Learning to TODDLE: inspiring the paediatricians of tomorrow.

With numbers of children and young people waiting for treatment rising to record-high levels in the UK, the need for paediatricians is emphasised. In order to accommodate these demands, it is essential that more medical students are encouraged to pursue paediatric careers. By providing vital career support to aspiring paediatricians at an undergraduate level, recruitment into paediatrics can be amplified. An important way in which medical students gain early exposure to paediatrics is through local paediatric organisations like university societies, who can nurture interest towards the specialty and provide links to exploring and building upon paediatric career development. By empowering student initiatives to create opportunities for students to pursue paediatrics, we can build and support the next generation of paediatricians from the ground up. This was demonstrated by the Edinburgh University Paediatrics Society's free virtual career building series TODDLE: 'The building blOcks to Developing your paeDiatric portfoLio and carEer'. Feedback from the TODDLE series evidently showed an appetite for paediatric career support at an undergraduate level internationally, with attendees commenting on the usefulness, novelty and accessibility of the series. TODDLE emphasised the importance of providing paediatric career advice to medical students and showed the feasibility and practicality of student-led initiatives in providing this support as well as other paediatric exposures. Through collaborative work and the sharing of resources, any organisation at a student level can offer opportunities for engagement in paediatrics on a national and international basis.

Confirmed SARS-CoV-2 infection in Scottish neonates 2020-2022: a national, population-based cohort study.

OBJECTIVES: To examine neonates in Scotland aged 0-27 days with SARS-CoV-2 infection confirmed by viral testing; the risk of confirmed neonatal infection by maternal and infant characteristics; and hospital admissions associated with confirmed neonatal infections. DESIGN: Population-based cohort study. SETTING AND POPULATION: All live births in Scotland, 1 March 2020-31 January 2022. RESULTS: There were 141 neonates with confirmed SARS-CoV-2 infection over the study period, giving an overall infection rate of 153 per 100 000 live births (141/92 009, 0.15%). Among infants born to women with confirmed infection around the time of birth, the confirmed neonatal infection rate was 1812 per 100 000 live births (15/828, 1.8%). Two-thirds (92/141, 65.2%) of neonates with confirmed infection had an associated admission to neonatal or (more commonly) paediatric care. Six of these babies (6/92, 6.5%) were admitted to neonatal and/or paediatric intensive care; however, none of these six had COVID-19 recorded as their main diagnosis. There were no neonatal deaths among babies with confirmed infection. IMPLICATIONS AND RELEVANCE: Confirmed neonatal SARS-CoV-2 infection was uncommon over the first 23 months of the pandemic in Scotland. Secular trends in the neonatal confirmed infection rate broadly followed those seen in the general population, although at a lower level. Maternal confirmed infection at birth was associated with an increased risk of neonatal confirmed infection. Two-thirds of neonates with confirmed infection had an associated admission to hospital, with resulting implications for the baby, family and services, although their outcomes were generally good. Ascertainment of confirmed infection depends on the extent of testing, and this is likely to have varied over time and between groups: the extent of unconfirmed infection is inevitably unknown.

Uptake of infant and preschool immunisations in Scotland and England during the COVID-19 pandemic: An observational study of routinely collected data.

BACKGROUND: In 2020, the SARS-CoV-2 (COVID-19) pandemic and lockdown control measures threatened to disrupt routine childhood immunisation programmes with early reports suggesting uptake would fall. In response, public health bodies in Scotland and England collected national data for childhood immunisations on a weekly or monthly basis to allow for rapid analysis of trends. The aim of this study was to use these data to assess the impact of different phases of the pandemic on infant and preschool immunisation uptake rates. METHODS AND FINDINGS: We conducted an observational study using routinely collected data for the year prior to the pandemic (2019) and immediately before (22 January to March 2020), during (23 March to 26 July), and after (27 July to 4 October) the first UK "lockdown". Data were obtained for Scotland from the Public Health Scotland "COVID19 wider impacts on the health care system" dashboard and for England from ImmForm. Five vaccinations delivered at different ages were evaluated; 3 doses of "6-in-1" diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B vaccine (DTaP/IPV/Hib/HepB) and 2 doses of measles, mumps, and rubella (MMR) vaccine. This represented 439,754 invitations to be vaccinated in Scotland and 4.1 million for England. Uptake during the 2020 periods was compared to the previous year (2019) using binary logistic regression analysis. For Scotland, uptake within 4 weeks of a child becoming eligible by age was analysed along with geographical region and indices of deprivation. For Scotland and England, we assessed whether immunisations were up-to-date at approximately 6 months (all doses 6-in-1) and 16 to 18 months (first MMR) of age. We found that uptake within 4 weeks of eligibility in Scotland for all the 5 vaccines was higher during lockdown than in 2019. Differences ranged from 1.3% for first dose 6-in-1 vaccine (95.3 versus 94%, odds ratio [OR] compared to 2019 1.28, 95% confidence intervals [CIs] 1.18 to 1.39) to 14.3% for second MMR dose (66.1 versus 51.8%, OR compared to 2019 1.8, 95% CI 1.74 to 1.87). Significant increases in uptake were seen across all deprivation levels. In England, fewer children due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in-1 (95.8 versus 96.3%, OR compared to 2019 0.89, 95% CI 0.86- to 0.91) to 2.1% for third 6-in-1 (86.6 versus 88.7%, OR compared to 2019 0.82, 95% CI 0.81 to 0.83). The use of routinely collected data used in this study was a limiting factor as detailed information on potential confounding factors were not available and we were unable to eliminate the possibility of seasonal trends in immunisation uptake. CONCLUSIONS: In this study, we observed that the national lockdown in Scotland was associated with an increase in timely childhood immunisation uptake; however, in England, uptake fell slightly. Reasons for the improved uptake in Scotland may include active measures taken to promote immunisation at local and national levels during this period and should be explored further. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination campaigns.

Rosetting revisited: a critical look at the evidence for host erythrocyte receptors in Plasmodium falciparum rosetting.

Malaria remains a major cause of mortality in African children, with no adjunctive treatments currently available to ameliorate the severe clinical forms of the disease. Rosetting, the adhesion of infected erythrocytes (IEs) to uninfected erythrocytes, is a parasite phenotype strongly associated with severe malaria, and hence is a potential therapeutic target. However, the molecular mechanisms of rosetting are complex and involve multiple distinct receptor-ligand interactions, with some similarities to the diverse pathways involved in P. falciparum erythrocyte invasion. This review summarizes the current understanding of the molecular interactions that lead to rosette formation, with a particular focus on host uninfected erythrocyte receptors including the A and B blood group trisaccharides, complement receptor one, heparan sulphate, glycophorin A and glycophorin C. There is strong evidence supporting blood group A trisaccharides as rosetting receptors, but evidence for other molecules is incomplete and requires further study. It is likely that additional host erythrocyte rosetting receptors remain to be discovered. A rosette-disrupting low anti-coagulant heparin derivative is being investigated as an adjunctive therapy for severe malaria, and further research into the receptor-ligand interactions underlying rosetting may reveal additional therapeutic approaches to reduce the unacceptably high mortality rate of severe malaria.

Antenatal vaccination against Group B streptococcus: attitudes of pregnant women and healthcare professionals in the UK towards participation in clinical trials and routine implementation.

INTRODUCTION: Maternal vaccination is increasingly part of antenatal care in the UK and worldwide. Trials of Group B streptococcus vaccines are ongoing. This study investigated the attitudes of pregnant women and healthcare professionals towards antenatal vaccination, both in routine care and a clinical trial setting. MATERIAL AND METHODS: Survey of 269 pregnant women, 273 midwives/obstetricians and 97 neonatal doctors across seven sites in the UK assessing attitudes towards antenatal vaccinations, knowledge of Group B streptococcus, a hypothetical Group B streptococcus vaccine, and participation in clinical vaccine trials. RESULTS: 68% of pregnant women intended to receive a vaccine during their current pregnancy (183/269) and 43% (of all respondents, 115/269) reported they would be very/fairly likely to accept a vaccine against Group B streptococcus despite only 29% (55/269) knowing what Group B streptococcus was. This increased to 69% after additional information about Group B streptococcus was provided. Twenty-four percent of pregnant women reported they would be likely to take part in a clinical trial of an unlicensed Group B streptococcus vaccine. Fifty-nine percent of maternity professionals and 74% of neonatologists would be likely to recommend participation in a Group B streptococcus vaccine trial to women, with the vast majority (>99%) willing to be involved in such a study. Incentives to take part cited by pregnant women included extra antenatal scans and the opportunity to be tested for Group B streptococcus. CONCLUSION: Pregnant women and healthcare professionals were open to the idea of an antenatal Group B streptococcus vaccine and involvement in clinical trials of such a vaccine. Education and support from midwives would be key to successful implementation.

Non-specific immunological effects of selected routine childhood immunisations: systematic review.

OBJECTIVE:  To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus. DESIGN:  Systematic review of randomised controlled trials, cohort studies, and case-control studies. DATA SOURCES:  Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:  All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines. RESULTS:  The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in lymphoproliferation to microbial antigens from tetanus toxoid and C albicans Increases in immunogenicity to heterologous antigens were noted after diphtheria-tetanus (herpes simplex virus and polio antibody titres) and diphtheria-tetanus-pertussis (pneumococcus serotype 14 and polio neutralising responses) vaccination. CONCLUSIONS:  The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-γ responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the clinical importance of the findings.

Attitudes towards antenatal vaccination, Group B streptococcus and participation in clinical trials: Insights from focus groups and interviews of parents and healthcare professionals.

INTRODUCTION: Antenatal vaccination has become a part of routine care during pregnancy in the UK and worldwide, leading to improvements in health for both pregnant women and their infants. However, uptake remains sub-optimal. Other antenatal vaccines targeting major neonatal pathogens, such as Group B streptococcus (GBS), the commonest cause of sepsis and meningitis in the neonatal period, are undergoing clinical trials but more information is needed on how to improve acceptance of such vaccines. METHODS: Qualitative study using focus groups and interviews; involving 14 pregnant women, 8 mothers with experience of GBS, and 28 maternity healthcare professionals. Questions were asked regarding antenatal vaccines, knowledge of GBS, attitudes to a potential future GBS vaccine and participation in antenatal vaccine trials. RESULTS: All participants were very cautious about vaccination during pregnancy, with harm to the baby being a major concern. Despite this, the pregnant women and parents with experience of GBS were open to the idea of an antenatal GBS vaccine and participating in research, while the maternity professionals were less positive. Major barriers identified included lack of knowledge about GBS and the reluctance of maternity professionals to be involved. INTERPRETATION: In order for a future GBS vaccine to be acceptable to both pregnant women and the healthcare professionals advising them, a major awareness campaign would be required with significant focus on convincing and training maternity professionals.

Factors influencing women's attitudes towards antenatal vaccines, group B Streptococcus and clinical trial participation in pregnancy: an online survey.

OBJECTIVES: To explore factors influencing the likelihood of antenatal vaccine acceptance of both routine UK antenatal vaccines (influenza and pertussis) and a hypothetical group B Streptococcus (GBS) vaccine in order to improve understanding of how to optimise antenatal immunisation acceptance, both in routine use and clinical trials. SETTING: An online survey distributed to women of childbearing age in the UK. PARTICIPANTS: 1013 women aged 18-44 years in England, Scotland and Wales. METHODS: Data from an online survey conducted to gauge the attitudes of 1013 women of childbearing age in England, Scotland and Wales to antenatal vaccination against GBS were further analysed to determine the influence of socioeconomic status, parity and age on attitudes to GBS immunisation, using attitudes to influenza and pertussis vaccines as reference immunisations. Factors influencing likelihood of participation in a hypothetical GBS vaccine trial were also assessed. RESULTS: Women with children were more likely to know about each of the 3 conditions surveyed (GBS: 45% vs 26%, pertussis: 79% vs 63%, influenza: 66% vs 54%), to accept vaccination (GBS: 77% vs 65%, pertussis: 79% vs 70%, influenza: 78% vs 68%) and to consider taking part in vaccine trials (37% vs 27% for a hypothetical GBS vaccine tested in 500 pregnant women). For GBS, giving information about the condition significantly increased the number of respondents who reported that they would be likely to receive the vaccine. Health professionals were the most important reported source of information. CONCLUSIONS: Increasing awareness about GBS, along with other key strategies, would be required to optimise the uptake of a routine vaccine, with a specific focus on informing women without previous children. More research specifically focusing on acceptability in pregnant women is required and, given the value attached to input from healthcare professionals, this group should be included in future studies.

Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). INTERPRETATION: 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.

Persistence of bactericidal antibodies to 5 years of age after immunization with serogroup B meningococcal vaccines at 6, 8, 12 and 40 months of age.

BACKGROUND: A serogroup B meningococcal vaccine (4CMenB) has been licensed by the European commission for use in various infant schedules. However, data are limited on persistence of serum bactericidal antibodies (SBA), which is necessary to inform cost-effectiveness analysis. METHODS: Sera were obtained from 3 groups of 5-year-old children previously immunized at 6, 8, 12 and 40 months with either 4CMenB or rMenB (which lacks the outer membrane vesicle of 4CMenB) or at 40 and 42 months with 4CMenB only. Forty-nine control children were also recruited and blood obtained before and after 2 doses of 4CMenB at 60 and 62 months of age. Sera were tested for SBA to meningococcal B reference strains. RESULTS: At 5 years of age, 67% of those receiving 4CMenB in infancy had SBA titers ≥1:4 for strain 44/76, 100% for 5/99, 17% for NZ98/254 and 45% for M10713. Results for rMenB recipients varied from 0 (NZ98/254) to 100% (5/99). Of those immunized with 4CMenB at 40 and 42 months, 38% had SBA titers ≥1:4 at age 5 for 44/76, 100% for 5/99, 0% (NZ98/254) and 83% (M10713). Among controls, SBA titers were ≥1:4 in 4% (H44/76, 5/99), 0% (NZ98/254) and 67% (M10713) at baseline, increasing to 100% (H44/76 and 5/99), 89% (NZ98/254) and 97% (M10713) postimmunization. CONCLUSION: The variable rates of waning of antibody to the 4 components of 4CMenB complicates estimates of duration of protection and should be taken into account in cost-effectiveness analyses. A 2-dose schedule of 4CMenB in 5-year-old children was immunogenic.

Will booster doses be required for serogroup B meningococcal vaccine?

The European licensure of 4CMenB, the first vaccine licensed to prevent non-epidemic meningococcal B (MenB) disease, marked an important milestone in the fight against meningococcal disease. However, the potential introduction of 4CMenB into the routine infant schedule is complicated by a number of factors. The recent decline in the number of cases of invasive MenB disease in the UK has important implications for cost effectiveness, though the unpredictable nature of meningococcal disease epidemiology (as evidenced by a recent outbreak in MenB disease at Princeton University) means that it is not clear whether this decline will be sustained. The variable waning of antibody levels against each of the four key vaccine components also complicates the assessment of the likely duration and breadth of protection. After considering these factors, the UK Joint Committee on Vaccination and Immunisation (JCVI) released an interim statement in July 2013 indicating that the introduction of 4CMenB to the routine infant schedule was unlikely to be cost effective but highlighted the need for further data on strain coverage and persistence of immunity. This brief editorial discusses the possible role that booster doses of 4CMenB may have in prolonging persistence of immunity.