Explore the vast range of titles available.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.

Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017–20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03–9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity. The impact of other pathogens on disease outcome was studied in European infants with RSV infection. Additional viruses were commonly co-detected during infection but were weakly linked to severity. However, presence of Haemophilus bacteria strongly associated with severe cases.

Background. In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7–2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. Methods. A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. Results. After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. Conclusions. The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation.

The 2009 influenza A H1N1 pandemic placed unprecedented demand on public health authorities and the vaccine industry. Efforts were coordinated internationally to maximise the speed of vaccine development, distribution, and delivery, and the European Union's novel fast-track authorisation procedures mandated increased postmarketing surveillance to monitor vaccine safety. Clinicians in Finland and Sweden later identified an apparent increase in the incidence of narcolepsy associated with a specific adjuvanted pandemic influenza vaccine. After extensive review, the European Medicines Agency confirmed the existence of this association, which has since been detected in England, Ireland, France, and Norway. Assessments of the causal mechanisms continue. In this Review, we discuss how the narcolepsy association was detected, and we present the evidence according to the causality assessment criteria for adverse events following immunisation. The lessons learnt emphasise the central role of alert clinicians in reporting of suspected adverse reactions, and the importance of internationally robust postmarketing surveillance strategies as crucial components in future mass immunisation programmes.

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post‐vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP‐IPV‐Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post‐vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G‐CSF, IL‐1RA and IL‐6. Post‐vaccination fever was associated with increased expression of SELL , involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin‐3, ‐5 and GM‐CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine. SYNOPSIS A randomised clinical trial evaluates transcriptomic and proteomic profiles following infant concomitant 4CMenB vaccination, compared with control vaccines alone. A novel framework is provided for both understanding and predicting vaccine immunogenicity and reactogenicity. 4CMenB vaccination is associated with a distinct gene expression and plasma protein signature. Post‐vaccination fever is associated with increased expression of SELL, involved in neutrophil recruitment. Transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine are presented. Graphical Abstract A randomised clinical trial evaluates transcriptomic and proteomic profiles following infant concomitant 4CMenB vaccination, compared with control vaccines alone. A novel framework is provided for both understanding and predicting vaccine immunogenicity and reactogenicity.

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based. Emerging SARS-CoV-2 viral variants of concern may have the potential to escape vaccine-elicited immunity. Global strategies involving integration of clinical rollout with systematic investigation are presented.

The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18–20 months after their last dose (at about 3.5 years of age). We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%–100% against matched strains, 60%–100% against mismatched strains) or at 40 and 42 months (n = 29) (31%–100% against matched strains, 41%–81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%–100% and against mismatched strains in 59%–100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. Trial registration:ClinicalTrials.gov, no. NCT01027351

BackgroundDifferentiating infants with adverse events following immunisation (AEFIs) or invasive bacterial infection (IBI) is a significant clinical challenge. Young infants post vaccination are therefore often admitted to the hospital for parenteral antibiotics to avoid missing rare cases of IBI.MethodsDuring a service evaluation project, we conducted a single-centre retrospective observational study of infants with IBI, urinary tract infection (UTI) or AEFI from two previously published cohorts. All patients presented to hospital in Oxfordshire, UK, between 2011 and 2018, spanning the introduction of the capsular group-B meningococcal vaccine (4CMenB) into routine immunisation schedules. Data collection from paper and electronic notes were unblinded. Clinical features, including National Institute for Health and Care Excellence (NICE) ‘traffic light’ risk of severe illness and laboratory tests performed on presentation, were described, and comparisons made using regression models, adjusting for age and sex. We also compared biochemical results on presentation to those of well infants post vaccination, with and without 4CMenB regimens.ResultsThe study included 232 infants: 40 with IBI, 97 with probable AEFI, 24 with possible AEFI, 27 with UTI and 44 post vaccination ‘well’ infants. C-reactive protein (CRP) was the only discriminatory blood marker, with CRP values above 83 mg/L only observed in infants with IBI or UTI. NICE risk stratification was significantly different between groups but still missed cases of IBI, and classification as intermediate risk was non-differential. Fever was more common in probable AEFI cases, while seizures and rashes were equally frequent. Diarrhoea and clinician-reported irritability or rigours were all more common in IBI.ConclusionsClinical features on presentation may aid risk stratification but cannot reliably differentiate IBI from AEFI in infants presenting to the emergency department. Blood results are generally unhelpful due to post vaccination inflammatory responses, particularly in children receiving 4CMenB vaccination. Improved biomarkers and clinical prediction tools are required to aid management in febrile infants post vaccination.