort study and test-negative case-control study design (TND) analyses, which compared recipients of TCV with non-vaccinees in the 75 geographical clusters where TCV was administered. We further conducted negative-control exposure (NCE) and negative-control outcome (NCO) analyses as bias indicators. FINDINGS: 41 344 (67%) of 62 025 age-eligible children in the study area received the TCV or Japanese encephalitis vaccine during the baseline vaccination campaign. Among the 62 025 age-eligible children, 5582 blood-culture specimens were collected by passive surveillance, including 2546 (46%) specimens from the 75 TCV clusters. The estimated vaccine efficacy was 89% (95% CI 81-93) in the cluster-randomised controlled trial analysis, 79% (70-86) by the cohort design, 88% (79-93) by the TND when pan-negatives were used as test-negative controls, and 90% (75-96) by the TND when specimens positive for pathogens other than Salmonella enterica serotype Typhi were used as test-negative controls. Using NCE analysis, Japanese encephalitis vaccination was associated with an increased risk of typhoid fever compared with non-vaccinees in the 75 Japanese encephalitis clusters in the cohort design (incidence rate ratio 1·98 [95% CI 1·56-2·52]), but no significant association between Japanese encephalitis vaccination and typhoid fever was found with the TND. Similarly, an increased risk of non-typhoid infections was observed in the cohort NCO analyses when comparing vaccinees with non-vaccinees in both Japanese encephalitis vaccine clusters and TCV clusters, but not in the TND NCO analyses. INTERPRETATION: Our findings suggests that the TND provides reliable estimates of TCV effectiveness, whereas the cohort design can bias vaccine effectiveness estimates, possibly due to unmeasured confounding effects, such as health-care-seeking behaviours. NCE and NCO approaches are useful tools for identifying such biases. FUNDING: The Bill & Melinda Gates Foundation.

Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK.

OBJECTIVE: The UK government's response to the COVID-19 pandemic included a 'test, trace and isolate' strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services. DESIGN: Scoping review. SEARCH STRATEGY: PubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA). DATA EXTRACTION AND SYNTHESIS: Data were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme. RESULTS: This study included 40 sources, including 17 from projects that informed UKHSA's decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing. CONCLUSIONS: Universal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.

What is the current evidence base for measles vaccination earlier than 9 months of age?: Report from an informal technical consultation of the World Health Organization.

Measles is one of the most contagious vaccine preventable diseases, causing severe complications and deaths globally. While vaccination with a measles-containing vaccine (MCV) has prevented millions of measles deaths, recent trends, especially from low- and middle-income countries, are discouraging. Measles cases have increased since 2021 as MCV coverage has decreased; and an estimated 107,500 measles deaths, mostly in children under-five years, occurred in 2023. Thus, a renewed focus on proven and innovative strategies to control measles is needed. The World Health Organization (WHO) recommends a first MCV dose administered at 9-15 months of age (routine MCV1), however MCV1 below 9 months of age (early MCV1) may increase vaccination coverage because uptake of all vaccines tends to be higher the younger the child, and this might protect vulnerable infants earlier in life. However, due to concerns about possible reduced vaccine performance, early MCV1 is not routinely recommended by WHO. WHO hosted an informal technical consultation on December 6-7, 2023, in Geneva, Switzerland to evaluate recent evidence on early MCV1 and identify evidence gaps for policy making. The recent evidence suggests a robust humoral immune response shortly after early MCV1 at 5-8 months of age. Immune blunting of a routine second MCV dose (e.g., MCV2) after early MCV1 was not demonstrated in the presented data. However, 3-7 years after MCV1, children receiving early MCV1 had lower measles antibodies than children receiving routine MCV1, suggesting faster waning of immunity. The totality of evidence on immune blunting remains inconsistent. Meeting participants thought more data are needed before revisiting WHO's current recommendation for a potential revision. Evidence gaps include: understanding measles disease burden and severity in infants; early MCV1 effectiveness and duration; vaccine-induced cellular immunogenicity; whether measles in infants is acquired from other infants or older children or adults; and blunting of routine MCV2. Addressing evidence gaps through targeted studies and measles outbreak investigations, as well as evaluations of country-level introductions of early MCV1 are warranted. Ensuring high MCV1 and MCV2 coverage remains the priority in measles control.

The TyphiNET data visualisation dashboard: unlocking Salmonella Typhi genomics data to support public health.

BACKGROUND: Salmonella enterica subspecies enterica serovar Typhi (abbreviated as 'Typhi') is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed typhoid conjugate vaccines (TCVs). National immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high, and the Gavi vaccine alliance has provided financial support for their introduction. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance. RESULTS: We developed TyphiNET ( https://www.typhi.net ), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n = 11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers. CONCLUSIONS: The TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.

Hot, swollen or stiff joints in children and young people: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of children and young people (CYP) who present with one or more hot, swollen or stiff joints. It will incorporate assessment, diagnosis, monitoring, non-pharmacological and initial pharmacological management preceding definitive diagnosis. This is the first British Society for Rheumatology guideline for hot, swollen or stiff joints in CYP <18 years of age and will complement the hot, swollen joint guideline created for adults ≥18 years of age. The guideline will be developed using the methods and rigorous processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.4.

Real-world uptake of nirsevimab, RSV maternal vaccine, and RSV vaccines for older adults: a systematic review and meta-analysis

Background: In clinical trials, recently introduced respiratory syncytial virus (RSV) immunisation products have shown high efficacy in preventing severe RSV outcomes. Implementing successful immunisation programmes is however key to realising these benefits in real-world settings. We aimed to investigate uptake of the long-acting monoclonal antibody nirsevimab, the RSV maternal vaccine, and RSV vaccines for older adults in countries where immunisation programmes have been introduced, and to explore how uptake varies between countries and population subgroups. Methods: In this systematic review and meta-analysis, we carried out four monthly searches in Medline, Embase, and Global Health databases for studies reporting uptake of nirsevimab, the RSV maternal vaccine, and RSV vaccines for older adults. We included population-based studies published between December 1, 2022 and February 5, 2025. Two independent reviewers screened studies, extracted data, and completed a risk of bias assessment using the Joanna Briggs Institute (JBI) Critical Appraisal Tools. We assessed uptake stratified by country and socio-demographic and clinical subgroups. Meta-analyses were conducted using random-effects modelling. PROSPERO registration number: CRD42025643585. Findings: We screened a total of 1267 studies, 43 of which met the inclusion criteria reporting data on over 1.38 million individuals from six countries. Nirsevimab uptake data were reported in 34 studies: 16 from Spain, eight from the United States, seven from France, one with combined data from Andorra and Spain, and one from each of Italy and Luxembourg. Our pooled estimates showed that nirsevimab uptake on population level was 90.1% (95% confidence interval (CI): 86.4–92.9) in Spain and 51.2% (95% CI: 29.3–72.7) in the United States during the 2023/24 RSV season. Uptake data for the RSV maternal vaccine and RSV vaccines for older adults were reported in five and eight studies, respectively, all from the United States. Meta-analysis showed population-level uptake of 30.5% (95% CI: 20.6–42.6) and 18.2% (95% CI: 10.8–28.9), respectively. Uptake varied across subgroups. Interpretation: Uptake of nirsevimab varied substantially between the countries that have implemented infant RSV immunisation programmes. Despite the limited number of studies and the lack of more accurate data at national level the low uptake estimates for RSV maternal vaccine and RSV vaccines for older adults are concerning. National, clinical, and public health initiatives are needed to increase uptake of RSV immunisation products and ensure maximum benefit to people currently at risk of severe RSV outcomes. Funding: Health Data Research UK, Inflammation and Immunity Driver Programme.

Translational science at the undergraduate level: awakening talents to overcome the valley of death - case report.

BACKGROUND: In the biomedical field, translational science is the process of applying basic scientific knowledge to advance clinical research through the creation of new drugs, devices, medical procedures, preventive measures, and diagnostic kits. The Covid-19 pandemic exposed a shortage of professionals trained in translational research, essential for responding to global demands. To drive advancements, researchers must overcome the 'valley of death', a critical phase in clinical investigation. In response, CEVAP at São Paulo State University (UNESP), Botucatu, Brazil, has developed a strong 'knowledge industry' centered on Translational Science. As part of its research and innovation efforts, CEVAP has developed two biopharmaceuticals, the fibrin sealant and the apilic antivenom, which are currently in the final stage of development. In 2024, CEVAP began the first Brazilian Contract Development and Manufacturing Organization (CDMO) for developing and producing validated and qualified pilot-scale batches to generate clinical trial material. CASE PRESENTATION: The implementation of the optional undergraduate course in Translational Science marks a crucial step in strengthening the 'knowledge industry'. The program, developed in collaboration with São Paulo's three public universities (USP, UNESP, and UNICAMP), also involves an international partnership with the University of Oxford's Department of Pediatrics and the Oxford Research Group LATAM. The successful launch of this course underscores its importance in interdisciplinary education and institutional collaboration. By bridging gaps between research and application, the program equips professionals to meet the growing demand for expertise in translational science. Given the project's success, it will transition into a one-year 'Qualification in Translational Science', available to students enrolled in São Paulo state universities. CONCLUSION: The preparation of these professionals will be strategic for transforming basic research into products for health, saving lives, and combating future pandemics that will emerge around the world.

Effectiveness of biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: the BATCH RCT.

BACKGROUND: Procalcitonin is a biomarker specific for bacterial infection, with a more rapid response than other commonly used biomarkers, such as C-reactive protein, but it is not routinely used in the National Health Service. OBJECTIVE: To determine if using a procalcitonin-guided algorithm may safely reduce duration of antibiotic therapy compared to standard of care in hospitalised children with suspected or confirmed infection. DESIGN: A pragmatic, multicentre, open-label, parallel two-arm, individually randomised controlled trial with internal pilot phase, qualitative study and health economic evaluations. SETTING: Paediatric wards or paediatric intensive care units within children's hospitals (n = 6) and district general hospitals (n = 9) in the United Kingdom. PARTICIPANTS: Children aged between 72 hours and 18 years admitted to hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. INTERVENTIONS: Procalcitonin-guided algorithm versus usual standard care alone. MAIN OUTCOME MEASURES: Coprimary outcomes were duration of intravenous antibiotic use and a composite safety measure. RESULTS: Between 11 June 2018 and 12 October 2022, 1949 children were recruited: 977 to the procalcitonin group [427 female (43.7%), 550 male (56.3%)], and 972 to the usual care group [478 female (49.2%), 494 male (50.8%)]. Duration of intravenous antibiotics was not significantly different between the procalcitonin group (median 96.0 hours) and the usual care group (median 99.7 hours) [hazard ratio = 0.96 (0.87, 1.05)], and the procalcitonin-guided algorithm was non-inferior to usual care [risk difference = -0.81% (95% confidence interval upper bound 1.11%)]. At clinical review, a procalcitonin result was available for 81.8% of the time, which was considered as part of clinical decision-making 66.6% of the time, and the algorithm was adhered to 57.2% of the time. Incremental cost-effectiveness ratio per duration of intravenous antibiotics hour avoided from bootstrapped samples was £467.62 per intravenous antibiotic hour avoided. Cost analysis of complete cases was also higher in the procalcitonin arm for all age groups, and for children aged 5 years and over. The intervention is not cost-effective as it is more expensive with no significant improvement in intravenous antibiotic duration. LIMITATIONS: Robust antimicrobial stewardship programmes were already implemented in the lead recruiting sites, and adherence to the algorithm was poor. Clinicians may be reluctant to adhere to biomarker-guided algorithms, due to unfamiliarity with interpreting the test result. CONCLUSIONS: In children hospitalised with confirmed or suspected bacterial infection, the addition of a procalcitonin-guided algorithm to usual care is non-inferior in terms of safety, but does not reduce duration of intravenous antibiotics, and is not cost-effective. In the presence of robust antimicrobial stewardship programmes to reduce antibiotic use, a procalcitonin-guided algorithm may offer little added value. FUTURE WORK: Future trials must include an implementation framework to improve trial intervention fidelity, and repeated cycles of education and training to facilitate implementation of biomarker-guided algorithms into routine clinical care. TRIAL REGISTRATION: This trial is registered as ISRCTN11369832. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/42) and is published in full in Health Technology Assessment; Vol. 29, No. 16. See the NIHR Funding and Awards website for further award information.

Safety and broad immunogenicity of HIVconsvX conserved mosaic candidate T-cell vaccines vectored by ChAdOx1 and MVA in HIV-CORE 006: a double-blind, randomised, placebo-controlled phase 1 trial in healthy adults living without HIV-1 in eastern and southern Africa

Background: Even within the context of antiretroviral treatment and prevention, an HIV-1 vaccine remains the best strategy for ending the HIV/AIDS epidemic. A vaccine is particularly needed in sub-Saharan Africa, where HIV-1 greatly affects people's lives and economy. Here, we aimed to assess the safety and immunogenicity of candidate T-cell vaccines in African populations. Methods: HIV-CORE 006 was a double-blind, randomised, placebo-controlled phase 1 trial conducted across four clinical research centres in Uganda, Kenya, and Zambia. Eligible participants were not pregnant, were living without HIV-1 or HIV-2, had a low likelihood of acquiring HIV-1, were aged 18–50 years, fully comprehended the purpose and details of this study as outlined in the participant information sheet, and passed an assessment of understanding before providing written informed consent. Participants were randomly assigned (9:2) to receive either a vaccine regimen or a placebo. The vaccine was administered as ChAdOx1.tHIVconsv1 (C1) followed by MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) in regimen C1-M3M4. The first primary outcome was the vaccines’ safety assessment, assessed in all participants who received at least one vaccine or placebo dose. The second primary outcome evaluated the C1-M3M4 regimen's induction of HIVconsvX-specific T-cell responses by assessing the proportion of vaccine recipients who responded to the vaccination, assessed in all participants who received all doses of vaccine or placebo as per protocol. This study is registered with ClinicalTrials.gov, NCT04553016, and the Pan-African Clinical Trials Registry PACTR202006495409011, and is now closed. Findings: Between July 15, 2021, and Nov 2, 2022, 89 healthy adults living without HIV-1 were randomly assigned, with 88 receiving either the vaccine (n=72) or placebo (n=16). Of these 88 participants, 57 (65%) were male and 31 (35%) were female. The C1, M3, and M4 vaccine components were well tolerated and induced HIVconsvX-specific responses in 70 (99%) of the 71 participants who completed all vaccine doses. Vaccine-elicited T cells peaked at a median of 2310 (IQR 1080–4480) IFN-γ spot-forming units per 106 peripheral blood mononuclear cells and recognised a median of eight (five to ten) of ten peptide pools spanning the HIVconsvX immunogen. The total frequencies of elicited T cells decreased 4·6 times over a 40-week follow-up period compared with the peak responses. Upon antigenic re-exposure, T cells proliferated, exhibited multiple effector functions, and inhibited HIV-1 representatives from clades A, B, C, and D. Interpretation: Results from key sub-Saharan African populations supported the safety of the vaccine regimen previously shown in the first-in-human trial in the UK. The induction of T cells and their characteristics encourage vaccine integration into HIV-1 cure strategies, which could inform HIV-1 prevention efforts. Funding: The European and Developing Countries Clinical Trials Partnership.

Maternal views on RSV vaccination during the first season of implementation in England and Scotland.

Severe Parvovirus B19-Associated Myocarditis in Children in the Post-COVID-19 Era: A Multicenter Observational Cohort Study.

This study describes a cluster of severe parvovirus B19-associated myocarditis cases in children across England in the context of an increase in circulating virus. Cases were identified across 3 large children's centers. Eight cases presented from 1 January 2019 to 31 December 2023 as compared with 19 from 1 January 2024 to 31 August 2024. Almost all (n = 25, 93%) required intensive care, and 24 (88%) received inotropes and 4 (15%) extracorporeal membrane oxygenation. Myocarditis appears to be temporally associated and a late sequela of parvovirus B19, resulting in high rates of intensive care unit admission. Testing with serology and blood polymerase chain reaction should be part of a syndromic screen for all children with severe myocarditis.

The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial.

BACKGROUND: Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). METHODS: In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry-India (CTRI/2022/06/043608) and is completed. FINDINGS: 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8-99·9) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9-99·2) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4-100·0) with Sii-PTCV and 3·3% (0·1-17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9-99·2) with Sii-PTCV and 0% (0·0-11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. INTERPRETATION: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. FUNDING: Serum Institute of India.

Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

OBJECTIVES: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. METHODS: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. RESULTS: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. CONCLUSIONS: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.