An open label Phase I/IIa clinical trial to assess the safety, immunogenicity and efficacy of the malaria vaccine candidate RH5.2-virus-like particle (VLP) (BIO001) - NHS DigiTrials Recruitment Service

The Oxford Vaccine Group (OVG) based at the University of Oxford requires access to NHS England Data for the purpose of the following clinical trial :

'An open label Phase I/IIa clinical trial to assess the safety, immunogenicity and efficacy of the malaria vaccine candidate RH5.2-virus-like particle (VLP) in Matrix-MTM, and to compare the safety and immunogenicity of the malaria vaccine candidates RH5.2-VLP in Matrix-MTM and RH5.1 soluble protein in Matrix-MTM used in various regimens' (Known as Study Reference: BIO-001)

THE AIM OF THE TRIAL

Malaria in humans is caused by five species – Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. Plasmodium falciparum causes the most morbidity and mortality of the Plasmodium species, accounting for an estimated 241 million cases of malaria and 627,000 deaths worldwide in 2020. The currently available methods for preventing and treating malaria remain inadequate. Although focused efforts have led to substantial reductions in morbidity and mortality worldwide, progress has now stalled.

Although the World Health Organisaiton (WHO) has now recommended the deployment of the RTS,S vaccine in high risk populations, work on a more efficacious vaccine is ongoing. There are promising data from RH5 (next generation blood-stage malaria) candidate vaccines, both in the UK and malaria endemic regions in sub-Saharan Africa. RH5.2-VLP has not yet been trialed in humans, however, pre-clinical studies are encouraging.

The BIO001 challenge study is an open-label, single-centre Phase I/ IIa P. falciparum blood-stage controlled human malaria infection (CHMI) trial to assess the safety, immunogenicity and efficacy of the candidate malaria vaccine RH5.2-VLP formulated in adjuvant* Matrix-M.

*An adjuvant is an ingredient used in some vaccines that helps create a stronger immune response in people receiving the vaccine. In other words, adjuvants help vaccines work better.

As part of the study, a small number of vaccinated and unvaccinated participants will be infected with the malaria parasite (with their consent) for a short period of time to see whether the vaccine is effective in preventing disease. To do this, the study will include 6 groups:

• Groups 1 and 3-5 will have three doses of malaria vaccine.

• Group 2 will have three doses of malaria vaccine followed by a malaria ‘challenge’. A challenge is when we deliberately infect volunteers with malaria by injecting a tiny amount of malaria infected blood into the vein.

• Group 6 will not receive any malaria vaccines and will only take part in the malaria ‘challenge’.

By using this very controlled setting to expose people to malaria parasite, the BIO-001 study team hope to see if an experimental vaccine can protect against p. falciparum infection and to understand which parts of the immune response may be important in preventing disease. They hope that the knowledge gained from this trial will help in the development of vaccines and make Malaria a preventable disease.

The Primary Objective of the BIO-001 study is to:

1. To assess the safety of RH5.2-VLP in Matrix-M and RH5.1 soluble protein in Matrix-M in healthy adult volunteers at different doses and used in various regimens (Groups 1-5).

2. To assess efficacy of the RH5.2-VLP in Matrix-M by assessing its impact on parasite multiplication rate (PMR) in vaccinated subjects (Group 2) compared to infectivity controls (Group 6), against 3D7 clone P. falciparum parasites in a Phase IIa blood-stage controlled human malaria infection (CHMI) model (only to be evaluated if the GIA target is met in Group 1).

This Data Sharing Agreement (DSA) is specifically to support the recruitment of a cohort for the BIO-001 study by writing out to approximately 4,000 individuals who meet the initial recruitment eligibility criteria of age and post-code area.

Although past methods of recruitment have been sufficient to meet study target recruitment numbers across studies, the OVG's portfolio of studies has grown substantially over recent years, and in particular ‘human challenge model’ studies such as BIO-001 can be difficult to recruit to (particularly due to the comprehensive screening process, strict study inclusion/exclusion criteria and the intensive nature of the study requiring frequent visits to the study site/s for safety and to ensure participants are closely monitored), requiring additional methods in order to optimize recruitment and effective delivery of trials. This is in order to achieve key study outcomes (in design, development and evaluation of vaccines), provide high quality and robust scientific data, and inform vaccine policy locally and globally.

The BIO-001 team hope to recruit approximately 56 participants to the study. Since the start of recruitment, the trial team have used a range of routine recruitment methods which include advertisements across OVG platforms and other social media accounts of collaborators); posters, flyers and post-card drops (thousands distributed); public and community events/engagement; newsletters and email circulars (including to thousands of people who have subscribed to our monthly newsletters. However, in spite of this concerted efforts, the recruitment rate has been very low and are unlikely to meet the recruitment target within the planned time period. Recruitment to BIO-0001 started on 18 August 2023 and so far only 8 people have been recruited.

In the past, OVG has found, for more intensive and complex studies such as those involving a challenge agent, that the enrolment rate is ~ 0.1%. Therefore, to enrol approx. 50 participants into these types of studies, OVG would need to reach out directly to over 50,000 individuals. This type of recruitment method is time and resource intensive. Furthermore, previous participants from previous studies are not always able to re-enrol in new studies (due to study exclusion criteria). Additionally, Oxford is a highly research-intensive area, with several different drug and vaccine clinical research studies competing for a relatively small pool of interested potential participants. Therefore, OVG need to expand their outreach to beyond what they have already utilised (i.e., university mailing lists, posters, social media, GP surgeries) and perhaps exhausted. For this reason the study is inclusive and open to all healthy individuals between the ages of 18 and 45 years, without targeting any specific sub-groups (noting of course the key exclusion criteria).

The NHS DigiTrials Recruitment service has undertaken several Recruitment Service pilots, with a response rate of 1.5 -2%, and so it is estimated that approximately 4,000 invitations would be required to meet the objective of 56 participants. Therefore the OVG study team wish to use the NHS DigiTrials Recruitment service (extended pilot) to undertake this recruitment. Being able to use NHS England data extracts to generate large mailing lists, in order to send invitational material to members of the public on joining the BIO001 study (and thus significantly increase their recruitment reach) will be vitally important in order to reach their recruitment target and complete delivery of the trial in a timely, effective and efficient manner.

Should the number of participants not be met by the time approximately 4,000 invitations are sent out, then the OVG will submit a further amendment to request more invitations, based on the recruitment rate calculated from the original batch of approximately 4,000 mail-outs.

The BIO-001 team at the University of Oxford will provide NHS England specific inclusion and exclusion criteria to identify potential individuals to be invited to participate by a postal letter.

BIO001 is part of a series of recruitment pilots testing new user cases and capabilities for minimal viable product (MVP) recruitment service. As part of the pilot OVG will provide suitable feedback regarding response rates to the invitations in order for NHS DigiTrials to undertake suitable analysis to validate if it is a valid user case (challenge). Additionally, OVG will inform DigiTrials of dropout rates at the screening stage, and the reasons, so changes to the MVP design e.g. datasets available, automated production pipeline etc; can be considered to improve the results and/or minimise the size of the cohort required.

PATIENT AND PUBLIC INVOLVEMENT AND ENGAGEMENT

The Oxford Vaccine Group (OVG) has a Public and Patient Involvement (PPI) strategic group which is consulted on matters such as how best to perform recruitment for our trials, how to better design our studies, how to ensure participant-facing documents have appropriate content, language and are easily understood, and how to disseminate and communicate our findings to the wider public. They also regularly seek feedback from participants who have completed their studies about their motivation for taking part, as well as their experience of the research process and how this could be improved. OVG incorporates PPI input in their studies through reviewing study materials (such as lay summaries and public-facing documents), funding applications and focus group discussions. Feedback from the PPI group reviews are provided to the study team for their review, reflection and integration into study design, document content and communication of research to the public, among other impacts.

INCLUSION AND EXCLUSION CRITERIA FOR INVITATION

Lists of potentially eligible individuals will be generated from electronic searches of the Person Demographics Service (PDS), a centrally held NHS Dataset at NHS England.

• Individuals will be between 18 and 55 years of age.

• Living in England within specific postcode areas provided by the OVG

NHS England will generate extracts on the basis of date of birth and postcode details as provided by OVG. NHS England will ensure they exclude any flag patients or national data opt outs. NHS England will upload a final .csv file containing name and addresses of potentially eligible participants to Datagraphic Ltd, who will send out invitation letters in batches according to the areas and numbers specified by OVG. The invitation letters will include a link to the BIO-001 trial website, detailed Patient Information Sheet and how to join the pre-screening element of the trial.

UK GDPR LEGAL BASIS FOR PROCESSING OF PERSONAL DATA

University of Oxford, as Controller, are using 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." As part of the application process, the requirement for the Data requested has been assessed and the University of Oxford is content that it is appropriate, necessary and proportionate for the performance of the task described in the purpose statement and that there is no other reasonable and less intrusive means for the Processor to achieve their purpose.

Additionally (as health data is a special category of Personal Data), University of Oxford is using Article 9(2)(j): Special category Data used for “Archiving in the public interest, scientific or historical research or statistical purposes”.

ORGANISATION’S ROLES AND RESPONSIBILITIES:

• The University of Oxford is the Sponsor and Controller. They are responsible for the BIO-001 study and overseeing the work carried out to aid recruitment into the study, and for ensuring that the data will only be processed for the purpose described above. They are also responsible for providing the core eligibility criteria for participants. The University of Oxford will not process NHS England data described in this DSA.

• NHS England are acting as a Processor on behalf of University of Oxford and are responsible for applying the inclusion and exclusion criteria to NHS England Data sets to generate a list of invitees and forwarding the resultant cohort of potential individuals identifiable contact information to PSL Print Management Ltd via Datagraphic Ltd. NHS England does not specify what data are required to deliver the work nor how the data shall be processed to achieve that purpose. Such decisions are taken by the University of Oxford.

• PSL Print Management Ltd are acting as a data processor on behalf of NHS England and are responsible for maintaining a service contract with NHS England and managing the mailout performed by Datagraphic Ltd. PSL Print Management Ltd will not receive, store or have access to NHS England record level Data under this DSA. *

• Datagraphic Ltd are acting as a data processor on behalf of NHS England and PSL Print Management Ltd and are responsible for receiving the list of updated cohort participants from NHS England and mailing out to them accordingly.*

* PSL Print Management Ltd and Datagraphic Ltd work in partnership to provide robust, secure and time critical communication solutions. PSL Print Management Ltd provide project management, training and implementation skill and knowledge. Datagraphic Ltd develop, maintain and host the systems that enable secure and resilient communication to occur. Datagraphic Ltd also provide secure data processing, document composition, sortation, mail item production, enclosing, despatch and inbound mail services from their UK Midlands based development and production hub. NHS England maintains a service contract with PSL Print Management Ltd, and Datagraphic Ltd, in turn, are contracted to PSL, therefore both organisations are considered Processors in this DSA.

• The study is funded by PATH (www.path.org), through a grant from United States Agency for International Development (USAID). PATH is an international public health organization. USAID is an international development agency funded by the U.S. government. The funding is specifically for the BIO-001 trial described. The funder will have no ability to suppress or otherwise limit the publication of findings and will not have access to NHS England Data as described in this Data Sharing Agreement (DSA)

• The BIO-001 Data Safety and Monitoring Committee are acting in an advisory capacity and will not have access to NHS England Data as described in this DSA.

COMMERCIAL INVOLVEMENT

For the purposes of transparency, it is noted here that this study is funded by PATH (www.path.org), through a grant from USAID. PATH is an international public health organization. USAID is an international development agency funded by the U.S. government. The candidate vaccine (RH5.2-SpyTag drug substance and the final SpyTag-SpyCatcher conjugated RH5.2-VLP drug product) will be manufactured initially by Oxford at Genlbet, Portugal and then further in partnership with the Serum Institute of India PVT Limited (SII), while Novavax is the manufacturer and provider of the vaccine adjuvant (Matrix-M). These institutions are biopharmaceutical institutions engaged in the drug discovery, drug development, manufacture of active substances for Investigation Medical Products, vaccines, bio-therapeutics, pharmaceuticals and health care products. Using the funding provided by PATH, University of Oxford scientists and investigators working with Genlbet, SII and Novavax generated Good Manufacturing Practice (GMP) material for use in the trial to generate a finished vaccine product.

USAID, PATH, Genlbet, SII and Novavax will have no involvement in the academic coordination and delivery of the study and will have no ability to suppress or otherwise limit the publication of findings and will have no access to NHS England data. The Senior Laboratory Investigator has an interest in patents relating to the RH5-based vaccines and is a shareholder in a company developing vaccines using SpyTag-SpyCatcher technology used to manufacture the RH5.2-VLP used in this study. The Chief Investigator has a family member who is an inventor on patents for RH5-based vaccines and a shareholder in a company developing vaccines using SpyTag-SpyCatcher technology. While both individuals therefore have a conflict of interest, the integrity of the trial is maintained by samples being analysed by non-clinical researchers who cannot link them to individuals (thereby ensuring no bias), as well as the monitoring of safety by an independent Data Safety Monitoring Committee.

At the current stage the BIO-001 study team aim to provide the proof in principle that the vaccine is safe and immunogenic and warrants further development. If the results of the trial show that the information can be used to contribute to the development of a safe and effective P. falciparum vaccine and make malaria a preventable disease, Oxford, SII and Novavax will continue to work on further clinical development of the vaccine by conducting further phase I/II/III immunogenicity and safety and/or efficacy studies, supported by various funders which could include USAID and PATH, to provide data for potential licensure. These commercial institutions may ultimately benefit financially from the successful licensing and sale of this vaccine, if this comes to pass (in line with NHS England's DAS Standard for Commercial Purpose). However, any further detail on these benefits are impossible to predict at this stage.

The University of Oxford will provide to NHS England the core eligibility criteria for those potential participants who will receive invitations.

The Oxford Vaccine Group (OVG) offers an alternative for individuals who:

• Do not want to receive invitations for vaccine trials.

• Still want to contribute to health research.

• Prefer not to register a National Data Opt-out.

How it works:

• Individuals opt-out of vaccine trials with OVG.

• OVG filters this list for those meeting the specific criteria for their study, BIO-001.

• The filtered list is shared with the Digitrials platform, ensuring their removal from potential invite lists.

The benefits of this approach is that participants maintain control of their research involvement allowing OVG to efficiently conduct the study and Digitrials avoids contacting unsuitable or unwilling individuals.

The OVG opt-out form (https://apps.ovg.ox.ac.uk/redcap/surveys/?s=A3NJMTCFK8) states, “All data will be stored on secured University of Oxford servers where the data will only be available to authorised University or NHS staff solely for the purpose of ensuring an individual is not contacted with regards OVG clinical studies.”

NHS England will interrogate the PDS Dataset to identify potential living individuals based on the inclusion and exclusion criterion and extract one batch of potential candidates up to approximately 4,000 individuals.

NHS England will apply National Data Opt Out to the file of potential candidates.

NHS England will securely send the identifiable file to Datagraphic Ltd, containing:

- Individual Study Identifier called a 'GUID'

- Title

- Given Name

- Family Name

- Address and Post Code

- Batch Reference number

- Type of Comms and Letter reference number

Datagraphic Ltd will send out invitations in ad-hoc batches up to approximately 4,000 mailouts using an automated system.

The Data will be stored on servers at Datagraphic Ltd. Access to confidential patient identifiable data is restricted to employees or agents of Datagraphic Ltd using devices owned by Datagraphic Ltd. All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will not leave England at any time.

Datagraphics Ltd will delete the confidential patient identifiable data 2 weeks post mail-out.

The University of Oxford and other recruiting sites will not have access to NHS England Data as described in this Data Sharing Agreement. The University of Oxford and other recruiting sites will not have access to individual’s data unless they are contacted directly by said individual following the mailout.

As a result of this DSA with NHS England to use the NHS DigiTrials' Recruitment Service, the BIO-001 trial team are hoping to recruit to target having posted out adequate numbers of invitations to potentially eligible participants.

Identifiable health Data requested from NHS England will only be used to identify and invite potential participants.

The ability to utilise large mailouts will help to optimize recruitment, in order to deliver this clinical trial in a timely, effective and efficient manner. This is in order to achieve key study outcomes (as stated in the design, development and evaluation of vaccines), provide high quality and robust scientific data, and inform malaria vaccine policy both locally in the UK and globally.

Additionally, for more intensive and complex studies such as those involving a challenge agent, OVG have found that the enrolment rate is ~ 0.1% from previous experience. Therefore, to enrol ~50 participants into these types of studies, a trial would need to reach out directly to over 50,000 individuals. Furthermore, previous participants from previous studies are not always able to re-enrol in new studies (due to study exclusion criteria) and therefore, OVG need to expand their outreach to beyond what they have already utilised (i.e., university mailing lists, posters, social media, GP surgeries) and perhaps exhausted. OVG believe it may be a deterrent to research participation long-term if they repeatedly contact the same potential participants about the same ongoing studies. Additionally, Oxford is a highly research-intensive area, with several different drug and vaccine clinical research studies competing for a relatively small pool of interested potential participants.

Therefore, being able to use NHS England's NHS DigiTrials Recruitment Service to generate mailing lists in order to send invitational material to members of the public on joining the BIO001 study (and thus significantly increase their recruitment reach) will be vitally important in order to reach their recruitment target and complete delivery of the trial in a timely, effective and efficient manner.

Ultimately, the information gained from this trial may contribute to the development of a safe and effective P. falciparum vaccine. This would ultimately benefit UK travellers to malaria-endemic areas, as well as reduce the risk of imported malaria cases to the UK. Accruing valuable data on performance of next generation vaccine platforms such as the virus-like particle used in this study may also help inform on vaccine development for other infectious diseases that affect the UK population.

Yielded Benefits is not a requirement for new applications.