Adaptive immune responses to two-dose COVID-19 vaccine series in healthy Canadian adults ≥ 50 years: a prospective, observational cohort study.

To evaluate immune responses to COVID-19 vaccines in adults aged 50 years and older, spike protein (S)-specific antibody concentration, avidity, and function (via angiotensin-converting enzyme 2 (ACE2) inhibition surrogate neutralization and antibody dependent cellular phagocytosis (ADCP)), as well as S-specific T cells were quantified via activation induced marker (AIM) assay in response to two-dose series. Eighty-four adults were vaccinated with either: mRNA/mRNA (mRNA-1273 and/or BNT162b2); ChAdOx1-S/mRNA; or ChAdOx1-S/ChAdOx1-S. Anti-S IgG concentrations, ADCP scores and ACE2 inhibiting antibody concentrations were highest at one-month post-second dose and declined by four-months post-second dose for all groups. mRNA/mRNA and ChAdOx1-S/mRNA schedules had significantly higher antibody responses than ChAdOx1-S/ChAdOx1-S. CD8+ T-cell responses one-month post-second dose were associated with increased ACE2 surrogate neutralization. Antibody avidity (total relative avidity index) did not change between one-month and four-months post-second dose and did not significantly differ between groups by four-months post-second dose. In determining COVID-19 correlates of protection, a measure that considers both antibody concentration and avidity should be considered.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Clinical perspective on topical vaccination strategies.

Vaccination is one of the most successful measures in modern medicine to combat diseases, especially infectious diseases, and saves millions of lives every year. Vaccine design and development remains critical and involves many aspects, including the choice of platform, antigen, adjuvant, and route of administration. Topical vaccination, defined herein as the introduction of a vaccine to any of the three layers of the human skin, has attracted interest in recent years as an alternative vaccination approach to the conventional intramuscular administration because of its potential to be needle-free and induce a superior immune response against pathogens. In this review, we describe recent progress in developing topical vaccines, highlight progress in the development of delivery technologies for topical vaccines, discuss potential factors that might impact the topical vaccine efficacy, and provide an overview of the current clinical landscape of topical vaccines.

Vaccination during pregnancy and modulation of IgG response to pertussis vaccines in infants: The impact of different vaccine formulations.

The IgG response following infant diphtheria-tetanus-acellular pertussis (DTaP) immunization is influenced by the formulation of the infant and/or the adult vaccine (Tdap) given during pregnancy. DTaP vaccines containing either 3 (DTaP3) or 5 (DTaP5) pertussis antigens are commonly used. By conducting a secondary analysis of a large randomized controlled trial, we compared IgG levels against pertussis vaccine antigens in children of Td- and Tdap5-vaccinated mothers, after stratifying by infant vaccine formulation. After immunization with a primary series of DTaP5, but not DTaP3, IgG GMCs against pertussis antigens were significantly lower in infants of Tdap-immunized mothers compared with infants of Td-vaccinated mothers (pertussis toxin: GMC = 52.3[Tdap5] vs 83.5[Td], p < 0.001). Before and after the DTaP booster dose, IgG GMCs were similar in infants of Tdap- and Td-immunized mothers specifically when infants received the DTaP3 vaccine. The combination of the TdaP5 vaccine for mothers and the DTaP3 vaccine for children could attenuate Tdap-associated immunomodulation.

The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis.

Background: Human Immunodeficiency Virus (HIV)-exposed uninfected (HEU) infants have a higher burden of infectious diseases related morbidity and mortality compared with HIV-unexposed uninfected (HUU). Immunization of pregnant women living with HIV (PWLWH) could reduce the severity and burden of infectious diseases for HEU in early infancy. Methods: We conducted a systematic review of safety and immunogenicity of vaccines administered to PWLWH and meta-analyses to test the overall effect of immunogenicity comparing pregnant women without HIV (PWWH) to PWLWH. We searched MEDLINE, Embase, Web of Science, Virtual Health Library and Cochrane databases in accordance with PRISMA guidelines for randomized controlled trials and observational studies. Review articles, case series, conference abstracts, and animal studies were excluded. Studies were included from inception to 6th September 2023, with no language restrictions. Random effects meta-analyses were performed for immunogenicity using Review manager (RevMan) analysis software version 5.4.1, Geometric Mean Titer (GMT) values were transformed to obtain the mean and standard deviation within RevMan, the effect size was computed and reported as mean difference with respective 95% confidence intervals. The review was registered with PROSPERO CRD42021289081. Findings: We included 12 articles, comprising 3744 pregnant women, 1714 were PWLWH given either influenza, pneumococcal or an investigational Group B streptococcal (GBS) vaccine. Five studies described safety outcomes, and no increase in adverse events was reported in PWLWH compared to PWWH. The GMT increase from baseline to 28-35 weeks post vaccination in HA units ranged from 12.4 (95% CI: 9.84-14.9) to 238.8 (95% CI: 0.35-477.9). Meta-analyses of influenza vaccines showed the pooled geometric mean difference in Hemagglutination Inhibition (HAI) titers post vaccination was 56.01 (95% CI: 45.01-67.01), p < 0.001. The increase was less in PWLWH when compared with PWWH: -141.76 (95% CI: -194.96, -88.55), p < 0.001. Interpretation: There are limited data on the safety and immunogenicity of vaccines given to PWLWH making policy consideration in this group difficult when new vaccines are introduced. With new vaccines on the horizon, PWLWH need to be included in studies to promote vaccine confidence for this special population. Funding: This work was funded by Medical Research Council Joint Clinical Trials Round 9 [MR/T004983/1].

Indirect impact of childhood 13-valent pneumococcal conjugate vaccine (PCV13) in Canadian older adults: a Canadian Immunization Research Network (CIRN) retrospective observational study.

BACKGROUND: 13-valent pneumococcal conjugate vaccine (PCV13) has been part of publicly funded childhood immunisation programmes in Ontario and British Columbia (BC) since 2010. We assessed the indirect impact of infant PCV13 programmes on invasive pneumococcal disease (IPD) and all-cause pneumonia hospitalisation in older adults (aged ≥65 years) using a retrospective observational study. METHODS: We extracted monthly IPD and all-cause pneumonia cases from laboratory and health administrative databases between January 2005 and December 2018. Using a quasi-experimental difference-in-differences design, we calculated the ratio of risk ratios (RRRs) using incidence rates of IPD or all-cause pneumonia cases before (pre-PCV13 period) and after (PCV13 period) 2010 with rates of fractures as controls. RESULTS: The rates of all IPD or PCV serotype-specific IPD for older adults in both Ontario and BC did not change in 8 years after childhood PCV13 programme implementation. All-cause pneumonia increased in Ontario (RRR 1.38, 95% CI 1.11 to 1.71) but remained unchanged in BC. CONCLUSIONS: Indirect community protection of older adults from hospitalisation with pneumococcal disease stalled despite maturation of childhood PCV13 vaccination programmes in two Canadian provinces.

Distinguishing community-acquired bacterial and viral meningitis: Microbes and biomarkers.

Diagnostic tools to differentiate between community-acquired bacterial and viral meningitis are essential to target the potentially lifesaving antibiotic treatment to those at greatest risk and concurrently spare patients with viral meningitis from the disadvantages of antibiotics. In addition, excluding bacterial meningitis and thus decreasing antibiotic consumption would be important to help reduce antimicrobial resistance and healthcare expenses. The available diagnostic laboratory tests for differentiating bacterial and viral meningitis can be divided microbiological pathogen-focussed methods and biomarkers of the host response. Bacterial culture-independent microbiological methods, such as highly multiplexed nucleic acid amplification tests, are rapidly making their way into the clinical practice. At the same time, more conventional host protein biomarkers, such as procalcitonin and C-reactive protein, are supplemented by newer proteomic and transcriptomic signatures. This review aims to summarise the current state and the recent advances in diagnostic methods to differentiate bacterial from viral meningitis.

Evaluating the Impact of the BioFire FilmArray in Childhood Meningitis: An Observational Cohort Study.

BACKGROUND: Multiplex polymerase chain reaction assays have the potential to reduce antibiotic use and shorten length of inpatient stay in children with suspected central nervous system infection by obtaining an early microbiological diagnosis. The clinical impact of the implementation of the BioFire FilmArray Meningitis/Encephalitis Panel on the management of childhood meningitis was evaluated at the John Radcliffe Hospital in Oxford and Children's Health Ireland at Temple Street in Dublin. METHODS: Children who had lumbar punctures performed as part of a septic screen were identified retrospectively through clinical discharge coding and microbiology databases from April 2017 to December 2018. Anonymized clinical and laboratory data were collected. Comparison of antibiotic use, length of stay and outcome at discharge was made with a historical cohort in Oxford (2012-2016), presenting before implementation of the FilmArray. RESULTS: The study included 460 children who had a lumbar puncture as part of an evaluation for suspected central nervous system infection. Twelve bacterial cases were identified on the FilmArray that were not detected by conventional bacterial culture. Bacterial culture identified one additional case of bacterial meningitis, caused by Escherichia coli , which had not been identified on the FilmArray. Duration of antibiotics was shorter in children when FilmArray was used than before its implementation; enterovirus meningitis (median: 4 vs. 5 days), human parechovirus meningitis (median: 4 vs. 4.5 days) and culture/FilmArray-negative cerebrospinal fluid (median: 4 vs. 6 days). CONCLUSIONS: The use of a FilmArray can identify additional bacterial cases of meningitis in children that had been negative by traditional culture methods. Children with viral meningitis and culture-negative meningitis received shorter courses of antibiotics and had shorter hospital stays when FilmArray was used. Large studies to evaluate the clinical impact and cost effectiveness of incorporating the FilmArray into routine testing are warranted.

Factors associated with SARS-CoV-2 infection in unvaccinated children and young adults.

BACKGROUND AND OBJECTIVES: Pediatric COVID-19 cases are often mild or asymptomatic, which has complicated estimations of disease burden using existing testing practices. We aimed to determine the age-specific population seropositivity and risk factors of SARS-CoV-2 seropositivity among children and young adults during the pandemic in British Columbia (BC). METHODS: We conducted two cross-sectional serosurveys: phase 1 enrolled children and adults < 25 years between November 2020-May 2021 and phase 2 enrolled children < 10 years between June 2021-May 2022 in BC. Participants completed electronic surveys and self-collected finger-prick dried blood spot (DBS) samples. Samples were tested for immunoglobulin G antibodies against ancestral spike protein (S). Descriptive statistics from survey data were reported and two multivariable analyses were conducted to evaluate factors associated with seropositivity. RESULTS: A total of 2864 participants were enrolled, of which 95/2167 (4.4%) participants were S-seropositive in phase 1 across all ages, and 61/697 (8.8%) unvaccinated children aged under ten years were S-seropositive in phase 2. Overall, South Asian participants had a higher seropositivity than other ethnicities (13.5% vs. 5.2%). Of 156 seropositive participants in both phases, 120 had no prior positive SARS-CoV-2 test. Young infants and young adults had the highest reported seropositivity rates (7.0% and 7.2% respectively vs. 3.0-5.6% across other age groups). CONCLUSIONS: SARS-CoV-2 seropositivity among unvaccinated children and young adults was low in May 2022, and South Asians were disproportionately infected. This work demonstrates the need for improved diagnostics and reporting strategies that account for age-specific differences in pandemic dynamics and acceptability of testing mechanisms.

Neurological involvement in hospitalized children with SARS-CoV-2 infection: a multinational study.

BACKGROUND AND OBJECTIVES: Neurological involvement associated with SARS-CoV-2 infection is increasingly recognized. However, the specific characteristics and prevalence in pediatric patients remain unclear. The objective of this study was to describe the neurological involvement in a multinational cohort of hospitalized pediatric patients with SARS-CoV-2. METHODS: This was a multicenter observational study of children <18 years of age with confirmed SARS-CoV-2 infection or multisystemic inflammatory syndrome (MIS-C) and laboratory evidence of SARS-CoV-2 infection in children, admitted to 15 tertiary hospitals/healthcare centers in Canada, Costa Rica, and Iran February 2020-May 2021. Descriptive statistical analyses were performed and logistic regression was used to identify factors associated with neurological involvement. RESULTS: One-hundred forty-seven (21%) of 697 hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Headache (n = 103), encephalopathy (n = 28), and seizures (n = 30) were the most reported. Neurological signs/symptoms were significantly associated with ICU admission (OR: 1.71, 95% CI: 1.15-2.55; p = 0.008), satisfaction of MIS-C criteria (OR: 3.71, 95% CI: 2.46-5.59; p < 0.001), fever during hospitalization (OR: 2.15, 95% CI: 1.46-3.15; p < 0.001), and gastrointestinal involvement (OR: 2.31, 95% CI: 1.58-3.40; p < 0.001). Non-headache neurological manifestations were significantly associated with ICU admission (OR: 1.92, 95% CI: 1.08-3.42; p = 0.026), underlying neurological disorders (OR: 2.98, 95% CI: 1.49-5.97, p = 0.002), and a history of fever prior to hospital admission (OR: 2.76, 95% CI: 1.58-4.82; p < 0.001). DISCUSSION: In this study, approximately 21% of hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Future studies should focus on pathogenesis and long-term outcomes in these children.

Bloodstream Infections in Children Hospitalized for Influenza, the Canadian Immunization Monitoring Program Active (IMPACT).

BACKGROUND: We aimed to estimate the proportion of children hospitalized for influenza whose illness was complicated by bloodstream infection, describe their clinical course, and identify the factors associated with bloodstream infection. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from the 2010-2011 to 2020-2021 influenza seasons. Factors associated with bloodstream infection were identified using multivariable logistic regression analyses. RESULTS: Among 9179 laboratory-confirmed influenza hospital admissions, bloodstream infection occurred in 87 children (0.9%). Streptococcus pyogenes (22%), Staphylococcus aureus (18%) and Streptococcus pneumoniae (17%) were the most common bloodstream infection pathogens identified. Children with cancer [adjusted odds ratio (aOR): 2.78; 95% confidence interval (CI): 1.23-5.63], a laboratory-confirmed nonbloodstream bacterial infection (aOR: 14.1; 95% CI: 8.04-24.3) or radiographically-confirmed pneumonia (aOR: 1.87; 95% CI: 1.17-2.97) were more likely to experience a bloodstream infection, whereas children with chronic lung disorders were less likely (aOR: 0.41; 95% CI: 0.19-0.80). Disease severity markers such as intensive care unit admission (aOR: 2.11; 95% CI: 1.27-3.46), mechanical ventilation (aOR: 2.84; 95% CI: 1.63-4.80) and longer hospital length of stay (aOR: 1.02; 95% CI: 1.01-1.03) were associated with bloodstream infection. Bloodstream infection also increased the odds of death (aOR: 13.0; 95% CI: 4.84-29.1) after adjustment for age, influenza virus type and the presence of any at-risk chronic condition. CONCLUSIONS: Bloodstream infections, although infrequent, are associated with intensive care unit admission, mechanical ventilation, increased hospital length of stay and in-hospital mortality, thus requiring increased levels of care among pediatric influenza hospitalizations.

Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT.

Background: Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50-60%). Standard technique includes lying infants on their side and removing the stylet 'late', that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet 'early', that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives: The aim of the Neonatal Champagne Lumbar punctures Every time - An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of 'early' rather than 'late' stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods: This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results: Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations: This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners' seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion: Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work: The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators' previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration: This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50­60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the 'stylet', which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. 'early stylet removal') or once the tip is thought to have reached the spinal fluid (i.e. 'late stylet removal'). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and 'early' with 'late' stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide.

The success of publicly funded rotavirus vaccine programs for preventing community- and hospital-acquired rotavirus infections in Canadian pediatric hospitals: an observational study.

BACKGROUND: Canadian immunization programs for rotavirus started in 2011. We sought to determine their effect on the burden of community-acquired admissions and hospital-acquired rotavirus at pediatric hospitals. METHODS: The Canadian Immunization Monitoring Program Active (IMPACT) network conducted active surveillance for rotavirus-positive hospital admissions between 2005 and 2020 at 12 pediatric hospitals. We used yearly rates of community-acquired rotavirus per 10 000 admissions and hospital-acquired rotavirus infections per 1000 patient-days to determine changes in the pre- and post-vaccine program periods. RESULTS: During the 15-year study period, 5691 rotavirus hospital admissions and hospital-acquired infections were detected, including 4323 (76%) community-acquired infections and 1368 (24%) hospital-acquired infections. The average community-acquired rate in the pre-vaccine period was 60.3 (95% confidence interval [CI] 53.7-68.3) per 10 000 admissions, with a decline to 11.0 (95% CI 7.5-15.1) per 10 000 admissions in the post-vaccine period, resulting in an average reduction of 81.7% (95% CI 74.4%-87.8%). The rate of hospital-acquired rotavirus declined from 0.35 (95% CI 0.29-0.41) per 1000 patient-days in the pre-vaccine period to 0.05 (95% CI 0.03-0.07) per 1000 patient-days in the post-vaccine period, resulting in an 85.3% (95% CI 77.7%-91.9%) average decline. Herd protection was present among children aged 2-16 years. INTERPRETATION: Although start dates of rotavirus vaccine programs across provinces varied, there was around an 80% average decrease in both community-acquired and hospital-acquired rotavirus infections at pediatric hospitals in Canada in the 1- to 9-year interval after implementation of rotavirus vaccine programs. Herd protection is an important aspect of rotavirus vaccines for other children who are not vaccine eligible, and rotavirus vaccines continue to provide important benefits both for children and health care systems.

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial.

OBJECTIVE: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness. DESIGN: Phase 3b multicentre, double-blind, randomised placebo-controlled trial. SETTING: Twenty-one hospitals in the UK. PARTICIPANTS: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308. INTERVENTION: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24-36 hours apart, in addition to standard treatment. MAIN OUTCOME MEASURE: The primary outcome was a 'good recovery' at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended. SECONDARY OUTCOME MEASURES: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data. RESULTS: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG. CONCLUSIONS: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Antibiotic use in children hospitalised for influenza, 2010-2021: the Canadian Immunization Monitoring Program Active (IMPACT).

PURPOSE: To determine characteristics associated with inappropriate antibiotic use amongst children hospitalised for influenza. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations amongst children ≤ 16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from September 2010 to August 2021. Antibiotic use was presumed appropriate if any of the following indications were met: age < 1 month, immunocompromised, hemoglobinopathy, laboratory-confirmed bacterial infection, radiographically confirmed pneumonia, admission to an intensive care unit and mechanical ventilation. Regression analyses were used to identify baseline and clinical characteristics associated with antibiotic use amongst patients without an appropriate indication. RESULTS: Amongst 8971 children, 6424 (71.6%) received any antibiotics during their hospitalisation. Amongst the 4429 children without an appropriate indication, 2366 (53.2%) received antibiotics. Antibiotic use amongst children without appropriate indication differed between study centres, ranging from 33.2% to 66.1% (interquartile range [IQR] 50.6-56.3%); it did not change significantly over time (p-value for trend = 0.28). In multivariable analyses, older age (adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI] 0.96-0.99), presence of any high-risk condition (aOR 0.80, 95% CI 0.70-0.92), influenza virus type B (aOR 0.8, 95% CI 0.70-0.91) and croup (aOR 0.64, 95% CI 0.49-0.83) were associated with less, whilst fever ≥ 38.5 °C (aOR 1.82, 95% CI 1.42-2.35) and hospitalisation duration (aOR 1.12, 95% CI 1.09-1.15) were associated with more inappropriate antibiotic use. CONCLUSIONS: Over two-third of children hospitalised for influenza received antibiotics, including over half of those without an appropriate indication for antibiotic treatment. Differences amongst study centres suggest the importance of contextual determinants of antibiotic use.

Antibody and B-cell Immune Responses Against Bordetella Pertussis Following Infection and Immunization.

Neither immunization nor recovery from natural infection provides life-long protection against Bordetella pertussis. Replacement of a whole-cell pertussis (wP) vaccine with an acellular pertussis (aP) vaccine, mutations in B. pertussis strains, and better diagnostic techniques, contribute to resurgence of number of cases especially in young infants. Development of new immunization strategies relies on a comprehensive understanding of immune system responses to infection and immunization and how triggering these immune components would ensure protective immunity. In this review, we assess how B cells, and their secretory products, antibodies, respond to B. pertussis infection, current and novel vaccines and highlight similarities and differences in these responses. We first focus on antibody-mediated immunity. We discuss antibody (sub)classes, elaborate on antibody avidity, ability to neutralize pertussis toxin, and summarize different effector functions, i.e. ability to activate complement, promote phagocytosis and activate NK cells. We then discuss challenges and opportunities in studying B-cell immunity. We highlight shared and unique aspects of B-cell and plasma cell responses to infection and immunization, and discuss how responses to novel immunization strategies better resemble those triggered by a natural infection (i.e., by triggering responses in mucosa and production of IgA). With this comprehensive review, we aim to shed some new light on the role of B cells and antibodies in the pertussis immunity to guide new vaccine development.

Pediatric RSV-Associated Hospitalizations Before and During the COVID-19 Pandemic.

Importance: Respiratory syncytial virus (RSV) is a leading cause of pediatric hospitalizations. Objective: To describe the epidemiology and burden of RSV-associated hospitalizations among children and adolescents in Canadian tertiary pediatric hospitals from 2017 to 2022, including changes during the COVID-19 pandemic. Design, Setting, and Participants: This cross-sectional study was conducted during 5 RSV seasons (2017-2018 to 2021-2022) at 13 pediatric tertiary care centers from the Canadian Immunization Monitoring Program Active (IMPACT) program. Hospitalized children and adolescents aged 0 to 16 years with laboratory-confirmed RSV infection were included. Main Outcomes and Measures: The proportion of all-cause admissions associated with RSV and counts and proportions of RSV hospitalizations with intensive care unit (ICU) admission, prolonged stay (≥7 days), and in-hospital mortality were calculated overall and by season, age group, and region. Seasonality was described using epidemic curves. RSV hospitalizations for 2021-2022 were compared with those in the prepandemic period of 2017-2018 through 2019-2020. Bonferroni corrections were applied to P values to adjust for multiple statistical comparisons. Results: Among 11 014 RSV-associated hospitalizations in children and adolescents (6035 hospitalizations among male patients [54.8%]; 5488 hospitalizations among patients aged <6 months [49.8%]), 2594 hospitalizations (23.6%) had admission to the ICU, of which 1576 hospitalizations (60.8%) were among children aged less than 6 months. The median (IQR) hospital stay was 4 (2-6) days. The mean (SD) number of RSV-associated hospitalizations during prepandemic seasons was 2522 (88.8) hospitalizations. There were 58 hospitalizations reported in 2020-2021, followed by 3170 hospitalizations in 2021-2022. The proportion of all-cause hospitalizations associated with RSV increased from a mean of 3.2% (95% CI, 3.1%-3.3%) before the pandemic to 4.5% (95% CI, 4.3%-4.6%) in 2021-2022 (difference, 1.3 percentage points; 95% CI, 1.1-1.5 percentage points; corrected P < .001). A significant increase in RSV-associated hospitalizations was found in 2021-2022 for 3 provinces (difference range, 2.5 percentage points; 95% CI, 1.4-3.6 percentage points for Quebec to 2.9 percentage points; 95% CI, 1.4-3.5 percentage points for Alberta; all corrected P < .001). Age, sex, ICU admission, prolonged length of stay, and case fatality rate did not change in 2021-2022 compared with the prepandemic period. Interregional differences in RSV seasonality were accentuated in 2021-2022, with peaks for 1 province in October, 4 provinces in December, and 3 provinces in April, or May. Conclusions and Relevance: This study found that the burden of RSV-associated hospitalizations in Canadian pediatric hospitals was substantial, particularly among infants aged less than 6 months, and RSV hospitalizations increased in 2021-2022 compared with the prepandemic period, while severity of illness remained similar. These findings suggest that RSV preventive strategies for infants aged less than 6 months would be associated with decreased RSV disease burden in children.

Immunity of Canadians and risk of epidemics workshop - Conference report.

On November 18-19, 2019, the Immunity of Canadians and Risk of Epidemics (iCARE) Network convened a workshop in Toronto, Ontario, Canada. The objectives of the workshop were to raise the profile of sero-epidemiology in Canada, discuss best practice and methodological innovations, and strategize on the future direction of sero-epidemiology work in Canada. In this conference report, we describe the presentations and discussions from the workshop, and comment on the impact of the COVID-19 pandemic on serosurveillance initiatives, both in Canada and abroad.

Tdap vaccine in pregnancy and immunogenicity of pertussis and pneumococcal vaccines in children: What is the impact of different immunization schedules?

BACKGROUND: In 2019, the 3 + 1 schedule for children's vaccination (2-4-6-18 months old) was changed for a reduced 2 + 1 schedule (2-4-12 months old) in Quebec, Canada. We compared the post-booster anti-pertussis and anti-pneumococcus IgG antibody concentrations among children of Tdap-vaccinated and unvaccinated mothers for different vaccine schedules and vaccine formulations. METHODS: We conducted an observational cohort study. An invitation letter to potential participants was provided during a routine vaccination visit. Children's blood samples were analyzed post-booster at 13 (2 + 1 schedule) or 19 (3 + 1 schedule) months of age for antibodies against pertussis antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)) and pneumococcal antigens (serotypes 4, 18C, 19A, and 19F). IgG concentrations among children of Tdap-vaccinated and unvaccinated mothers for each vaccination schedule were compared using geometric mean concentrations (GMCs) and GMC ratios (GMRs), adjusting for potentially immune-response-influencing factors (aGMR). Serotype-specific pneumococcal seroprotection rates were also compared. RESULTS: A total of 360 children were included for pertussis analysis and 248 for pneumococcal analysis. For the 2 + 1 schedule, 13-month-old children of Tdap-vaccinated mothers had lower GMCs against PT, FHA, and PRN, with aGMR (95 %CI) of 0.77 (0.65-0.90), 0.66 (0.55-0.79), 0.72 (0.52-0.99), respectively. For the 3 + 1 schedule, at 19 months old, the interference appeared to be attenuated (higher aGMR values). GMCs against PT were slightly higher in the 3 + 1 than the 2 + 1 schedule: 126.5 IU/ml vs 91.6 IU/ml; aGMR = 1.27. GMCs against PT, FHA and PRN were slightly higher among children who received Infanrix hexa® compared to those who received Pediacel® at 12 months old. For pneumococcal antibodies, at 13 months old, there was no strong evidence of immune interference in children of Tdap-vaccinated mothers. CONCLUSION: Infant vaccination schedule may influence immune interference associated with maternal Tdap vaccination. More studies are needed to assess the clinical impact of this interference on children's protection.

Parent and healthcare provider views of live varicella vaccination of pediatric solid organ transplant recipients.

BACKGROUND: Live attenuated varicella vaccine (LAVV) has historically been contraindicated in children who are immunocompromised due to solid organ transplant (SOT) because of safety concerns. Recently, clinical guidelines were developed that support post-transplant varicella vaccination in selected SOT recipients based on emerging evidence of LAVV safety. This qualitative study sought to explore barriers and facilitators to implementing the new guidelines, as well as acceptability of LAVV among healthcare providers (HCPs) and parents. METHODS: HCPs and parents of transplant recipients were recruited from four sites using purposive sampling. Data from semi-structured interviews were analyzed using an Interpretive Description approach that incorporated data from the interviews, academic knowledge and clinical experience, and drew from Grounded Theory and Thematic Analysis. The theoretical framework used was Adaptive Leadership. RESULTS: Thirty-four participants (16 HCPs and 18 parents) were included in the analysis. Parents developed skills in adaptive leadership that included strategies to protect their child against infectious diseases. Foundational information that live vaccines were absolutely contraindicated post-transplant "stuck" with parents and led them to develop strategies other than vaccination to keep their child safe. Some parents struggled to understand that information previously presented as a certainty (contraindication of LAVV) could change. Their approach to adaptive leadership informed their appraisal of the new vaccination guidelines and willingness to accept vaccination. CONCLUSIONS: HCPs should adopt a family-centered approach to communicating changing guidelines that considers parents' approach to adaptive leadership and discusses the changing nature of medical evidence. Trust between HCPs and parents can facilitate these conversations.