Marc Far Ruiz

Els enfocaments establerts basats en el curs de vida suggereixen que l’estat de salut en l’edat adulta pot estar influenciat per esdeveniments ocorreguts durant el període de desenvolupament prenatal. Tot i així, intervencions com ara canvis en la dieta i l’estil de vida durant l’embaràs han tingut un impacte limitat tant en la salut materna com en la dels descendents. Actualment, hi ha un volum creixent de literatura que destaca la importància de la salut materna abans de la concepció (mesos o anys abans de l’embaràs) per a la salut futura de les criatures. Tot i que alguns estudis han explorat factors com la composició corporal materna, la nutrició i l’estil de vida en aquest àmbit, les exposicions ambientals i socioeconòmiques basades en la localització abans de la concepció també poden contribuir a la salut futura de la descendència. En aquesta línia, l’estudi de la història geogràfica d’una persona representa una via de recerca prometedora. Tanmateix, una de les principals raons per les quals la història residencial ha estat majoritàriament ignorada en estudis epidemiològics és que aquestes dades han estat difícils i costoses d’obtenir. Per omentar la recerca en aquesta direcció, fonts noves de dades massives de salut, com ara les històries clíniques electròniques registrades a l’atenció primària, ofereixen un marc únic. Un exemple d’aquesta font de dades és el Sistema d’Informació per al Desenvolupament de la Investigació a l’Atenció Primària (SIDIAP), creat l’any 2010 per proporcionar una base de dades vàlida i fiable amb informació seleccionada de les històries clíniques electròniques de pacients amb finalitats d’investigació. La base de dades SIDIAP inclou, entre d’altres, la història residencial dels pacients registrada a nivell anual i de secció censal (SC). A més, també inclou una base de dades mare-fill vinculada; un component essencial per estudiar la relació entre les exposicions aternes abans de la concepció i la salut futura de les seves criatures. En conjunt, les dades geoespacials i les bases de dades de salut es poden combinar i aprofitar mitjançant mètodes de mineria de dades per extreure coneixement significatiu i oferir coneixements aplicables per millorar la salut humana.

Establecer redes de investigación colaborativa en atención primaria tiene el potencial de mejorar la eficacia, eficiencia y aturaleza centrada en el paciente de la atención sanitaria. El consorcio INTRePID, establecido en 2020, es una coalición dinámica de expertos en atención primaria que actualmente proceden de Argentina, Australia, Brasil, Bélgica, Canadá, Chile, China, Ghana,
Indonesia, Israel, Japón, México, Noruega, Perú, España, Singapur, Suecia, Togo, Uganda, Reino Unido, Estados Unidos y Estados Unidos, con nuevos países que se unen continuamente. Su misión común es llevar a cabo investigaciones omparativas internacionales en atención primaria para mejorar la comprensión y promover cambios positivos. Los países participantes prroporcionan datos agregados, y por tanto no personales, sobre las visitas de atención primaria en su país para análisis itrospectivos. Para cada país participante, la población del estudio incluye a todas las personas que reciben servicios de tención primaria desde 0 hasta 100+ años y de ambos sexos, y todos los datos de interés desde 2018 hasta los datos más recientes
disponibles con actualizaciones regulares. Las variables de interés para este proyecto consisten en el recuento mensual de visitas clasificado por 1) datos demográficos de los pacientes, 2) indicadores socioeconómicos, 3) modalidad de atención recibida y 4) problemas de salud registrados durante la visita relacionados con la enfermedad pulmonar obstructiva crónica (EPOC), el asma, la esteatisis hepática asociada a disfunción metabólica (anteriormente conocida como hígado graso no alcohólico) y la demencia. Investigaciones recientes realizadas dentro del consorcio INTRePID han aportado valiosas perspectivas sobre diversos aspectos de la atención primaria, como la adopción variable de la atención virtual en respuesta a la pandemia en distintos países o el impacto de la pandemia en consultas de salud mental, prácticas preventivas y enfermedades crónicas. Estos hallazgos no solo contribuyen al cuerpo de conocimiento en atención primaria, sino que también informan las decisiones políticas y las prácticas sanitarias en todo el mundo. Al unirse a sus esfuerzos colaborativos, IDIAP Jordi Gol tendrá acceso a una gran cantidad de datos y experiencia de investigadores líderes en atención primaria de todo el mundo.

The main research question is: What is the occurrence of safety events of interest, in particular, preterm birth, preterm delivery or any reduction in time between vaccination and live and non-live births, among all pregnant women who receive ABRYSVO (and their offspring) compared to a matched group of pregnant women who do not receive ABRYSVO during pregnancy (and their offspring)?

Primary objective
The primary study objective is to estimate the incidence, birth prevalence, prevalence ratios and risk ratios (depending on the specific outcome) and time between vaccination and birth (live or non-live) of the following adverse pregnancy, maternal and birth outcomes in women who receive ABRYSVO during pregnancy (and their offspring), compared with a matched group of pregnant women who do not receive ABRYSVO during pregnancy (and their offspring):
• Pregnancy outcomes
o Preterm delivery or birth (less than 37 weeks) among livebirths:
? Extremely preterm delivery or birth (less than 28 weeks)
? Very preterm delivery or birth (28 to less than 32 weeks)
? Moderate to late preterm delivery or birth (32 to less than 37 weeks)
o Time between vaccination and birth among live and non-live births (vaccination date for unvaccinated pregnant woman is the vaccination date of their matched vaccinated pregnant woman)
o Stillbirth among live and non-live births

• Maternal outcomes during pregnancy
o Hypertensive disorders of pregnancy
o Guillain-Barré Syndrome (GBS)
• Birth outcomes (at birth)
o Low birth weight among live births
o Small for gestational age among live births

Secondary objectives
The secondary objectives are:
1. To estimate the incidence, birth prevalence, prevalence ratios and risk ratios (depending on the specific outcome) of the above mentioned pregnancy, maternal and birth outcomes and time between vaccination and birth (live or non-live) in immunocompromised pregnant women or women with high-risk pregnancies who receive ABRYSVO during pregnancy (and their offspring), compared with a matched group of immunocompromised pregnant women or women with high-risk pregnancies who do not receive ABRYSVO during pregnancy (and their offspring).
2. To estimate the prevalence ratio of preterm delivery or birth and time between vaccination and birth (live or non-live) between pregnant women who receive ABRYSVO (and their offspring) compared with a matched group of pregnant women who do not receive ABRYSVO during pregnancy (and their offspring), by week of gestation of vaccination.

On 23 August 2023, PF-06928316 (hereafter ABRYSVO) was approved by the European Commission for active immunisation of individuals 60 years of age and older for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV), a major cause of respiratory illness in older adults. This marketing authorization is valid in all 27 European Union (EU) member states plus Iceland, Liechtenstein, and Norway. On 31 May 2023, the Food and Drug Administration (FDA) approved ABRYSVO for active immunization for the prevention of LRTD caused by RSV in individuals 60 years of age and older.
The EU marketing authorization for ABRYSVO in older adults is based on evidence from the pivotal Phase 3 clinical trial, RENOIR (C3671013, NCT05035212) which evaluated the efficacy, immunogenicity, and safety of a single 120 µg dose of PF-06928316 or prefusion F vaccine in adults 60 years or older.
As immunocompromised, renally and hepatically impaired older adults were not included in clinical trials that supported regulatory approvals, the safety profile of ABRYSVO in these populations is unknown.
This protocol describes a post-authorization safety study (PASS) to assess the safety of ABRYSVO in immunocompromised, or renally or hepatically impaired adults aged 60 and older in select European countries and in the UK, with data sources that can capture vaccine exposure in the target populations, and where outcomes and key covariates can be ascertained. This study is an additional pharmacovigilance activity (Category 3 study) in the approved EU risk management plan (RMP) for ABRYSVO.
Research question and objectives
The research question is: What is the incidence of safety events of interest among immunocompromised, or renally or hepatically impaired adults aged 60 years and older who receive ABRYSVO compared to a relevant comparator group who does not receive ABRYSVO?
The primary study objective is:
To estimate the incidence rates and rate ratios of safety events of interest in immunocompromised, or renally or hepatically impaired adults aged 60 years and older who receive ABRYSVO compared to a relevant comparator group who does not receive ABRYSVO (evaluated as separate populations and if appropriate, as a combined population).
Study design
This is a retrospective, comparative cohort study using data access providers of the Vaccine Monitoring Collaboration for Europe (VAC4EU) that meet fit-for-purpose criteria. If appropriate, based on the outcome of interest, the study will also use a self-controlled risk interval (SCRI) design.
Population
The target population will consist of individuals who are immunocompromised, or renally or hepatically impaired (evaluated as separate populations and if appropriate, as a combined population) who are at least 60 years of age on the date of vaccination (i.e, index date for the vaccinated cohort) or on the matched index date (for the unvaccinated cohort), and who have at least 12 months of medical history in one of the data sources with no record of RSV vaccination in that 12 month period and who have at least one day of post-index follow up. Immunocompromised or renally impaired or hepatically impaired status will be ascertained via coded diagnoses, treatments, procedures, and/or laboratory values, as appropriate, at index date or in the 12-month baseline period prior to the index date.
Variables
The exposure of interest is ABRYSVO vaccination, which will be obtained from pharmacy dispensing records, general practice records, immunization registers, vaccination records, medical records, or other secondary data sources. Outcomes will be identified in participating databases with algorithms based on codes for diagnoses, procedures, and treatments. Standard algorithms for each outcome definition will be applied to participant data sources, based on the results of the ACCESS project, and will be tailored to the data source. Potential covariates may include the following information, as available in each data source: demographics; personal lifestyle characteristics; and clinical characteristics including comorbidities, comedication use, healthcare utilisation descriptors, other vaccinations, and surrogates of frailty. Covariates will be identified on the index date (or during the 12-month baseline period prior to the index date). These variables will be used to further characterize the patient populations of interest and/or to control for confounding.
Data sources
The study will utilise data from the following selected data sources: Clinical Practice Research Datalink (CPRD) Aurum (UK), Valencia Health System Integrated Database (VID) (ES), Sistema d’Informació per el Desenvolupament de la Investigació en Atenció Primària (SIDIAP) [Information System for the Improvement of Research in Primary Care] (ES), EpiChron Research Group on Chronic Diseases at the Aragon Health Sciences Institute (EpiChron) (ES), and Système National des Données de Santé (SNDS) (FR).
Study size
All individuals who meet the eligibility criteria during the study period in the select data sources will be included. The sample size will depend on the number of individuals administered ABRYSVO identified within the data sources during the study period, which will increase over time. The relative increases in rates to be detected will vary across outcomes of interest. For example, analyses using a comparative cohort design will have sufficient power (80%) to detect a 2-fold and 3-fold increased rate of arrhythmia associated with ABRYSVO, with a sample size of 1,178 and 393 individuals per cohort, respectively, assuming a baseline rate of 2,000 arrhythmia events per 100,000 person-years and equal numbers of individuals in the vaccinated and unvaccinated cohorts.
Data analysis
Baseline demographics and clinical characteristics for ABRYSVO vaccinated and unvaccinated individuals will be summarized using descriptive statistics. Descriptive statistics will also be used to summarize ABRYSVO uptake characteristics. Incidence rates per 1,000 patient years (and corresponding 95% CIs) will be calculated for all outcomes of interest in the ARBYSVO vaccinated and unvaccinated cohorts separately.
For the comparative cohort design, outcome specific incidence rates in the ABRYSVO vaccinated cohort will be compared to incidence rates in the unvaccinated cohort. Average treatment effect for the treated (ATT) weighting based on the propensity scores (PS) will be used to ensure baseline comparability between the vaccinated and unvaccinated cohorts. Stabilized inverse probability of censoring weighting (IPCW) will also be used if informative censoring between the cohorts is observed. After weighting, the distribution of baseline characteristics will be evaluated between the vaccinated cohort and the unvaccinated cohort, and variables that are inadequately balanced (standardized difference >10%) between the two cohorts will be included as regression model covariates in a doubly robust approach. Weighted Poisson regression models will be conducted, and incidence rate ratios and corresponding 95% confidence intervals (CIs) will be summarized.
For the SCRI design, the study population will include individuals who have received ABRYSVO, and experienced the specific outcomes of interest during the post-vaccination risk or control interval. Individuals who experienced a prespecified outcome following ABRYSVO vaccination serve as their own control by comparing the incidence of the outcome in the post-vaccination risk interval to the incidence of the outcome in a post-vaccination control interval using a conditional Poisson regression model. From this model, incidence rate ratios and 95% CIs will be reported.
Meta-analysis: Using the main estimates from each data source, appropriate random-effects meta-analytic methods may be used to obtain a combined effect estimate within each population of interest for both the comparative cohort and SCRI design analyses.

L’establiment de xarxes de recerca col·laboratives en atenció primària té el potencial de millorar l’eficàcia, l’eficiència i la naturalesa centrada en el pacient de l’atenció sanitària. El consorci INTRePID, establert el 2020, és una coalició dinàmica d’experts en atenció primària d’Argentina, Austràlia, Brasil, Canadà, Xile, Xina, Japó, Noruega, Perú, Singapur, Suècia, Regne Unit, Togo i els Estats Units. La seva missió compartida és dur a terme recerca comparativa internacional en atenció primària per millorar la comprensió i impulsar un canvi positiu. Els països s’uneixen a INTRePID proporcionant dades agregades, i per tant no personals, sobre visites a l’atenció primària al seu país per a l’anàlisi retrospectiva de dades. Per cada país participant, la població d’estudi inclou totes les persones que reben serveis d’atenció primària des dels 0 fins als 100+ anys i d’ambdós sexes, i s’inclouen totes les dades d’interès des del 2018 fins a les dades més recents disponibles amb actualitzacions anuals. Les variables d’interès consisteixen en el recompte mensual de visites classificat per 1) dades demogràfiques dels pacients, 2) indicadors socioeconòmics, 3) modalitat de l’atenció rebuda, i 4) problemes de salut registrats durant la visita en relació a l’ansietat, la depressió, el trastorn per dèficit d’atenció amb hiperactivitat, l’obesitat i la diabetis. Recerques recents dutes a terme dins del consorci INTRePID han aportat informació valuosa sobre diversos aspectes de l’atenció primària, com per exemple l’adopció variable de l’atenció virtual en resposta a la pandèmia en diferents països o l’impacte de la pandèmia en les consultes de salut mental. Aquestes troballes no només contribueixen al conjunt de coneixements en atenció primària, sinó que també informen les decisions polítiques i les pràctiques sanitàries a tot el món. En unir-se als seus esforços de col·laboració, l’IDIAP Jordi Gol tindrà accés a una gran quantitat de dades i experiència d’investigadors líders en atenció primària de tot el món.

Research question and objectives:
Research question: Is there a difference in the risk of selected adverse events of special interest (AESIs) after vaccination with BIMERVAX® compared with vaccination by other vaccines for the same indication?
Primary objectives:
?? To characterise recipients of BIMERVAX® in relation to demographics and clinical characteristics at the time of vaccination, including the following: pregnancy status, age of childbearing potential, immunocompromised status, comorbidities, presence of
autoimmune and inflammatory disorders, and interaction with other vaccines (influenza).
?? To estimate the risk ratio and risk difference of prespecified AESIs comparing recipients of BIMERVAX® with recipients of other COVID-19 vaccines with the same indication, using a cohort design.
?? To estimate the incidence rate ratio of selected AESIs comparing a prespecified risk interval following BIMERVAX® vaccination with a later post-risk interval, using a selfcontrolled risk interval (SCRI) design.
Secondary objectives (study size allowing):
?? To estimate the risk ratio and risk difference of prespecified AESIs comparing recipients of BIMERVAX® with recipients of other COVID-19 vaccines with the same indication, using a cohort design in subgroups defined by the following baseline variables:
pregnancy status, immunocompromised status, frailty due to comorbidities, presence of autoimmune or inflammatory disorders, prior use of influenza vaccine and calendar time.
?? To estimate the incidence rate ratio of selected AESIs comparing a prespecified risk interval following BIMERVAX® vaccination with a later post-risk interval, using an SCRI design in subgroups defined by the following baseline variables: immunocompromised status, frailty due to comorbidities, presence of autoimmune or inflammatory disorders, prior use of influenza vaccine and calendar time.Study design:
The study will comprise:
?? A vaccine utilisation study component, which will use a descriptive study design to characterise individuals at the time of vaccination
?? A component on comparative safety studies, including:
– A cohort design to estimate the incidence of AESIs after receiving a BIMERVAX® vaccine dose compared with the incidence in a comparator group vaccinated by other COVID-19 vaccines.
– A self-controlled risk interval design to evaluate the risk of AESIs in a time interval following the receipt of a BIMERVAX® vaccine (the risk interval) compared with the risk of the same AESI during a subsequent post-risk time interval (the control
interval).
Population: The eligible population for the vaccine utilisation study will be all individuals actively enrolled in each of the selected European health data sources for at least 12 months before receiving a dose of the BIMERVAX® vaccine within the study period. For the comparative safety studies, the main eligibility criterion will be receiving BIMERVAX® or other COVID-19 vaccine at baseline (matched cohort design) or receiving BIMERVAX® and have experienced an AESI during the risk or control interval (self-controlled risk interval design). The study period will begin from the date of first availability of the BIMERVAX® original vaccine in each participating data source/country and will end 36 months (48 months for pregnancy outcomes) after the start of data collection. The start of data collection will be anchored on the threshold of a total of 4,000 BIMERVAX® doses administered across the participating data sources.
Variables:
?? In the vaccine utilisation study, the following variables will be measured at the time of vaccination: demographics; pregnancy status and trimester of pregnancy, as feasible; immunocompromised status; comorbidities that may determine frailty; autoimmunity,
and inflammatory conditions; prior COVID-19 vaccination (brand, doses); prior use of other vaccines (influenza); comedications; and COVID-19 history.
?? In the comparative safety studies, exposures will be based on recorded prescription, dispensing, or administration of COVID-19 vaccines during the study period. The outcomes will be based on the BIMERVAX® risk management plan that included AESIs
proposed by the ACCESS project for a cohort and an SCRI study design. Key confounders will include demographics, COVID-19 history, vaccinations, personal lifestyle characteristics, comorbidities, comedications, immunocompromising conditions,
and others. Subgroups will be defined by baseline variables, such as immunocompromised status, vaccinations, and others.
Data sources: The planned data sources for this study, pending confirmation of vaccine rollout, are EpiChron (Spain), Information System for Research in Primary Care (SIDIAP) (Spain), and Valencia Health System Integrated Database (VID) (Spain). Rollout in other European countries will be monitored to evaluate other potential data sources.
Study size: The study size for both the vaccine utilisation study and the comparative safety studies will be determined by the uptake of BIMERVAX® in the participating data sources during the study period.
Data analysis: The vaccine utilisation study will summarise the variables of interest at the time of vaccination using standard measures of central tendency and of dispersion for continuous variables as well as counts and percentages for categorical variables.
The comparative safety cohort study will use matching and inverse probability weighting to adjust for the measured baseline confounders. Outcomes will be treated as time-to-event variables and will be analysed accordingly. Effect estimates will be provided as risk ratios and as risk differences scales.
The SCRI study will compare the risk of each AESI during a prespecified period following the index date (the “risk interval” during which there is a hypothesised increased risk of the outcome) with that of a self-matched “control interval,” used to assess the baseline risk of the outcome.