R25 - A phase 2/3 study to determine the efficacy, safety and immunogenicity of the candidate Coronavirus Disease (COVID-19) vaccine ChAdOx1 nCoV-19 (COV002)

A new virus causing respiratory disease emerged in Wuhan, China in December 2019 and has since rapidly spread to many other countries around the world, despite unprecedented containment efforts. The virus is part of the Coronavirus family which may cause respiratory infections ranging from the common cold to more severe diseases. This recently discovered coronavirus causes coronavirus disease COVID-19. The WHO declared the COVID-19 epidemic a Public Health Emergency of International Concern on 30th January 2020. The COVID-19 epidemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Containment measures have failed to stop the spread of virus, which has reached pandemic levels. There are no currently licensed vaccines or specific treatments for COVID-19. Vaccines are the most cost effective way of controlling outbreaks and the international community have stepped-up their efforts towards developing one against COVID-19. Accelerated vaccine development is urgently needed.

This study will enable the Oxford Vaccine Group at the University of Oxford to assess if healthy people can be protected from COVID-19 with this new vaccine called ChAdOx1 nCoV-19. It will also give valuable information on safety aspects of the vaccine and its ability to generate good immune responses against the virus. University of Oxford will do this by randomly allocating participants to receive the vaccine or a placebo injection in addition to doing blood tests and collecting information about any symptoms that occur after vaccination.

The vaccine acts by encouraging the immune system to recognise and attack the coronavirus. It is made from a harmless virus called an adenovirus that has been altered to produce the surface spike protein of COVID-19. The study will assess if healthy people can be protected from COVID-19 with this new vaccine. It will give information on the safety of the vaccine and how well it can create a good immune response against the virus. The first trials will be in younger adults, followed by people over 55 and, then larger trials in adults over 18 years, before studies in later school age children

The phase I trial in healthy adult volunteers began in April 2020. More than 1,000 volunteers were recruited and follow-up is currently ongoing. Phase 1 is now closed to recruitment. (COV001) Phase II and Phase III are now in place (COV002). COV001 was also prioritised by the NIHR.

The two clinical studies are aligned in terms of study procedures and endpoints to allow data to be compared and combined across the two studies. The safety data from animal studies and from COV001 will be reviewed prior to vaccinating the first participant in COV002, and at each time point prior to expansion into additional age groups.

The next phase of the study (II/III) will enrol up to 10,260 adults and children and will involve recruitment of participants by a number of partner institutions across the country. To recruit the large number of participants needed for this trial, nine clinical research sites across the UK are involved in delivering the study. This is a collaborative effort led by the University of Oxford. Vaccinations took place across the sites in May 2020 onwards.

The main focus of the study is to find out if this vaccine is going to work against COVID-19, if it won’t cause unacceptable side effects and if it induces good immune responses. The dose used in this trial was chosen based on previous experiences with other ChAdOx1 based vaccines.

The phase II part of the study involves expanding the age range of people the vaccine is assessed in, to include a small number of older adults and children:

• Aged 56-69

• Aged over 70

• Aged between 5-12 years

Deaths from COVID-19 infections are more common in adults aged 70 or older, and in those with pre-existing co-morbidities such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension and cancer. SARS-CoV-2 infects children as well as adults and the elderly. However, COVID-19 infections in children are less severe and rarely result in death. It is the oldest age group that is most at risk of death following natural infection, and in whom the vaccine would most likely be used first if deployed in a future public health campaign.

Reports of COVID-19 amongst children are increasing and the majority of cases are considered to be milder or even asymptomatic 20-22. Despite significantly lower case-fatality rates, severe presentations have been reported and at least 11 deaths recorded in England in paediatric groups (as of 30th April 2020, NHS England). Preliminary evidence suggests that children are just as likely to become infected with SARS-CoV-2 as adults but the importance of children in virus transmission remains uncertain 23. Nonetheless, the WHO preferred target product profile for COVID-19 vaccines has all ages as target population, recognizing that herd immunity (and transmission blocking) will depend on broad immunization, likely including children (WHO, COVID-19 Vaccine TPP). In influenza, which has a similar age-dependent severity profile, universal vaccination of primary-school age children is an important strategy in UK immunisation policy to control disease through herd immunity. Since the benefit for children is lower than for adults in the population, University of Oxford will accrue safety data from the phase I-III adult studies before embarking on the paediatric trial. For this version of the Data Sharing Agreement issued by NHS Digital - the applicant at University of Oxford has confirmed that data related to children will not be requested at this time and a separate application / amendment will be submitted closer to the start of this particular phase.

Participants must:

• Be in good health

• Be in one of the relevant age categories

• Based in one of the recruiting areas

Participants must NOT:

• Have tested positive for COVID-19

• Be pregnant, intending to become pregnant, or breastfeeding during the study

• Have previously taken part in a trial with an adenoviral vaccine or received any other coronavirus vaccines

Full inclusion and exclusion criteria is available in the participant information sheet which is given to all participants.

For these groups, researchers will be assessing the immune response to the vaccine in people of different ages, to find out if there is variation in how well the immune system responds in older people or children.

The phase III part of the study involves assessing how the vaccine works in a large number of people over the age of 18. This group will assess how well the vaccine works to prevent people from becoming infected and unwell with COVID-19.

Adult participants in both the Phase II and Phase III groups will be randomised to receive one or two doses of either the ChAdOx1 nCoV-19 vaccine or a licensed vaccine (MenACWY) that will be used as a ‘control’ for comparison.

ChAdOx1 nCoV-19 is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees, that has been genetically changed so that it is impossible for it to grow in humans. Genetic material has been added to the ChAdOx1 construct, that is used to make proteins from the COVID-19 virus (SARS-CoV-2) called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus. The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.

By vaccinating with ChAdOx1 nCoV-19, University of Oxford are hoping to make the body recognise and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection.

The MenACWY vaccine is a licensed vaccine against group A, C, W and Y meningococcus which has been given routinely to teenagers in the UK since 2015 and protects against one of the most common causes of meningitis and sepsis. This vaccine is also given as a travel vaccine for high risk countries.

The MenACWY vaccine is being used as an ‘active control’ vaccine in this study, to help University of Oxford understand participants’ response to ChAdOx1 nCoV-19. The reason for using this vaccine, rather than a saline control, is because University of Oxford expect to see some minor side effects from the ChAdOx1 nCOV-19 vaccine such as a sore arm, headache and fever. Saline does not cause any of these side effects. If participants were to receive only this vaccine or a saline control, and went on to develop side effects, they would be aware that they had received the new vaccine. It is critical for this study that participants remain blinded to whether or not they have received the vaccine, as, if they knew, this could affect their health behaviour in the community following vaccination, and may lead to a bias in the results of the study.

Some participants will be given an E-diary to record any symptoms experienced for 7 days after receiving the vaccine and if they feel unwell for the following 3 weeks. There is also a weekly survey that participants will be asked to complete about any household exposure to COVID-19.

In order to monitor the effect of the vaccine on asymptomatic infection with COVID-19, all participants will be asked to collect weekly nasal/throat swabs at home for PCR testing.

Following vaccination, participants will attend a series of short follow-up visits. During these visits, the team will check participants’ observations, take a blood sample and review the completed E-diary and questionnaire. These blood samples will be used to assess the immune response to the vaccine.

To monitor the results of the weekly PCR swabs, University of Oxford requires NHS Digital to provide them with Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data - which contains information on CV19 Testing. This is referred to as 'Pillar 2' of the CV19 Testing Data. There are several 'Pillars' of the testing data being brought into NHS Digial.

Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data has feeds from:

- Drive through test centre

- Mobile Testing Unit

- Satellite Test Centre

- Home testing

- Care Home testing

- Other testing delivery mechanisms as these are rolled out

University of Oxford are providing participants in the Phase II/III part of the study with home swab testing kits. University of Oxford require NHS Digital to return the results of those home swab testings kits from the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset - back to the University - to assess the effect of the vaccine of asymptomatic infection and the consequent implications on herd immunity. Although the University of Oxford is able to obtain details of the number of positive/negative/void processed per day the lab are not able to identify the individual this data relates to and as such University of Oxford needs NHS Digital to provide this linked data.

Further objectives of this study are:

- To assess efficacy of the candidate ChAdOx1 nCoV-19 against severe and non-severe COVID-19 by measuring

o Hospital admissions associated with COVID-19

o Intensive care unit (ICU) admissions associated with COVID-19

o Deaths associated with COVID-19

o Antibodies against SARS-CoV-2 spike protein post-vaccination.

o Comparing difference in viral load.

As a result of these further objectives - it is anticipated that further data will be required from NHS Digital to supplement and fulfil these objectives. This will include (but not limited to) Hospital Episode Statistics Data, Outcome and Mortality Data via Civil Registrations Data, and potentially GPES Data for Pandemic Planning and Research. Future iterations of the DSA will be issued to reflect if this is the case, with valid data sharing agreements and controls in place. For clarity - only Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data is required under this version of the Agreement.

NHS Digital originally supplied data under the COPI Notices until 30/09/2021 - the expiry date at time of approval. The COPI Notices have now been extended until 31/03/2022. University of Oxford must have in place by that time, an exit strategy to rely on data provision and retention facilitated by patient consent and a data sharing agreement approved by NHS Digital that allows for this.

The legal basis for processing the data held under this Agreement is Article 6 (1) (e) (processing is necessary for the performance of a task carried out in the public interest) and Article 9 (2) (j) (processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes) of the GDPR.

University of Oxford are the sole Data Controller under this Agreement and also process the data.

COVID-19 is a pathogen which presents a significant threat to the population in terms of increased morbidity and mortality, particularly among vulnerable groups such as those with pre-existing disease.

The data requested will be used to evaluate the efficacy and safety of the vaccine treatments and will help shape the public health response.

A significant proportion of vaccines that are tested in clinical trials do not work. If University of Oxford are unable to show that the vaccine is protective against the virus, University of Oxford would review progress, examine alternative approaches, such as using different numbers of doses, and would potentially stop the programme.

As of September 2021, the global COVID-19 pandemic has resulted in over 200 million infections and 4.5 million deaths. Vaccination is key part of controlling the pandemic. The data requested has been used to evaluate the efficacy of the Oxford-AZ COVID-19 vaccine. The results of these analyses been provided to national drug regulatory authorities including the MHRA, leading to emergency use authorisation of the vaccine in the UK and in multiple countries overseas. Over a billion doses of the OxfordAZ vaccine have been used worldwide and it is estimated that approximately 1 million deaths have been averted by its use.

While no further data extracts are required, the existing data will need to be retained for further interrogation by national drug regulatory authorities. Further analyses of vaccine efficacy against emerging novel virus variants may also be performed on the existing data set.

The following benefits have been yielded to date using the data disseminated under this Agreement:

1. Analysis of ChAdOx1 nCov19 vaccine efficacy against asymptomatic disease

2. Identification of reduction in likelihood of viral transmission (as seen by reduced duration of NAAT positivity and Ct value) post vaccination

3. Linkage with the COGUK consortium has allowed identification of the emergence of new viral lineages and investigation of vaccine efficacy against novel variants

The primary analysis on the data has now been completed and no new benefits are expected to be yielded. The data already disseminated is still required for audit-related purposes, for example, to help answer questions asked by national drug regulatory authorities.

A new virus causing respiratory disease emerged in Wuhan, China in December 2019 and has since rapidly spread to many other countries around the world, despite unprecedented containment efforts. The virus is part of the Coronavirus family which may cause respiratory infections ranging from the common cold to more severe diseases. This recently discovered coronavirus causes coronavirus disease COVID-19. The WHO declared the COVID-19 epidemic a Public Health Emergency of International Concern on 30th January 2020. The COVID-19 epidemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Containment measures have failed to stop the spread of virus, which has reached pandemic levels. There are no currently licensed vaccines or specific treatments for COVID-19. Vaccines are the most cost effective way of controlling outbreaks and the international community have stepped-up their efforts towards developing one against COVID-19. Accelerated vaccine development is urgently needed.

This study will enable the Oxford Vaccine Group at the University of Oxford to assess if healthy people can be protected from COVID-19 with this new vaccine called ChAdOx1 nCoV-19. It will also give valuable information on safety aspects of the vaccine and its ability to generate good immune responses against the virus. University of Oxford will do this by randomly allocating participants to receive the vaccine or a placebo injection in addition to doing blood tests and collecting information about any symptoms that occur after vaccination.

The vaccine acts by encouraging the immune system to recognise and attack the coronavirus. It is made from a harmless virus called an adenovirus that has been altered to produce the surface spike protein of COVID-19. The study will assess if healthy people can be protected from COVID-19 with this new vaccine. It will give information on the safety of the vaccine and how well it can create a good immune response against the virus. The first trials will be in younger adults, followed by people over 55 and, then larger trials in adults over 18 years, before studies in later school age children

The phase I trial in healthy adult volunteers began in April. More than 1,000 volunteers were recruited and follow-up is currently ongoing. Phase 1 is now closed to recruitment. (COV001) Phase II and Phase III are now in place (COV002). COV001 was also prioritised by the NIHR.

The two clinical studies are aligned in terms of study procedures and endpoints to allow data to be compared and combined across the two studies. The safety data from animal studies and from COV001 will be reviewed prior to vaccinating the first participant in COV002, and at each time point prior to expansion into additional age groups.

The next phase of the study (II/III) will enrol up to 10,260 adults and children and will involve recruitment of participants by a number of partner institutions across the country. To recruit the large number of participants needed for this trial, nine clinical research sites across the UK are involved in delivering the study. This is a collaborative effort led by the University of Oxford. Vaccinations will be taking place across the sites in May onwards.

The main focus of the study is to find out if this vaccine is going to work against COVID-19, if it won’t cause unacceptable side effects and if it induces good immune responses. The dose used in this trial was chosen based on previous experiences with other ChAdOx1 based vaccines.

The phase II part of the study involves expanding the age range of people the vaccine is assessed in, to include a small number of older adults and children:

• Aged 56-69

• Aged over 70

• Aged between 5-12 years

Deaths from COVID-19 infections are more common in adults aged 70 or older, and in those with pre-existing co-morbidities such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension and cancer. SARS-CoV-2 infects children as well as adults and the elderly. However, COVID-19 infections in children are less severe and rarely result in death. It is the oldest age group that is most at risk of death following natural infection, and in whom the vaccine would most likely be used first if deployed in a future public health campaign.

Reports of COVID-19 amongst children are increasing and the majority of cases are considered to be milder or even asymptomatic 20-22. Despite significantly lower case-fatality rates, severe presentations have been reported and at least 11 deaths recorded in England in paediatric groups (as of 30th April 2020, NHS England). Preliminary evidence suggests that children are just as likely to become infected with SARS-CoV-2 as adults but the importance of children in virus transmission remains uncertain 23. Nonetheless, the WHO preferred target product profile for COVID-19 vaccines has all ages as target population, recognizing that herd immunity (and transmission blocking) will depend on broad immunization, likely including children (WHO, COVID-19 Vaccine TPP). In influenza, which has a similar age-dependent severity profile, universal vaccination of primary-school age children is an important strategy in UK immunisation policy to control disease through herd immunity. Since the benefit for children is lower than for adults in the population, University of Oxford will accrue safety data from the phase I-III adult studies before embarking on the paediatric trial. For this version of the data sharing agreement issued by NHS Digital - the applicant at University of Oxford has confirmed that data related to children will not be requested at this time and a separate application / amendment will be submitted closer to the start of this particular phase.

Participants must:

• Be in good health

• Be in one of the relevant age categories

• Based in one of the recruiting areas

Participants must NOT:

• Have tested positive for COVID-19

• Be pregnant, intending to become pregnant, or breastfeeding during the study

• Have previously taken part in a trial with an adenoviral vaccine or received any other coronavirus vaccines

Full inclusion and exclusion criteria is available in the participant information sheet which is given to all participants.

For these groups, researchers will be assessing the immune response to the vaccine in people of different ages, to find out if there is variation in how well the immune system responds in older people or children.

The phase III part of the study involves assessing how the vaccine works in a large number of people over the age of 18. This group will assess how well the vaccine works to prevent people from becoming infected and unwell with COVID-19.

Adult participants in both the Phase II and Phase III groups will be randomised to receive one or two doses of either the ChAdOx1 nCoV-19 vaccine or a licensed vaccine (MenACWY) that will be used as a ‘control’ for comparison.

ChAdOx1 nCoV-19 is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees, that has been genetically changed so that it is impossible for it to grow in humans. Genetic material has been added to the ChAdOx1 construct, that is used to make proteins from the COVID-19 virus (SARS-CoV-2) called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus. The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.

By vaccinating with ChAdOx1 nCoV-19, University of Oxford are hoping to make the body recognise and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection.

The MenACWY vaccine is a licensed vaccine against group A, C, W and Y meningococcus which has been given routinely to teenagers in the UK since 2015 and protects against one of the most common causes of meningitis and sepsis. This vaccine is also given as a travel vaccine for high risk countries.

The MenACWY vaccine is being used as an ‘active control’ vaccine in this study, to help University of Oxford understand participants’ response to ChAdOx1 nCoV-19. The reason for using this vaccine, rather than a saline control, is because University of Oxford expect to see some minor side effects from the ChAdOx1 nCOV-19 vaccine such as a sore arm, headache and fever. Saline does not cause any of these side effects. If participants were to receive only this vaccine or a saline control, and went on to develop side effects, they would be aware that they had received the new vaccine. It is critical for this study that participants remain blinded to whether or not they have received the vaccine, as, if they knew, this could affect their health behaviour in the community following vaccination, and may lead to a bias in the results of the study.

Some participants will be given an E-diary to record any symptoms experienced for 7 days after receiving the vaccine and if they feel unwell for the following 3 weeks. There is also a weekly survey that participants will be asked to complete about any household exposure to COVID-19.

In order to monitor the effect of the vaccine on asymptomatic infection with COVID-19, all participants will be asked to collect weekly nasal/throat swabs at home for PCR testing.

Following vaccination, participants will attend a series of short follow-up visits. During these visits, the team will check participants’ observations, take a blood sample and review the completed E-diary and questionnaire. These blood samples will be used to assess the immune response to the vaccine.

To monitor the results of the weekly PCR swabs, University of Oxford requires NHS Digital to provide them with Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data - which contains information on CV19 Testing. This is referred to as 'Pillar 2' of the CV19 Testing Data. There are several 'Pillars' of the testing data being brought into NHS Digial.

Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data has feeds from:

- Drive through test centre

- Mobile Testing Unit

- Satellite Test Centre

- Home testing

- Care Home testing

- Other testing delivery mechanisms as these are rolled out

University of Oxford are providing participants in the Phase II/III part of the study with home swab testing kits. University of Oxford require NHS Digital to return the results of those home swab testings kits from the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset - back to the University - to assess the effect of the vaccine of asymptomatic infection and the consequent implications on herd immunity. Although the University of Oxford is able to obtain details of the number of positive/negative/void processed per day the lab are not able to identify the individual this data relates to and as such University of Oxford needs NHS Digital to provide this linked data.

Further objectives of this study are:

- To assess efficacy of the candidate ChAdOx1 nCoV-19 against severe and non-severe COVID-19 by measuring

o Hospital admissions associated with COVID-19

o Intensive care unit (ICU) admissions associated with COVID-19

o Deaths associated with COVID-19

o Antibodies against SARS-CoV-2 spike protein post-vaccination.

o Comparing difference in viral load.

As a result of these further objectives - it is anticipated that further data will be required from NHS Digital to supplement and fulfil these objectives. This will include (but not limited to) Hospital Episode Statistics Data, Outcome and Mortality Data via Civil Registrations Data, and potentially GPES Data for Pandemic Planning and Research. Future iterations of the DSA will be issued to reflect if this is the case, with valid data sharing agreements and controls in place. For clarity - only Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) data is required under this version of the agreement.

NHS Digital will supply data under the COPI Notices until 30/09/2021 - in line with the current expiry date. University of Oxford must have in place by that time, an exit strategy to rely on data provision and retention facilitated by patient consent and a data sharing agreement approved by NHS Digital that allows for this.

COVID-19 is an emerging pathogen which presents a significant threat to the population in terms of increased morbidity and mortality, particularly among vulnerable groups such as those with pre-existing disease.

The data requested will be used to evaluate the efficacy and safety of the vaccine treatments and will help shape the public health response.

A significant proportion of vaccines that are tested in clinical trials do not work. If University of Oxford are unable to show that the vaccine is protective against the virus, University of Oxford would review progress, examine alternative approaches, such as using different numbers of doses, and would potentially stop the programme.

1. Analysis of ChAdOx1 nCov19 vaccine efficacy against asymptomatic disease

2. Identification of reduction in likelihood of viral transmission (as seen by reduced duration of NAAT positivity and Ct value) post vaccination

3. Linkage with the COGUK consortium has allowed identification of the emergence of new viral lineages and investigation of vaccine efficacy against novel variants

A new virus causing respiratory disease emerged in Wuhan, China in December 2019 and has since rapidly spread to many other countries around the world, despite unprecedented containment efforts. The virus is part of the Coronavirus family which may cause respiratory infections ranging from the common cold to more severe diseases. This recently discovered coronavirus causes coronavirus disease COVID-19. The WHO declared the COVID-19 epidemic a Public Health Emergency of International Concern on 30th January 2020. The COVID-19 epidemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Containment measures have failed to stop the spread of virus, which has reached pandemic levels. There are no currently licensed vaccines or specific treatments for COVID-19. Vaccines are the most cost effective way of controlling outbreaks and the international community have stepped-up their efforts towards developing one against COVID-19. Accelerated vaccine development is urgently needed.

This study will enable the Oxford Vaccine Group at the University of Oxford to assess if healthy people can be protected from COVID-19 with this new vaccine called ChAdOx1 nCoV-19. It will also give valuable information on safety aspects of the vaccine and its ability to generate good immune responses against the virus. University of Oxford will do this by randomly allocating participants to receive the vaccine or a placebo injection in addition to doing blood tests and collecting information about any symptoms that occur after vaccination.

The vaccine acts by encouraging the immune system to recognise and attack the coronavirus. It is made from a harmless virus called an adenovirus that has been altered to produce the surface spike protein of COVID-19. The study will assess if healthy people can be protected from COVID-19 with this new vaccine. It will give information on the safety of the vaccine and how well it can create a good immune response against the virus. The first trials will be in younger adults, followed by people over 55 and, then larger trials in adults over 18 years, before studies in later school age children

The phase I trial in healthy adult volunteers began in April. More than 1,000 volunteers were recruited and follow-up is currently ongoing. Phase 1 is now closed to recruitment. (COV001) Phase II and Phase III are now in place (COV002). COV001 was also prioritised by the NIHR.

The two clinical studies are aligned in terms of study procedures and endpoints to allow data to be compared and combined across the two studies. The safety data from animal studies and from COV001 will be reviewed prior to vaccinating the first participant in COV002, and at each time point prior to expansion into additional age groups.

The next phase of the study (II/III) will enrol up to 10,260 adults and children and will involve recruitment of participants by a number of partner institutions across the country. To recruit the large number of participants needed for this trial, nine clinical research sites across the UK are involved in delivering the study. This is a collaborative effort led by the University of Oxford. Vaccinations will be taking place across the sites in May onwards.

The main focus of the study is to find out if this vaccine is going to work against COVID-19, if it won’t cause unacceptable side effects and if it induces good immune responses. The dose used in this trial was chosen based on previous experiences with other ChAdOx1 based vaccines.

The phase II part of the study involves expanding the age range of people the vaccine is assessed in, to include a small number of older adults and children:

• Aged 56-69

• Aged over 70

• Aged between 5-12 years

Deaths from COVID-19 infections are more common in adults aged 70 or older, and in those with pre-existing co-morbidities such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension and cancer. SARS-CoV-2 infects children as well as adults and the elderly. However, COVID-19 infections in children are less severe and rarely result in death. It is the oldest age group that is most at risk of death following natural infection, and in whom the vaccine would most likely be used first if deployed in a future public health campaign.

Reports of COVID-19 amongst children are increasing and the majority of cases are considered to be milder or even asymptomatic 20-22. Despite significantly lower case-fatality rates, severe presentations have been reported and at least 11 deaths recorded in England in paediatric groups (as of 30th April 2020, NHS England). Preliminary evidence suggests that children are just as likely to become infected with SARS-CoV-2 as adults but the importance of children in virus transmission remains uncertain 23. Nonetheless, the WHO preferred target product profile for COVID-19 vaccines has all ages as target population, recognizing that herd immunity (and transmission blocking) will depend on broad immunization, likely including children (WHO, COVID-19 Vaccine TPP). In influenza, which has a similar age-dependent severity profile, universal vaccination of primary-school age children is an important strategy in UK immunisation policy to control disease through herd immunity. Since the benefit for children is lower than for adults in the population, University of Oxford will accrue safety data from the phase I-III adult studies before embarking on the paediatric trial. For this version of the data sharing agreement issued by NHS Digital - the applicant at University of Oxford has confirmed that data related to children will not be requested at this time and a separate application / amendment will be submitted closer to the start of this particular phase.

Participants must:

• Be in good health

• Be in one of the relevant age categories

• Based in one of the recruiting areas

Participants must NOT:

• Have tested positive for COVID-19

• Be pregnant, intending to become pregnant, or breastfeeding during the study

• Have previously taken part in a trial with an adenoviral vaccine or received any other coronavirus vaccines

Full inclusion and exclusion criteria is available in the participant information sheet which is given to all participants.

For these groups, researchers will be assessing the immune response to the vaccine in people of different ages, to find out if there is variation in how well the immune system responds in older people or children.

The phase III part of the study involves assessing how the vaccine works in a large number of people over the age of 18. This group will assess how well the vaccine works to prevent people from becoming infected and unwell with COVID-19.

Adult participants in both the Phase II and Phase III groups will be randomised to receive one or two doses of either the ChAdOx1 nCoV-19 vaccine or a licensed vaccine (MenACWY) that will be used as a ‘control’ for comparison.

ChAdOx1 nCoV-19 is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees, that has been genetically changed so that it is impossible for it to grow in humans. Genetic material has been added to the ChAdOx1 construct, that is used to make proteins from the COVID-19 virus (SARS-CoV-2) called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus. The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.

By vaccinating with ChAdOx1 nCoV-19, University of Oxford are hoping to make the body recognise and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection.

The MenACWY vaccine is a licensed vaccine against group A, C, W and Y meningococcus which has been given routinely to teenagers in the UK since 2015 and protects against one of the most common causes of meningitis and sepsis. This vaccine is also given as a travel vaccine for high risk countries.

The MenACWY vaccine is being used as an ‘active control’ vaccine in this study, to help University of Oxford understand participants’ response to ChAdOx1 nCoV-19. The reason for using this vaccine, rather than a saline control, is because University of Oxford expect to see some minor side effects from the ChAdOx1 nCOV-19 vaccine such as a sore arm, headache and fever. Saline does not cause any of these side effects. If participants were to receive only this vaccine or a saline control, and went on to develop side effects, they would be aware that they had received the new vaccine. It is critical for this study that participants remain blinded to whether or not they have received the vaccine, as, if they knew, this could affect their health behaviour in the community following vaccination, and may lead to a bias in the results of the study.

Some participants will be given an E-diary to record any symptoms experienced for 7 days after receiving the vaccine and if they feel unwell for the following 3 weeks. There is also a weekly survey that participants will be asked to complete about any household exposure to COVID-19.

In order to monitor the effect of the vaccine on asymptomatic infection with COVID-19, all participants will be asked to collect weekly nasal/throat swabs at home for PCR testing.

Following vaccination, participants will attend a series of short follow-up visits. During these visits, the team will check participants’ observations, take a blood sample and review the completed E-diary and questionnaire. These blood samples will be used to assess the immune response to the vaccine.

To monitor the results of the weekly PCR swabs, University of Oxford requires NHS Digital to provide them with National Pathology Exchange (NPeX Data - which contains information on CV19 Testing. This is referred to as 'Pillar 2' of the CV19 Testing Data. There are several 'Pillars' of the testing data being brought into NHS Digial.

NPeX data has feeds from:

- Drive through test centre

- Mobile Testing Unit

- Satellite Test Centre

- Home testing

- Care Home testing

- Other testing delivery mechanisms as these are rolled out

University of Oxford are providing participants in the Phase II/III part of the study with home swab testing kits. University of Oxford require NHS Digital to return the results of those home swab testings kits from the NPeX dataset - back to the University - to assess the effect of the vaccine of asymptomatic infection and the consequent implications on herd immunity. Although the University of Oxford is able to obtain details of the number of positive/negative/void processed per day the lab are not able to identify the individual this data relates to and as such University of Oxford needs NHS Digital to provide this linked data.

Further objectives of this study are:

- To assess efficacy of the candidate ChAdOx1 nCoV-19 against severe and non-severe COVID-19 by measuring

o Hospital admissions associated with COVID-19

o Intensive care unit (ICU) admissions associated with COVID-19

o Deaths associated with COVID-19

o Antibodies against SARS-CoV-2 spike protein post-vaccination.

o Comparing difference in viral load.

As a result of these further objectives - it is anticipated that further data will be required from NHS Digital to supplement and fulfil these objectives. This will include (but not limited to) Hospital Episode Statistics Data, Outcome and Mortality Data via Civil Registrations Data, and potentially GPES Data for Pandemic Planning and Research. Future iterations of the DSA will be issued to reflect if this is the case, with valid data sharing agreements and controls in place. For clarity - only NPeX data is required under this version of the agreement.

NHS Digital will supply data under the COPI Notices until 31/03/2021 - in line with the current expiry date. University of Oxford must have in place by that time, an exit strategy to rely on data provision and retention facilitated by patient consent and a data sharing agreement approved by NHS Digital that allows for this.

COVID-19 is an emerging pathogen which presents a significant threat to the population in terms of increased morbidity and mortality, particularly among vulnerable groups such as those with pre-existing disease.

The data requested will be used to evaluate the efficacy and safety of the vaccine treatments and will help shape the public health response.

A significant proportion of vaccines that are tested in clinical trials do not work. If University of Oxford are unable to show that the vaccine is protective against the virus, University of Oxford would review progress, examine alternative approaches, such as using different numbers of doses, and would potentially stop the programme.

A new virus causing respiratory disease emerged in Wuhan, China in December 2019 and has since rapidly spread to many other countries around the world, despite unprecedented containment efforts. The virus is part of the Coronavirus family which may cause respiratory infections ranging from the common cold to more severe diseases. This recently discovered coronavirus causes coronavirus disease COVID-19. The WHO declared the COVID-19 epidemic a Public Health Emergency of International Concern on 30th January 2020. The COVID-19 epidemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Containment measures have failed to stop the spread of virus, which has reached pandemic levels. There are no currently licensed vaccines or specific treatments for COVID-19. Vaccines are the most cost effective way of controlling outbreaks and the international community have stepped-up their efforts towards developing one against COVID-19. Accelerated vaccine development is urgently needed.

This study will enable the Oxford Vaccine Group at the University of Oxford to assess if healthy people can be protected from COVID-19 with this new vaccine called ChAdOx1 nCoV-19. It will also give valuable information on safety aspects of the vaccine and its ability to generate good immune responses against the virus. University of Oxford will do this by randomly allocating participants to receive the vaccine or a placebo injection in addition to doing blood tests and collecting information about any symptoms that occur after vaccination.

The vaccine acts by encouraging the immune system to recognise and attack the coronavirus. It is made from a harmless virus called an adenovirus that has been altered to produce the surface spike protein of COVID-19. The study will assess if healthy people can be protected from COVID-19 with this new vaccine. It will give information on the safety of the vaccine and how well it can create a good immune response against the virus. The first trials will be in younger adults, followed by people over 55 and, then larger trials in adults over 18 years, before studies in later school age children

The phase I trial in healthy adult volunteers began in April. More than 1,000 volunteers were recruited and follow-up is currently ongoing. Phase 1 is now closed to recruitment. (COV001) Phase II and Phase III are now in place (COV002). COV001 was also prioritised by the NIHR.

The two clinical studies are aligned in terms of study procedures and endpoints to allow data to be compared and combined across the two studies. The safety data from animal studies and from COV001 will be reviewed prior to vaccinating the first participant in COV002, and at each time point prior to expansion into additional age groups.

The next phase of the study (II/III) will enrol up to 10,260 adults and children and will involve recruitment of participants by a number of partner institutions across the country. To recruit the large number of participants needed for this trial, nine clinical research sites across the UK are involved in delivering the study. This is a collaborative effort led by the University of Oxford. Vaccinations will be taking place across the sites in May onwards.

The main focus of the study is to find out if this vaccine is going to work against COVID-19, if it won’t cause unacceptable side effects and if it induces good immune responses. The dose used in this trial was chosen based on previous experiences with other ChAdOx1 based vaccines.

The phase II part of the study involves expanding the age range of people the vaccine is assessed in, to include a small number of older adults and children:

• Aged 56-69

• Aged over 70

• Aged between 5-12 years

Deaths from COVID-19 infections are more common in adults aged 70 or older, and in those with pre-existing co-morbidities such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension and cancer. SARS-CoV-2 infects children as well as adults and the elderly. However, COVID-19 infections in children are less severe and rarely result in death. It is the oldest age group that is most at risk of death following natural infection, and in whom the vaccine would most likely be used first if deployed in a future public health campaign.

Reports of COVID-19 amongst children are increasing and the majority of cases are considered to be milder or even asymptomatic 20-22. Despite significantly lower case-fatality rates, severe presentations have been reported and at least 11 deaths recorded in England in paediatric groups (as of 30th April 2020, NHS England). Preliminary evidence suggests that children are just as likely to become infected with SARS-CoV-2 as adults but the importance of children in virus transmission remains uncertain 23. Nonetheless, the WHO preferred target product profile for COVID-19 vaccines has all ages as target population, recognizing that herd immunity (and transmission blocking) will depend on broad immunization, likely including children (WHO, COVID-19 Vaccine TPP). In influenza, which has a similar age-dependent severity profile, universal vaccination of primary-school age children is an important strategy in UK immunisation policy to control disease through herd immunity. Since the benefit for children is lower than for adults in the population, University of Oxford will accrue safety data from the phase I-III adult studies before embarking on the paediatric trial. For this version of the data sharing agreement issued by NHS Digital - the applicant at University of Oxford has confirmed that data related to children will not be requested at this time and a separate application / amendment will be submitted closer to the start of this particular phase.

Participants must:

• Be in good health

• Be in one of the relevant age categories

• Based in one of the recruiting areas

Participants must NOT:

• Have tested positive for COVID-19

• Be pregnant, intending to become pregnant, or breastfeeding during the study

• Have previously taken part in a trial with an adenoviral vaccine or received any other coronavirus vaccines

Full inclusion and exclusion criteria is available in the participant information sheet which is given to all participants.

For these groups, researchers will be assessing the immune response to the vaccine in people of different ages, to find out if there is variation in how well the immune system responds in older people or children.

The phase III part of the study involves assessing how the vaccine works in a large number of people over the age of 18. This group will assess how well the vaccine works to prevent people from becoming infected and unwell with COVID-19.

Adult participants in both the Phase II and Phase III groups will be randomised to receive one or two doses of either the ChAdOx1 nCoV-19 vaccine or a licensed vaccine (MenACWY) that will be used as a ‘control’ for comparison.

ChAdOx1 nCoV-19 is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees, that has been genetically changed so that it is impossible for it to grow in humans. Genetic material has been added to the ChAdOx1 construct, that is used to make proteins from the COVID-19 virus (SARS-CoV-2) called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus. The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.

By vaccinating with ChAdOx1 nCoV-19, University of Oxford are hoping to make the body recognise and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection.

The MenACWY vaccine is a licensed vaccine against group A, C, W and Y meningococcus which has been given routinely to teenagers in the UK since 2015 and protects against one of the most common causes of meningitis and sepsis. This vaccine is also given as a travel vaccine for high risk countries.

The MenACWY vaccine is being used as an ‘active control’ vaccine in this study, to help University of Oxford understand participants’ response to ChAdOx1 nCoV-19. The reason for using this vaccine, rather than a saline control, is because University of Oxford expect to see some minor side effects from the ChAdOx1 nCOV-19 vaccine such as a sore arm, headache and fever. Saline does not cause any of these side effects. If participants were to receive only this vaccine or a saline control, and went on to develop side effects, they would be aware that they had received the new vaccine. It is critical for this study that participants remain blinded to whether or not they have received the vaccine, as, if they knew, this could affect their health behaviour in the community following vaccination, and may lead to a bias in the results of the study.

Some participants will be given an E-diary to record any symptoms experienced for 7 days after receiving the vaccine and if they feel unwell for the following 3 weeks. There is also a weekly survey that participants will be asked to complete about any household exposure to COVID-19.

In order to monitor the effect of the vaccine on asymptomatic infection with COVID-19, all participants will be asked to collect weekly nasal/throat swabs at home for PCR testing.

Following vaccination, participants will attend a series of short follow-up visits. During these visits, the team will check participants’ observations, take a blood sample and review the completed E-diary and questionnaire. These blood samples will be used to assess the immune response to the vaccine.

To monitor the results of the weekly PCR swabs, University of Oxford requires NHS Digital to provide them with National Pathology Exchange (NPeX Data - which contains information on CV19 Testing. This is referred to as 'Pillar 2' of the CV19 Testing Data. There are several 'Pillars' of the testing data being brought into NHS Digial.

NPeX data has feeds from:

- Drive through test centre

- Mobile Testing Unit

- Satellite Test Centre

- Home testing

- Care Home testing

- Other testing delivery mechanisms as these are rolled out

University of Oxford are providing participants in the Phase II/III part of the study with home swab testing kits. University of Oxford require NHS Digital to return the results of those home swab testings kits from the NPeX dataset - back to the University - to assess the effect of the vaccine of asymptomatic infection and the consequent implications on herd immunity. Although the University of Oxford is able to obtain details of the number of positive/negative/void processed per day the lab are not able to identify the individual this data relates to and as such University of Oxford needs NHS Digital to provide this linked data.

Further objectives of this study are:

- To assess efficacy of the candidate ChAdOx1 nCoV-19 against severe and non-severe COVID-19 by measuring

o Hospital admissions associated with COVID-19

o Intensive care unit (ICU) admissions associated with COVID-19

o Deaths associated with COVID-19

o Antibodies against SARS-CoV-2 spike protein post-vaccination.

o Comparing difference in viral load.

As a result of these further objectives - it is anticipated that further data will be required from NHS Digital to supplement and fulfil these objectives. This will include (but not limited to) Hospital Episode Statistics Data, Outcome and Mortality Data via Civil Registrations Data, and potentially GPES Data for Pandemic Planning and Research. Future iterations of the DSA will be issued to reflect if this is the case, with valid data sharing agreements and controls in place. For clarity - only NPeX data is required under this version of the agreement.

NHS Digital will supply data under the COPI Notices until 30/09/2020 - in line with the current expiry date. University of Oxford must have in place by that time, an exit strategy to rely on data provision and retention facilitated by patient consent and a data sharing agreement approved by NHS Digital that allows for this.

COVID-19 is an emerging pathogen which presents a significant threat to the population in terms of increased morbidity and mortality, particularly among vulnerable groups such as those with pre-existing disease.

The data requested will be used to evaluate the efficacy and safety of the vaccine treatments and will help shape the public health response.

A significant proportion of vaccines that are tested in clinical trials do not work. If University of Oxford are unable to show that the vaccine is protective against the virus, University of Oxford would review progress, examine alternative approaches, such as using different numbers of doses, and would potentially stop the programme.

Yielded Benefits is not a requirement for new applications.