Study Title: A randomised, phase II UK multi-centre study to determine reactogenicity and immunogenicity of booster vaccination against ancestral and novel variants of SARS-CoV-2 Short Title: Evaluating COVID-19 Vaccine Boosters (Covboost)

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Objective for processing

[2 paragraphs unchanged] NHS Digital has agreed to work in partnership with the National Institute [25 words unchanged] can register their details and give their permission to be contacted by NHS Digital about researchers working on NIHR approved UK coronavirus vaccine trials about with a view to participating in those trials. This PtC Service, which is called “Sign Up to be Contacted about Coronavirus Vaccine Studies” on the nhs.uk website website, was launched as a national service on 20th July 2020. The registry that holds the details provided by members of the public who sign up is called the ‘NHS Digital COVID-19 Vaccine Research Registry’. This Th PtC Service enables participants to: • Provide their permission for to be contacted by NHS Digital to share an individual’s details provided through the Service with the researchers undertaking COVID-19 UK vaccine trials for the purposes purpose of researchers contacting that individual about taking part in those COVID-19UK vaccine trials. [2 paragraphs unchanged] • Matching potentially eligible participants to eligibility criteria provided by the vaccine trials for their specific studies. This data will comprise of age, sex, geographic locations, type of employment, and a number of health question questions e.g. about whether they have long-term health conditions. • Providing relevant details of potentially eligible participants which have been obtained through the Service to researchers. This will allow the researchers to contact the participants with a view to discussing their taking part in a trial and if so, to obtain their further permission to take part in the trial. • Sending invitations to participants regarding possible studies to take part in. • NHS Digital will provide access to the information obtained from individuals through the Service via the existing Data Access Request Service (DARS) process available to researchers working on UK COVID-19 vaccine trials sponsored by the National Institute of Health Research. The Service will only provide researchers with the data collected directly from individuals themselves through the Service. NHS Digital will assess applications to invite participants via the existing Data Access Request Service (DARS) process (as utilised by the DigiTrials Team) The contact details will be used to invite potentially eligible individuals to undertake an eligibility assessment and, if eligible, assessment. Eligible individuals will be asked to give informed consent to participate in this trial. NHS Digital, as data processor Data Processor acting on behalf of University Hospital Southampton NHS Foundation Trust will be sending the email to eligible participants. This request relates specifically to a vaccine trial. trial (studies detailed below in order of most recent) The initial version of this Data Sharing Agreement (version 0) for this study was to determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. ------------------------------------------------------------------------ As of April 2021 the MHRA in the UK has granted Regulation 174 approval for emergency use of 3 vaccines for protection against COVID-19 in the UK, including the mRNA vaccines BNT162b2 (Pfizer) the mRNA-1273 (Moderna) vaccine, and the chimpanzee adenovirus vector vaccine ChAdOx1-nCov19 (AstraZeneca/Oxford). So far over 33 million people in the UK have received at least one dose of either BNT162b2, ChAdOx1-nCov19, or mRNA-1273. Annual or seasonal booster vaccination for high risk groups is thought likely to be required, especially in light of the emergence of new variants of the SARS-CoV-2 virus. There is concern from studies in South Africa and elsewhere that existing vaccines may be less effective against these variant strains. It is currently unclear which booster vaccine schedule will provide the best safety profile and immune responses, according to which vaccine was originally given. The Joint Committee for Vaccination and Immunisation and UK Chief Medical Officers need timely information regarding the effects of different booster vaccinations on the safety profile and immunity to previous and new variants of SARS-CoV-2 in order to inform national policy for autumn and winter 2021. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. VERSION 3 – JULY 2022 (***CURRENT VERSION***) The aim for the initial agreement (version 0) was to recruit a total of 2886 participants. The study successfully achieved this recruitment. The initial mailout aimed for around four / five times the number of potential participants to be recruited and therefore the estimate was for around 14430 individuals to be contacted. This agreement is being amended for a third time (version 3 - JULY 2022) in order to add an additional sub-study of the initial study called "Cov-Boost Moderna Bivalent vaccine study" This agreement was subsequently amended (Version 1) to add a sub-study of the initial study called Cov-Boost Young Adult Fractional Dosing. The sub-study aims to recruit a further 961 individuals aged 18–30 who have previously received two doses of either Pfizer or Moderna vaccines. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a third dose as part of the study. BACKGROUND OF THE SUB STUDY COV-BOOST MODERNA BIVALENT VACCINE STUDY: Following the development of new vaccines designed which are specifically targeted to the spike protein of the Omicron variant of concern (VOC), including one based on the original mRNA-1273 vaccine, further vaccines have been developed including both new VOC targeted antigens as well as the original antigen based on the ancestral virus. The purpose of these bivalent vaccines is to stimulate a stronger and potentially broader immune response which may provide additional protection against current or future variants of SARS-CoV-2. The aim for this sub-study is to recruit a total of 200 participants. The mailout aims for around four / five times the number of potential participants to be recruited and therefore the estimate is for around 800 - 1,000 individuals to be contacted. This sub-study aims to compare safety and immunogenicity responses of an omicron specific vaccine, mRNA-1273.214 as a fourth dose booster to a full dose of BNT162b2 as a fourth dose booster. The study hypothesis is that the mRNA-1273.214 as a fourth dose compared with BNT162b2 can induce higher antibodies against Omicron variant and non-inferior antibodies against wide type. ------------------------------------------------------------------------ VERSION 2 – FEBRUARY 2022 This agreement was amended for a second time (version 2 - FEBRUARY 2022) in order to add a sub-study of the initial study called Cov-Boost Omicron Variant Fourth Dose Booster. This second sub-study aimed to recruit a further 200-400 people 30 years or older who have had 3 doses of COVID-19 vaccine. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a fourth dose as part of the study. BACKGROUND OF OMICRON VARIANT FOURTH DOSE BOOSTER SUB STUDY: The Cov-Boost trial wish to study the use of a new COVID-19 vaccine designed against the Omicron variant when given as a fourth dose booster, compared to a dose of BNT162b2 (the Pfizer COVID-19 vaccine). The Omicron variant has a large number of mutations to the “spike” protein on its surface, which is the protein most COVID-19 vaccines have used to train the body to recognise the virus which causes COVID-19 (SARS-CoV-2). This has made Omicron more effective at evading the immune response generated from existing vaccines. The pharmaceutical company Moderna which produced the mRNA-1273 vaccine for COVID-19, has adapted it and made a new vaccine (mRNA-1273.529) which produces a version of the spike protein which more closely resembles the one found on Omicron. The study team also know that giving a third dose of the Pfizer vaccine (BNT162b2) significantly increased the immune system’s ability to recognise the Omicron variant spike protein. This sub-study is to evaluate the safety and side effect profile of giving a dose of mRNA-1273.529 compared to BNT162b2 COVID-19 vaccine to healthy adults, as a fourth dose COVID-19 booster, as well as assessing its impact on the immune response to different variants of SARS-CoV-2, including the Omicron and Delta variants. The mailout aimed for around four / five times the number of potential participants to be recruited and therefore the estimate was for around 1,000 - 2,000 individuals to be contacted. This sub-study was aiming to determine the side effect profile, safety and immune response of giving a fourth COVID-19 vaccine booster doses of BNT162b2 (Pfizer) and mRNA-1273.529 (Moderna) to people who have previously received 3 doses of COVID-19 vaccine. ------------------------------------------------------------------------ VERSION 1 – JANUARY 2022 This agreement was subsequently amended (Version 1 - JANUARY 2022) to add a sub-study of the initial study called Cov-Boost Young Adult Fractional Dosing. The sub-study aimed to recruit a further 961 individuals aged 18–30 who have previously received two doses of either Pfizer or Moderna vaccines. Participants were randomised to receive a fractional dose of either Pfizer or Moderna as a third dose as part of the study. [2 paragraphs unchanged] The aim for the Fractional-Dose sub-study is was to recruit a total of 961 participants. The mailout aims for around four / five times the number of potential participants to be recruited and therefore the estimate is was for around 3844-4805 individuals to be contacted. ***** This agreement is being amended for a second time (version 2) in order to add a sub-study of the initial study called Cov-Boost Omicron Variant Fourth Dose Booster. This second sub-study is aiming to recruit a further 200-400 people 30 years or older who have had 3 doses of COVID-19 vaccine. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a fourth dose as part of the study. ------------------------------------------------------------------------ BACKGROUND OF OMICRON VARIANT FOURTH DOSE BOOSTER SUB STUDY: VERSION 0 - MAY 2021 The Cov-Boost trial wish to study the use of a new COVID-19 vaccine designed against the Omicron variant when given as a fourth dose booster, compared to a dose of BNT162b2 (the Pfizer COVID-19 vaccine). The Omicron variant has a large number of mutations to the “spike” protein on its surface, which is the protein most COVID-19 vaccines have used to train the body to recognise the virus which causes COVID-19 (SARS-CoV-2). This has made Omicron more effective at evading the immune response generated from existing vaccines. The pharmaceutical company Moderna which produced the mRNA-1273 vaccine for COVID-19, has adapted it and made a new vaccine (mRNA-1273.529) which produces a version of the spike protein which more closely resembles the one found on Omicron. The study team also know that giving a third dose of the Pfizer vaccine (BNT162b2) significantly increased the immune system’s ability to recognise the Omicron variant spike protein. This sub-study is to evaluate the safety and side effect profile of giving a dose of mRNA-1273.529 compared to BNT162b2 COVID-19 vaccine to healthy adults, as a fourth dose COVID-19 booster, as well as assessing its impact on the immune response to different variants of SARS-CoV-2, including the Omicron and Delta variants. The initial version of this Data Sharing Agreement (version 0 - MAY 2021) for this study was to determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. The mailout aims for around four / five times the number of potential participants to be recruited and therefore the estimate is for around 1,000 - 2,000 individuals to be contacted. As of April 2021 the MHRA in the UK has granted Regulation 174 approval for emergency use of 3 vaccines for protection against COVID-19 in the UK, including the mRNA vaccines BNT162b2 (Pfizer) the mRNA-1273 (Moderna) vaccine, and the chimpanzee adenovirus vector vaccine ChAdOx1-nCov19 (AstraZeneca/Oxford). So far over 33 million people in the UK have received at least one dose of either BNT162b2, ChAdOx1-nCov19, or mRNA-1273. Annual or seasonal booster vaccination for high risk groups is thought likely to be required, especially in light of the emergence of new variants of the SARS-CoV-2 virus. There is concern from studies in South Africa and elsewhere that existing vaccines may be less effective against these variant strains. It is currently unclear which booster vaccine schedule will provide the best safety profile and immune responses, according to which vaccine was originally given. The Joint Committee for Vaccination and Immunisation and UK Chief Medical Officers need timely information regarding the effects of different booster vaccinations on the safety profile and immunity to previous and new variants of SARS-CoV-2 in order to inform national policy for autumn and winter 2021. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. This sub-study is trying to determine the side effect profile, safety and immune response of giving a fourth COVID-19 vaccine booster doses of BNT162b2 (Pfizer) and mRNA-1273.529 (Moderna) to people who have previously received 3 doses of COVID-19 vaccine. The aim for the initial agreement (version 0 - MAY 2021) was to recruit a total of 2886 participants. The study successfully achieved this recruitment. The initial mailout aimed for around four / five times the number of potential participants to be recruited and therefore the estimate was for around 14430 individuals to be contacted. ***** ------------------------------------------------------------------------ GDPR LEGAL BASIS FOR PROCESSING AND DISSEMINATION [10 paragraphs unchanged] In the interests of full transparency, it is noted here that the data will be used in support of the development of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation. Some of the current vaccines do not yet have emergency or full regulatory approval, and the Vaccine Taskforce is funding this trial in order to generate data that can be used to inform UK policy in autumn/winter 2021/22: it will be appropriate for the data from this trial to be shared with regulatory authorities, potentially as part of a regulatory application. NHS Digital is content that the purpose of this study is the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials and such research is in the public interest for the benefit of public health. The data will be used to create a research cohort in support of the development or refinement of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation. Some of the current vaccines do not yet have emergency or full regulatory approval, and the Vaccine Taskforce is funding this trial in order to generate data that can be used to inform UK policy in autumn/winter 2021/22: it will be appropriate for the data from this trial to be shared with regulatory authorities, potentially as part of a regulatory application. [1 paragraph unchanged]

Processing activities

NHS Digital will extract a list of patients meeting the following criteria, where that criteria can be ascertained using the NHS Digital COVID-19 Vaccine Research Registry: [5 paragraphs unchanged] High level of face to face contact? Have you had a coronavirus test? [4 paragraphs unchanged] Lung conditions The selection criteria noted above are based solely on the information provided by members on the NHS Digital COVID-19 Vaccine Research Registry (where it can be obtained from this dataset). There is no linkage to other data held by NHS Digital, and such data is not used in assessing the selection criteria. Liver conditions NHS Digital will seek to identify the required number of individuals within the NHS Digital COVID-19 Vaccine Research Registry meeting the relevant criteria and will extract their names and email addresses. Heart conditions It is not known in advance how many individuals meeting the above criteria will respond to the invitation. The process may be repeated, with amended numbers and selection criteria, depending on the level of response. This could encompass any part of the criteria, depending on how the recruitment progresses. Cancer treatment NHS Digital will contact individuals in the subset inviting them to participate within the trial using ethically approved text provided by University Hospital Southampton NHS Foundation Trust. The communication will remind the individuals of the background of the Permission to Contact programme and give them the opportunity to state that they do not wish to be contacted again. The communication will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information. NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of the consent taken when joining the Permission to Contact service. Furthermore, to ensure that NHS Digital are able to update the registry with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information. Bleeding disorders It should be noted that the following inclusion and exclusion criteria will be used by the recruitment sites during the Screening phases: (studies detailed in order of most recent). These inclusion and exclusion criteria are in place to minimise the likelihood of harm to participants and to increase the likelihood of producing reliable results for the trial. All inclusion and exclusion criteria are detailed within the study protocol which have received ethical approval by the Research and Ethics Committee (REC). Immune system disorders ------------------------------------------------------------------------ NHS Digital will identify all individuals within the PtC dataset meeting the relevant criteria and will extract their names, email addresses and postcodes. VERSION 3 – JULY 2022 (***THIS AGREEMENT***) It is not known in advance how many individuals meeting the above criteria will have records in the PtC dataset. The number may be amended, and the process may be repeated depending on the level of response. In the event of the trial not achieving a suitable balance in recruited participants, subsequent mail outs may restrict the required criteria to a greater degree than previously. This could encompass any part of the criteria, such as age, gender, ethnicity or location and various others, depending on how the recruitment progresses. COV-BOOST BIVALENT VACCINE STUDY - INCLUSION CRITERIA (third sub-study version 3 - JULY 2022) NHS Digital will write to the individuals in the subset inviting them to participate within the trial using ethically approved text provided by University Hospital Southampton NHS Foundation Trust. The email will remind the individuals of the background of the permission to contact programme and give them the opportunity to state that they do not wish to be contacted again. The email will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information. Individuals will not be contacted multiple times under this Agreement and NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of consent. Furthermore, in order to ensure that NHS Digital are able to update the register with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information. The rollout of licensed vaccines is impacting on the volunteers available to recruit to studies and the inclusion criteria, e.g., age range, as listed below will be adjusted in line with the current progress of vaccine deployment. It should be noted that the following inclusion and exclusion criteria will be used by the recruitment sites during the Screening phase: COV BOOST MAIN STUDY INCLUSION CRITERIA (version 0); Participants in the original trial must have received two doses of trial vaccine with the first vaccine given in Dec 2020 / Jan 2021 and the second vaccine given at least 84 days prior to enrolment in the trial. As a result volunteers aged 70+ and health care workers were targeted in the mailout. [1 paragraph unchanged] • Male or Female, aged 30 years or above over and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. [5 paragraphs unchanged] • Received priming dose of COVID-19 vaccination between December 2020 and January 2021 (inclusive) and booster dose no less than 84 days prior to day 0. Due to the NHS deployment timelines, some sites may need to invite people who have been prime-boosted with their second dose of AstraZeneca with a minimum of 70 days from their second dose. Sites need Sponsor approval for this prior to enrolment of people with a 70-83 day gap since their second dose in any study arm. • Has received 3 doses of approved COVID-19 vaccine, with the third dose being either BNT162b2 30mcg or mRNA-1273 50mcg and is at least 3 months (84 days) since their third dose by day 0. COV BOOST MAIN STUDY EXCLUSION CRITERIA (version 0): COV-BOOST BIVALENT VACCINE STUDY - EXCLUSION CRITERIA (third sub-study version 3 - JULY 2022 The participant may not enter the trial if ANY of the following apply: • Previous receipt of a fourth COVID-19 vaccine • COVID-19 infection (confirmed by rt-PCR, lateral flow tests or saliva LAMP) within 84 days before day 0 [1 paragraph unchanged] • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus COVID-19 variant specific investigational vaccines) • Participants who are pregnant at enrolment or planning to become pregnancy within pregnant during the first 3 months after receiving the study vaccine following vaccination. • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines • Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) • History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the SmPC-listed ingredients of the Pfizer vaccine) • Any history of anaphylaxis • Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture • Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) • History of cerebral venous sinus thrombosis, antiphospholipid syndrome or heparin induced thrombocytopenia and thrombosis (HITT or HIT type 2) • Suspected or known current alcohol or drug dependency • Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data • Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) • History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion Significant renal or hepatic impairment • Scheduled elective surgery during the trial • Participant with life expectancy of less than 6 months • Participants who have participated in another research trial involving an investigational product in the past 12 weeks. This does not exclude participants in trials of AZD1222 (ChAdOx1 nCOV-19) who were originally recipients of placebo and who received AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 as part of the “national schedule” with AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 dose 1 from mid-Dec 20 through end January 21 and then AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 second dose 12 twelve weeks later (this is allowed by the COV001 and COV002 protocols) • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. YOUNG PERSON FRACTIONAL DOSING INCLUSION CRITERIA (sub-study version 1); The rollout of licensed vaccines is impacting on the volunteers available to recruit to studies and the inclusion criteria, e.g., age range, as listed below will be adjusted in line with the current progress of vaccine deployment. • Participant is willing and able to give written informed consent for participation in the trial. • Male or Female, aged 18 to 30 years and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. • In the Investigator’s opinion, is able and willing to comply with all trial requirements. • Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial • Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures. • Agreement to refrain from blood donation during the study. • Has received 2 doses of BNT162b2 or mRNA-1273 and is at least 3 months (84 days) since their second dose by day 0 YOUNG PERSON FRACTIONAL DOSING EXCLUSION CRITERIA (sub-study version 1); The participant may not enter the trial if ANY of the following apply: • Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) [14 paragraphs unchanged] • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. *** *********** OMICRON VARIANT FOURTH DOSING STUDY Temporary exclusion criteria If at Visit 1 Screening & Vaccination the volunteer has any of the following, they will not be enrolled that day. - Acute respiratory illness (moderate or severe illness with or without fever) - Fever (oral temperature greater than 37.8°C) They may be considered for enrolment later in the trial, if they recover in sufficient time. ------------------------------------------------------------------------ VERSION 2 – FEBRUARY 2022 OMICRON VARIANT FOURTH DOSING STUDY (second sub-study version 2 - FEBRUARY 2022) [1 paragraph unchanged] OMICRON VARIANT FOURTH DOSING STUDY - INCLUSION CRITERIA (second sub-study version 2): 2 - FEBRUARY 2022): [31 paragraphs unchanged] **************** ------------------------------------------------------------------------ Individual trial recruitment sites will supply NHS Digital with details of those who have signed up to take part in their trial so that NHS Digital can suitably capture this information within the Permission To Contact registry. All data that flows to NHS Digital in this context falls under the controllership of the data controller, regardless of whether they themselves are specifically involved in the processing of that data as it flows to NHS Digital. For this agreement there may be flows from each individual site. Once the data is received at NHS Digital then NHS Digital become controller for that data in their existing role as controller of the Permission To Contact Registry. VERSION 1 – JANUARY 2022 Due to the nature of trial recruitment sites, they often only become confirmed as sites very close to recruitment, and so NHS Digital will leave the responsibility with the lead site / data controller to appointment data processors themselves under their own due diligence. This practice aligns with their obligations under GDPR as a data controller and the emphasis will be on the lead site / data controller to appoint appropriate data processors on their behalf. Ordinarily NHS Digital would carry out these checks, but attempting to do so for this service would cause unnecessary delay to the initial application, as well as potentially multiple and costly amendments thereafter. Therefore, all recruitment sites / data processors and their processing activities will be covered under a suitable processing agreement between themselves and the lead site / data controller which does not require NHS Digital’s inclusion. Specific details of recruitment sites, such as key contact, location, will therefore not be made known to NHS Digital unless there is a specific reason to do so. YOUNG PERSON FRACTIONAL DOSING INCLUSION CRITERIA (sub-study version 1 - JANUARY 2022); The rollout of licensed vaccines is impacting on the volunteers available to recruit to studies and the inclusion criteria, e.g., age range, as listed below will be adjusted in line with the current progress of vaccine deployment. • Participant is willing and able to give written informed consent for participation in the trial. • Male or Female, aged 18 to 30 years and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. • In the Investigator’s opinion, is able and willing to comply with all trial requirements. • Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial • Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures. • Agreement to refrain from blood donation during the study. • Has received 2 doses of BNT162b2 or mRNA-1273 and is at least 3 months (84 days) since their second dose by day 0 YOUNG PERSON FRACTIONAL DOSING EXCLUSION CRITERIA (sub-study version 1 - JANUARY 2022); The participant may not enter the trial if ANY of the following apply: • Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines • Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) • History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the SmPC-listed ingredients of the Pfizer vaccine) • Any history of anaphylaxis • Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture • Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) • Suspected or known current alcohol or drug dependency • Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data • Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) • History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion • Significant renal or hepatic impairment • Participant with life expectancy of less than 6 months • Participants who have participated in another research trial involving an investigational product in the past 12 weeks. • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. *** ------------------------------------------------------------------------ VERSION 0 – MAY 2021 COV BOOST MAIN STUDY INCLUSION CRITERIA (version 0 - MAY 2021); Participants in the original trial must have received two doses of trial vaccine with the first vaccine given in Dec 2020 / Jan 2021 and the second vaccine given at least 84 days prior to enrolment in the trial. As a result volunteers aged 70+ and health care workers were targeted in the mailout. • Participant is willing and able to give written informed consent for participation in the trial. • Male or Female, aged 30 years or above and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. • Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception from 1 month prior to first immunisation continuously until 3 months after boost immunisation. See Section “Contraception and Pregnancy” for definition of child-bearing potential and definition of effective contraception. • In the Investigator’s opinion, is able and willing to comply with all trial requirements. • Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial • Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures. • Agreement to refrain from blood donation during the study. • Received priming dose of COVID-19 vaccination between December 2020 and January 2021 (inclusive) and booster dose no less than 84 days prior to day 0. Due to the NHS deployment timelines, some sites may need to invite people who have been prime-boosted with their second dose of AstraZeneca with a minimum of 70 days from their second dose. Sites need Sponsor approval for this prior to enrolment of people with a 70-83 day gap since their second dose in any study arm. COV BOOST MAIN STUDY EXCLUSION CRITERIA (version 0 - MAY 2021): • Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) • Participants who are pregnant at enrolment or planning to become pregnancy within 3 months after receiving the study vaccine • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines • Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) • History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the SmPC-listed ingredients of the Pfizer vaccine) • Any history of anaphylaxis • Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture • Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) • History of cerebral venous sinus thrombosis, antiphospholipid syndrome or heparin induced thrombocytopenia and thrombosis (HITT or HIT type 2) • Suspected or known current alcohol or drug dependency • Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data • Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) • History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion Significant renal or hepatic impairment • Scheduled elective surgery during the trial • Participant with life expectancy of less than 6 months • Participants who have participated in another research trial involving an investigational product in the past 12 weeks. This does not exclude participants in trials of AZD1222 (ChAdOx1 nCOV-19) who were originally recipients of placebo and who received AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 as part of the “national schedule” with AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 dose 1 from mid-Dec 20 through end January 21 and then AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 second dose 12 twelve weeks later (this is allowed by the COV001 and COV002 protocols) • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. ------------------------------------------------------------------------ Individual trial recruitment sites will supply NHS Digital with details of those who have signed up to take part in their trial so that NHS Digital can suitably capture this information within the NHS Digital COVID-19 Vaccine Research Registry. All data that flows to NHS Digital in this context falls under the controllership of the Data Controller, regardless of whether they themselves are specifically involved in the processing of that data as it flows to NHS Digital. For this agreement there may be flows from each individual site. Once the data is received at NHS Digital then NHS Digital become controller for that data in their existing role as controller of the NHS Digital COVID-19 Vaccine Research Registry. University Hospital Southampton NHS Foundation Trust have an appropriate data processing agreement in place with NHS Digital to support the recruitment into the trial under University Hospital Southampton NHS Foundation Trusts controllership. [1 paragraph unchanged] University Hospital Southampton NHS Foundation Trust will not have access to any of the data being disseminated by NHS Digital Data under this agreement.

Expected measurable benefits

The primary benefit of using the data will be to allow researchers [19 words unchanged] to recruit into the trials. This is expected to accelerate the delivery and refinement of an effective vaccine vaccines to treat individuals to manage the COVID-19 outbreak and to save lives. It is expected that this will reduce the burden on research staff [15 words unchanged] the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research research, produce and then produce a refine coronavirus vaccine vaccines and make sure one is new and improved vaccines are made available to the public as quickly as possible.

Benefits reported

[1 paragraph unchanged] Further achievements directly related to the study can be found in the following journal: The Lancet , VOLUME 398, ISSUE 10318, P2258-2276, DECEMBER 18, 2021 ***UPDATE for Version 3, JULY 2022*** (link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02717-3/fulltext) Use of the Vaccine Research Registry for the main COV-Boost study resulted in approximately 13000 unique visits to the study pre-screener. 490 volunteers who completed the pre-screener were eligible to be referred on to sites. Mailouts for the Fractional Dosing Sub-Study have resulted in 459 unique visits to the pre-screener. 132 participants recruited to the Omicron Variant sub-study reported that they heard about the study when they were contacted via the NHS Registry. Data from the COV-Boost study has helped to inform government and the Joint Committee on Vaccination and Immunisation (JCVI) decisions on 3rd and 4th dose NHS COVID-19 booster campaigns. Further achievements directly related to the study can be found in the following three journals: 1. The Lancet , VOLUME 398, ISSUE 10318, P2258-2276, Published DECEMBER 18, 2021 (link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02717-3/fulltext ) 2. The Lancet Infectious Diseases, Online, published MAY 09, 2022 (link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00271-7/fulltext ) 3. Journal of Infection, VOLUME 84, ISSUE 6, P795-813, JUNE 01, 2022 (link: https://www.journalofinfection.com/article/S0163-4453(22)00200-6/fulltext )

Unchanged: Expected output.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

[14 paragraphs unchanged] The aim for the initial agreement (version 0) was to recruit a total of 2886 participants. The study successfully achieved this recruitment. The initial mailout aimed for around four / five times the number of potential participants to be recruited and therefore the estimate was for around 14430 individuals to be contacted. The initial mailout aimed for around four / five times the number of potential participants to be recruited and therefore the estimate was for around 14430 individuals to be contacted. This agreement was subsequently amended (Version 1) to add a sub-study of the initial study called Cov-Boost Young Adult Fractional Dosing. The sub-study aims to recruit a further 961 individuals aged 18–30 who have previously received two doses of either Pfizer or Moderna vaccines. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a third dose as part of the study. ****** BACKGROUND OF YOUNG ADULT FRACTIONAL DOSING SUB STUDY: This version of the Data Sharing Agreement (version 1) is for a sub-study of the initial study called Cov-Boost Young Adult Fractional Dosing. The sub-study is aiming to recruit a further 961 individuals aged 18–30 who have previously received two doses of either Pfizer or Moderna vaccines. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a third dose as part of the study. BACKGROUND OF YOUNG ADULT FRACTIONAL DOSING SUB STUDY; [2 paragraphs unchanged] The mailout will aim aims for around four / five times the number of potential participants to be recruited and therefore the estimate if is for around 3844-4805 individuals to be contacted. ****** ***** This agreement is being amended for a second time (version 2) in order to add a sub-study of the initial study called Cov-Boost Omicron Variant Fourth Dose Booster. This second sub-study is aiming to recruit a further 200-400 people 30 years or older who have had 3 doses of COVID-19 vaccine. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a fourth dose as part of the study. The GDPR legal basis for processing the data is GDPR Article 6 (1) (e). Processing is carried out by an NHS organisation in the public interest, in order to understand and help this patient population in the future. Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects. BACKGROUND OF OMICRON VARIANT FOURTH DOSE BOOSTER SUB STUDY: NHS Digital is content that the purpose of this study is the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in the UK. The Cov-Boost trial wish to study the use of a new COVID-19 vaccine designed against the Omicron variant when given as a fourth dose booster, compared to a dose of BNT162b2 (the Pfizer COVID-19 vaccine). The Omicron variant has a large number of mutations to the “spike” protein on its surface, which is the protein most COVID-19 vaccines have used to train the body to recognise the virus which causes COVID-19 (SARS-CoV-2). This has made Omicron more effective at evading the immune response generated from existing vaccines. The pharmaceutical company Moderna which produced the mRNA-1273 vaccine for COVID-19, has adapted it and made a new vaccine (mRNA-1273.529) which produces a version of the spike protein which more closely resembles the one found on Omicron. The study team also know that giving a third dose of the Pfizer vaccine (BNT162b2) significantly increased the immune system’s ability to recognise the Omicron variant spike protein. This sub-study is to evaluate the safety and side effect profile of giving a dose of mRNA-1273.529 compared to BNT162b2 COVID-19 vaccine to healthy adults, as a fourth dose COVID-19 booster, as well as assessing its impact on the immune response to different variants of SARS-CoV-2, including the Omicron and Delta variants. However, in the interests of full transparency, it is noted here that the data will be used in support of the development of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation. Some of the current vaccines do not yet have emergency or full regulatory approval, and the VTF is funding this trial in order to generate data that can be used to inform UK policy in autumn/winter 2021/22: it will be appropriate for the data from this trial to be shared with regulatory authorities, potentially as part of a regulatory application. The mailout aims for around four / five times the number of potential participants to be recruited and therefore the estimate is for around 1,000 - 2,000 individuals to be contacted. This sub-study is trying to determine the side effect profile, safety and immune response of giving a fourth COVID-19 vaccine booster doses of BNT162b2 (Pfizer) and mRNA-1273.529 (Moderna) to people who have previously received 3 doses of COVID-19 vaccine. ***** University Hospital Southampton NHS Foundation Trust rely upon two Articles of the GDPR to provide a legal basis for the processing of personal data. Article 6 (1) (e) (processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller). The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. The FOI Act 2000 Part 1, section 3 (1)(a)(i) specifies that a public authority means any body which is listed in Schedule 1. Schedule 1 part 3 of the FOI Act 2000 lists the National Health Service. Chapter 5 of The NHS Act 2006 defines the role of NHS Foundation Trusts . Public Task: The NHS Act 2006 section 43(5), which describes the functions of authorised NHS Foundation Trusts, states that 'The authorisation must authorise and may require the NHS foundation trust— (a) to carry out research in connection with the provision of health care, (b) to make facilities and staff available for the purposes of education, training or research carried on by others' ‘Necessity’: Throughout the application process, the necessity of the processing for the performance of the task has been assessed. This includes but is not limited to ensuring appropriate minimisation of the data to ensure that only the minimum amount of data required are processed. Consideration has been given to whether the volume of data being requested is proportionate to the expected benefit and, through examination of the expected benefits consideration has been given to whether the task is itself necessary. NHS Digital are satisfied that this request is appropriate, necessary and proportionate for the performance of the task described in the Purpose statement and that there is no other reasonable means that is less intrusive to the data subjects for the study to achieve its purpose. Processing is carried out by an NHS organisation in the public interest, in order to understand and help this patient population in the future. In addition to the above GDPR Legal Basis for Processing, this agreement refers to health data, which is a Special Category of Personal Data and therefore University Hospital Southampton NHS Foundation Trust also relies upon 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). NHS Digital is content that the purpose of this study is the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in the UK. The data are required for research purposes in the public interest- meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) - which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public – thereby demonstrating that the processing is in the public interest – are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’. - In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include: i. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS Digital’s acceptance criteria (see sections 2 and 5b of this application for further details) although it should be noted that University Hospital Southampton NHS Foundation Trust is not receiving data from NHS Digital in this agreement; ii. The requested data has been assessed as proportionate to the aim pursued (see section 5a of this application for further details); iii. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection; iv. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights. In the interests of full transparency, it is noted here that the data will be used in support of the development of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation. Some of the current vaccines do not yet have emergency or full regulatory approval, and the Vaccine Taskforce is funding this trial in order to generate data that can be used to inform UK policy in autumn/winter 2021/22: it will be appropriate for the data from this trial to be shared with regulatory authorities, potentially as part of a regulatory application. [1 paragraph unchanged]

Processing activities

[20 paragraphs unchanged] ORIGINAL COV BOOST MAIN STUDY INCLUSION CRITERIA (version 0); [9 paragraphs unchanged] ORIGINAL COV BOOST MAIN STUDY EXCLUSION CRITERIA (version 0): [20 paragraphs unchanged] ****** [28 paragraphs unchanged] ****** *********** OMICRON VARIANT FOURTH DOSING STUDY Participants from the main study in Group B who received a 3rd dose booster of BNT162b2 (regardless of whether primary course was BNT162b2 or ChAdOx1-nCov19) will be invited to participate. Participants will be eligible for booster vaccination at the Fourth Dose Booster Sub-Study unless they have had a previous severe adverse reaction to mRNA vaccines or have acquired an additional COVID-19 vaccine outside of the study since enrolling. Other medical criteria will be checked prior to immunisation (including diagnosis of cancer, autoimmune conditions, neurological conditions, blood clotting conditions and pregnancy), but will not be considered a contraindication to vaccination unless the investigator feels there is a specific clinical reason to withhold vaccination for the safety of the participant. OMICRON VARIANT FOURTH DOSING STUDY - INCLUSION CRITERIA (second sub-study version 2): • Participant is willing and able to give written informed consent for participation in the trial. • Male or Female, aged 30 years or above and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. • Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception from 1 month prior to first immunisation continuously until 3 months after boost immunisation. • In the Investigator’s opinion, is able and willing to comply with all trial requirements. • Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial • Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures. • Agreement to refrain from blood donation during the study. • Received priming dose of COVID-19 vaccination in December 2020, January or February 2021 and is at least 84 days post second vaccination. Due to the NHS deployment timelines, some sites may need to invite people who have been prime-boosted with their second dose of AstraZeneca with a minimum of 70 days from their second dose. Sites need Sponsor approval for this prior to enrolment of people with a 70-83 day gap since their second dose in any study arm. OMICRON VARIANT FOURTH DOSING STUDY - EXCLUSION CRITERIA (second sub-study version 2): The participant may not enter the trial if ANY of the following apply: • Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) • Participants who are pregnant at enrolment or planning to become pregnant during the first 3 months following vaccination. • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines • Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) • History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the SmPC-listed ingredients of the Pfizer vaccine) • Any history of anaphylaxis • Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture • Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) • History of cerebral venous sinus thrombosis, antiphospholipid syndrome or heparin induced thrombocytopenia and thrombosis (HITT or HIT type 2) • Suspected or known current alcohol or drug dependency • Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data • Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) • History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion • Significant renal or hepatic impairment • Scheduled elective surgery during the trial • Participant with life expectancy of less than 6 months • Participants who have participated in another research trial involving an investigational product in the past 12 weeks. This does not exclude participants in trials of AZD1222 (ChAdOx1 nCOV-19) who were originally recipients of placebo and who received AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 as part of the “national schedule” with AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 dose 1 from mid-Dec 2020 through end February 2021 and then AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 second dose 12 twelve weeks later (this is allowed by the COV001 and COV002 protocols) • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. **************** [4 paragraphs unchanged]

Unchanged: Expected output, Expected measurable benefits, Benefits reported.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

[11 paragraphs unchanged] This request relates specifically to a vaccine trial. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. This request relates specifically to a vaccine trial. The initial version of this Data Sharing Agreement (version 0) for this study was to determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines. [1 paragraph unchanged] The aim for this application is the initial agreement was to recruit a total of 2886 participants. The study successfully achieved this recruitment. The initial mailout will aim aimed for around four / five times the number of potential participants to be recruited and therefore the estimate is was for around 14430 individuals to be contacted. ****** This version of the Data Sharing Agreement (version 1) is for a sub-study of the initial study called Cov-Boost Young Adult Fractional Dosing. The sub-study is aiming to recruit a further 961 individuals aged 18–30 who have previously received two doses of either Pfizer or Moderna vaccines. Participants will be randomised to receive a fractional dose of either Pfizer or Moderna as a third dose as part of the study. BACKGROUND OF YOUNG ADULT FRACTIONAL DOSING SUB STUDY; Following analysis of the results of stage one of the COV-BOOST study, a half dose of BNT162b2 was found to have comparable immunogenicity to a full dose of BNT162b2, with a similar and acceptable side effect profile. A half dose of mRNA1273 has been licensed and deployed as a 3rd dose booster by the NHS. Initial data from the Pfizer own immunobridging studies of children aged 5 – 11 years who received 10mcg of BNT162b2 showed equivalent immune responses to those seen in the studies of 12 – 15 years who received 30mcg. As young people generally have a more robust immune response and experience more side effects from vaccination than elderly people, the Coalition for Epidemic Preparedness Innovations (CEPI) have requested a sub-study of fractional doses of mRNA vaccines given to young adults (aged 18 – 30 years). Dose sparing regimes also allow the same amount of vaccine supply to be distributed to more people. The aim for the Fractional-Dose sub-study is to recruit a total of 961 participants. The mailout will aim for around four / five times the number of potential participants to be recruited and therefore the estimate if for around 3844-4805 individuals to be contacted. ****** The GDPR legal basis for processing the data is GDPR Article 6 (1) (e). Processing is carried out by an NHS organisation in the public interest, in order to understand and help this patient population in the future. Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects. NHS Digital is content that the purpose of this study is the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in the UK. However, in the interests of full transparency, it is noted here that the data will be used in support of the development of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation. Some of the current vaccines do not yet have emergency or full regulatory approval, and the VTF is funding this trial in order to generate data that can be used to inform UK policy in autumn/winter 2021/22: it will be appropriate for the data from this trial to be shared with regulatory authorities, potentially as part of a regulatory application. No commercial organisations will have access to NHS Digital record-level data. Commercial companies are providing vaccines for this trial free of charge.

Processing activities

NHS Digital will extract a list of patients meeting the following criteria, where that criteria can be ascertained using the PtC registry: NHS Digital COVID-19 Vaccine Research Registry: INCLUSION CRITERIA; Personal Information: Participants in this trial must have received two doses of trial vaccine with the first vaccine given in Dec 2020 / Jan 2021 and the second vaccine given at least 84 days prior to enrolment in the trial. As a result volunteers aged 70+ and health care workers will be targeted in the mailout. Age Location Sex at birth Ethnic Group Health questions: Flu Jab Diabetes Asthma Lung conditions Liver conditions Heart conditions Cancer treatment Bleeding disorders Immune system disorders NHS Digital will identify all individuals within the PtC dataset meeting the relevant criteria and will extract their names, email addresses and postcodes. It is not known in advance how many individuals meeting the above criteria will have records in the PtC dataset. The number may be amended, and the process may be repeated depending on the level of response. In the event of the trial not achieving a suitable balance in recruited participants, subsequent mail outs may restrict the required criteria to a greater degree than previously. This could encompass any part of the criteria, such as age, gender, ethnicity or location and various others, depending on how the recruitment progresses. NHS Digital will write to the individuals in the subset inviting them to participate within the trial using ethically approved text provided by University Hospital Southampton NHS Foundation Trust. The email will remind the individuals of the background of the permission to contact programme and give them the opportunity to state that they do not wish to be contacted again. The email will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information. Individuals will not be contacted multiple times under this Agreement and NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of consent. Furthermore, in order to ensure that NHS Digital are able to update the register with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information. It should be noted that the following inclusion and exclusion criteria will be used by the recruitment sites during the Screening phase: ORIGINAL STUDY INCLUSION CRITERIA (version 0); Participants in the original trial must have received two doses of trial vaccine with the first vaccine given in Dec 2020 / Jan 2021 and the second vaccine given at least 84 days prior to enrolment in the trial. As a result volunteers aged 70+ and health care workers were targeted in the mailout. [8 paragraphs unchanged] EXCLUSION CRITERIA: ORIGINAL STUDY EXCLUSION CRITERIA (version 0): [20 paragraphs unchanged] The inclusion and exclusion criteria noted above is based on the information provided by cohort members on the permission to contact dataset (where it can be obtained from this dataset), and is not collected from other NHS data sources. Some of the above inclusion and exclusion criteria will be used by the sites during the Screening phase. ****** NHS Digital will identify all individuals within the PtC dataset meeting the relevant criteria and will extract their names, email addresses and postcodes. YOUNG PERSON FRACTIONAL DOSING INCLUSION CRITERIA (sub-study version 1); It is not known in advance how many individuals meeting the above criteria will have records in the PtC dataset. The number may be amended and the process may be repeated depending on the level of response. In the event of the trial not achieving a suitable balance in recruited participants, such as an uneven ratio of males to females, subsequent mail outs may restrict the required criteria to a greater degree than previously, for example, only requesting details for male participants as opposed to both males and females. This could encompass any part of the criteria, such as age, gender, ethnicity or location and various others, depending on how the recruitment progresses. The rollout of licensed vaccines is impacting on the volunteers available to recruit to studies and the inclusion criteria, e.g., age range, as listed below will be adjusted in line with the current progress of vaccine deployment. NHS Digital will write to the individuals in the subset inviting them to participate within the trial using ethically approved text provided by University Hospital Southampton NHS Foundation Trust. The email will remind the individuals of the background of the permission to contact programme and give them the opportunity to state that they do not wish to be contacted again. The email will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information. Individuals will not be contacted multiple times under this Agreement and NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of consent. Furthermore, in order to ensure that NHS Digital are able to update the register with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information. • Participant is willing and able to give written informed consent for participation in the trial. • Male or Female, aged 18 to 30 years and in good health as determined by a trial clinician. Participants may have well controlled or mild-moderate comorbidity. • In the Investigator’s opinion, is able and willing to comply with all trial requirements. • Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial • Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures. • Agreement to refrain from blood donation during the study. • Has received 2 doses of BNT162b2 or mRNA-1273 and is at least 3 months (84 days) since their second dose by day 0 YOUNG PERSON FRACTIONAL DOSING EXCLUSION CRITERIA (sub-study version 1); The participant may not enter the trial if ANY of the following apply: • Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) • Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines • Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) • History of allergic disease or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the SmPC-listed ingredients of the Pfizer vaccine) • Any history of anaphylaxis • Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture • Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) • Suspected or known current alcohol or drug dependency • Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data • Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) • History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion • Significant renal or hepatic impairment • Participant with life expectancy of less than 6 months • Participants who have participated in another research trial involving an investigational product in the past 12 weeks. • Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available. *** ****** [1 paragraph unchanged] The inclusion and exclusion criteria noted above is based on the information provided by cohort members on the permission to contact dataset (where it can be obtained from this dataset), and is not collected from other NHS data sources. Some of the above inclusion and exclusion criteria will be used by the sites during the Screening phase. Due to the nature of trial recruitment sites, they often only become confirmed as sites very close to recruitment, and so NHS Digital will leave the responsibility with the lead site / data controller to appointment data processors themselves under their own due diligence. This practice aligns with their obligations under GDPR as a data controller and the emphasis will be on the lead site / data controller to appoint appropriate data processors on their behalf. Ordinarily NHS Digital would carry out these checks, but attempting to do so for this service would cause unnecessary delay to the initial application, as well as potentially multiple and costly amendments thereafter. Therefore, all recruitment sites / data processors and their processing activities will be covered under a suitable processing agreement between themselves and the lead site / data controller which does not require NHS Digital’s inclusion. Specific details of recruitment sites, such as key contact, location, will therefore not be made known to NHS Digital unless there is a specific reason to do so. Due to the nature of trial recruitment sites, they often only become confirmed as sites very close to recruitment, and so NHS Digital will leave the responsibility with the lead site / data controller to appointment data processors themselves under their own due diligence. This practice aligns with their obligations under GDPR as a data controller and the emphasis will be on the lead site / data controller to appoint appropriate data processors on their behalf. Ordinarily NHS Digital would carry out these checks, but attempting to do so for this service would cause unnecessary delay to the initial application, as well as potentially multiple and costly amendments thereafter. Therefore all recruitment sites / data processors and their processing activities will be covered under a suitable processing agreement between themselves and the lead site / data controller which does not require NHS Digital’s inclusion. Specific details of recruitment sites, such as key contact, location, will therefore not be made known to NHS Digital unless there is a specific reason to do so. [1 paragraph unchanged] University Hospital Southampton NHS Foundation Trust will not have access to any of the data being disseminated by NHS Digital Data under this agreement.

Expected measurable benefits

The primary benefit of using the data will be to recruit participants for the clinical study/trial in a manner which: The primary benefit of using the data will be to allow researchers to identify a suitable cohort and recruit them quickly into the vaccine trial – thus reducing the overall time to recruit into the trials. This is expected to accelerate the delivery of an effective vaccine to treat individuals to manage the COVID-19 outbreak and to save lives. • Enables individuals to volunteer in advance to participate in COVID-19 vaccine trials as an alternative to other potentially more intrusive mechanisms, e.g. sharing data with researchers about individuals under section 251 consents or COPI notices, which although lawful is initially less transparent. It is expected that this will reduce the burden on research staff in identifying and contacting potential clinical trial participants. It is anticipated this will also support the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research and then produce a coronavirus vaccine and make sure one is made available to the public as quickly as possible. • Allows researchers to identify a suitable cohort and recruit them quickly into the vaccine trials – thus reducing the overall time to recruit into the trials and to accelerate the delivery of an effective vaccine to treat individuals to manage the COVID-19 outbreak and to save lives. • Reduces burden on research staff in identifying and contacting potential clinical trial participants. • Supports the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research and then produce a coronavirus vaccine and make sure one is made available to the public as quickly as possible.

Benefits reported

Yielded Benefits is not a requirement for new applications. Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. Further achievements directly related to the study can be found in the following journal: The Lancet , VOLUME 398, ISSUE 10318, P2258-2276, DECEMBER 18, 2021 (link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02717-3/fulltext)

Unchanged: Expected output.