The seroprevalence of SARS-CoV-2-specific antibodies in Australian children: a cross sectional study (preprint)

Background: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated. Objective: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years. Methods: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. S and N seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework. Results: Blood was collected from 2,046 participants (median age: 6.6 years). Adjusted seroprevalence of spike-antibody was 92.1 % (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence increased with age but was similar across geographic distribution and socioeconomic quintiles. Conclusion: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia. Funding: Australian Government Department of Health and Aged Care.

A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of coadministration of seasonal influenza and COVID-19 vaccines (The FluVID study) (preprint)

Objectives: We evaluated the frequency of moderate and severe adverse events following coadministration of seasonal influenza vaccine (SIV) versus placebo with COVID-19 vaccines among adults to support practice guidelines. Methods: FluVID is a participant-blinded, phase IV, randomised control trial. On the same day as the participant's scheduled COVID-19 vaccine, participants were randomised to receive SIV or saline placebo; those assigned placebo at visit one then received SIV a week later, and vice versa. Self-reported adverse events were collected for daily seven days following each visit. The primary endpoint was any solicited adverse event of at least moderate severity occurring up to seven days following receipt of SIV or placebo. This was modelled using a Bayesian logistic regression model. Analyses were performed by COVID-19 vaccine type and dose number. Results: Overall, 248 participants were enrolled; of these, 195 had received BNT162b2 and 53 had received mRNA1273 COVID-19 vaccines according to national guidelines. After randomisation, 119 were assigned to receive SIV and 129 were assigned to receive placebo at visit one. Adverse events were most frequently reported as mild (grade 1) in nature. Among 142 BNT162b2 booster dose one and 43 BNT162b2 booster dose two recipients, the posterior median risk difference for moderate/severe adverse events following SIV versus placebo was 13% (95% credible interval [CrI] -0.03 to 0.27) and 13% (95%CrI -0.37 to 0.12), respectively. Among 18 mRNA1273 booster dose one and 35 mRNA1273 booster dose two recipients, the posterior median risk difference of moderate/severe adverse events following influenza vaccine versus placebo was 6% (95%CrI -0.29 to 0.41) and -4% (95%CrI -0.30 to 0.23), respectively. Conclusion: Adverse events following SIV and COVID-19 co-administration were generally mild and occurred with similar frequency to events following COVID-19 vaccine alone. We found no evidence to justify routine separation of SIV and COVID-19 vaccine doses.

Infection and vaccine induced Spike antibody responses against SARS-CoV-2 Variants of concern in immune naïve children and adults (preprint)

A more efficient and effective adaptive humoral immune response has been proposed as the basis of the usually favourable outcome of paediatric COVID-19. The breadth of virus and vaccine immunogenicity towards the ever-mutating Spike protein amongst variants of concern (VOC) have not yet been compared between children and adults. We utilized molecular cloning and sensitive antibody detection against conformational Spike by flow cytometry to assess Spike antibodies and delineate the immunogenic region in immune naïve children and adults vaccinated by BNT162b2 and ChAdOx1, and naturally infected with Early Clade, Delta, and Omicron variants. Patient sera were analysed against SARS-CoV-2 Spike antigens including naturally occurring VOCs Alpha, Beta, Gamma, Delta, Omicron BA.1, BA.2, and BA.5 variants of interest Epsilon, Kappa, Eta, D.2, and artificial Spike mutants. There was no notable difference between breadth and longevity of antibody responses generated against VOCs in children and adults. Vaccinated individuals displayed similar immunoreactivity profiles across variants to naturally infected individuals. Delta-infected patients had an enhanced immunogenicity toward Delta and some VOCs compared to patients infected by Early Clade SARS-CoV-2. Although Omicron BA.1, BA.2, and BA.5 antibody levels were increased after Omicron infection in both children and adults, immunogenicity against Omicron subvariants was reduced. This decrease was observed across VOC infection, immunization, and age groups. Selected epistatically combined mutations led to an increase of immunogenicity in artificial Spikes, but were unable to compensate overall within Omicron. Our results reveal important molecular features central to the generation of high antibody titers and broad immunoreactivity that should be considered in future vaccine design and global serosurveillance.

Active safety surveillance of COVID-19 mRNA vaccines in children aged 5-15 years in Australia (preprint)

AusVaxSafety (the Australian active safety surveillance system) used SMS/email delivered surveys to actively solicit the short-term (within first 3 days after vaccination) adverse event profile of mRNA COVID-19 vaccines in children (aged 5-15 years) by age, dose, brand and pre-existing comorbidity. 392,268 survey responses for children aged 5-15 who received a COVID-19 vaccine between July 2021 and May 2022 (211,994 following BNT162b2 10mcg in children aged 5-11 years, 173,329 following BNT162b2 30mcg and 6,945 following mRNA-1273 100mcg in adolescents aged 12-15 years) were analysed. Adverse event rates were higher following dose 2 and 3 compared to dose 1 after all vaccines and highest following dose 2 of mRNA-1273 in 12-15 years. Fever was low in the youngest children (5 years old, any dose; 1,090/26,181 (4%)). Medical review rates remained low (0.3% overall) and impact on daily activities was also low (7% overall). No self-reported cases of myocarditis or pericarditis were identified. Ongoing active safety surveillance of lower dose mRNA vaccines in children under 5 years old is required to better understand safety as the vaccines roll out into this population age-group.

Genome-wide determinants of mortality and clinical progression in Parkinson’s disease (preprint)

ABSTRACT Background There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. Methods We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality). Findings There was a robust effect of the APOE ε4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10 -10 ). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10 -8 ). A genomic variant associated with the expression of ADORA2A , encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94×10 -9 ). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD. Interpretation We report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD. RESEARCH IN CONTEXT Evidence before this study We searched PubMed for articles on Parkinson’s disease (PD) with no language restrictions from database inception up to February 9, 2022. We used the search terms “Parkinson disease AND genetics” and “disease progression OR survival OR mortality OR prognosis OR longitudinal studies”. We also conducted this search with the addition of “genome-wide association study” (GWAS) to focus on these genome-wide analyses. There are now three published large-scale GWASs investigating PD progression, and many candidate variant studies. However, no genome-wide studies have reported on survival/mortality in PD. Added value of this study To our knowledge, this is the first GWAS of survival in PD. Our study highlights new loci influencing survival in PD, including TBXAS1 and SYT10 . We also conducted GWASs of progression to other clinical milestones, Hoehn and Yahr stage 3 or greater, and cognitive impairment. We show that APOE influences both mortality and cognitive progression in PD, and report an additional locus influencing expression of ADORA2A which affects the rate of motor progression. Implications of all the available evidence With the exception of APOE , we report new loci which have not been previously associated with PD progression or for mortality and ageing in the general population. These loci could be investigated in functional studies as potential drug targets to stop or slow progression of PD. In addition, new genetic loci can help to improve our understanding of the biology of PD progression and prediction of progression. Further replication of these loci is also needed in independent, longitudinal PD cohorts.

COVID-19 in children in NSW, Australia, during the 2021 Delta outbreak: Severity and Disease spectrum (preprint)

Objective(s): To describe the severity and clinical spectrum of SARS-CoV-2 infection in Australian children during the 2021 Delta outbreak. Design, Setting & Participants: A prospective cohort study of children <16 years with a positive SARS-CoV-2 nucleic acid test cared for by the Sydney Children's Hospital Network (SCHN) virtual and inpatient medical teams between 1 June-31 October 2021. Main outcome measures: Demographic and clinical data from all admitted patients and a random sample of outpatients managed under the SCHN virtual care team were analysed to identify risk factors for admission to hospital. Results: There were 17,474 SARS-CoV-2 infections in children <16 years in NSW during the study period, of whom 11,985 (68.6%) received care coordinated by SCHN. Twenty one percent of children infected with SARS-CoV-2 were asymptomatic. For every 100 SARS-CoV-2 infections in children <16 years, 1.26 (95% CI 1.06 to 1.46) required hospital admission for medical care; while 2.46 (95% CI 2.18 to 2.73) required admission for social reasons only. Risk factors for hospitalisation for medical care included age <6 months, a history of prematurity, age 12 to <16 years, and a history of medical comorbidities (aOR 7.23 [95% CI 2.92 to 19.4]). Of 17,474 infections, 15 children (median age 12.8years) required ICU admission; and 294 children required hospital admission due to social or welfare reasons. Conclusion: The majority of children with SARS-CoV-2 infection (Delta variant) had asymptomatic or mild disease. Hospitalisation was uncommon and occurred most frequently in young infants and adolescents with comorbidities. More children were hospitalised for social reasons than for medical care.

Cervical Cancer and COVID: A collaborative assessment of the effect of the COVID pandemic on the presentation of Cervical cancer in the North of England (preprint)

Objective: To review the effect of the COVID-19 pandemic on the presentation of Cervical cancer. Design/ Setting: Retrospective study involving the Regional Cancer Centres in the M62 Group. Methods: Data was collected for two equal time periods. All cervical cancers were included and FIGO 2018 staging was used for the data collection. P values were calculated using binomial hypothesis test for the difference in staging. Time from symptoms to diagnosis was assessed using a normal distribution test. All other calculations were performed using chi-squared test. Statistical significance was considered if p values were <0.05. Main outcome measures: Histology, stage at diagnosis, date of onset of symptoms, investigation and type of treatment. Results: A total of 406 cases of cervical cancer were reviewed; 233 from May – October 2019 (pre-COVID) and 173 between May – October 2020 (post COVID); representing a significant reduction in new cervical cancer diagnoses of 25% post COVID (p<0.001) There was a 42% increase in the delay from start of symptoms to diagnosis Post COVID. Pre COVID, 27% of patients presented with Stage 3 or 4 disease, whilst during COVID this was 38%; statistically significant (p <0.001). When we evaluated the treatments received between the two time periods, this was also statistically significant (chi-squared, p=0.0005). Conclusions: This study has demonstrated a statistically significant increase in the stage of cervical cancer at diagnosis and a change in treatment for cervical cancer following the onset of COVID-19. The implications of this are discussed.