Considerations for unblinding individual study participants during vaccine trials.

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization.

Snotwatch COVID-toes: An ecological study of chilblains and COVID-19 diagnoses in Victoria, Australia

The COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions. We conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two. Our study collated data from three Primary Health Networks across Victoria, Australia, from 2017–2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations. We found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria. Our study statistically suggests that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data in identifying an uncommon manifestation of COVID-19 infections, which will be significantly beneficial to treating physicians.

Shoulder injury following COVID-19 vaccine administration: a case series and proposed diagnostic algorithm.

BACKGROUND: Shoulder Injury Related to Vaccine Administration (SIRVA) is a preventable adverse event following incorrect vaccine administration, which can result in significant long-term morbidity. There has been a notable surge in reported cases of SIRVA as a rapid national population-based COVID-19 immunization program has been rolled out across Australia. METHODS: Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) in Victoria identified 221 suspected cases of SIRVA following the commencement of the COVID-19 vaccination program, reported between February 2021 and February 2022. This review describes the clinical features and outcomes of SIRVA in this population. Additionally, a suggested diagnostic algorithm is proposed, in order to facilitate early recognition and management of SIRVA. RESULTS: 151 cases were confirmed as SIRVA, with 49.0% having received vaccines at state vaccination centers. 75.5% were suspected incorrect administration site, with most patients experiencing shoulder pain and restricted movement within 24 hours of vaccination, lasting on average 3 months. CONCLUSION: Improved awareness and education regarding SIRVA is imperative in a pandemic vaccine roll-out. The development of a structured framework for evaluating and managing suspected SIRVA will aid in timely diagnosis and treatment, essential to mitigate potential long-term complications.

Pediatric Hepatitis and Respiratory Viruses: A Spatiotemporal Ecologic Analysis.

INTRODUCTION: Beginning in early 2022, clusters of severe pediatric hepatitis were reported in Europe and the United States. To date, no cause has been identified although human adenovirus 41 has been proposed in a proportion of cases. We examined population data >11 years for hepatitis clusters in Victoria, Australia, and whether any were spatiotemporally associated with community transmission of common respiratory viruses. METHODS: We used SaTScan to analyze for clusters of pediatric hepatitis and respiratory adenoviruses in Victoria. Negative binomial regression analysis was performed to determine any associations between hepatitis and respiratory viruses across Victoria between July 1, 2011, and June 30, 2022. RESULTS: A number of positive associations were observed in Victoria between pediatric hepatitis clusters and respiratory viruses in our spatiotemporal analysis. A positive association was not found with respiratory adenoviruses or SARS-CoV-2. Increased hepatitis clusters were observed in 2021 and 2022 as noted internationally. CONCLUSION: The current hepatitis outbreak is novel and, although respiratory viruses are broadly associated with hepatitis, SARS-CoV-2 and respiratory adenoviruses are unlikely to be related.

AIDH Summit 2022 - Automated social media surveillance for detection of vaccine safety signals: a validation study.

BACKGROUND: Social media platforms have emerged as a valuable data source for public health research and surveillance. Monitoring of social media and user-generated data on the web enables timely and inexpensive collection of information, overcoming time lag and cost of traditional health reporting systems. OBJECTIVES: To identify personally experienced COVID-19 vaccine reactions expressed on Twitter and validate the findings against an established vaccine reactions reporting system. METHODS: We collected around three million tweets from 1.4 million users between 1 February 2021 - 31 January 2022, using COVID-19 vaccines and vaccine reactions keyword lists. We performed topic modelling on a sample of the data and applied a modified F1 scoring technique to identify a topic that best differentiated vaccine-related personal health mentions. We then manually annotated 4,000 of the records from this topic, which were used to train a transformer-based classifier to identify likely personally experienced vaccine reactions. Applying the trained classifier to the entire dataset allowed us to select records we could use to quantify potential vaccine side effects. Adverse events following immunization (AEFI) referred to in these records were compared with those reported to the state of Victoria's spontaneous vaccine safety surveillance system, SAEFVIC. RESULTS: The most frequently mentioned potential vaccine reactions generally aligned with SAEFVIC data. Notable exceptions were increased Twitter reporting of bleeding-related AEFI and allergic reactions, and more frequent SAEFVIC reporting of cardiac AEFI. CONCLUSIONS: Social media conversation can be used as a supplementary data source for detecting vaccine adverse event mentions. More work is required to verify the data.

Guillain-Barré syndrome temporally associated with COVID-19 vaccines in Victoria, Australia.

Guillain-Barré syndrome (GBS) is an adverse event of special interest (AESI) for surveillance systems monitoring adverse events following immunisation (AEFI) with COVID-19 vaccines. Emerging data support a temporal association between GBS and adenovirus-vector COVID-19 vaccines. We present a case series of GBS reports submitted between February and November 2021 to our enhanced spontaneous surveillance system (SAEFVIC) in Victoria, Australia, following vaccination with either the adenovirus-vector vaccine Vaxzevria ChadOx1-S (AstraZeneca) or an mRNA vaccine (Comirnaty BNT162b2 [Pfizer-BioNTech] or Spikevax mRNA-1273 [Moderna]). For each report, Brighton Collaboration case definitions were used to describe diagnostic certainty. Severity was graded using the GBS Disability Score. The observed incidence of GBS following immunisation against COVID-19 was compared to expected background ICD10-AM G61.0 coded hospitalisations. There were 41 total cases of GBS reported to SAEFVIC following Vaxzevria (n = 38), Comirnaty (n = 3), or Spikevax (n = 0) vaccines. The observed GBS incidence rate exceeded the expected background rate for Vaxzevria only, with 1.85 reports per 100,000 doses following dose 1, higher than the expected rate of 0.39 hospital admissions per 100,000 adults within 42 days of vaccination. Of 38 GBS reports following Vaxzevria, the median age at vaccination was 66 years and median onset of symptoms was 14 days following immunisation. There was one death. Four cases initially categorised as GBS were later reclassified as acute-onset chronic inflammatory demyelinating polyneuropathy. Fatigue was the predominant persisting symptom reported at follow up. Additional global studies are required to characterise risk factors, clinical variability, and to provide precision and generalizability regarding AEFI risks such as GBS associated with different vaccine platforms, which will help inform communication of the potential benefits and risks of COVID19 vaccination.

Information systems for vaccine safety surveillance.

Immunization implementation in the community relies upon post-licensure vaccine safety surveillance to maintain safe vaccination programs and to detect rare AEFI not observed in clinical trials. The increasing availability of electronic health-care related data and correspondence from both health-related providers and internet-based media has revolutionized health-care information. Many and varied forms of health information related to adverse event following immunization (AEFI) are potentially suitable for vaccine safety surveillance. The utilization of these media ranges from more efficient use of electronic spontaneous reporting, automated solicited surveillance methods, screening various electronic health record types, and the utilization of natural language processing techniques to scan enormous amounts of internet-based data for AEFI mentions. Each of these surveillance types have advantages and disadvantages and are often complementary to each other. Most are "hypothesis generating," detecting potential safety signals, where some, such as vaccine safety datalinking, may also serve as "hypothesis testing" to help verify and investigate those potential signals.

Snotwatch COVID-toes: An ecological study of chilblains and COVID-19 diagnoses in Victoria, Australia.

The COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions. We conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two. Our study collated data from three Primary Health Networks across Victoria, Australia, from 2017-2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations. We found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria. Our study statistically suggests that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data in identifying an uncommon manifestation of COVID-19 infections, which will be significantly beneficial to treating physicians.

Vaccine safety in Australia during the COVID-19 pandemic: Lessons learned on the frontline.

Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC), Victoria's vaccine safety service for reporting adverse events following immunisation (AEFI), has provided integrated spontaneous surveillance and clinical services for individuals affected by AEFI since 2007. We describe SAEFVIC's response to the COVID-19 vaccine program, and reflect on lessons learned for vaccine safety. The massive scale of the Australian COVID-19 vaccine program required rapid adaptations across all aspects of SAEFVIC's vaccine safety services. Collection of AEFI reports was streamlined and expanded, incorporating both spontaneous and active surveillance data. Dramatically increased report volumes were managed with additional staffing, and innovations to automate, filter, and triage reports for priority follow up. There were two major adverse events of special interest (AESI): thrombosis with thrombocytopaenia syndrome and myocarditis, with multiple other AESI also investigated. Rapid escalation mechanisms to respond to AESI were established, along with AESI-specific databases for enhanced monitoring. Vaccine education and training resources were developed and public-facing vaccine safety reports updated weekly. Frequent communication with local and national government and regulatory bodies, and consultation with specialist groups was essential. The COVID-19 vaccine program has highlighted the importance of vaccine safety in supporting public confidence in vaccines and informing evidence-based immunisation policy. Supporting the COVID-19 vaccine program has required flexibility in adapting to policy changes and evolving vaccine safety signals, careful triage and prioritisation, informatics innovation, and enhanced engagement with the public regarding vaccine safety. Long-term investment to continue strengthening vaccine safety systems, building on lessons learned, will be essential for the ongoing success of Australian vaccination programs.

Myocarditis and myopericarditis cases following COVID-19 mRNA vaccines administered to 12–17-year olds in Victoria, Australia

Importance COVID-19 mRNA vaccine-associated myocarditis has previously been described;however specific features in the adolescent population are currently not well understood. Objective To describe myocarditis adverse events following immunisation reported following any COVID-19 mRNA vaccines in the adolescent population in Victoria, Australia. Design Statewide, population-based study. Setting Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) is the vaccine-safety service for Victoria, Australia. Participants All SAEFVIC reports of myocarditis and myopericarditis in 12–17-year-old COVID-19 mRNA vaccinees submitted between 22 February 2021 and 22 February 2022, as well as accompanying diagnostic investigation results where available, were assessed using Brighton Collaboration criteria for diagnostic certainty. Exposures Any mRNA COVID-19 vaccine. Main outcomes/Mmeasure Confirmed myocarditis as per Brighton Collaboration criteria (levels 1–3). Results Clinical review demonstrated definitive (Brighton level 1) or probable (level 2) diagnoses in 75 cases. Confirmed myocarditis reporting rates were 8.3 per 100 000 doses in this age group. Cases were predominantly male (n=62, 82.7%) and post dose 2 (n=61, 81.3%). Rates peaked in the 16–17-year-old age group and were higher in males than females (17.7 vs 3.9 per 100 000, p=<0.001). The most common presenting symptoms were chest pain, dyspnoea and palpitations. A large majority of cases who had a cardiac MRI had abnormalities (n=33, 91.7%). Females were more likely to have ongoing clinical symptoms at 1-month follow-up (p=0.02). Conclusion Accurate evaluation and confirmation of episodes of COVID-19 mRNA vaccine-associated myocarditis enabled understanding of clinical phenotypes in the adolescent age group. Any potential vaccination and safety surveillance policies needs to consider age and gender differences.

A case report describing the immune response of an infant with congenital heart disease and severe COVID-19.

Background: Children with SARS-CoV-2 infection generally present with milder symptoms or are asymptomatic in comparison with adults, however severe disease occurs in a subset of children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterised. Methods: We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19 using high-dimensional flow cytometry and multiplex cytokine analysis. Results: Systemic cellular and cytokine profiling show an initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8 + T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4 + T (but not CD8 + T) cells occurred over time, with a predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Substantial in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory. Conclusions: These findings provide important insights into the immune response of a young infant with severe COVID-19 and will help to inform future research into therapeutic targets for high-risk groups.

Victorian Specialist Immunisation Services (VicSIS) - bolstering adult clinics for COVID-19 vaccines.

The Victorian Specialist Immunization Services (VicSIS) was established in Victoria, Australia, in February 2021, aiming to enhance vaccine safety services for Coronavirus disease (COVID-19) vaccines. VicSIS supports practitioners and patients with complex vaccine safety questions, including those who experience adverse events following immunization (AEFI) after COVID-19 vaccines. VicSIS provides individual vaccination recommendations, allergy testing, vaccine challenges, and vaccination under supervision. VicSIS initially comprised of eight adult COVID-19 specialist vaccination clinics, subsequently, expanding to better support pediatric patients as the Australian vaccine roll-out extended to adolescents and children. Since their establishment to September 2021, the inaugural VicSIS clinics received a total of 26,401 referrals and reviewed 6,079 patients. Consults were initially predominantly for pre-vaccination reviews, later predominantly becoming post-vaccination AEFI reviews as the program progressed. Regardless of the type of consult, the most common consult outcome was a recommendation for routine vaccination (73% and 55% of consult outcomes respectively). VicSIS is an integral component of the COVID-19 vaccination program and supports confidence in COVID-19 vaccine safety by providing consistent advice across the state. VicSIS aims to strengthen the health system through the pandemic, bolstering specialist immunization services beyond COVID-19 vaccines, including training the next generation of vaccinology experts.

Prospective characterisation of SARS-CoV-2 infections among children presenting to tertiary paediatric hospitals across Australia in 2020: a national cohort study.

OBJECTIVE: To present Australia-wide data on paediatric COVID-19 and multisystem inflammatory syndromes to inform health service provision and vaccination prioritisation. DESIGN: Prospective, multicentre cohort study. SETTING: Eight tertiary paediatric hospitals across six Australian states and territories in an established research surveillance network-Paediatric Active Enhanced Disease (PAEDS). PARTICIPANTS: All children aged <19 years with SARS-CoV-2 infection including COVID-19, Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) and Kawasaki-like disease TS infection (KD-TS) treated at a PAEDS site from 24 March 2020 to 31 December 2020. INTERVENTION: Laboratory-confirmed SARS-CoV-2 infection. MAIN OUTCOME: Incidence of severe disease among children with COVID-19, PIMS-TS and KD-TS. We also compared KD epidemiology before and during the COVID-19 pandemic. RESULTS: Among 386 children with SARS-CoV-2 infection, 381 (98.7%) had COVID-19 (median 6.3 years (IQR 2.1-12.8),53.3% male) and 5 (1.3%) had multisystem inflammatory syndromes (PIMS-TS, n=4; KD-TS, n=1) (median 7.9 years (IQR 7.8-9.8)). Most children with COVID-19 (n=278; 73%) were Australian-born from jurisdictions with highest community transmission. Comorbidities were present in 72 (18.9%); cardiac and respiratory comorbidities were most common (n=32/72;44%). 37 (9.7%) children with COVID-19 were hospitalised, and two (0.5%) required intensive care. Postinfective inflammatory syndromes (PIMS-TS/KD-TS) were uncommon (n=5; 1.3%), all were hospitalised and three (3/5; 60%) required intensive care management. All children recovered and there were no deaths. KD incidence remained stable during the pandemic compared with prepandemic. CONCLUSIONS: Most children with COVID-19 had mild disease. Severe disease was less frequent than reported in high prevalence settings. Preventative strategies, such as vaccination, including children and adolescents, could reduce both the acute and postinfective manifestations of the disease.

Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine, Victoria, Australia.

Emerging evidence suggest a possible association between immune thrombocytopenia (ITP) and some formulations of COVID-19 vaccine. We conducted a retrospective case series of ITP following vaccination with Vaxzevria ChadOx1-S (AstraZeneca) and mRNA Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) vaccines and compare the incidence to expected background rates for Victoria during the first six months of the Australian COVID-19 vaccination roll-out in 2021. Cases were identified by reports to the Victorian state vaccine safety service, SAEFVIC, of individuals aged 18 years or older presenting with thrombocytopenia following COVID-19 vaccination without evidence of thrombosis. Twenty-one confirmed or probable cases of ITP were identified following receipt of AstraZeneca (n = 17) or Pfizer-BioNTech (n = 4) vaccines. This translates to an observed incidence of 8 per million doses for AstraZeneca vaccine, twice the expected background rate of 4.1 per million. The observed rate for Pfizer-BioNTech was consistent with the expected background rate. The median time to onset for the cases post AstraZeneca vaccination was 10 days (range 1-78) and median platelet nadir 5 × 109/L (range 0-67 × 109/L). Hospital presentations or admissions for management of symptoms such as bleeding occurred in 18 (86%) of the cases. The majority of cases (n = 11) required intervention with at least 2 therapy modalities. In conclusion, we observed a substantially higher than expected rate of ITP following AstraZeneca vaccination. ITP is the second haematological adverse event, distinct from that of thrombosis with thrombocytopenia syndrome (TTS), observed following AstraZeneca vaccination.