BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists.

Background: Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children. Aim: To investigate heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children. Methods: A whole blood stimulation assay was used to investigate in vitro cytokine responses to heterologous stimulants (killed pathogens, Toll-like receptor ligands) and SARS-CoV-2 antigens. Samples from 29 children, aged 5-11 years, before and 28 days after a second BNT162b2 vaccination were analysed (V2 + 28). Samples from eight children were analysed six months after BNT162b2 vaccination. Results: At V2 + 28, interferon-γ and monocyte chemoattractant protein-1 responses to S. aureus, E. coli, L. monocytogenes, BCG vaccine, H. influenzae, hepatitis B antigen, poly(I:C) and R848 stimulations were decreased compared to pre-vaccination. For most of these heterologous stimulants, IL-6, IL-15 and IL-17 responses were also decreased. There were sustained decreases in cytokine responses to viral, but not bacterial, stimulants six months after BNT162b2 vaccination. Cytokine responses to irradiated SARS-CoV-2, and spike glycoprotein subunits (S1 and S2) were increased at V2 + 28 for most cytokines and remained higher than pre-vaccination responses 6 months after BNT162b2 vaccination for irradiated SARS-CoV-2 and S1. There was no correlation between BNT162b2 vaccination-induced anti-SARS-CoV2-receptor binding domain IgG antibody titre at V2 + 28 and cytokine responses. Conclusions: BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants, particularly one month after vaccination. This study is the first to report the immunological heterologous effects of COVID-19 vaccination in children.

Influenza vaccine administration in a paediatric intensive care unit.

AIM: We describe the clinical profile of children and outcomes of influenza immunisation for patients in a paediatric intensive care unit (PICU). METHODS: Over two influenza seasons: 19/04/2018 to 07/08/2018 and 02/05/2019 to 10/10/2019, an immunisation nurse and PICU nurse coordinator met weekly and identified patients to receive the influenza vaccine. An inpatient list of PICU patients was screened for eligible patients: greater than 6 months of age, did not have imminent procedures (e.g. surgery) or were not critically unwell, as determined by the treating team, to receive the influenza vaccine. Patients were excluded if they had undergone surgery in the previous 24 hours or were being treated palliatively. RESULTS: Sixty patients in PICU were identified, with 43% (26/60) receiving the vaccine while in PICU and 17% (10/60) once discharged from PICU to the general ward environment. The majority of patients immunised were in PICU due to cardiac surgery/cardiology or general medical conditions, such as cerebral palsy or RSV bronchiolitis. There were no reported adverse events following immunisation. CONCLUSIONS: We have demonstrated the suitability and acceptability of children in the PICU receiving the seasonal influenza vaccine and tailored interventions to follow-up once discharged from PICU to optimise protection.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial).

INTRODUCTION: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. METHODS AND ANALYSIS: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. ETHICS AND DISSEMINATION: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Minimising Immunisation Pain of childhood vaccines: The MIP pilot study.

AIM: Pain associated with immunisations can result in distress and/or anxiety for children and parents. We assessed the feasibility and acceptability of two novel devices; Coolsense (cold) and Buzzy (vibration ± cooling pads) versus standard care to minimise pain during immunisations. We also evaluated compliance to the devices and parent's perception of the effectiveness of the devices/standard care for minimising pain during immunisation. DESIGN: Open label, pilot, randomised controlled trial (RCT). METHODS: Forty children aged 3.5 to 6 years attending an Immunisation Centre at The Royal Children's Hospital in Melbourne, Australia, were randomised (1:1:1:1) into four groups: (i) Coolsense plus standard care; (ii) Buzzy with cold plus standard care; (iii) Buzzy without cold plus standard care; and (iv) Standard care alone (distraction with bubbles). RESULTS AND ANALYSIS: Recruitment was completed in 12 days. Seventy percent were compliant with Buzzy (±cold), 82% with Coolsense, and 60% with standard care. Buzzy (with cold) was identified as effective by 70% of parents, Coolsense by 64%, Buzzy without cold by 50% and standard care by 60%. CONCLUSIONS: This pilot study demonstrated feasibility. A larger RCT is needed to provide definitive evidence to inform best practice for minimising immunisation pain in young children.

Impact of Australian mandatory 'No Jab, No Pay' and 'No Jab, No Play' immunisation policies on immunisation services, parental attitudes to vaccination and vaccine uptake, in a tertiary paediatric hospital, the Royal Children's Hospital, Melbourne.

INTRODUCTION: 'No Jab, No Play' and 'No Jab, No Pay' mandatory immunisation policies were introduced in the state of Victoria and Australia-wide, respectively, in January 2016. They restrict access to childcare/kindergarten and family assistance payments respectively, for under-vaccinated children. We aimed to describe the proportion of attendees to immunisation services of a tertiary hospital, the Royal Children's Hospital Melbourne (RCH), who were motivated by the policies to discuss or catch-up vaccination. We explored the association between motivation by policies, vaccine hesitancy (VH) and intent to seek medical exemption, with vaccine-uptake. METHODS: Parents/Guardians and clinicians completed surveys October 2016-May 2017 from the nurse-led immunisation Drop in Centre (DIC) or physician-led Specialist Immunisation Clinic (SIC). Vaccine-uptake was measured using the Australian Immunisation Register (AIR) at baseline, 1 and 7 months post-attendance. The association between vaccine-uptake, motivation by policies and VH was explored by logistic regression. RESULTS: Of 607 children, 393 (65%) were from the DIC and 214 (35%) SIC. 74 (12%) parents were motivated by the policies to attend immunisation services and 19% were VH. Only 50% of VH parents planned to catch-up vaccination for enrolment to childcare/kindergarten. Seven months post-attendance there was no association between motivation by policies and full vaccination status (difference 10%, OR 0.42, CI 0.17-1.1, p 0.08). Fewer children were fully immunised at 7 months if their parents were VH (difference 18%; OR 0.24, CI 0.1-0.54, p < 0.001) or seeking medical exemption (difference 33%, OR 0.08, CI 0.01-0.6, p 0.015). CONCLUSION: The 'No Jab' policies motivated attendance to a tertiary immunisation service. However, children of vaccine hesitant parents and those seeking medical exemption to immunisation were less likely to be fully immunised after attendance, than at baseline. The 'No Jab' policies may not be changing vaccination behavior as intended for vaccine hesitant parents who are one of the key target groups, with further evaluation required.

Recurrence risk of a hypotonic hyporesponsive episode in two Australian specialist immunisation clinics.

BACKGROUND: A hypotonic hyporesponsive episode (HHE) is a well-described adverse event following immunisation (AEFI) in young children. There is limited data regarding recurrence post re-vaccination. METHOD: A retrospective analysis of HHEs reported to two tertiary paediatric hospitals in Australia: The Royal Children's Hospital, Melbourne [2006-11] and the Children's Hospital Westmead, Sydney [1997-2014]. HHE definition level of confidence was allocated according to Brighton Collaboration (BC) criteria and defined immediate if within 30 min post vaccination. The Australian Immunisation Register (AIR) was utilised to document current immunisation status. RESULTS: 235 HHE cases (135 Melbourne, 100 Sydney) were identified: 47% were female and 67% (157/235) occurred following the routine dose one vaccines at 6-8 weeks of age. Median time following immunisation was 120 min (range 1 min to 14 days) An immediate HHE occurred in 43% (102/235) and by BC criteria, 74% (173/235) were level 1 (definite). Subsequent vaccines were administered under supervision in hospital in 37% overall (86/235); 43% (58/135) in Melbourne and 28% (28/100) in Sydney. HHE recurrence rate was 3% (7/235) [95% confidence interval 1-6%]. AIR records were available in 94% (221/235). At a median age of 3.1 years, 84% (186/221) were up-to-date with recommended vaccines. CONCLUSION: This study highlights the importance of specialist immunization clinics in supporting the National Immunisation Program, through follow-up and management of serious adverse events following immunization.

Immunizations under sedation at a paediatric hospital in Melbourne, Australia from 2012-2016.

BACKGROUND: Sedation for immunizations is of particular importance in a subset of paediatric patients with anxiety disorders, needle phobia, developmental or behavioural disorders. The Royal Children's Hospital (RCH) Melbourne offers a unique immunization under sedation service for these patients. We aimed to evaluate the number and types of patients using inpatient sedation for immunizations, distraction and sedation techniques used, and outcomes of these procedures. METHODS: A medical record review was conducted on all patients who had immunization under sedation between January 2012 to December 2016 in the RCH Day Medical Unit (DMU). RESULTS: A total of 139 children and adolescents had 213 vaccination encounters. More than half of the vaccination encounters involved multiple vaccines. A total of 400 vaccines were administered. One third of patients (32.3%) had multiple DMU admissions for vaccinations. The median age of patients was 13 years. There were only 10 (4.7%) failed attempts at vaccination; all due to patient non-compliance with prescribed sedation. The majority of patients (58.9%) had a diagnosis of needle phobia. Sedation was most commonly adequately achieved with inhaled nitrous oxide (54.7% sole agent). Midazolam was often used as an adjunct therapy (42.8%). Local anaesthetic cream or play therapy, were used in only 5.9% and 3.9% of patients respectively, although this may reflect poor documentation rather than actual practice. CONCLUSIONS: For a subset of paediatric patients for which standard immunization procedures have failed, distraction techniques and conscious sedation enable immunizations to be given safely and effectively. Future research will develop protocols to streamline immunization procedures under sedation.

No jab, no record: Catch-up vaccination of children in immigration detention.

International Health and Medical Services (IHMS) are contracted to provide health services, including catch-up vaccination, for individuals in immigration detention. Our audit of catch-up vaccination in asylum seeker children who spent time in held detention demonstrates inadequate and suboptimal vaccine delivery in this setting, and no evidence that IHMS recorded vaccines on the Australian Childhood Immunisation Register at the time. We also found substantial shortfalls in vaccination for these children after they were released from detention. Immunisation in this cohort falls well below Australian community standards, does not demonstrate assurance in IHMS provision of care, and has implications for similar asylum seeker cohorts nationally as well as people in held detention.

Distribution of Bacillus Calmette-Guérin (BCG) Vaccine in Victoria 2013-2015.

BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine has an important role mitigating tuberculosis (TB) disease in high risk children. In Victoria, immunisation services at the Royal Children's Hospital (RCH) and Monash Health (MH) have been funded as the major providers of BCG vaccine since 2013. METHODS: In this article, we performed retrospective analysis of patients who attended RCH and MH for BCG between 1st November 2013- 30th November 2015. This was compared with local birth data in order to portray the distribution of BCG vaccine across various cohorts. OUTCOMES: A total of 3,975 patients received BCG vaccine (1,775 at Monash, 2,200 from RCH). Detailed data is only available on 830 RCH patients. The median age of the study population was 6.9 months (IQR 3.9-11.3). The majority of children (98.9%, 2,575/2,604) received BCG vaccine prior to overseas travel. Of these, 96.0% (2,474/2,575) were travelling to countries in Asia. Only 13/2,604 (0.5%) were given BCG vaccine prior to travel to a country with low incidence of TB. Most infants were of Asian descent (93.3% mothers [2,425/2,604], 90.4% [2,346/2,604] fathers). A much smaller proportion was African (1.4% mothers [35/2,604], 1.5% [39/2,604] fathers). This contrasts with 2012 Victorian birth data, which showed that 82.2% (7,508/ 9,134) babies born to mothers from high TB prevalence countries were of Asian descent, whereas 8.9% (816/ 9,134) were of African descent. These results highlight scope to improve awareness and equity of BCG vaccine service, particularly to infants of African background.

Providing opportunistic immunisations for at-risk inpatients in a tertiary paediatric hospital.

Attaining high immunisation coverage rates for children with medical conditions is vital. The Royal Children's Hospital (RCH) Immunisation Service has the opportunity to check each inpatient's immunisation status and provide opportunistic vaccines and/or bring the Australian Childhood Immunisation Register (ACIR) up-to-date. This paper highlights that during admission, one quarter of children were not up-to-date with routine scheduled immunisations and 42% of those inpatients due or overdue for immunisation were vaccinated. The model of establishing routine checking of immunisation records and reminding hospital staff about immunisation can result in improvements in vaccination coverage. Healthcare providers have a responsibility to check immunisation status and offer vaccines when necessary; however, often there are missed opportunities to immunise. This paper demonstrates that having a dedicated Immunisation Service, a partnership with a relevant government agency, and effective collaboration with inpatient clinical teams, opportunistic immunisation can be achieved for inpatients.

Establishing intra- and inter-rater agreement of the Face, Legs, Activity, Cry, Consolability scale for evaluating pain in toddlers during immunization.

BACKGROUND: The Face, Legs, Activity, Cry, Consolability (FLACC) scale is a five-item tool that was developed to assess postoperative pain in young children. The tool is frequently used as an outcome measure in studies investigating acute procedural pain in young children; however, there are limited published psychometric data in this context. OBJECTIVE: To establish inter-rater and intrarater agreement of the FLACC scale in toddlers during immunization. METHODS: Participants comprised a convenience sample of toddlers recruited from an immunization drop-in service, who were part of a larger pilot randomized controlled trial. Toddlers were video- and audiotaped during immunization procedures. The first rater scored each video twice in random order over a period of three weeks (intrarater agreement), while the second rater scored each video once and was blinded to the first rater's scores (inter-rater agreement). The FLACC scale was scored at four timepoints throughout the procedure. Intraclass correlation coefficients were used to assess agreement of the FLACC scale. RESULTS: Thirty toddlers between 12 and 18 months of age were recruited, and video data were available for 29. Intrarater agreement coefficients were 0.88 at baseline, 0.97 at insertion of first needle, and 0.80 and 0.81 at 15 s and 30 s following the final injection, respectively. Inter-rater coefficients were 0.40 at baseline, 0.95 at insertion of first needle, and 0.81 and 0.78 at 15 s and 30 s following the final injection, respectively. CONCLUSIONS: The FLACC scale has sufficient agreement in assessing pain in toddlers during immunizations, especially during the most painful periods of the procedure.

Pain management strategies used during early childhood immunisation in Victoria.

AIM: The study aims to identify pain management practices used during scheduled childhood immunisation. METHODS: A survey of members of the Australian Nurses Federation (Victorian Branch) Immunisation Nurses Special Interest Group. Questions included frequency of use of pain reduction strategies during immunisations for infants, toddlers and children, injection techniques and existence of an articulated pain management policy. RESULTS: The survey was emailed to 274 Immunisation Nurses Special Interest Group members with registered email addresses, and 125 (46%) completed the survey. Nineteen respondents (15.2%) stated their main place of employment had a pain management policy during immunisations and 20 (16.0%) respondents were not sure. Distraction strategies were frequently used during immunisation for all age groups, with 95 (76.0%) replying that distraction was used often or always. Breastfeeding during immunisation for infants younger than 6 months was used occasionally (n = 54, 44.6%), often (n = 11, 9.1%) or never (n = 55, 45.5%) and was used even less frequently for infants aged 6-12 months. Sucrose or other sweet solutions were almost never used for infants prior to, or during, immunisation. As a reward, lollies were frequently given to children after immunisations. Topical anaesthetics were almost never used in any age groups. Over half the respondents used a rapid injection technique; 55 (44.7%) used a slow technique and four respondents aspirated the needle before injections. CONCLUSIONS: Many distraction strategies were used during and following immunisation but sweet solutions, breastfeeding or topical anaesthetics were rarely used. Use of these strategies where feasible, should be facilitated in diverse settings where immunisations take place.

Syncope and seizures following human papillomavirus vaccination: a retrospective case series.

OBJECTIVE: To quantify and characterise the reports of syncope and seizures following quadrivalent (4v) human papillomavirus (HPV) vaccination. DESIGN AND SETTING: Retrospective case series of notifications to SAEFVIC (Surveillance of Adverse Events Following Vaccination In the Community), May 2007 - April 2009. MAIN OUTCOME MEASURES: Incidence of syncope and seizure following 4vHPV vaccination; clinical outcomes. RESULTS: 97/1653 SAEFVIC reports met the study criteria: afebrile seizures (3), syncopal seizures (31) and syncope alone (63). Median age at vaccination was 15 years (range, 8-26 years). Injuries were reported in seven cases, including one vertebral fracture. A SAEFVIC clinic review was undertaken in 41% (40/97) and 22 patients received further 4vHPV vaccine doses administered supine, with no recurrences. The reporting rate after 4vHPV vaccine for syncope and syncopal seizures was 7.8/100, 000 and 2.6/100, 000 doses distributed, respectively. CONCLUSION: Syncope and syncopal seizures occurred after 4vHPV vaccination in Victoria at rates similar to those seen internationally. Clinical review allowed clarification of the diagnosis and management, including safe administration of further doses under supervision.

Immunisation rates of children with cystic fibrosis using the Australian Childhood Immunisation Register.

AIM: The Australian Immunisation Handbook (ninth edition) recommends children with cystic fibrosis (CF) receive routine scheduled immunisations plus annual influenza vaccine and an additional pneumococcal vaccine at both 12 months and 4-5 years. Adherence with these recommendations is unknown. This study aimed to determine the immunisation status of children with CF attending the Royal Children's Hospital (RCH), Melbourne. METHODS: A retrospective audit of children with CF aged 6 months to 7 years (at 1 January 2008) was performed on the RCH CF outpatient clinic database. The Australian Childhood Immunisation Register (ACIR) and RCH Immunisation Service records were used to determine immunisation status. RESULTS: Eighty-nine children with CF were identified, 52 (58%) were male, with median age of 3.6 years. Eighty-two of 89 children (92%) were up to date with routine immunisations. According to the ACIR, of the 89 children sampled, 24 (27%) were given influenza vaccine in accordance with recommendations in 2007. Eighty children were older than 12 months of age at 1 January 2008 and 17 (21%) of these children had received the additional pneumococcal vaccine at 12 months. Thirty-eight children were older than 4 years of age at 1 January 2008 and 6 (16%) received the recommended 23vPPV booster. CONCLUSION: Most children with CF received their routine childhood immunisations but not the additional recommended immunisations. This highlights the potential value of the ACIR to accurately record all vaccines administered and for ACIR reminder letters to include the additional vaccines for children in special-risk groups.

Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: retrospective cohort study.

OBJECTIVE: To describe the outcomes of clinical evaluation, skin testing, and vaccine challenge in adolescent schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine introduced in Australian schools in 2007. DESIGN: Retrospective cohort study. SETTING: Two tertiary paediatric allergy centres in Victoria and South Australia, Australia. PARTICIPANTS: 35 schoolgirls aged 12 to 18.9 years with suspected hypersensitivity reactions to the quadrivalent human papillomavirus vaccine. MAIN OUTCOME MEASURES: Clinical review and skin prick and intradermal testing with the quadrivalent vaccine and subsequent challenge with the vaccine. RESULTS: 35 schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine were notified to the specialised immunisation services in 2007, after more than 380 000 doses had been administered in schools. Of these 35 schoolgirls, 25 agreed to further evaluation. Twenty three (92%) experienced reactions after the first dose. Thirteen (52%) experienced urticaria or angio-oedema, and of these, two experienced anaphylaxis. Thirteen had generalised rash, one with angio-oedema. The median time to reaction was 90 minutes. Nineteen (76%) underwent skin testing with the quadrivalent vaccine: all were skin prick test negative and one was intradermal test positive. Eighteen (72%) were subsequently challenged with the quadrivalent vaccine and three (12%) elected to receive the bivalent vaccine. Seventeen tolerated the challenge and one reported limited urticaria four hours after the vaccine had been administered. Only three of the 25 schoolgirls were found to have probable hypersensitivity to the quadrivalent vaccine. CONCLUSION: True hypersensitivity to the quadrivalent human papillomavirus vaccine in Australian schoolgirls was uncommon and most tolerated subsequent doses.