Investigating confounding in network-based test-negative design influenza vaccine effectiveness studies-Experience from the DRIVE project.

BACKGROUND: Establishing a large study network to conduct influenza vaccine effectiveness (IVE) studies while collecting appropriate variables to account for potential bias is important; the most relevant variables should be prioritized. We explored the impact of potential confounders on IVE in the DRIVE multi-country network of sites conducting test-negative design (TND) studies. METHODS: We constructed a directed acyclic graph (DAG) to map the relationship between influenza vaccination, medically attended influenza infection, confounders, and other variables. Additionally, we used the Development of Robust and Innovative Vaccines Effectiveness (DRIVE) data from the 2018/2019 and 2019/2020 seasons to explore the effect of covariate adjustment on IVE estimates. The reference model was adjusted for age, sex, calendar time, and season. The covariates studied were presence of at least one, two, or three chronic diseases; presence of six specific chronic diseases; and prior healthcare use. Analyses were conducted by site and subsequently pooled. RESULTS: The following variables were included in the DAG: age, sex, time within influenza season and year, health status and comorbidities, study site, health-care-seeking behavior, contact patterns and social precautionary behavior, socioeconomic status, and pre-existing immunity. Across all age groups and settings, only adjustment for lung disease in older adults in the primary care setting resulted in a relative change of the IVE point estimate >10%. CONCLUSION: Our study supports a parsimonious approach to confounder adjustment in TND studies, limited to adjusting for age, sex, and calendar time. Practical implications are that necessitating fewer variables lowers the threshold for enrollment of sites in IVE studies and simplifies the pooling of data from different IVE studies or study networks.

Prevalence and genotype distribution of human papillomavirus infection of the cervix in Spain: the CLEOPATRE study.

Human papillomavirus (HPV) infection is a necessary cause of cervical cancer. The aim of this study was to estimate the prevalence of cervical HPV infection and HPV type-specific distribution among women attending cervical cancer screening in Spain during 2007 and 2008. Women aged 18-65 years were recruited according to an age-stratified sampling method. Liquid-based cervical samples were collected and analyzed for cytology, HPV detection, and genotyping. HPV genotyping was determined using the INNO-LiPA HPV Genotyping Extra Reverse Hybridization Line Probe Assay. Prevalence estimates were age-standardized using 2001 Spanish census data. The present study included 3,261 women. Age-standardized HC2-based HPV prevalence was 14.3% (95% CI, 13.1-15.5) among women aged 18-65 years, and 28.8% (26.6-31.1) among women aged 18-25 years. High-risk HPV types were detected in 12.2% (95% CI, 11.1-13.4) of HPV-tested women, representing 84.0% of HPV-positive samples. Multiple infections were present in 4.1% (95% CI, 3.4-4.8) of HPV-tested women (25.0% of HPV-positive samples). The most common high-risk HPV-types among HPV-tested women were 16 (2.9%), 52 (1.8%), 51 (1.6%), 31 (1.3%), and 66 (1.2%). HPV-type 16 was present in 16.9% of HPV-positive samples. One or more of the HPV vaccine types 6/11/16/18 were detected in 3.8% of HPV-tested women (22.1% of HPV-positive samples). Though not a true population-based survey, this study provides valuable baseline data for future assessment of the impact of current HPV vaccination programs in Spain. The high prevalence of HPV infection among young women may reflect recent changes in sexual behavior.

Predictors of human papillomavirus infection in women undergoing routine cervical cancer screening in Spain: the CLEOPATRE study.

BACKGROUND: Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. METHODS: The CLEOPATRE Spain study enrolled 3 261 women aged 18-65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. RESULTS: A lifetime number of two or more sexual partners, young age (18-25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). CONCLUSION: This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection.

The value of public-private collaborative real-world evidence platforms to monitor vaccine performance post authorization: DRIVE - a European initiative.

INTRODUCTION: Fighting pandemics requires an established infrastructure for pandemic preparedness, with existing, sustainable platforms ready to be activated. This includes platforms for disease surveillance, virus circulation, and vaccine performance monitoring based on Real-World data, to complement clinical trial evidence. AREAS COVERED: Because of its complexity, this can best be done by combining efforts between public and private sectors, developing a multi-stakeholder approach. Public-Private-Partnerships increasingly play a critical role in combating infectious diseases but are still looked at with hesitancy. The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project, which established a platform for measuring brand-specific influenza vaccine effectiveness in Europe, exemplifies how to build a collaborative platform with transparent governance, state-of-the-art methodology, and a large network of participating sites. Lessons learned from DRIVE have been cardinal to set up COVIDRIVE, a platform for brand-specific COVID-19 vaccine effectiveness monitoring. EXPERT OPINION: The DRIVE partners propose that a debate on the benefits of Public-Private-Partnership-generated real-world evidence for vaccine effectiveness monitoring should be pursued to clarify roles and responsibilities, set up expectations, and decide the future environment for vaccine monitoring in Europe. In parallel, the driving factors behind PPP hesitancy should be studied.

Challenges and Adaptation of a European Influenza Vaccine Effectiveness Study Platform in Response to the COVID-19 Emergence: Experience from the DRIVE Project.

The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project is a public-private partnership aiming to build capacity in Europe for yearly estimation of brand-specific influenza vaccine effectiveness (IVE). DRIVE is a five-year project funded by IMI (Innovative Medicines Initiative). It was initiated as a response to the guidance on influenza vaccines by EMA (European Medicines Agency), which advised vaccine manufacturers to work with public health institutes to set up a joint IVE study platform. The COVID-19 pandemic reached Europe in February 2020 and overlapped with the 2019/2020 influenza season only in the last weeks. However, several elements of the DRIVE study network were impacted. The pandemic specifically affected the study sites' routines and the subsequent assessment of the 2019/20 influenza season. Moreover, the current social distancing measures and lockdown policies across Europe are expected to also limit the circulation of influenza for the 2020/21 season, and therefore the impact of COVID-19 will be higher than in the season 2019/20. Consequently, DRIVE has planned to adapt its study platform to the COVID-19 challenge, encompassing several COVID-19 particularities in the study procedures, data collection and IVE analysis for the 2020/21 season. DRIVE will study the feasibility of implementing these COVID-19 components and establish the foundations of future COVID-19 vaccine effectiveness studies.

Why we need more collaboration in Europe to enhance post-marketing surveillance of vaccines.

The influenza A/H1N1 pandemic in 2009 taught us that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better (public health institutes (PHIs), regulatory authorities, research institutes, vaccine manufacturers). The Innovative Medicines Initiative (IMI) subsequently issued a competitive call to establish a public-private partnership to build and test a novel system for monitoring vaccine benefits and risks in Europe. The ADVANCE project (Accelerated Development of Vaccine benefit-risk Collaboration in Europe) was created as a result. The objective of this paper is to describe the perspectives of key stakeholder groups of the ADVANCE consortium for vaccine benefit-risk monitoring and their views on how to build a European system addressing the needs and challenges of such monitoring. These perspectives and needs were assessed at the start of the ADVANCE project by the European Medicines Agency together with representatives of the main stakeholders in the field of vaccines within and outside the ADVANCE consortium (i.e. research institutes, public health institutes, medicines regulatory authorities, vaccine manufacturers, patient associations). Although all stakeholder representatives stated they conduct vaccine benefit-risk monitoring according to their own remit, needs and obligations, they are faced with similar challenges and needs for improved collaboration. A robust, rapid system yielding high-quality information on the benefits and risks of vaccines would therefore support their decision making. ADVANCE has developed such a system and has tested its performance in a series of proof of concept (POC) studies. The system, how it was used and the results from the POC studies are described in the papers in this supplementary issue.

Determinants of shingles vaccine acceptance in the United Kingdom.

BACKGROUND: The United Kingdom (UK) was the first European country to introduce a national immunisation program for shingles (2013-2014). That year, vaccination coverage ranged from 50 to 64% across the UK, but uptake has declined ever since. This study explored determinants of the acceptance of the shingles vaccine in the UK. METHODS: Vaccinated and unvaccinated individuals, who were eligible for the last catch-up cohort of the 2014-2015 shingles vaccination campaign, were identified using the Clinical Practice Research Datalink (the National Health Service data research service) and invited to participate by their general practitioner (GP). An anonymised self-administered questionnaire was developed using the Health Belief Model as a theoretical framework, to collect data on demographic and socio-economic characteristics, health status, knowledge, influences, experiences and attitudes to shingles and the shingles vaccine. Multivariable logistic regression was used to identify the factors associated with vaccination. Physicians' views concerning perceived barriers to vaccination were also assessed. RESULTS: Of the 2,530 questionnaires distributed, 536 were returned (21.2%) from 69 general practices throughout the UK. The majority of responders were female (58%), lived in care homes (56%) and had completed secondary or higher education (88%). There were no differences between vaccinated and unvaccinated responders. Being offered the shingles vaccine by a GP/nurse (odds ratio (OR) = 2.3), and self-efficacy (OR = 1.2) were associated with being vaccinated (p<0.05). In contrast, previous shingles history (OR = 0.4), perceived barriers to vaccination (OR = 0.7) and perceived control of the disease (OR = 0.7) were associated with not being vaccinated against shingles (p<0.05). Less than half (44.0%) of GPs were aware of the local communication campaigns regarding shingles and the shingles vaccine. CONCLUSIONS: Socio-psychological factors largely influence shingles vaccination acceptance in this study. The results add to existing evidence that healthcare providers (HCPs) have a pivotal role against vaccine hesitancy. Campaigns focusing on GPs and accessible information offered to eligible members of the public can further enhance shingles vaccine uptake.

Guidance for the governance of public-private collaborations in vaccine post-marketing settings in Europe.

INTRODUCTION: The 2009 influenza pandemic highlighted challenges for vaccine post-marketing monitoring in Europe, particularly the need to have appropriate infrastructures to strengthen public-private collaborations (PPCs) with suitable processes to improve stakeholder interactions and collection and analysis of safety and effectiveness data. The ADVANCE consortium comprises public and private stakeholders who have worked together to build and test new system components for vaccine post-marketing projects, one component being a governance framework for efficient, transparent and trustworthy PPCs. METHODS: Based on the results of a landscape analysis and screening of formalised existing governance structures, we identified the elements of a governance framework and developed recommendations to support stakeholders willing and able to implement collaborative projects. These proposals and their implementation were discussed by 70 experts during a workshop to gain from their experience. RESULTS: We identified core governance principles and defined five fundamental functions (decision-making, scientific advice, quality control and audit, implementation and management, and financial administration) that can be attributed to individual partner organisations or to a committee with representatives from more than one partner organisation. We propose a generic governance model with options for its adaptation to specific contexts and projects. The advantages and disadvantages of PPCs were also examined. Stakeholders' concerns (e.g. scientific integrity and public trust) were addressed through recommendations about transparent decision-making rules and conflict of interest management. CONCLUSIONS: No one-size-fits-all solution for PPC governance exists but our recommendations could be used to set-up a tailored-made and fully transparent governance structure supporting collaborative projects in the European vaccine post-marketing environment. To allow the rapid establishment of robust projects, the next steps will involve this guidance being used by real-world collaborations to assess what works and what does not work and what added-value can be obtained from these collaborations.

Impact of Underlying Conditions on Zoster-Related Pain and on Quality of Life Following Zoster.

BACKGROUND: Chronic conditions have been investigated as risk factors for developing zoster, but in patients suffering from zoster, the impact of underlying conditions in zoster-related pain and quality of life (QOL) remains unclear. METHODS: We performed a post hoc analysis of a prospective cohort study in immunocompetent zoster patients aged 50 years or older, conducted by general practitioners in Italy between 2009 and 2010. Zoster symptoms, pain intensity and characteristics, and physical and mental health scores were assessed at baseline (zoster diagnosis) and at 1, 3, and 6 months of follow-up. RESULTS: Among 413 patients enrolled in the study, 73% (303/413) suffered from underlying conditions of which 69% (209/303) were aged 65 or older. Cardiovascular diseases (75%), diabetes (24%), and respiratory diseases (17%) were most frequent. One to three months after onset, zoster patients with underlying conditions experienced more intense zoster-related pain than those without. QOL scores were significantly lower in patients with underlying conditions, and age-adjusted difference in QOL scores between the groups increased over time, demonstrating a slower recovery for patients with underlying conditions. CONCLUSIONS: In addition to age, the main risk factor of zoster occurrence and severity, the presence of underlying conditions results in more painful and impactful zoster episodes, creating a significant burden for these patients.

Sustained High Effectiveness of RotaTeq on Hospitalizations Attributable to Rotavirus-Associated Gastroenteritis During 4 Years in Finland.

KEY POINTS: The effectiveness of pentavalent rotavirus vaccine against rotavirus-associated hospitalization was more than 90% 4 years after introduction into the national immunization program in Finland. A major impact on hospitalization for all-cause gastroenteritis was observed also. BACKGROUND: Rotavirus vaccination with exclusive use of RotaTeq was added to the National Immunization Programme (NIP) of Finland in September 2009. The objective of our study was to estimate the effectiveness and impact of RotaTeq after 4 years of follow-up. METHODS: Between 2009 and 2013, we conducted a prospective surveillance study of children aged <16 years with acute gastroenteritis (AGE) and admitted in 2 hospitals in Finland. Rotavirus and other gastroenteritis viruses were detected in stool samples by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays. The effectiveness of RotaTeq was investigated by using a case-control design; wild-type rotavirus-positive children were classified as "cases" and rotavirus-negative children as "controls." Hospital discharge records were used to estimate the impact of RotaTeq on rotavirus-associated AGE (RV-AGE) and all-cause AGE (AC-AGE) hospitalizations of age-eligible children in the NIP by comparing the prevaccination (2001-2006) and post-NIP seasons (2009-2013). RESULTS: The crude estimate of the effectiveness of RotaTeq to prevent RV-AGE hospitalization in NIP age-eligible children was 94.4% (95% confidence interval, 79.8%-98.4%). No change in prevalent wild-type rotavirus genotypes was observed. Vaccine-derived rotaviruses were detected in 8% of the children with RV-AGE, with a probable causal association in 2 children. Hospital discharge records revealed that RV-AGE and AC-AGE hospitalizations in children aged <16 years decreased in the two post-NIP seasons by 79% and 58%, respectively, compared to those in the prevaccination seasons. CONCLUSIONS: Over 4 years of follow-up, high rotavirus vaccine coverage in the NIP (>95%) has led to a major reduction in RV-AGE and AC-AGE hospitalizations without a resurgence of rotavirus activity. However, rotavirus continues to circulate in older unvaccinated children.

Impact and effectiveness of RotaTeq® vaccine based on 3 years of surveillance following introduction of a rotavirus immunization program in Finland.

BACKGROUND: Finland introduced universal rotavirus (RV) vaccination in September 2009, with exclusive use of the pentavalent human-bovine reassortant RV vaccine RotaTeq® and following a vaccination schedule at 2, 3 and 5 months of age. This study monitored the impact of RV vaccination on hospitalizations due to RV acute gastroenteritis (RVGE). The results following the first 3 RV seasons after implementation of universal RV vaccination are presented. METHODS: Prospective hospital-based surveillance identified children with acute gastroenteritis admitted to 2 University Hospitals (Tampere and Oulu, Finland), from December 2009 to August 2012. The surveillance covered a population of approximately 173,000 children from the 2 hospitals' catchment areas. Stool samples were taken and analyzed centrally for RV by enzyme-linked immunosorbent assay, with genotyping by reverse transcription polymerase chain reaction. International Classification of Diseases discharge codes were collected retrospectively pre- and postvaccination. RESULTS: During the 3-year prospective surveillance, 127 RVGE episodes were identified. Of these, 117 were in unvaccinated children and 6 were in fully vaccinated children (RotaTeq, n = 3; Rotarix, n = 3). The vaccine effectiveness against hospitalized RVGE for fully vaccinated children was 92.1% [95% confidence interval (CI): 50.0-98.7] among children eligible for the National Immunization Program. When analyzing retrospectively the Tampere and Oulu hospital databases for all children aged <16 years, hospitalizations for RVGE had decreased by 78% in the postvaccination period (2009-2012) compared with the prevaccination data (2001-2006). CONCLUSIONS: Severe RVGE requiring hospitalization was virtually eliminated in vaccine-eligible children in the 3 years following implementation of universal RotaTeq vaccination in Finland.