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Background: Although COVID-19 booster vaccination is widely recommended, there is limited long-term, population-level, real-world evidence on the magnitude of improved protection against severe COVID-19 conferred by boosting with monovalent COVID-19 vaccines developed against ancestral SARS-CoV-2, especially in low- or middle-income countries. We present interim results from the first large-scale assessment of the relative vaccine effectiveness (rVE) of first and second booster doses against severe COVID-19 in a low-/middle-income country., Methods: REFORCO-Brazil is an ongoing, test-negative case-control study (NCT05697705) utilizing Brazil national severe acute respiratory syndrome (SARS) surveillance and vaccination data. In SARS hospitalizations from August 1, 2021 to July 31, 2022, we matched test-positive (via SARS-CoV-2 antigen/reverse transcription polymerase chain reaction [RT-PCR]) cases and test-negative case-controls (via RT-PCR) based on admission date, preceding vaccinations, and age. We evaluated the rVEs of four monovalent COVID-19 vaccines (AZD1222, Ad26.COV2.S, CoronaVac, and BNT162b2) as second boosters compared with any first boosters received ≥4 months previously, and as first boosters compared with primary-series vaccinations completed ≥4 months previously., Results: The overall rVE of second boosters, from 5668 (2238 test-positive) evaluated hospitalizations, was 24.7 % (95 % confidence interval [CI]: 12.6-35.1); the overall rVE of first boosters, from 30,272 (12,063 test-positive) hospitalizations, was 46.8 % (95 % CI: 43.3-50.0). The rVEs of AZD1222 and BNT162b2 were similar: 29.4 % (95 % CI: 8.6-45.5) and 25.5 % (95 % CI: 4.2-42.2), respectively, for second boosters; and 42.5 % (95 % CI: 28.0-54.0) and 50.8 % (95 % CI: 47.5-54.0), respectively, for first boosters. In general, rVEs were higher in elderly (≥80 years) and immunocompromised/high-risk individuals., Conclusions: Our results support the use of AZD1222 and other adenoviral/mRNA vaccine boosters to maintain protection against COVID-19 hospitalization from Omicron subvariants, including in elderly and immunocompromised individuals at increased risk of accelerated waning or severe outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, article publishing charges, statistical analysis, and writing assistance were provided by AstraZeneca. André Santa Maria, Bárbara Emoingt Furtado, Christen M. Gray, Mario Ouwens, Hugo Gomes da Silva, Sylvia Taylor, and Wilhelmine Meeraus report relationships with AstraZeneca that include: employment and equity or stocks. Anke L. Stuurman and Eduardo Conde-Sousa report relationships with P95 that includes: employment; Ilgaz Durukal reports a relationship with ZS Associates that includes: employment; Andrew Lee reports a relationship with Source Group International that includes: employment. All worked on behalf of AstraZeneca. Douglas Andreas Valverde reports a relationship with Techtrials Healthcare Data Science that includes: employment., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Development of Robust and Innovative Vaccine Effectiveness (DRIVE) was a European public-private partnership (PPP) that aimed to provide annual, brand-specific estimates of influenza vaccine effectiveness (IVE) for regulatory and public health purposes. DRIVE was launched in 2017 under the umbrella of the Innovative Medicines Initiative (IMI) and conducted IVE studies from its pilot season in 2017-2018 to its final season in 2021-2022., Methods: In 2021-2022, DRIVE conducted four primary care-based test-negative design (TND) studies (Austria, Italy, Iceland, and England; involving >1,000 general practitioners), nine hospital-based TND studies (France, Iceland, Italy, Romania, and Spain, for a total of 21 hospitals), and one population-based cohort study in Finland. In the TND studies, patients with influenza-like illness (primary care) or severe acute respiratory infection (hospital) were enrolled, and laboratory tested for influenza using RT-PCR. Study contributor-specific IVE was calculated using logistic regression, adjusting for age, sex, and calendar time, and pooled by meta-analysis., Results: In 2021-2022, pooled confounder-adjusted influenza vaccine effectiveness (IVE) estimates against laboratory-confirmed influenza (LCI) overall and per type and subtype/lineage was produced, albeit with wide confidence intervals (CI). The limited circulation of influenza in Europe did not allow the network to reach the optimal sample size to produce precise IVE estimates for all the brands included. The most significant IVE estimates were 76% (95% CI 23%-93%) for any vaccine and 81% (22%-95%) for Vaxigrip Tetra in adults ≥65 years old and 64% (25%-83%) for Fluenz Tetra in children (TND primary care setting), 85% (12%-97%) for any vaccine in adults 18-64 years (TND hospital setting), and 38% (1%-62%) in children 6 months-6 years (population-based cohort, mixed setting)., Discussion: Over five seasons, DRIVE collected data on >35,000 patients, more than 60 variables, and 13 influenza vaccines. DRIVE demonstrated that estimating brand-specific IVE across Europe is possible, but achieving sufficient sample size to obtain precise estimates for all relevant stratifications remains a challenge. Finally, DRIVE's network of study contributors and lessons learned have greatly contributed to the development of the COVID-19 vaccine effectiveness platform COVIDRIVE., Competing Interests: AS and JB declare that they were employees of P95; P95 has held/holds contracts with Seqirus, Sanofi, GSK, and AstraZeneca. AC reports remunerated collaborations with HIPRA, GSK, and MSD for lectures and seminars. JD-D declares that FISABIO receives research grants from Sanofi, GSK, and Seqirus, that he has been principal investigator in clinical trials with influenza vaccine for GSK, SP, Abbott, and that he has acted as an advisor for Sanofi and MSD. He also declares he is a Member of Monitoring committee of clinical trials for Janssen and GSK. AD reports grants from Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 777363) and from Sanofi (outside the submitted work). SL reports that through his University he has had grants not directly relating to this work, from AstraZeneca, GSK, Sanofi, Seqirus, and Takeda for vaccine related research, and membership of advisory boards for AstraZenca Sanofi and Seqirus. CR declares that she has received funding for participating in AB from Seqirus, Sanofi and MSD. HN declares that she is an employee of the Finnish Institute for Health and Welfare, which has a major phase IV study on influenza vaccine funded by Sanofi; however, she is not personally involved in the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stuurman, Carmona, Biccler, Descamps, Levi, Baum, Mira-Iglesias, Bellino, Hoang, Lusignan, Bonaiuti, Lina, Rizzo, Nohynek, Díez-Domingo and DRIVE Study Contributors.)

Background: Vaccine effectiveness (VE) studies with long-term follow-up are needed to understand durability of protection against severe COVID-19 outcomes conferred by primary-series vaccination in individuals not receiving boosters. COVIDRIVE is a European public-private partnership evaluating brand-specific vaccine effectiveness (VE). We report a prespecified interim analysis of primary-series AZD1222 (ChAdOx1 nCoV-19) VE., Methods: Seven Study Contributors in Europe collected data on individuals aged ≥18 years who were hospitalised with severe acute respiratory infection (June 1st, 2021-September 5th, 2022) and eligible for COVID-19 vaccination prior to hospitalisation. In this test-negative case-control study, individuals were defined as test-positive cases or test-negative controls (SARS-CoV-2 RT-PCR) and were either fully vaccinated (two AZD1222 doses, 4-12 weeks apart, completed ≥14 days prior to symptom onset; no booster doses) or unvaccinated (no COVID-19 vaccine prior to hospitalisation). The primary objective was to estimate AZD1222 VE against COVID-19 hospitalisation. A literature review and meta-regression were conducted to contextualise findings on durability of protection., Findings: 761 individuals were included during the 15-month analysis period. Overall AZD1222 VE estimate was 72.8% (95% CI, 53.4-84.1). VE was 93.8% (48.6-99.3) in participants who received second AZD1222 doses ≤8 weeks prior to hospitalisation, with spline-based VE estimates demonstrating protection (VE ≥ 50%) 30 weeks post-second dose. Meta-regression analysis (data from seven publications) showed consistent results, with ≥80% protection against COVID-19 hospitalisation through ∼43 weeks post-second dose, with some degree of waning., Interpretation: Primary-series AZD1222 vaccination confers protection against COVID-19 hospitalisation with enduring levels of VE through ≥6 months., Funding: AstraZeneca., Competing Interests: WM, CMG, MO, and ST declare employment by AstraZeneca and ownership of AstraZeneca stocks/shares. LdM, AD, CW-T, WH-M, LD, GR, ALS, TYCN, and KB declare employment by P95. ALS and TYCN were contracted to AstraZeneca at the time of this work. P95 received consulting fees from several COVID-19 vaccine manufacturers, including AstraZeneca, for the COVIDRIVE study. AC declares funding from COVIDRIVE industry partners (AstraZeneca, Janssen, Moderna, Novavax, CureVac, Sanofi, Valneva, GlaxoSmithKline, Bavarian Nordic) for the COVIDRIVE consortium, of which FISABIO is the coordinator, and honoraria for lectures and educational events from GlaxoSmithKline and for presentations from MSD and HIPRA. GM declares no conflicts of interest related to this analysis, and honoraria from GlaxoSmithKline associated with herpes virus vaccine. AM-I declares funding from COVIDRIVE industry partners (AstraZeneca, Janssen, Moderna, Novavax, CureVac, Sanofi, Valneva, GlaxoSmithKline, Bavarian Nordic) for the COVIDRIVE consortium, of which FISABIO is the coordinator, and honoraria for educational events from MSD and for presentations from Sanofi Pasteur. GI declares no conflicts of interest. SO-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from EXCEMED and Sanofi. SB declares speaker honorarium from GlaxoSmithKline. CM declares advisory board participation for AstraZeneca in 2021., (© 2023 The Author(s).)

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., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Most perinatal and neonatal deaths occur in low- and middle-income countries (LMICs), yet, quality data on burden of adverse outcomes of pregnancy is limited in such countries., Methods: A network of 21 maternity units, across seven countries, undertook surveillance for low birthweight, preterm birth, small for gestational age (SGA), stillbirths, congenital microcephaly, in-hospital neonatal deaths, and neonatal infections in a cohort of over 85,000 births from May 2019 - August 2020. For each outcome, site-specific rates per 1,000 livebirths (or per 1,000 total births for stillbirth) and 95% confidence intervals (CI) were calculated. Descriptive sensitivity analysis was conducted to gain insight regarding underreporting of four outcomes at 16 sites., Findings: Estimated rates varied across countries and sites, ranging between 43·3-329·5 and 21·4-276·6/1000 livebirths for low birthweight and preterm birth respectively and 11·8-81/1,000 livebirths for SGA. No cases of congenital microcephaly were reported by three sites while the highest estimated rate was 13/1,000 livebirths. Neonatal infection and neonatal death rates varied between 1·8-73 and 0-59·9/1000 livebirths respectively while stillbirth rates ranged between 0-57·1/1000 total births across study sites. Results from the sensitivity analysis confirmed the underreporting of congenital microcephaly and SGA in our study., Interpretation: Our study establishes site-specific baseline rates for important adverse perinatal and neonatal outcomes and addresses a critical evidence gap towards improved monitoring of benefits and risks of emerging pregnancy and neonatal interventions., Funding: The study was sponsored by the World Health Organization with funding from the Bill and Melinda Gates Foundation., Competing Interests: Margarita Riera-Montes (P95) & Christine Guillard Maure (WHO) declare that their institutions received funding support for this manuscript from the WHO and the Bill & Melinda Gates Foundation respectively. All the remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 World Health Organization.)

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christine Guillard Maure reports financial support was provided by Bill & Melinda Gates Foundation., (© 2021 The Authors.)

DRIVE (Development of Robust and Innovative Vaccine Effectiveness) is an IMI funded public-private platform that aims to annually estimate brand-specific influenza vaccine effectiveness (IVE), for public health and regulatory purposes. IVE analyses and reporting are conducted by public partners in the consortium. In 2019/20, four primary care-based test-negative design (TND) studies (Austria, England, Italy (n = 2)), eight hospital-based TND studies (Finland, France, Italy, Romania, Spain (n = 4)), and one population-based cohort study (Finland) were conducted. The COVID-19 pandemic affected influenza surveillance in all participating study sites, therefore the study period was truncated on February 29, 2020. Age-stratified (6 m-17y, 18-64y, ≥65y), confounder-adjusted, site-specific adjusted IVE estimates were calculated and pooled through meta-analysis. Parsimonious confounder-adjustment was performed, adjusting the estimates for age, sex and calendar time. TND studies included 3531 cases (351 vaccinated) and 5546 controls (1415 vaccinated) of all ages. IVE estimates were available for 8/11 brands marketed in Europe in 2019. Most children and adults < 64y were captured in primary care setting and the most frequently observed vaccine brand was Vaxigrip Tetra. The estimate against any influenza for Vaxigrip Tetra in primary care setting was 61% (95%CI 38-77) in children and 32% (95%CI -13-59) in adults up to 64y. Most adults ≥ 65y were captured in hospital setting and the most frequently observed brand was Fluad, with an estimate of 52% (95%CI 27-68). The population-based cohort covered 511,854 person-years and two vaccine brands. In children aged 2-6y, the IVE against any influenza was 68% (95%CI 58-75) for Fluenz Tetra and 71% (56-80) for Vaxigrip Tetra. In adults ≥ 65y, IVE against any influenza was 29% (20-36) for Vaxigrip Tetra. DRIVE is a growing platform. Public health institutes with surveillance data and hospitals in countries with high influenza vaccine coverage are encouraged to join DRIVE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Anke L. Stuurman, Kaatje Bollaerts, Jorne Biccler, Tom De Smedt, and Margarita Riera-Montes declare that P95 Epidemiology and Pharmacovigilance has held contracts for research work with GSK and Seqirus. Odile Launay and Florence Galtier declare that they are principal investigator for clinical trials sponsored by Janssen, GSK, Pfizer, Sanofi Pasteur and MSD. Phillips Vanhems declares to have received grants and fees from Pfizer, Sanofi, Anios, MSD and Astellas. Hanna Nohynek and Ulrike Baum declare that THL holds / has held a research contract with influenza vaccine manufactures GSK and Sanofi Pasteur on both non-influenza and influenza related research but the authors are not recipients of these fund. Anca Cristina Drăgănescu, Oana Săndulescu, Victor Daniel Miron, Simona Paraschiv, Marius Surleac, Dragoș Florea, Ovidiu Vlaicu, Anuta Bilașco, Dan Oțelea, Monica Luminița Luminos, Daniela Pițigoi, and Adrian Streinu-Cercel declare being part of the GIHSN project research team that was co-funded by Foundation for Influenza Epidemiology. Oana Săndulescu, Anca Streinu-Cercel, and Adrian Streinu-Cercel declare being (sub)investigators in influenza clinical trials by Shionogi and F. Hoffmann-La Roche.]., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Influenza vaccine effectiveness (IVE) assessment is increasingly stratified by vaccine type or brand, such as done by the European network of DRIVE. In 2019/2020, eleven influenza vaccines were licensed in Europe. If more than one vaccine type is recommended or if more than one vaccine brand is available for a specific risk group, it is not clear which factors affect the choice of a specific vaccine (type or brand) by a health practitioner for individual patients. This is important for IVE assessment. A survey tailored to the 2019/20 local vaccine recommendations was conducted among GPs in four European countries (Austria, Italy, Spain, UK) to understand how influenza vaccine is offered to recommended risk groups and, if GPs have a choice between 2 or more vaccines, what factors influence their vaccine choice for patients. Overall, 360 GPs participated. In Austria, Italy and Spain GPs indicated that influenza vaccines are commonly offered when patients present for consultation, whereas in the UK all GPs indicated that all relevant patients are contacted by letter. In Austria and Italy, roughly 80% of GPs had only one vaccine type available for patients <65y. The use of any specific vaccine type in this age group is mostly determined by the availability of specific vaccine type(s) at the clinic. GPs frequently reported availability of more than one vaccine type for patients ≥65y in Austria (45%), Italy (70%) and Spain (79%). In this group, patient characteristics played a role in choice of vaccine, notably older age and presence of (multiple) comorbidities. Knowing that a non-patient related factor usually determines the vaccine type a patient receives in settings where more than one vaccine type is recommended for risk groups <65y, simplifies IVE assessment in this age group. However, patient characteristics need careful consideration when assessing IVE in those ≥65y., Competing Interests: Phillipe Beutels reports grants from Innovative Medicines Initiative of the European Commission and attended meetings of an advisory board on economic evaluations of vaccines convened by Pfizer in 2019, outside the submitted work. Anke Stuurman is employed by P95 Epidemiology & Pharmacovigilance. Mendel Haag is employed by Seqirus BV. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Timely knowledge of which influenza vaccine brands are procured and where is of interest to inform site-selection for brand-specific influenza vaccine effectiveness (VE) studies. Vaccine procurement is a key determinant of brand availability. We therefore sought to understand how the procurement for seasonal influenza vaccine in Europe is organized, how this drives brand availability and how procurement data could enable to determine brand availability pre-season., Methods: Structured telephone interviews were conducted with 15 experts in 16 European countries between 2017 and 2019 to collect information on the influenza vaccine procurement systems. Sources of (brand-specific) procurement data were identified and assessed on public accessibility. Vaccine type and brand availability and timelines were determined for the 2019-20 season to understand how procurement systems drive brand availability and diversity., Results: Four main types of procurement systems for seasonal influenza vaccination campaigns were identified: national public tenders (Croatia, Denmark, Finland, Ireland, Lithuania, Netherlands, Norway, Scotland, Slovenia), regional public tenders (Italy, Spain, Sweden), direct purchase of vaccines by GPs (England, Wales) or pharmacies (Belgium, France, Germany, Greece) from manufacturers or wholesalers. National public tender outcomes are publicly available and timely; brand availability at clinic level can generally be deduced or narrowed down to two brands. Regional tender outcomes are more difficult to find, known very late or not available. In Italian and Spanish regions tenders may be awarded only a few weeks before the seasonal campaign. No public procurement information is available for countries with direct purchase., Conclusion: At the country-level, brand diversity is generally lower for countries with national public tenders than for countries with regional public tenders or direct purchase. In only a few countries, procurement data at the brand level is both publicly available and timely. Therefore the usefulness of procurement data for prospective site-selection for brand-specific VE studies is limited., Competing Interests: MH is an employee of Seqirus. AS is an employee of P95 Epidemiology and Pharmacovigilance. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The DRIVE project aims to establish a sustainable network to estimate brand-specific influenza vaccine effectiveness (IVE) annually. DRIVE is a public-private partnership launched in response to EMA guidance that requires effectiveness evaluation from manufacturers for all individual influenza vaccine brands every season. IVE studies are conducted by public partners in DRIVE. Private partners (vaccine manufacturers from the European Federation of Pharmaceutical Industries and Association (EFPIA)) provide written feedback moderated by an independent scientific committee. Test-negative design (TND) case-control studies (4 in primary care and five in hospital) were conducted in six countries in Europe during the 2018/19 season. Site-specific confounder-adjusted vaccine effectiveness (VE) estimates for any vaccine exposure were calculated by age group (<18 years (y), 18-64y and 65 + y) and pooled by setting (primary care, hospital) through random effects meta-analysis. In addition, one population-based cohort study was conducted in Finland. TND studies included 3339 cases and 6012 controls; seven vaccine brands were reported. For ages 65 + y, pooled VE against any influenza strain was estimated at 27% (95%CI 6-44) in hospital setting. Sample size was insufficient for meaningful IVE estimates in other age groups, in the primary care setting, or by vaccine brand. The population-based cohort study included 274,077 vaccinated and 494,337 unvaccinated person-years, two vaccine brands were reported. Brand-specific IVE was estimated for Fluenz Tetra (36% [95%CI 24-45]) for ages 2-6y, Vaxigrip Tetra (54% [43-62]) for ages 6 months to 6y, and Vaxigrip Tetra (30% [25-35]) for ages 65 + y. The results presented are from the second influenza season covered by the DRIVE network. While sample size from the pooled TND studies was still too low for precise (brand-specific) IVE estimates, the network has approximately doubled in size compared to the pilot season. Taking measures to increase sample size is an important focus of DRIVE for the coming years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Anke L. Stuurman, Kaatje Bollaerts, Maria Alexandridou, Jorne Biccler, Tom De Smedt, Nick De Smedt and Margarita Riera-Montes declare that P95 Epidemiology and Pharmacovigilance has held contracts for research work with GSK and Seqirus. Javier Díez-Domingo declares to have received honoraria from Sanofi Pasteur for advisory boards. Hanna Nohynek declares that her institution holds / has held a research contract with influenza vaccine manufactures GSK and Sanofi Pasteur on both non-influenza and influenza related research but she is not a recipient of these funds. Caterina Rizzo declares to have received an unconditional funding from Seqirus for a cost-effectiveness analysis in 2019. Topi Turunen declares to be the local subinvestigator in the FinFluHD study funded by the Finnish Institute for Health and Welfare and Sanofi Pasteur. Anca Cristina Dragonescu declares that she is the principal investigator for the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur. Anuta Bilasco, Ovidiu Vlaicu and Dan Otelea have no conflict of interest to declare. Adrian Streinu-Cercel declares that he is a member of the research team of the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur, and a subinvestigator in influenza clinical trials by Shionogi and F. Hoffmann-La Roche. Anca Streinu-Cercel declares that she is principal investigator for the I-MOVE + study funded through the European Union’s HORIZON 2020 research and innovation programme, and a subinvestigator in influenza clinical trials by Shionogi and F. Hoffmann-La Roche. Oana Sandulescu declares that she is a member of the research team of the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur, and a subinvestigator in influenza clinical trials by Shionogi and F. Hoffmann-La Roche. Victoria Arama declares that she is a member of the research team of the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur, and a member of the research team for the I-MOVE + study funded through the European Union’s HORIZON 2020 research and innovation programme. Daniela Pitigoi declares that she is principal investigator for the I-MOVE + study funded through the European Union’s HORIZON 2020 research and innovation programme, and a technical project manager for the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur. Dragos Florea declares that he is a member of the research team of the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur. Monica Luminita-Luminos declares that she is a member of the research team of the GIHSN project funded by Foundation for Influenza Epidemiology financed by Sanofi Pasteur. José Ángel Rodrigo-Pendás declares that he is a collaborator in two studies funded by GSK (Enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccines. EPI-FLU-056 VS EUR (2018–2019) & EPI-FLU- 056 VS EUR (2019–2020) and Safety and immunogenicity study of GSK Biologicals’ Herpes Zoster subunit vaccine (HZ/su) GSK1437173A on a two-dose schedule in adults ≥ 50 years of age with a prior episode of Herpes Zoster (ZOSTER-062 (204939)). EudraCT number: 2016–000744-34) and a collaborator in a clinical trial funded by a government grant (Phase IV, open, low-level intervention, clinical trial to compare the immunogenicity in immunosuppressed patients of an adjuvanted anti-hepatitis B vaccine with an anti-hepatitis B vaccine with increased antigenic load (HEPB-VAC-01). EudraCT number: 2018–002368-18). Paolo Bonanni declares that he has taken part as a co-author in different HTA evaluations of influenza vaccines in the Italian context for the elderly (co-financed by Seqirus) and for children (co-financed by Sanofi Pasteur) with no personal fees received. He has also taken part in advisory boards and formative events for Seqirus and Sanofi Pasteur with occasional payment of expenses and fees. Ritva K. Syrjänen declares that she is a co-investigator in pneumococcal studies for which her employer (Finnish Institute for Health and Welfare) has received research support from GSK; co-investigator in a clinical trial of influenza vaccines in the elderly funded by Sanofi Pasteur (not related to this study); and collaborator for the I-MOVE + study funded through the European Union’s HORIZON 2020 research and innovation programme. Ulrike Baum declares that her employer (Finnish Institute for Health and Welfare) has been contracted for a clinical trial of influenza vaccines in the elderly funded by Sanofi Pasteur. Anuta Bilasco, Ovidiu Vlaicu, Ainara Mira-Iglesias, Alfredo Vannacci, Claudia Ravaldi, Eva del Amo Morán, Miriam Levi, Monika Redlberger-Fritz, Roberto Bonaiuti, Cristina Andrés, Maria Chironna, Harshana Liyanage, Uy Hoang, Ornella Punzo, Stefania Bellino, Kirsi Skogberg, Simon de Lusignan, Andrés Antón, Antonino Bella, Raija Auvinen, Sonia Uriona Tuma, Ilaria Manini, Niina Ikonen, Raisa Loginov, Christian Napoli, F. Xavier López-Labrador, Giancarlo Icardi, Donatella Panatto, Piero Luigi Lai, Andrea Orsi, Stefano Mosca and Dan Otelea have no conflict of interest to declare., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Assess the risk of progression to cirrhosis and hepatocellular carcinoma (HCC) due to hepatitis B virus (HBV)-infection in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM)., Methods: Retrospective cohort study in the UK Clinical Practice Research Datalink with three cohorts: subjects with T2DM and HBV infection (T2DM+HBV cohort; N = 297), with T2DM without HBV-infection (T2DM cohort; N = 261 865), and with HBV-infection without T2DM (HBV cohort; N = 3630). Primary analyses were performed on the three cohorts and secondary analyses on subcohorts including patients with NAFLD diagnosis code (N = 6599). Case/outcome definitions were formulated with International Classification of Diseases/Read codes/laboratory results and classified using validated algorithms. Adjusted incidence rate ratios (IRR) were estimated with a Poisson regression model., Results: When comparing the T2DM+HBV and T2DM cohorts, adjusted IRRs were 14.06 (95% confidence interval: 4.47-44.19) for cirrhosis and 2.83 (1.06-7.55) for HCC. When comparing the T2DM+HBV and HBV cohorts, adjusted IRRs were 0.68 (0.21-2.27) for cirrhosis and 1.39 (0.46-4.20) for HCC. No cirrhosis cases were identified in T2DM+NAFLD+HBV patients; IRs were 16.92/10 000 person-years (12.97-21.69) and 85.24/10 000 person-years (10.32-307.91) in the T2DM+NAFLD and NAFLD+HBV cohorts., Conclusion: HBV-infection increased significantly the risk for cirrhosis among T2DM patients, however, not beyond the expected incremental risk among infected non-T2DM subjects. Our approach to evaluate the role of T2DM/NAFLD and HBV-infection in liver disease progression could be applied to other settings with higher HBV prevalence.

Background: Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination., Methods: Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty., Results: Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them., Discussion: GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: S. pneumoniae can cause a wide spectrum of diseases, including invasive pneumococcal disease and pneumonia. Two types of pneumococcal vaccines are indicated for use in adults: 23-valent pneumococcal polysaccharide vaccines (PPV23) and a 13-valent pneumococcal conjugate vaccine (PCV13)., Objective: To systematically review the literature assessing pneumococcal vaccine effectiveness (VE) against community-acquired pneumonia (CAP) in adults among the general population, the immunocompromised and subjects with underlying risk factors in real-world settings., Methods: We searched for peer-reviewed observational studies published between 1980 and 2015 in Pubmed, SciELO or LILACS, with pneumococcal VE estimates against CAP, pneumococcal CAP or nonbacteremic pneumococcal CAP. Meta-analyses and meta-regression for VE against CAP requiring hospitalization in the general population was performed., Results: 1159 unique articles were retrieved of which 33 were included. No studies evaluating PCV13 effectiveness were found. Wide ranges in PPV23 effectiveness estimates for any-CAP were observed among adults ≥65 years (-143% to 60%). The meta-analyzed VE estimate for any-CAP requiring hospitalization in the general population was 10.2% (95%CI: -12.6; 33.0). The meta-regression indicates that VE against any-CAP requiring hospitalization is significantly lower in studies with a maximum time since vaccination ≥60 months vs. <60 months and in countries with the pediatric PCV vaccine available on the private market. However, these results should be interpreted cautiously due to the high influence of two studies. The VE estimates for pneumococcal CAP hospitalization ranged from 32% (95%CI: -18; 61) to 51% (95%CI: 16; 71) in the general population., Conclusions: Wide ranges in PPV23 effectiveness estimates for any-CAP were observed, likely due to a great diversity of study populations, circulation of S. pneumoniae serotypes, coverage of pediatric pneumococcal vaccination, case definition and time since vaccination. Despite some evidence for short-term protection, effectiveness of PPV23 against CAP was not consistent in the general population, the immunocompromised and subjects with underlying risk factors.

The WHO recommends integration of universal mass vaccination (UMV) against hepatitis A virus (HAV) in national immunization schedules for children aged ≥1 year, if justified on the basis of acute HAV incidence, declining endemicity from high to intermediate and cost-effectiveness. This recommendation has been implemented in several countries. Our aim was to assess the impact of UMV using monovalent inactivated hepatitis A vaccines on incidence and persistence of anti-HAV (IgG) antibodies in pediatric populations. We conducted a systematic review of literature published between 2000 and 2015 in PubMed, Cochrane Library, LILACS, IBECS identifying a total of 27 studies (Argentina, Belgium, China, Greece, Israel, Panama, the United States and Uruguay). All except one study showed a marked decline in the incidence of hepatitis A post introduction of UMV. The incidence in non-vaccinated age groups decreased as well, suggesting herd immunity but also rising susceptibility. Long-term anti-HAV antibody persistence was documented up to 17 y after a 2-dose primary vaccination. In conclusion, introduction of UMV in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of hepatitis A in vaccinated and in non-vaccinated age groups alike.

Background: ​​The European Medicines Agency (EMA) calls for a strategy for enhanced safety surveillance of seasonal influenza vaccines., Objective: We assessed the feasibility of collecting reactogenicity data within one month of the start of the vaccination campaign in Belgium., Methods: One hundred subjects aged 18 to 65 years who had received inactivated seasonal influenza vaccine in occupational setting were enrolled. For 7 days after vaccination, subjects received a daily SMS with a link to a web-based questionnaire where reactogenicity events and their severity were solicited., Results: Data collection was completed by October 13th, 2016, before the peak of the vaccination campaign in Belgium. 68% of participants reported a local reaction and 65% a general reaction; 51% reported both a local and a general reaction., Conclusion: Here we show that it has been possible to collect reactogenicity data in adults for enhanced safety surveillance in Belgium in a timely manner. The observed reactogenicity is higher compared to previous observations for this vaccine measured in clinical trials.

To assess the risk of autoimmune disease (AD) in 9-25 year-old women within 1 year after the first AS04-HPV-16/18vaccine dose, a retrospective, observational database cohort study was conducted using CPRD GOLD. From CPRD GOLD 4 cohorts (65,000 subjects each) were retrieved: 1 exposed female cohort (received ≥1 AS04-HPV-16/18 vaccine dose between Sep2008-Aug2010) and 3 unexposed cohorts: historical female (Sep2005-Aug2007), concurrent male, and historical male. Co-primary endpoints were confirmed neuroinflammatory/ophthalmic AD and other AD, secondary endpoints were confirmed individual AD. Risk of new onset of AD was compared between cohorts (reference: historical cohort) using Poisson regression. The main analysis using confirmed cases showed no neuroinflammatory/ophthalmic AD cases in the female exposed cohort. Incidence rate ratio (IRR) (95% CI) of other AD was 1.41 (0.86 to 2.31) in female and 1.77 (0.94 to 3.35) in male cohorts when compared to the female and male historical cohort, respectively. Secondary endpoints were evaluated for diseases with >10 cases, which were Crohn's disease (IRR: 1.21 [0.37 to 3.95] for female and 4.22 [0.47 to 38.02] for male cohorts), autoimmune thyroiditis (IRR: 3.75 [1.25 to 11.31] for female and no confirmed cases for male cohorts) and type 1 diabetes (IRR: 0.30 [0.11 to 0.83] for female and 2.46 [1.08 to 5.60] for male cohorts). Analysis using confirmed and non-confirmed cases showed similar results, except for autoimmune thyroiditis in females, IRR: 1.45 (0.79 to 2.64). There was no evidence of an increased risk of AD in women aged 9 to 25 years after AS04-HPV-16/18 vaccination.

Background: Latent tuberculosis infection (LTBI) control relies on high initiation and completion rates of preventive treatment to preclude progression to tuberculosis disease. Specific interventions may improve initiation and completion rates. The objective was to systematically review data on determinants of initiation, adherence and completion of LTBI treatment, and on interventions to improve initiation and completion., Methods: A systematic review of the literature (PubMed, Embase) published up to February 2014 was performed. Relevant prospective intervention studies were assessed using GRADE., Results: Sixty-two articles reporting on determinants of treatment initiation and completion were included and 23 articles on interventions. Determinants of LTBI treatment completion include shorter treatment regimen and directly observed treatment (DOT, positive association), adverse events and alcohol use (negative association), and specific populations with LTBI (both positive and negative associations). A positive effect on completion was noted in intervention studies that used short regimens and social interventions; mixed results were found for intervention studies that used DOT or incentives., Conclusion: LTBI treatment completion can be improved by using shorter regimens and social interventions. Specific needs of the different populations with LTBI should be addressed taking into consideration the setting and condition in which the LTBI treatment programme is implemented.

Background: Efficient and reliable surveillance and notification systems are vital for monitoring public health and disease outbreaks. However, most surveillance and notification systems are affected by a degree of underestimation (UE) and therefore uncertainty surrounds the 'true' incidence of disease affecting morbidity and mortality rates. Surveillance systems fail to capture cases at two distinct levels of the surveillance pyramid: from the community since not all cases seek healthcare (under-ascertainment), and at the healthcare-level, representing a failure to adequately report symptomatic cases that have sought medical advice (underreporting). There are several methods to estimate the extent of under-ascertainment and underreporting., Methods: Within the context of the ECDC-funded Burden of Communicable Diseases in Europe (BCoDE)-project, an extensive literature review was conducted to identify studies that estimate ascertainment or reporting rates for salmonellosis and campylobacteriosis in European Union Member States (MS) plus European Free Trade Area (EFTA) countries Iceland, Norway and Switzerland and four other OECD countries (USA, Canada, Australia and Japan). Multiplication factors (MFs), a measure of the magnitude of underestimation, were taken directly from the literature or derived (where the proportion of underestimated, under-ascertained, or underreported cases was known) and compared for the two pathogens., Results: MFs varied between and within diseases and countries, representing a need to carefully select the most appropriate MFs and methods for calculating them. The most appropriate MFs are often disease-, country-, age-, and sex-specific., Conclusions: When routine data are used to make decisions on resource allocation or to estimate epidemiological parameters in populations, it becomes important to understand when, where and to what extent these data represent the true picture of disease, and in some instances (such as priority setting) it is necessary to adjust for underestimation. MFs can be used to adjust notification and surveillance data to provide more realistic estimates of incidence.