VidPrevtyn Beta® Vaccine Effectiveness against hospitalisation due to SARS-CoV-2 infection in the UK study

Sanofi Pasteur requires access to NHS England data for the purpose of the following research project:

VidPrevtyn Beta® Vaccine Effectiveness against hospitalisation due to SARS-CoV-2 infection - a secondary database study in the UK

The following is a summary of the aims of the research project provided by Sanofi Pasteur:

Specific populations are still at a high risk for severe COVID-19 outcomes including hospitalization and death following a SARS-CoV-2 infection. Vaccines effectiveness wanes over time and new variants of SARS-CoV-2 can result in some vaccines to be more or less effective than others. Thus, effective booster doses are required to protect at risk populations. In England, the vaccination guidelines as set out by the Joint Committee on Vaccination and Immunisation (JCVI) as of 27 January 2023 state that:

• Adults over 75+ years, residents in care homes and individuals aged 5 years and over who are immunocompromised will be offered a spring 2023 booster dose.

• Some people, including those aged 50 years or over, those at higher risk or who are pregnant, and frontline health and social care workers, will be offered a seasonal booster.

VidPrevtyn Beta® was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) on the 20th of December 2022 for use in seasonal booster programmes. Regulatory and health assessment agencies (e.g., MHRA and European Medicines Agency EMA) require additional real-world evidence to supplement and augment trial data. This additional information will help relevant agencies (e.g., The Joint Committee on Vaccination and Immunisation) inform decisions on priorities among these populations, anticipating health expenditure, and providing guidance on VidPrevtyn Beta® usage.

Research on the effectiveness of the VidPrevtyn Beta® booster in seasonal booster campaigns is needed to understand how well specific populations are protected with this booster.

Sanofi Pasteur and GSK (GlaxoSmithKline) co-created one of the COVID-19 vaccines that was widely deployed during the COVID-19 pandemic, and Sanofi Pasteur is the sponsor and holder of the marketing authorization for VidPrevtyn Beta®, a booster vaccine against COVID-19. GSK (GlaxoSmithKline) may be asked to comment on the protocol, but they will not have any authority over the protocol design and finalization. Aggregated summary statistics will be shared with GSK.

The overall purpose of this study is to assess the real-world vaccine effectiveness of VidPrevtyn Beta® as a booster vaccine against severe COVID-19 outcomes. This study will utilize the requested data to provide commercial services to Sanofi Pasteur, the creator of VidPrevtyn Beta®. Sanofi Pasteur will use the outputs and insights generated from this study to work collaboratively with NHS organisations to promote health and improve the wellbeing of patients. The use of the data supports the development of innovative solutions and service improvement, to track outcomes and provide the real-world evidence as required by the EMA and MHRA, the aim of which is to improve patient care and support enhanced access to improved services and innovative solutions. In addition, Sanofi Pasteur will utilize the findings of this study to provide supporting information required by the EMA and MHRA for business cases, epidemiological research, pathway analysis, burden of disease analysis, health economic research, and quality and outcome analysis. The outputs of this study will be shared directly with the EMA and MHRA to support improvements in patient care.

The Primary Study Objective is to:

1. Estimate the vaccine effectiveness of VidPrevtyn Beta® against hospitalisation due to COVID-19 with laboratory-confirmed SARS-CoV-2 infection in patients who have received at least one dose of VidPrevtyn Beta® as their last booster, compared with patients who have not received a booster dose within the same vaccination campaign period (between 3 April 2023 – 30 June 2023).

The Secondary Study Objectives are to:

1. Estimate the vaccine effectiveness of VidPrevtyn Beta® against death due to COVID-19 in patients who have received at least one dose of VidPrevtyn Beta® as their last booster, compared with patients who have not received a booster dose within the same campaign period (between 3 April 2023 – 30 June 2023).

2. Estimate the relative vaccine effectiveness of VidPrevtyn Beta® against hospitalisation due to COVID-19 with laboratory-confirmed SARS-CoV-2 infection in patients who have received at least one dose of VidPrevtyn Beta® as their last booster, compared with patients who have received an mRNA booster as their last dose within the same campaign period.

The Exploratory Study Objective is to:

1. Estimate the vaccine effectiveness of VidPrevtyn Beta® against hospitalisation due to COVID-19 with laboratory-confirmed SARS-CoV-2 infection in patients who have received at least one additional dose of VidPrevtyn Beta® as their last dose, compared with patients who have not received a booster dose within the same campaign period, stratified by:

• Age groups

• Gender

• COVID-19 vaccination history

• Subgroups defined by comorbidities (for example, immunocompromised patients, Charlson comorbidity scores).

For the Primary Objective, Secondary Objective 1, and Exploratory Objective, individuals in the VidPrevtyn Boosted Cohort will be based on individuals in the Un-Boosted Cohort. For Secondary Objective 2 individuals in the VidPrevtyn Boosted Cohort will be based on those in the mRNA Boosted Cohort. For all objectives, there will be two study periods; baseline and follow-up.

The commercial interests of Sanofi Pasteur in this project are to better understand the effectiveness of VidPrevtyn Beta® against severe COVID-19 outcomes, as well as to provide evidence requested by health authorities for the assessment of VidPrevtyn Beta® in a real-world setting. Potential benefits of the project to Sanofi Pasteur might include: a) if there is a reduction of the number of severe COVID-19 outcomes in the VidPrevtyn Beta® cohort, this will fulfill regulatory requirements which may result in the vaccine staying on the market; b) if there is a difference in effectiveness in favor of VidPrevtyn over other vaccines, regulatory agencies may be more likely to recommend VidPrevtyn over other vaccines and payors more likely to reimburse for the vaccine c) Evidera will benefit since they will deepen their knowledge of COVID-19 observational research and therefore additional clients might be more likely to approach them based on their experience in this field.

The following NHS England Data will be accessed:

> Hospital Episode Statistics Admitted Patient Care (HES APC), HES Critical Care (CC), HES Outpatients (OP) and Uncurated Low Latency Hospital Data Sets Emergency Care – necessary to identify COVID-19 diagnoses and hospitalizations, as well as risk factors for severe COVID-19 outcomes.

> Civil Registration Mortality – necessary to help define COVID-19 deaths. The date of death will be used to censor follow-up period and as part of the definition of a COVID-19 death.

> COVID-19 SGSS First Positives (Second Generation Surveillance System) – necessary because test results from Pillar 1 and Pillar 2 will be used to identify patients who have a laboratory diagnosis of COVID-19.

> COVID-19 Vaccination Status – necessary to provide information on patient vaccination status, dose, date of injection, and product, which will be used to identify if patients received VidPrevtyn Beta®, another vaccine, or were not boosted during the vaccination campaign. This dataset will also be used to determine how many vaccines a patient has received and the time from the last vaccine.

> COVID-19 General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR) – necessary to identify positive SARS-CoV-2 results, risk factors for severe COVD-19 Outcomes including immunosuppressive medication, and other demographic information. Some conditions (e.g., asthma) are routinely managed by primary care professionals and may not require care provided by specialists or consultants; while other conditions are more commonly managed by specialists (e.g., cancer) rather than general practitioners (GP). Therefore, primary and secondary care data sets are required to identify patient groups of interest that are at risk of severe covid-19 outcomes.

The level of the Data will be:

> Pseudonymised

The Data will be minimised as follows:

> Limited to data provided by NHS England to cover all individuals within England aged 18 or over as of 3rd of April 2023 who received a primary vaccination series (i.e., at least 2 doses of any COVID-19 vaccine prior to 3 April 2023). The COVID-19 vaccination status dataset will be used to identify patient’s vaccination status. All patients 18 and older in England who meet the above criteria are requested to ensure patients from each cohort can be properly matched.

> For vaccine estimates to be reliable, patients from each sub-cohort listed below will be matched on several criteria, including age, sex, and comorbidities (using data from HES and GDPPR). This matching will be conducted by Evidera Ltd. Patients who did not receive a booster during the spring campaign period may be younger and healthier than those boosted. A sample of these un-boosted patients may result in the exclusion of patients who may be a better match to the boosted patients. Therefore, all patients who meet the eligibility criteria above are requested for optimal matching that will reduce bias and increase the reliability of the results. Subject to them meeting the above criteria, three cohorts will be constituted:

• VidPrevtyn Boosted Cohort: Patients who received VidPrevtyn Beta® during the campaign

• mRNA Boosted Cohort: Patients who received an mRNA COVID-19 vaccine during the campaign

• Un-Boosted Cohort: Patients who did not receive any vaccine during the campaign and have no record of a primary vaccination.

> Limited to data to include the period between 3rd April 2018 and 31st December 2023. The baseline period will begin five years prior to the index date and end the day before the index date and is requested to ensure important chronic conditions are captured that could affect a patients’ risk of a severe COVID-19 outcomes. Some conditions such as solid organ transplants can place a patient at higher risk even 5 years after the transplant took place. The observation period has been minimised to end after the spring and autumn vaccine campaigns but only as much data that is needed for 6 months of follow-up after the autumn campaign begins (31st December 2023). The follow-up period will begin on the index date and end at the earliest of death, new vaccine, outcome of interest, or 6-months after the index date. The index date for the VidPrevtyn Boosted Cohort and for the Boosted Cohort will be 14 days after receiving the vaccine. The index date for the Un-Boosted Cohort will be the same date as their matched VidPrevtyn Boosted counterpart.

Sanofi Pasteur is the sponsor and controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

Sanofi Pasteur works under the larger 'Sanofi' trading name. Sanofi is not a legal entity and do not determine the means or purpose for data processing.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party.

Sanofi Pasteur has determined the processing is necessary for its legitimate interests in relation to the ongoing risk of severe COVID-19 in at risk NHS populations. Regulators need to have access to evidence to inform recommendations for booster campaigns and to ensure high risk populations receive the most effective vaccine.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

There is public interest to this research as it will help inform the effectiveness of the VidPrevtyn Beta® as a booster vaccine against severe COVID-19 related outcomes. If the vaccine is not as effective as shown in clinical trials agencies and clinicians may not want to offer the vaccine in future campaigns. If it is more effective than other vaccines, they may prefer to offer this vaccine. Additionally, subgroups of individuals at higher risk of sever outcomes regardless of booster dose may be identified. These patients may want to take additional precautions to prevent exposure to SARS-CoV-2.

The funding is provided by Sanofi Pasteur.

Evidera Ltd is a processor acting under the instructions of Sanofi Pasteur. Evidera Ltd's role is limited to accessing available data sources for executing this study.

Commerical purposes explanation:

Evidera is a business within Pharmaceutical Product Development LLC (PPD), a leading global contract research organisation. Evidera has been contracted by and received funding from Sanofi Pasteur to conduct the current research project. The contracted services include drafting the study protocol and statistical analysis plan and finalising these according to the review comments received from Sanofi Pasteur, data preparation, data analysis, results reporting and dissemination. There are no other known conflicts of interest.

Sanofi Pasteur co-created VidPrevtyn Beta® COVID-19 vaccine which is being used in the spring 2023 booster campaign. This study fulfils a requirement by the EMA and MHRA to assess the real-world vaccine effectiveness of VidPrevtyn Beta®. Benefits of this study might include:

• If the study identifies high vaccine effectiveness, Sanofi and GSK may benefit from this research which may in turn demonstrate the benefits of VidPrevtyn Beta®.

• If the study identifies there is a greater vaccine effectiveness in VidPrevtyn Beta® than other vaccines, than NICE or other regulatory agencies might be more likely to approve VidPrevtyn Beta® for prevention of COVID-19 over other vaccine options. NICE assesses whether the approval of new therapies should be used in the NHS

• Evidera will benefit from this research since it will deepen its knowledge of COVID-19 observational research and therefore other clients (i.e., pharmaceutical companies) will be more likely to approach them for this type of research. It is also benefitting from the study since Sanofi Pasteur is paying Evidera to conduct the research on its behalf.

The primary focus of this study is to understand the vaccine effectiveness of VidPrevtyn Beta® in preventing severe COVID-19 outcomes and to inform regulatory agencies (EMA, MHRA) of the results so that these agencies can update recommendations and approval if needed. Results of the studies may identify the unmet needs of the current COVID-19 vaccines being delivered, and specific populations that may benefit more from additional boosters or other treatments. The commercial interests of Sanofi in this project are to better understand the effectiveness of VidPrevtyn Beta® in preventing severe COVID-19 outcomes. The potential public benefits to healthcare in England are considered to outweigh the potential commercial benefit (i.e., the effectiveness of the vaccine inform regulatory agencies, clinicians, and the public on how well protected patients will be if given the booster and if current recommendations need to change to best protect those at a high risk of COVID-19).

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

NHS England will grant access to the Data via the Secure Data Environment (SDE). The SDE is a secure data and research analysis platform. It allows approved researchers with approved projects access to pseudonymised data and industry-leading analytics tools.

NHS England will provide access to the relevant records from the HES, Emergency Care, Deaths, COVID-19 SGSS, COVID-19 Vaccination Status and GDPPR datasets to Evidera Ltd via NHS England Secure Data Environment (SDE). The Data will contain no direct identifying data items. The Data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

The Data will not be transferred to any other location.

SDE users can request exportation of aggregated analysis results (suppressed and summarised according to the NHSE SDE Disclosure Control rules) subject to review and approval by the NHS England SDE Output Checking team. The SDE Output Checking team will ensure that no output contains information which could be used either on its own or in conjunction with other data to breach an individual's privacy.

Users must identify themselves via a multi-factor authentication mechanism and are only able to access the datasets detailed within this DSA. The access and use of the system is fully auditable, and all users must comply with the use of the Data as specified in this DSA.

Users are only authorised to access the Data specified in this DSA and can utilise a variety of analytical tools available within the SDE platform. Users are not permitted to export record-level data from the SDE.

The Data will be stored on servers at NHS England.

Remote processing will be from secure locations within the UK.

The Data will not leave the UK at any time.

Access is restricted to employees of Evidera Ltd who have authorisation from the Senior Investigator.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will not be linked with any other data.

Only analysts employed by Evidera Ltd will analyse the Data for the purposes described above.

The expected outputs of the processing will be:

> A report of findings to Sanofi at the end of the study.

> A report of final results will be submitted to the EMA and MHRA to demonstrate the benefit of the vaccine in a real-world setting.

> Submissions to peer reviewed journals [expected 1-2 abstract submissions in 2024 and 1-2 manuscript submissions in 2024 or early 2025]. High impact respiratory/infectious disease journals will be targeted, such as British Medical Journal (BMJ), New England Journal of Medicine and Lancet Infectious Disease.

> Presentations at appropriate conferences, such as European Congress of Clinical Microbiology and Infectious Disease (ECCMID), International Society for Pharmacoeconomics and Outcomes Research (ISPOR). High impact respiratory/infectious disease conferences will be targeted.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

Sanofi Pasteur will not suppress findings or receive exclusive access to findings.

The outputs will be communicated to relevant recipients through the following dissemination channels:

> Journals

> Conferences

> Reports aimed at Sanofi Pasteur

> Reports aimed at the EMA and MHRA

> Webinars to Physicians using key Sanofi Pasteur Medical Science staff to communicate results

The initial results for this study are expected within 6 months following access to the NHS England-linked datasets. Once study report has been drafted, manuscripts will be prepared for submission to peer-reviewed journals and abstracts for conference presentation in Q4 2024/Q1 2025.

Benefits from this study are expected to include the following:

1. Benefits for regulators (e.g., EMA, MHRA): the findings from this study will provide evidence to help with the EMA and MHRA’s evaluation of VidPrevtyn Beta® vaccine effectiveness in real-world setting and inform their decisions for future COVID-19 vaccine booster campaigns, such as updating their recommendations and approval if needed. The findings from this study will also allow for a contemporaneous comparative effectiveness assessment, following the administration of sufficient doses.

2. It is anticipated that there will be benefits for the UK Department of Health and Social Care, clinicians, and healthcare providers: The wide-spread vaccination of the British population has significantly improved the impact of COVID-19 on healthcare systems, thus reducing its pressure on the limited healthcare resources and allowing healthcare providers to plan and act proactively (as opposed to acting reactively when the pandemic first started). To appropriately plan for the management and administration of resources, healthcare agencies will benefit from understanding the effectiveness of vaccines in reducing the risk of severe COVID-19, especially as the SARS-CoV-2 virus continues to evolve. By understanding and monitoring the effectiveness of VidPrevtyn Beta®, healthcare agencies will also be able to provide accurate information to the public to improve vaccine uptake, thus further reduces future impact of COVID-19. In addition, clinicians will have increased knowledge about the effectiveness of VidPrevtyn Beta® on all patients and specific patient subgroups to recommend the best types of vaccines for those who are more vulnerable to the disease.

3. It is anticipated that there will be benefits for patients and the public: Patients and the public benefit from improved healthcare provision. By making the study results available in the public domain, the public can benefit from more accurate assessment of the effectiveness of VidPrevtyn Beta® and make informed health decisions (e.g., taking up vaccine boosters or seek advice on other treatments).

4. If the study identifies an increasing incidence of severe COVID-19 outcomes in specific groups, governments might make the decision to administer booster vaccinations in other populations as part of their booster programme or administer boosters more regularly in some groups.

The use of the data could:

> help the system to better understand the health and care needs of populations.

> lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

> advance understanding of regional and national trends in health and social care needs.

> advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as obesity and diabetes.

> inform planning health services and programmes, for example to improve equity of access and outcomes.

> inform decisions on how to effectively allocate and evaluate funding according to health needs.

> support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

Sanofi Pasteur will use utilize the findings of this study to provide supporting information required by the EMA and MHRA for business cases, epidemiological research, pathway analysis, burden of disease analysis, health economic research, and quality and outcome analysis. The outputs of this study will be shared directly with the EMA and MHRA to support improvements in patient care.

Yielded Benefits is not a requirement for new applications.