COVID-19NCT05421546
Improving Vaccination in Older Adults by Inducing Autophagy With Spermidine
A study of COVID-19 and Vaccine Reaction, run by University of Oxford at 1 site in United Kingdom.
Trial summary
Easing the morbidity and economic burden of age-related diseases is one of the major medical challenges. One of the key obstacles to healthy ageing is immune senescence, including the failure of lymphocytes to respond adequately to infection, malignancy and vaccination. Read more about this study
- Who is it for?
- Ages 65 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- COVID-19, Vaccine Reaction
- Type of treatment
- Vaccines, Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Aug 2022to 2 Dec 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 to 90 years
- All sexes
- Healthy volunteers accepted
- Older adult
Who may be able to join
- Participants must be 65 years old or more and must have the capacity to provide written consent after discussing the participant information sheet with a member of the clinical study team. Participants must have received 2 doses of the COVID vaccine and a booster dose.
Who cannot join
- Participants who are acutely unwell.
- Participants who have had a clear clinical history of COVID symptoms or a previous positive COVID PCR( polymerase chain reaction) swab or antibody test
- Participants who cannot provide informed written consent
- Participants who use systemic steroids for more than one week e.g prednisolone >0.5mg/kg/day in the three months prior to first study intervention
- Chronic administration (≥14 days in total) of immunosuppressants or other immune modifying drugs in the 3 months prior to first study intervention
- Receipt of blood, blood products and/or plasma derivatives or any immunoglobulin preparation in the three months prior to first study intervention
Show all 13Show fewer
- Participants who have been diagnosed with medical conditions that can suppress the immune system or diabetes
- Participants with previous allergy to or constituent parts of Spermidine supplements or who have gluten intolerance
- Participants already taking Spermidine supplements at the time of recruitment or for 6 months prior to recruitment to the study
- Participants that are in custody
- Participants that do not live in the UK
- Participants that are pregnant
- Participants who are shielding
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Characterisation of the Effects of Spermidine, a Nutrition Supplement, on the Immune Memory Response to Coronavirus Vaccine in Older People
Easing the morbidity and economic burden of age-related diseases is one of the major medical challenges. One of the key obstacles to healthy ageing is immune senescence, including the failure of lymphocytes to respond adequately to infection, malignancy and vaccination. Infectious diseases remain the fourth most common cause of death among the elderly in the developed world. Moreover, the gain of chronic low-grade non-specific inflammation with age contributes to many age-related diseases. Our early work showed that autophagy, the main cellular bulk degradation pathway in the cell, prevents ageing of the immune system. In preclinical models we showed an age-related decline in T cell autophagy. We rejuvenated the immune system by restoring autophagy in T and B cells with the autophagy-inducing metabolite spermidine. Here we are asking for matched funds for a small human clinical trial to confirm that spermidine has the same effect when administered to humans. We will give the nutraceutical spermidine to human volunteers aged >65 years either during or after vaccination against SARS-CoV-2 or influenza to test improvement of vaccine responses, immune senescence and inflamm-aging. We will also confirm whether a novel pathway we discovered that links spermidine to autophagy operates in humans, allowing us to make more specific drugs in the future. This small study of 120 volunteers overall will pave the way for a larger clinical trial with spermidine or novel related drugs.
Read the detailed description
The outbreak of SARS-CoV-2 and coronavirus disease (COVID-19) has caused a great threat to global public health with the majority of deaths occurring in older adults. The development of effective treatments and vaccines against COVID-19 has become a pressing and urgent challenge to overcome. Successful protective immune responses stimulated by vaccination of older people (people aged greater than 65 years old) against pathogens is considered one of the big challenges in our society.
Immune senescence is thought to be important in the reduced immune response that has been widely observed, following immunization of older adults. This is characterized by poor induction and recall of B and T cell memory responses upon exposure to viruses and vaccines.
Most vaccines are less immunogenic effective in the older population, in particular influenza vaccines. Autophagy is thought to be one of the few cellular processes that underlie many facets of cellular aging including immune senescence. Autophagy delivers 'unwanted' cytoplasmic material to lysosomes inside a cell for degradation. Autophagy also limits mitochondrial dysfunction and accumulation of reactive oxygen species (ROS).
Deletion of key autophagy genes leads to a change in cellular immunity, with loss of function in mouse memory CD8+ T cells, hematopoietic stem cells, and macrophages. We have seen that autophagy levels also decline with age in human peripheral CD8+ T cells and correlate with vaccine responses.
Importantly, we have demonstrated that we can improve CD8+ T memory responses in aged mice with a supplement called spermidine. Spermidine is a metabolite synthesised from arginine. It is commonly found in wheatgerm and soya and is available in the United Kingdom (UK) as a nutritional food supplement, often described as a polyamine. It's safety and tolerability has been studied and no adverse effects have been demonstrated and it is readily available to buy from mainstream retail companies e.g. Amazon. Our data showed for the first time that autophagy is indeed highly active in human CD8+ T cells in two different experimental vaccination trials. Polyamine levels also fall with age in peripheral mononuclear cells. When supplemented with spermidine, the autophagic function can be rejuvenated in CD8+ T cells from old donors, and levels of the important effector molecules increased. As a consequence, the immune response is enhanced.
Moreover, autophagy and effector function are maintained by spermidine in T cells from young donors. This demonstrates that the function of human CD8+ T cells can be improved with spermidine. Taken together with our previous work on B cells, this leads us to the hypothesis that both T and B cell responses to infections and vaccinations are exquisitely reliant on sufficient autophagy levels, which are maintained by intracellular spermidine. This work highlights the potential of spermidine as a vaccine adjuvant in the older adults.
This phase 1, double-blinded, randomised controlled trial is designed as a feasibility study to examine the safety of Spermidine supplements and its effects on the immune response (antibodies) to COVID vaccine in older people.
AIMS AND OBJECTIVES The primary objective of this feasibility study is to determine the safety of daily Spermidine supplements following vaccination for Coronavirus (SARS-CoV-2) and a booster and its effects on antibody levels in older people, using validated assays.
Our secondary objective is to determine the effects of daily Spermidine supplements on the immune 'memory' response to Coronavirus vaccine and a booster in older people. We will examine if Spermidine improves the duration of the antibody-mediated immune response after the Coronavirus vaccine/booster with validated assays and then determine the molecular and immunological signature driving immunity. We will also use data collected to perform a power calculation for future larger studies.
- Conditions
- COVID-19, Vaccine Reaction
- Being tested
- Spermidine or Placebo
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Spermidine or PlaceboDietary supplement
The supplement, Spermidine, is made mainly from wheatgerm and can be bought in health food shops. It is a powder that can be easily dissolved in water and taken as a drink. The 'placebo' is a sugar powder that can be similarly dissolved in water and taken as a drink.
| Study group | Role | What they receive |
|---|---|---|
| Spermidine arm | Active comparator | This arm will enrol 20 volunteers aged 65 years of age or older (65-90) who have received two doses of the Coronavirus vaccine, with the vaccination course completed more than 8 weeks before recruitment. Following a baseline venous blood sample, participants will receive Spermidine supplements 6mg/day and oral administration once daily. A research appointment and venous blood sample will be requested at the point of recruitment, 5 weeks, 13 weeks and 37 weeks after recruitment of the participant. Receives: Dietary Supplement: Spermidine or Placebo |
| Placebo arm | Placebo comparator | This arm will enrol 20 volunteers aged 65 years of age or older (65-90) who have received two doses of the Coronavirus vaccine, with the vaccination course completed more than 8 weeks before recruitment. Following a baseline venous blood sample, participants will receive placebo oral administration once daily. A research appointment and venous blood sample will be requested at the point of recruitment, 5 weeks, 13 weeks and 37 weeks after recruitment of the participant. Receives: Dietary Supplement: Spermidine or Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective of this study is to determine the safety of daily Spermidine supplements following the vaccine booster for Coronavirus (SARS-CoV-2) and its effects on antibody levels in older people, using validated assays.
- The safety of daily Spermidine supplements following the vaccine booster for Coronavirus (SARS-CoV-2).
- The SARS-CoV-2 antibody levels in older people, using validated assays.
Measured: 37 weeks
Secondary outcomes (1)
Our secondary objective is to determine the effects of daily Spermidine supplements on the immune 'memory' response to Coronavirus vaccine and the booster in older people.
- Longevity of immune 'memory' response to SARS-CoV-2 vaccine measuring antibody and T cell responses.
Measured: 37 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2022
- Study start1 Aug 2022
- Primary completion31 Aug 2023
- Study completion2 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for COVID-19Studies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Katja Simon, Prof., Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05421546
- Sponsor's protocol ID
- R75468/RE001
- Status last verified
- Aug 2022
- First submitted
- 13 Jun 2022
- Last updated
- 9 May 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Characterisation of the Effects of Spermidine, a Nutrition Supplement, on the Immune Memory Response to Coronavirus Vaccine in Older People
- ClinicalTrials.gov ID
- NCT05421546
- Acronym / sponsor ID
- R75468/RE001
- Conditions
- COVID-19, Vaccine Reaction
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- 1 Aug 2022 (actual)
- Primary completion
- 31 Aug 2023 (actual)
- Study completion
- 2 Dec 2023 (actual)
- First posted
- 16 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Easing the morbidity and economic burden of age-related diseases is one of the major medical challenges. One of the key obstacles to healthy ageing is immune senescence, including the failure of lymphocytes to respond adequately to infection, malignancy and vaccination. Infectious diseases remain the fourth most common cause of death among the elderly in the developed world. Moreover, the gain of chronic low-grade non-specific inflammation with age contributes to many age-related diseases. Our early work showed that autophagy, the main cellular bulk degradation pathway in the cell, prevents ageing of the immune system. In preclinical models we showed an age-related decline in T cell autophagy. We rejuvenated the immune system by restoring autophagy in T and B cells with the autophagy-inducing metabolite spermidine. Here we are asking for matched funds for a small human clinical trial to confirm that spermidine has the same effect when administered to humans. We will give the nutraceutical spermidine to human volunteers aged >65 years either during or after vaccination against SARS-CoV-2 or influenza to test improvement of vaccine responses, immune senescence and inflamm-aging. We will also confirm whether a novel pathway we discovered that links spermidine to autophagy operates in humans, allowing us to make more specific drugs in the future. This small study of 120 volunteers overall will pave the way for a larger clinical trial with spermidine or novel related drugs.
Detailed description
The outbreak of SARS-CoV-2 and coronavirus disease (COVID-19) has caused a great threat to global public health with the majority of deaths occurring in older adults. The development of effective treatments and vaccines against COVID-19 has become a pressing and urgent challenge to overcome. Successful protective immune responses stimulated by vaccination of older people (people aged greater than 65 years old) against pathogens is considered one of the big challenges in our society.
Immune senescence is thought to be important in the reduced immune response that has been widely observed, following immunization of older adults. This is characterized by poor induction and recall of B and T cell memory responses upon exposure to viruses and vaccines.
Most vaccines are less immunogenic effective in the older population, in particular influenza vaccines. Autophagy is thought to be one of the few cellular processes that underlie many facets of cellular aging including immune senescence. Autophagy delivers 'unwanted' cytoplasmic material to lysosomes inside a cell for degradation. Autophagy also limits mitochondrial dysfunction and accumulation of reactive oxygen species (ROS).
Deletion of key autophagy genes leads to a change in cellular immunity, with loss of function in mouse memory CD8+ T cells, hematopoietic stem cells, and macrophages. We have seen that autophagy levels also decline with age in human peripheral CD8+ T cells and correlate with vaccine responses.
Importantly, we have demonstrated that we can improve CD8+ T memory responses in aged mice with a supplement called spermidine. Spermidine is a metabolite synthesised from arginine. It is commonly found in wheatgerm and soya and is available in the United Kingdom (UK) as a nutritional food supplement, often described as a polyamine. It's safety and tolerability has been studied and no adverse effects have been demonstrated and it is readily available to buy from mainstream retail companies e.g. Amazon. Our data showed for the first time that autophagy is indeed highly active in human CD8+ T cells in two different experimental vaccination trials. Polyamine levels also fall with age in peripheral mononuclear cells. When supplemented with spermidine, the autophagic function can be rejuvenated in CD8+ T cells from old donors, and levels of the important effector molecules increased. As a consequence, the immune response is enhanced.
Moreover, autophagy and effector function are maintained by spermidine in T cells from young donors. This demonstrates that the function of human CD8+ T cells can be improved with spermidine. Taken together with our previous work on B cells, this leads us to the hypothesis that both T and B cell responses to infections and vaccinations are exquisitely reliant on sufficient autophagy levels, which are maintained by intracellular spermidine. This work highlights the potential of spermidine as a vaccine adjuvant in the older adults.
This phase 1, double-blinded, randomised controlled trial is designed as a feasibility study to examine the safety of Spermidine supplements and its effects on the immune response (antibodies) to COVID vaccine in older people.
AIMS AND OBJECTIVES The primary objective of this feasibility study is to determine the safety of daily Spermidine supplements following vaccination for Coronavirus (SARS-CoV-2) and a booster and its effects on antibody levels in older people, using validated assays.
Our secondary objective is to determine the effects of daily Spermidine supplements on the immune 'memory' response to Coronavirus vaccine and a booster in older people. We will examine if Spermidine improves the duration of the antibody-mediated immune response after the Coronavirus vaccine/booster with validated assays and then determine the molecular and immunological signature driving immunity. We will also use data collected to perform a power calculation for future larger studies.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Spermidine arm | Active comparator | Dietary Supplement: Spermidine or PlaceboThis arm will enrol 20 volunteers aged 65 years of age or older (65-90) who have received two doses of the Coronavirus vaccine, with the vaccination course completed more than 8 weeks before recruitment. Following a baseline venous blood sample, participants will receive Spermidine supplements 6mg/day and oral administration once daily. A research appointment and venous blood sample will be requested at the point of recruitment, 5 weeks, 13 weeks and 37 weeks after recruitment of the participant. |
| Placebo arm | Placebo comparator | Dietary Supplement: Spermidine or PlaceboThis arm will enrol 20 volunteers aged 65 years of age or older (65-90) who have received two doses of the Coronavirus vaccine, with the vaccination course completed more than 8 weeks before recruitment. Following a baseline venous blood sample, participants will receive placebo oral administration once daily. A research appointment and venous blood sample will be requested at the point of recruitment, 5 weeks, 13 weeks and 37 weeks after recruitment of the participant. |
Who may qualify
- Ages
- 65 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Older adult
Key inclusion criteria (1 listed)
- Participants must be 65 years old or more and must have the capacity to provide written consent after discussing the participant information sheet with a member of the clinical study team. Participants must have received 2 doses of the COVID vaccine and a booster dose.
Key exclusion criteria (13 listed)
- Participants who are acutely unwell.
- Participants who have had a clear clinical history of COVID symptoms or a previous positive COVID PCR( polymerase chain reaction) swab or antibody test
- Participants who cannot provide informed written consent
- Participants who use systemic steroids for more than one week e.g prednisolone >0.5mg/kg/day in the three months prior to first study intervention
- Chronic administration (≥14 days in total) of immunosuppressants or other immune modifying drugs in the 3 months prior to first study intervention
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Spermidine or PlaceboThe supplement, Spermidine, is made mainly from wheatgerm and can be bought in health food shops. It is a powder that can be easily dissolved in water and taken as a drink. The 'placebo' is a sugar powder that can be similarly dissolved in water and taken as a drink. | Dietary supplement | Placebo arm, Spermidine arm |
Primary outcome
The primary objective of this study is to determine the safety of daily Spermidine supplements following the vaccine booster for Coronavirus (SARS-CoV-2) and its effects on antibody levels in older people, using validated assays.
Time frame: 37 weeks
1. The safety of daily Spermidine supplements following the vaccine booster for Coronavirus (SARS-CoV-2). 2. The SARS-CoV-2 antibody levels in older people, using validated assays.
1 secondary outcome
Our secondary objective is to determine the effects of daily Spermidine supplements on the immune 'memory' response to Coronavirus vaccine and the booster in older people.
Time frame: 37 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Katja Simon, Prof. principal investigator
University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study of COVID-19 and Vaccine Reaction, run by University of Oxford at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary objective of this study is to determine the safety of daily Spermidine supplements following the vaccine booster for Coronavirus (SARS-CoV-2) and its effects on antibody levels in older people, using validated assays. (time frame: 37 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2024.