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.

Cohort profile: SARS-CoV-2/COVID-19 hospitalised patients in Switzerland.

BACKGROUND: SARS-CoV-2/COVID-19, which emerged in China in late 2019, rapidly spread across the world with several million victims in 213 countries. Switzerland was severely hit by the virus, with 43,000 confirmed cases as of 1 September 2020. AIM: In cooperation with the Federal Office of Public Health, we set up a surveillance database in February 2020 to monitor hospitalised patients with COVID-19, in addition to their mandatory reporting system. METHODS: Patients hospitalised for more than 24 hours with a positive polymerase chain-reaction test, from 20 Swiss hospitals, are included. Data were collected in a customised case report form based on World Health Organisation recommendations and adapted to local needs. Nosocomial infections were defined as infections for which the onset of symptoms was more than 5 days after the patient’s admission date. RESULTS: As of 1 September 2020, 3645 patients were included. Most patients were male (2168, 59.5%), and aged between 50 and 89 years (2778, 76.2%), with a median age of 68 (interquartile range 54–79). Community infections dominated with 3249 (89.0%) reports. Comorbidities were frequently reported, with hypertension (1481, 61.7%), cardiovascular diseases (948, 39.5%) and diabetes (660, 27.5%) being the most frequent in adults; respiratory diseases and asthma (4, 21.1%), haematological and oncological diseases (3, 15.8%) were the most frequent in children. Complications occurred in 2679 (73.4%) episodes, mostly respiratory diseases (2470, 93.2% in adults; 16, 55.2% in children), and renal (681, 25.7%) and cardiac (631, 23.8%) complications for adults. The second and third most frequent complications in children affected the digestive system and the liver (7, 24.1%). A targeted treatment was given in 1299 (35.6%) episodes, mostly with hydroxychloroquine (989, 76.1%). Intensive care units stays were reported in 578 (15.8%) episodes. A total of 527 (14.5%) deaths were registered, all among adults. CONCLUSION: The surveillance system has been successfully initiated and provides a robust set of data for Switzerland by including about 80% (compared with official statistics) of SARS-CoV-2/COVID-19 hospitalised patients, with similar age and comorbidity distributions. It adds detailed information on the epidemiology, risk factors and clinical course of these cases and, therefore, is a valuable addition to the existing mandatory reporting.

Detection of mostly viral pathogens and high proportion of antibiotic treatment initiation in hospitalised children with community-acquired pneumonia in Switzerland - baseline findings from the first two years of the KIDS-STEP trial.

AIMS OF THE STUDY: Globally, since the introduction of conjugate-vaccines against encapsulated bacteria, respiratory viruses have caused most hospitalisations for community-acquired pneumonia. The aim of this study was to describe pathogens detected and their association with clinical findings in Switzerland. METHODS: Baseline data were analysed for all trial participants enrolled between September 2018 and September 2020 into the KIDS-STEP Trial, a randomised controlled superiority trial on the effect of betamethasone on clinical stabilisation of children admitted with community-acquired pneumonia. Data included clinical presentation, antibiotic use and results of pathogen detection. In addition to routine sampling, nasopharyngeal specimens were analysed for respiratory pathogens using a panel polymerase chain reaction test covering 18 viral and 4 bacterial pathogens. RESULTS: 138 children with a median age of 3 years were enrolled at the eight trial sites. Fever (obligatory for enrolment) had been present for median 5 days before admission. Most common symptoms were reduced activity (129, 93.5%) and reduced oral intake (108, 78.3%). Oxygen saturation <92% was found in 43 (31.2%). Forty-three participants (29.0%) were already on antibiotic treatment prior to admission and 104 participants (75.4%) received antibiotic treatment on admission. Pathogen testing results were available from 132 children: 31 (23.5%) had respiratory syncytial virus detected, 21 (15.9%) human metapneumovirus. The pathogens detected showed expected seasonal and age preponderance and were not associated with chest X-ray findings. CONCLUSIONS: In the context of the predominantly viral pathogens detected, the majority of antibiotic treatment is probably unnecessary. The ongoing trial, as well as other studies, will be able to provide comparative pathogen detection data to compare pre- and post-COVID-19-pandemic settings.

[When are antibody determinations in serum before or after vaccination indicated and when not?] / Wann sind Antikörperbestimmungen im Serum vor oder nach Impfungen sinnvoll und wann nicht?: Stellungnahme der Kommission für Infektionskrankheiten und Impffragen des Bündnis Kinder- und Jugendgesundheit e. V.

Questions about the usefulness of determining antibody values or titers to demonstrate protection often arise before or after vaccinations in immunization clinics. Such measurements may be useful in exceptional situations, e.g., in immunocompromised patients or those with suspected immunodeficiency, in patients with unknown vaccination status, and in certain defined risk situations (e.g., hepatitis B serology after needlestick injuries or after COVID-19 vaccination in patients with certain forms of immunodeficiency). In contrast, individual serological antibody measurements are neither recommended nor useful after generally recommended vaccinations. This is because either it is known from licensure studies or long-term use that there is a sufficiently high individual probability of protection (e.g., > 99% for tetanus) when the recommended vaccination schedules are adhered to or because the vaccination strategy is primarily aimed at indirect protection of the population and not at protection of each individual person. The few individuals who are not sufficiently protected after vaccination (vaccination failures) will still benefit indirectly from the reduced risk of exposure. This has been demonstrated with oral poliomyelitis vaccination in the 1960s, MMR vaccination since the 1970s, and Hib vaccination since the 1990s. This statement of our committee shows the evidence for a sensible approach, when and which antibody determinations are helpful and meaningful after or before vaccination and which are not. The statement is based on Germany's Standing Committee on Vaccination (STIKO) recommendations and their administration instructions. We advise not to comply with the wish of some parents for titer determinations in their child that are not medically justified.

Vaccination in Pregnancy against Pertussis: A Consensus Statement on Behalf of the Global Pertussis Initiative.

Infants are at high risk for severe morbidity and mortality from pertussis disease during early infancy. Vaccination against pertussis in pregnancy has emerged as the ideal strategy to protect infants during these early, vulnerable, first months of life. On 30 November and 1 December 2021, the Global Pertussis Initiative held a meeting that aimed to discuss and review the most up-to-date scientific literature supporting vaccination against pertussis in pregnancy and outstanding scientific questions. Herein, we review the current and historically published literature and summarize the findings as consensus statements on vaccination against pertussis in pregnancy on behalf of the Global Pertussis Initiative.

Wann sind Antikörperbestimmungen im Serum vor oder nach Impfungen sinnvoll und wann nicht? : Stellungnahme der Kommission für Infektionskrankheiten und Impffragen des Bündnis Kinder- und Jugendgesundheit e. V. When are antibody determinations in serum before or after vaccination indicated and when not?Statement of the Committee for Infectious Diseases and Vaccinations of the Alliance Child and Adolescent Health

In der Praxis stellt sich häufig die Frage nach der Sinnhaftigkeit der Bestimmung von Antikörperwerten bzw. Titern zur Überprüfung des Impfschutzes vor bzw. nach Impfungen. Dies kann in Ausnahmesituationen sinnvoll sein, z. B. bei Personen unter immunsuppressiver Therapie bzw. bei Verdacht auf Immundefizienz, bei Patienten mit unbekanntem Impfstatus sowie in definierten Risikosituationen (z. B. Überprüfung des Hepatitis-B-Impfschutzes nach Nadelstichverletzungen bzw. des COVID-19-Impfschutzes bei bestimmten Formen einer Immundefizienz). Im Gegensatz dazu sind für keine allgemein empfohlenen Standardimpfungen individuelle serologische Kontrollen empfohlen oder sinnvoll. Zum einen deswegen, weil aus den Zulassungsstudien oder langjähriger Anwendung bekannt ist, dass bei Einhalten der Impfempfehlungen eine ausreichend hohe individuelle Schutzwahrscheinlichkeit besteht (z. B. > 99 % bei Tetanus), zum anderen, weil die Impfstrategie primär auf indirekten Populationsschutz und nicht auf Schutz jeder einzelnen Person abzielt. Die wenigen Personen, die trotz Impfung nicht direkt geschützt sind („Impfversager“), profitieren somit indirekt von dem reduzierten Expositionsrisiko. Dies wurde an den Beispielen der oralen Poliomyelitis-Impfung in den 1960er-, der MMR-Impfung seit den 1970er- und der Hib-Impfung seit den 1990er-Jahren gezeigt. Diese Stellungnahme unserer Kommission zeigt die Evidenz zum sinnvollen Vorgehen auf, wann welche Antikörperbestimmungen nach bzw. vor einer Impfung hilfreich und aussagekräftig sind, und wann man sie besser unterlassen sollte. Sie lehnt sich dabei eng an die STIKO-Impfempfehlungen bzw. deren Anwendungshinweise an. Wir raten davon ab, dem Wunsch mancher Eltern nach medizinisch nicht begründeten Titerbestimmungen bei ihrem Kind nachzukommen.

Determinants of SARS-CoV-2 transmission to guide vaccination strategy in an urban area.

Transmission chains within small urban areas (accommodating ∼30 per cent of the European population) greatly contribute to case burden and economic impact during the ongoing coronavirus pandemic and should be a focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in a European urban area, Basel-City (Switzerland). We combined detailed epidemiological, intra-city mobility and socio-economic data sets with whole-genome sequencing during the first SARS-CoV-2 wave. For this, we succeeded in sequencing 44 per cent of all reported cases from Basel-City and performed phylogenetic clustering and compartmental modelling based on the dominating viral variant (B.1-C15324T; 60 per cent of cases) to identify drivers and patterns of transmission. Based on these results we simulated vaccination scenarios and corresponding healthcare system burden (intensive care unit (ICU) occupancy). Transmissions were driven by socio-economically weaker and highly mobile population groups with mostly cryptic transmissions which lacked genetic and identifiable epidemiological links. Amongst more senior population transmission was clustered. Simulated vaccination scenarios assuming 60-90 per cent transmission reduction and 70-90 per cent reduction of severe cases showed that prioritising mobile, socio-economically weaker populations for vaccination would effectively reduce case numbers. However, long-term ICU occupation would also be effectively reduced if senior population groups were prioritised, provided there were no changes in testing and prevention strategies. Reducing SARS-CoV-2 transmission through vaccination strongly depends on the efficacy of the deployed vaccine. A combined strategy of protecting risk groups by extensive testing coupled with vaccination of the drivers of transmission (i.e. highly mobile groups) would be most effective at reducing the spread of SARS-CoV-2 within an urban area.

Evolution of COVID-19 mortality over time: results from the Swiss hospital surveillance system (CH-SUR).

BACKGROUND: When the periods of time during and after the first wave of the ongoing SARS-CoV-2/COVID-19 pandemic in Europe are compared, the associated COVID-19 mortality seems to have decreased substantially. Various factors could explain this trend, including changes in demographic characteristics of infected persons and the improvement of case management. To date, no study has been performed to investigate the evolution of COVID-19 in-hospital mortality in Switzerland, while also accounting for risk factors. METHODS: We investigated the trends in COVID-19-related mortality (in-hospital and in-intermediate/intensive-care) over time in Switzerland, from February 2020 to June 2021, comparing in particular the first and the second wave. We used data from the COVID-19 Hospital-based Surveillance (CH-SUR) database. We performed survival analyses adjusting for well-known risk factors of COVID-19 mortality (age, sex and comorbidities) and accounting for competing risk. RESULTS: Our analysis included 16,984 patients recorded in CH-SUR, with 2201 reported deaths due to COVID-19 (13.0%). We found that overall in-hospital mortality was lower during the second wave of COVID-19 than in the first wave (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.63- 0.78; p <0.001), a decrease apparently not explained by changes in demographic characteristics of patients. In contrast, mortality in intermediate and intensive care significantly increased in the second wave compared with the first wave (HR 1.25, 95% CI 1.05-1.49; p = 0.029), with significant changes in the course of hospitalisation between the first and the second wave. CONCLUSION: We found that, in Switzerland, COVID-19 mortality decreased among hospitalised persons, whereas it increased among patients admitted to intermediate or intensive care, when comparing the second wave to the first wave. We put our findings in perspective with changes over time in case management, treatment strategy, hospital burden and non-pharmaceutical interventions. Further analyses of the potential effect of virus variants and of vaccination on mortality would be crucial to have a complete overview of COVID-19 mortality trends throughout the different phases of the pandemic.

Pertussis in Asia: Recent country-specific data and recommendations.

The Global Pertussis Initiative (GPI) Roundtable Meeting held in 2019, which preceded the COVID-19 pandemic, focused on the incidence, surveillance, and immunization practices for pertussis in the Asian region. Participants from China, India, Indonesia, Malaysia, Pakistan, Philippines, South Korea, Taiwan, and Thailand presented country-specific information on pertussis prevalence, diagnosis, surveillance, vaccine administration and schedules, maternal and neonatal disease rates, and policies and practice of vaccination during pregnancy. In recent years, many Asian countries have seen an increase in pertussis cases, although underreporting of the disease is a concern. Currently, most Asian countries have only passive surveillance for pertussis in place. There is a need for improved surveillance to determine the disease burden and justify vaccination policies and recommendations, such as essential vaccination, boosters, and vaccination during pregnancy. Better awareness of the disease in adolescents and adults is necessary, and infant and childhood vaccination schedules need to be improved in many countries. Differences between private versus public sector vaccination schedules and between whole-cell and acellular pertussis vaccines should continue to be examined. It can be anticipated that unmet needs in the prevention and management of pertussis will continue as the COVID-19 pandemic evolves and that key recommendations highlighted in this meeting report will be of ongoing importance.

Randomised placebo-controlled multicentre effectiveness trial of adjunct betamethasone therapy in hospitalised children with community-acquired pneumonia: a trial protocol for the KIDS-STEP trial.

INTRODUCTION: Community-acquired pneumonia (CAP) causes around 10 hospitalisations per 1000 child-years, each associated with an average 13 non-routine days experienced and more than 4 parent workdays lost. In adults, steroid treatment shortens time to clinical stabilisation without an increase in complications in patients with CAP. However, despite promising data from observational studies, there is a lack of high-quality evidence for the use of steroids. METHODS AND ANALYSIS: The KIDS-STEP trial is a multicentre, randomised, double-blind, placebo-controlled superiority trial of betamethasone treatment on outcome of hospitalised children with CAP. Children are enrolled in paediatric emergency departments of hospitals across Switzerland and randomised to adjunct oral betamethasone for 2 days or matching placebo in addition to standard of care treatment. The co-primary outcomes are the proportion of children clinically stable 48 hours after randomisation and the proportion of children with CAP-related readmission within 28 days after randomisation. Secondary outcomes include length of hospital stay, time away from routine childcare and healthcare utilisation and total antibiotic prescriptions within 28 days from randomisation.Each of the co-primary outcomes will be analysed separately. We will test clinical stability rates using a proportion test; to test non-inferiority in readmission rates, we will construct 1-α % CI of the estimated difference and test if it contains the pre-defined margin of 7%. Success is conditional on both tests. A simulation-based sample size estimation determined that recruiting 700 patients will ensure a power of 80% for the study. ETHICS AND DISSEMINATION: The trial protocol and materials were approved by ethics committees in Switzerland (lead: Ethikkommission Nordwest und Zentralschweiz) and the regulatory authority Swissmedic. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate. TRIAL REGISTRATION NUMBER: NCT03474991 and SNCTP000002864.

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.

BACKGROUND: To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. METHODS: This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network-the Paediatric Tuberculosis Network European Trials Group (ptbnet)-that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. FINDINGS: 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5-12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2-11, range 1-34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16-21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir-ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20-1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. INTERPRETATION: COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. FUNDING: ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

Children and adolescents in the CoVid-19 pandemic: Schools and daycare centers are to be opened again without restrictions. The protection of teachers, educators, carers and parents and the general hygiene rules do not conflict with this.

In the opinion of the medical societies of hygiene and pediatrics undersigning the present statement, the analyses published to date regarding transmission of SARS-CoV-2 and the course of CoVid-19 show that children play a much less significant role in the spread of the virus than do adults. According to the findings available to date, not only do children and adolescents less frequently fall ill with CoVid-19, they also generally become less severely ill than do adults. The vast majority of infections in children and adolescents are asymptomatic or oligosymptomatic. Even the first analyses from China demonstrated that children and adolescents play a subordinate role in the transmission of the virus - not only to other children and adolescents, but also to adults. Taking into account regional infection rates and available resources, daycare centers, kindergartens and elementary schools promptly should be reopened. For children, this should be possible without excessive restrictions, such as clustering into very small groups, implementation of barrier precautions, maintaining appropriate distance from others or wearing masks. A factor more decisive than individual group size is the issue of sustaining the constancy of respective group members and the avoidance of intermixing. Children can be taught basic rules of hygiene such as handwashing and careful hygiene behavior when coming into contact with others during mealtimes and/or when using sanitary facilities. Independent of the prevention measures implemented for children and adolescents, the protection of teachers, educators and caregivers is crucial, (e.g., the maintenance of appropriate distance from others, use of medical masks, situation-dependent hand disinfection, when necessary, supported by regular pool testing). Children over the age of 10 and adolescents up to school graduation age are more capable of actively understanding and conforming to specific hygiene rules. For this group, maintaining appropriate distance from others (1.5 meters), wearing a mouth-and-nose protection (whenever they are not sitting in their assigned classroom seats) and consistent education regarding the basic rules of infection prevention may provide increased options for normalizing teaching activities. Children and adolescents suspected of infection with SARS-CoV-2 should be tested immediately in order to either confirm or rule out such an infection. Evidence of individual infections in children or students must not automatically lead to the closure of the entire daycare center or school. A detailed analysis of the chain of infection is a prerequisite for a balanced approach to infection control. The opening of schools and children's facilities should be accompanied by specifically structured, model surveillance studies that further clarify outstanding questions about infectious disease events and hygiene control. These prospective, concomitant examinations will be essential for the purpose of evaluating and verifying the effectiveness of the required hygiene measures.