Nirsevimab: Alleviating the burden of RSV morbidity in young children.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) and hospital admissions in early childhood. Recent advancements in novel preventive therapies, including extended half-life monoclonal antibodies and antenatal vaccination, have afforded new opportunities to significantly reduce the burden of this infection. Nirsevimab is a novel monoclonal antibody that provides sustained protection against RSV for at least 5 months among newborns and young children. It has received regulatory approval in numerous countries and is being implemented across various settings. Two pivotal Phase 3 trials (MELODY, HARMONIE) demonstrated significant reductions in RSV-associated LRTI hospitalisations following nirsevimab administration, with treatment efficacy of 62.1% and 83.2%. Emerging real-world data from early adopters of nirsevimab corroborates these findings. Studies from Spain, Luxembourg, France and the USA report effectiveness rates between 82% and 90% in preventing RSV-associated hospitalisations among infants entering their first RSV season. Current implementation strategies for nirsevimab have primarily focused on seasonal administration for all infants, aligned to local RSV seasons, and often include catch-up doses for those born before the season begins. Available cost-effectiveness analyses indicate that while nirsevimab offers significant potential public health benefits, its adoption must carefully consider economic factors such as treatment costs, implementation strategies tailored to local viral epidemiology, and logistics for vaccine delivery. Overall, nirsevimab presents a promising opportunity to alleviate the burden of severe RSV infections in young children. However, ongoing surveillance and refinements in implementation strategies are crucial to optimise its impact and ensure sustainability across diverse health-care settings.

COVID-19 vaccines in 2023.

Most Australian adults now have hybrid immunity to the SARS-CoV-2 virus, referring to a combination of protection from previous vaccine doses and past infection. Protection from both vaccination and past infection wanes over time. Booster doses are recommended to ensure that those who are at increased risk of severe COVID-19 remain protected. The optimal timing of future booster doses to maintain adequate protection against severe illness is not yet known. Older age remains the most important risk factor for severe COVID-19, including in the current Omicron variant era. The original COVID-19 vaccines are monovalent vaccines based on the ancestral strain of the SARS-CoV-2 virus. Bivalent vaccines have been developed based on earlier Omicron subvariants (BA.1 or BA.4-5) and the ancestral strain. These provide enhanced protection against severe illness from Omicron compared with the original monovalent vaccines. Updated monovalent vaccines based on a more recent Omicron subvariant (XBB.1.5) have been developed. COVID-19 vaccines have an excellent safety record, and serious adverse events are extremely rare.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

The Spectrum and Burden of Influenza-Associated Neurological Disease in Children: Combined Encephalitis and Influenza Sentinel Site Surveillance From Australia, 2013-2015.

Background: There are few longitudinal studies of seasonal influenza-associated neurological disease (IAND) and none from the Southern Hemisphere. Methods: We extracted prospectively acquired Australian surveillance data from 2 studies nested within the Paediatric Active Enhanced Disease Surveillance (PAEDS) network: the Influenza Complications Alert Network (FluCAN) study and the Australian Childhood Encephalitis (ACE) study between 2013 and 2015. We described the clinical features and severity of IAND in children, including influenza-associated encephalitis/encephalopathy (IAE). We calculated the proportion of hospitalized influenza that is associated with IAND and IAE, and incidence of IAE. Results: Over 3 influenza seasons, we identified 54 cases of IAND at 2 tertiary children's hospitals from Australia that accounted for 7.6% of hospitalized influenza. These included 10 cases of IAE (1.4% hospitalized influenza). The mean annual incidence of IAE among Australian children (aged ≤14 years) was 2.8 per 1000000. The spectrum of IAND was broad and included IAE (n = 10) including distinct acute encephalopathy syndromes, simple febrile seizures (n = 14), other seizures (n = 16), acute ataxia (n = 4), and other subacute syndromes (transverse myelitis [n = 1], opsoclonus myoclonus [n = 1]). Two-thirds of children with IAND were aged ≤4 years; less than half had preexisting neurological disease or other risk factors for severe influenza. IAE caused death or neurological morbidity in half of cases. Conclusions: Seasonal influenza is an important cause of acute neurological disease in Australian children. The spectrum of seasonal IAND appears similar to that described during the 2009 H1N1 pandemic. IAE is associated with high morbidity and mortality.

Influenza hospitalizations in Australian children.

Australia's National Immunisation Program (NIP) provides free influenza vaccination for children at high risk of severe influenza; a pilot-funded programme for vaccine in all children aged 6 months to <5 years in one of eight states, has seen poor vaccine impact, related to recent vaccine safety concerns. This retrospective review examined influenza hospitalizations in children aged <16 years from three seasons (2011-2013) at two paediatric hospitals on opposite sides of the country. Comparisons of this cohort were made with state-based data on influenza-coded hospitalizations and national immunization register data on population-level immunization coverage. Of 740 hospitalizations, the majority were aged <5 years (476/740, 64%), and a substantial proportion (57%) involved healthy children, not currently funded for influenza vaccine. Intensive care unit admission occurred in 8·5%, and 1·5% of all children developed encephalitis. Use of antiviral therapy was uncommon (20·5%) and decreasing. Of those hospitalized, only 5·0% of at-risk children, who are currently eligible for free vaccine, and 0·7% of healthy children were vaccinated prior to hospitalization. This was consistent with low population-wide estimates of influenza vaccine uptake. It highlights the need to examine alternative strategies, such as universally funded paediatric influenza vaccination, to address disease burden in Australian children.

Influenza vaccine efficacy in young children attending childcare: A randomised controlled trial.

AIM: Influenza causes a substantial burden in young children. Vaccine efficacy (VE) data are limited in this age group. We examined trivalent influenza vaccine (TIV) efficacy and safety in young children attending childcare. METHODS: A double-blind, randomised controlled trial in children aged 6 to <48 months was conducted with recruitment from Sydney childcare centres in 2011. Children were randomised to receive two doses of TIV or control hepatitis A vaccine. Efficacy was evaluated against polymerase chain reaction-confirmed influenza using parent-collected nose/throat swabs during influenza-like-illness. Safety outcomes were assessed during 6 months of follow-up. RESULTS: Fifty-seven children were allocated to influenza vaccine and 67 to control; all completed the study. The influenza attack rate was 1.8 vs 13.4% in the TIV and control groups, respectively; VE 87% (95%CI: 0-98%). For children aged 24 to <48 months, 0 vs 8 (18.6%) influenza infections occurred in the TIV and control groups respectively, giving a VE of 100% (16-100%). Efficacy was not shown in children 6 to <24 months, probably due to insufficient power. Injection site and systemic adverse events were mostly mild to moderate with no significant differences, apart from more mild diarrhoea following dose 2 in TIV recipients (11.8 vs 0%). CONCLUSIONS: Influenza vaccine appeared efficacious in the subgroup of children aged 24 to <48 months, although caution is required due to the small number of participants. There were no serious adverse events and most parents would vaccinate again. Influenza vaccination in a childcare setting could be valuable and a larger confirmatory study would be helpful.

Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."

Utility of early influenza diagnosis through point-of-care testing in children presenting to an emergency department.

AIM: Influenza causes a large burden of disease in children. Point-of-care testing (POCT) can rapidly diagnose influenza with the potential to reduce investigation and hospital admission rates, but information on its use in an Australian setting is limited. METHODS: Through a retrospective review of laboratory-confirmed influenza cases presenting at a paediatric emergency department (ED) in 2009, we evaluated children diagnosed by POCT versus standard testing (direct fluorescent antibody, polymerase chain reaction or viral culture) and assessed differences in investigations, admission requirements, length-of-stay (LOS) in ED/hospital and antibiotic/antiviral prescription. The rate of serious bacterial infection was examined. RESULTS: Compared with standard testing (n = 65), children diagnosed by positive POCT (n = 236) had a shorter median hospital LOS by 1 day (P = 0.006), increased antiviral prescription (odds ratio 3.31, P < 0.001) and a reduction in the time to influenza diagnosis (2.4 vs. 24.4 h, P < 0.001); however, a negative POCT result (n = 63) resulted in delayed diagnosis (44.0 h, P = 0.001). POCT did not decrease LOS in ED. Interpretation of reductions in admission and investigations with POCT may be limited by possible confounding. Approximately 4% of influenza patients had a serious bacterial infection; urinary tract infections were commonest (2.7%), but no cerebrospinal fluid cultures were positive. A single positive blood culture was seen among 332 immunocompetent influenza patients. CONCLUSIONS: Influenza diagnosis by POCT was quicker and reduced LOS of hospitalised children, whereas negative results delayed diagnosis. Negative POCT should not alter usual investigations if influenza remains suspected. A controlled prospective study during the influenza season is needed to clarify the direct benefits of POCT.

Australian vaccine preventable disease epidemiological review series: Influenza 2006 to 2015.

INTRODUCTION: Influenza is a major contributor to the preventable health burden of Australians each year. The National Immunisation Program provides influenza vaccine for those at highest risk of severe disease. This review of influenza epidemiology examines current data on influenza disease burden in Australia, in the context of several comparable countries having programs with much broader eligibility for influenza vaccine in children. METHODS: Influenza notifications (2006-2015), hospitalisations, and deaths (2006-2013) were sourced and age-specific rates calculated. Comparisons were made across age groups in the pre-pandemic, pandemic, and post-pandemic periods and by Indigenous and non-Indigenous status. RESULTS: The 2009 pandemic year and the 2012 non-pandemic season resulted in the highest rates of notification, hospitalisation and death. Influenza notification rates were 4.0 times higher and hospitalisation rates 2.1 times higher during 2011-2013 compared with 2006-2008. Death rates varied widely, but peaks corresponded to high-activity seasons. Influenza hospitalisation rates were highest among those aged <5 and ≥65 years, but influenza-attributable deaths were identified primarily in those aged ≥75 years. Significantly higher notification and hospitalisation rates were seen for all Indigenous people, but higher death rates were largely restricted to the 2009 pandemic year. CONCLUSIONS: Based on notifications, hospitalisations and deaths, burden of disease from influenza is highest at the extremes of life and is significantly higher among Indigenous people of all ages. This pattern of disease burden warrants consideration of widened eligibility for influenza vaccine under the National Immunisation Program to all Indigenous people and all children less than 5 years of age.

Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children.

In 2010, increased febrile convulsions (FC) occurred after administration of inactivated trivalent influenza vaccine (TIV) in Australia. We systematically reviewed the rates of fever, FC and serious adverse events (SAEs) after TIV, focussing on published and unpublished clinical trial data from 2005 to 2012, and performed meta-analysis of fever rates. From 4,372 records in electronic databases, 18 randomised controlled trials (RCTs), 14 non-randomised clinical trials, six observational studies and 12 registered trials (five RCTs and seven non-randomised) were identified. In published RCTs, fever ≥ 38 °C rates after first dose of non-adjuvanted TIV were 6.7% and 6.9% for children aged 6­35 months and ≥ 3 years, respectively. Analysis of RCTs by vaccine manufacturer showed pooled fever estimates up to 5.1% with Sanofi or GlaxoSmithKline vaccines; bioCSL vaccines were used in two non-randomised clinical trials and one unpublished RCT and were associated with fever in 22.5­37.1% for children aged 6­35 months. In RCTs, FCs occurred at a rate of 1.1 per 1,000 vaccinated children. While most TIVs induced acceptably low fever rates, bioCSL influenza vaccines were associated with much higher rates of fever in young children. Future standardised study methodology and access to individual level data would be illuminating.