Combining recombinant herpes zoster and influenza or COVID-19 vaccination
| ISRCTN | ISRCTN26495549 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN26495549 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | Nil known |
| Integrated Research Application System (IRAS) | 1006696 |
| Central Portfolio Management System (CPMS) | 54747 |
| Protocol serial number | VT/2022/7349 |
| Sponsor | University Hospitals Bristol and Weston NHS Foundation Trust |
| Funder | GlaxoSmithKline |
- Submission date
- 16/11/2022
- Registration date
- 30/05/2023
- Last edited
- 18/11/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Shingles is a common and painful disease, it can result in long-term pain and in rare cases can even be fatal. It is recommended that all adults in the UK are offered the shingles vaccine on their 70th birthday. Uptake of the shingles vaccine is suboptimal, therefore strategies to improve uptake are needed.
Routine reporting of the shingles vaccine suggests that uptake is greater during the influenza season, and it is assumed this is due to it being offered at the same time as the annual flu vaccine. A new vaccine for shingles has been recommended since 2021, a recombinant herpes zoster vaccination.
Up until May 2023 concomitant administration of RZV with either adjuvanted or COVID-19 vaccine (C19) was not recommended due to concern about misattribution of side-effects and limited experience with COVID-19 vaccines. The policy was updated in May 2023 to allow co-administration of COVID-19 vaccines with any vaccine. This was based on recent evidence supporting the acceptable safety profile of a COVID-19 vaccine with RZV and to improve timely protection and uptake. There is still a need however for safety data with co-administration of second dose of RZV as the adverse event profile differs between the doses and there is a lack of published data on the safety and immunogenicity of RZV and adjuvanted flu vaccine.
Who can participate?
Healthy volunteers aged 50 years and over who have not received a live shingles vaccine within 5 years
What does the study involve?
Participants will be required to attend six study appointments over a period of 5 months at their nearest participating site. They will be randomly allocated into one of five groups, and they do not know which group they are in. Participants will be required to provide blood samples at study visits, and complete an e-diary in-between visits.
What are the possible benefits and risks of participating?
The potential benefits will be protection against COVID-19, Herpes zoster and influenza. However, some participants may already be up to date with their COVID-19 and flu vaccines, and the additional COVID-19 and flu vaccine as part of the study would not offer them additional protection.
Localised bruising and discomfort can occur at the site of blood sampling. Infrequently fainting may occur. The total volume of blood drawn over a 6-week period will be approximately 260 ml (blood volumes may vary slightly for participants at different investigator sites due to the use of different volume vacutainers, following local Trust procedures). This should not compromise these otherwise healthy volunteers, as these volumes are within the limits of 470 ml every 3–4 months for blood donations to the National Blood Transfusion Service.
Allergic reactions from mild to severe may occur in response to any constituent of a medicinal product’s preparation. Anaphylaxis is extremely rare (about 1 in 1,000,000 vaccine doses) but can occur in response to any vaccine or medication. People very often have tenderness, pain, warmth, redness, itching, swelling or bruising or less commonly have a small lump in their arm where they have been vaccinated. After vaccination it is common to experience the following side effects for all vaccines: fatigue, joint aches, muscle aches, headaches, feeling sick/nauseated/vomiting or diarrhea, flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills, feeling unwell. With the shingles vaccine 1 in 10 people may experience these common side effects that are severe enough to interfere with their daily activities. They usually last for less than a week (more commonly 24-48 hours after vaccination). Other less common side effects are: abdominal pain, feeling dizzy, excessive sweating, itching skin or rash, decreased appetite, and swollen lymph nodes.
Where is the study run from?
University of Bristol (UK)
When is the study starting and how long is it expected to run for?
November 2022 to December 2025
Who is funding the study?
GlaxoSmithKline (UK)
Who is the main contact?
Ms Rachael Heys, zosterflucov-trial@bristol.ac.uk
Contact information
Scientific, Public
Trial Manager
Bristol Trials Unit
1-5 Whiteladies Road
Bristol
BS8 1NU
United Kingdom
| Phone | +44 (0)117 455 3012 |
|---|---|
| zosterflucov-trial@bristol.ac.uk |
Principal investigator
Marlborough Street
Bristol
BS1 3NU
United Kingdom
| Phone | +44 (0)117 3429266 |
|---|---|
| Rajeka.Lazarus@uhbw.nhs.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Double-blind randomized controlled parallel-group trial |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | A phase IV, multi-centre, randomised controlled trial to assess immunogenicity and safety of COVID-19 and seasonal influenza vaccine given to healthy adults or those with underlying medical conditions when co-administered with a recombinant herpes zoster vaccine with adjuvant |
| Study acronym | ZosterFluCOV |
| Study objectives | The ZosterFluCov study aims to evaluate whether shingles (herpes zoster) vaccine can be co-administered with an mRNA COVID-19 (Bivalent) vaccine or an adjuvanted influenza vaccine (aQIV) without a significant immune interference or adverse reactions of the COVID-19, influenza or RZ vaccines. 1. Cell-mediated responses to two doses of RZV, 1 month after the 2nd dose, given alone compared to co-administration with Bivalent vaccine with 1st or 2nd dose of RZV. 2. Exploratory evaluation of CD4+T-cells against COVID-19 after vaccination with RZV or aQIV in the CMI cohort. 3. S and N- protein immunoglobulin, before and 1 month after first vaccination in the exploratory immunology cohort. 4. Solicited systemic AEs over 7 days after 1st and 2nd doses of RZV given alone compared to co-administration with either Bivalent vaccine or aQIV. 5. Solicited local adverse reactions over 7 days after 1st and 2nd doses of RZV given alone compared to co-administration with either Bivalent vaccine or aQIV. 6. Grade 3 and 4 SSR after 1st RZV dose in group 1, 2 and 5 compared to grade 3 SSR after 1st dose of RZV with Bivalent vaccine in group 3 7. Grade 3 and 4 SSR after 2nd dose of RZV in group 1, 3 and 4 compared to grade 3 SSR after 2nd dose RZV 8. Describe participant and study nurse attitudes to vaccine co-administration. (added 23/11/2023) |
| Ethics approval(s) |
Approved 26/05/2023, South Central - Hampshire B Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 207 1048 088; hampshireb.rec@hra.nhs.uk), ref: 22/SC/0409 |
| Health condition(s) or problem(s) studied | Shingles, influenza, COVID-19 (SARS-CoV-2 infection) |
| Intervention | Current interventions as of 22/10/2024: To test the immunogenicity and safety of giving the recombinant herpes zoster with adjuvant (shingles) vaccine, at the same time as either the COVID-19 bivalent mRNA vaccine or the flu vaccine. Participants will be randomised by a computer in a 1:1:2:2:2 ratio to one of five groups; 129 participants to groups 1 and 2, and 258 participants to groups 3-5. Only 129 participants in group 3 will progress to the second and third vaccination time points required to assess COVID-19 vaccine/RZV co-administration. All five groups will receive two doses of RZV (except participants in group 3 who do not progress after the first vaccination timepoint and will not have any RZV doses as part of the trial). At the first and second vaccination timepoints, participants will receive two injections (combinations of RZV, COVID-19 vaccine, aQIV or placebo [P]). At the final vaccination visit participants will receive one injection (either a second RZV or flu or COVID-19 vaccine). Vaccines administered at visit 1, visit 3, and visit 5, respectively: Group 1: COVID-19/P, RZV/P, RZV Group 2: RZV/P, RZV/COVID-19, Flu Group 3: aQIV/P, COVID-19/RZV, RZV Group 4: RZV/aQIV, RZV/P, COVID-19 Group 5: RZV/P, RZV/aQIV, COVID-19 Group 1 will receive aQIV at visit 6 (day 140) Each participant will be in the study for 5 months and attend 6 study visits. _____ Previous interventions as of 09/01/2024 to 22/10/2024: To test the immunogenicity and safety of giving the recombinant herpes zoster with adjuvant (shingles) vaccine, at the same time as either the COVID-19 bivalent mRNA vaccine or the flu vaccine. Participants will be randomised by a computer in a 1:1:2:2:2 ratio to one of five groups; 129 participants to groups 1 and 2, and 258 participants to groups 3-5. Only 129 participants in group 3 will progress to the second and third vaccination time points required to assess Bivalent vaccine/RZV co-administration. All five groups will receive two doses of RZV (except participants in group 3 who do not progress after the first vaccination timepoint and will not have any RZV doses as part of the trial). At the first and second vaccination timepoints, participants will receive two injections (combinations of RZV, COVID-19 vaccine, aQIV or placebo [P]). At the final vaccination visit participants will receive one injection (either a second RZV or flu or COVID-19 vaccine). Vaccines administered at visit 1, visit 3, and visit 5, respectively: Group 1: COVID-19/P, RZV/P, RZV Group 2: RZV/P, RZV/COVID-19, Flu Group 3: aQIV/P, COVID-19/RZV, RZV Group 4: RZV/aQIV, RZV/P, COVID-19 Group 5: RZV/P, RZV/aQIV, COVID-19 Group 1 will receive aQIV at visit 6 (day 140) Each participant will be in the study for 5 months and attend 6 study visits. _____ Previous interventions: To test the immunogenicity and safety of giving the recombinant herpes zoster with adjuvant (shingles) vaccine, at the same time as either the COVID-19 bivalent mRNA vaccine or the flu vaccine. Participants will be randomised by a computer in a 1:1:2:2:2 ratio to one of five groups; 129 participants to groups 1 and 2, and 258 participants to groups 3-5. Only 129 participants in group 3 will progress to the second and third vaccination time points required to assess Bivalent vaccine/RZV co-administration. A subset of sites will be selected that will administer the second and third vaccination timepoints. All five groups will receive two doses of RZV (except participants in group 3 who do not progress after the first vaccination timepoint and will not have any RZV doses as part of the trial). At the first and second vaccination timepoints, participants will receive two injections (combinations of RZV, Bivalent vaccine, aQIV or placebo [P]). At the final vaccination visit participants will receive one injection (either a second RZV or placebo). Vaccines administered at D0, D56, and D112, respectively: Group 1: Bivalent/P, RZV/P, RZV Group 2: RSV/P, RZV/bivalent, P Group 3: aQIV/P, Bivalent/RZV, RZV Group 4: RZV/aQIV, RZV/P, P Group 5: RZV/P, RZV/aQIV, P Each participant will be in the study for 5 months and attend 6 study visits. |
| Intervention type | Biological/Vaccine |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Comirnaty JN.1(30 micrograms)/ dose dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified), adjuvanted quadrivalent influenza vaccine [influenza virus surface antigens (haemagglutinin and neuraminidase), inactivated], herpes zoster vaccine (recombinant adjuvanted) [Varicella Zoster Virus 1 glycoprotein E antigen] |
| Primary outcome measure(s) |
Current primary outcome measure as of 22/10/2024: |
| Key secondary outcome measure(s) |
Current secondary outcome measure as of 22/10/2024: |
| Completion date | 31/12/2025 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Mixed |
| Lower age limit | 50 Years |
| Upper age limit | 100 Years |
| Sex | All |
| Target sample size at registration | 960 |
| Total final enrolment | 967 |
| Key inclusion criteria | Current inclusion criteria as of 23/11/2023: 1. Participants who, in the opinion of the investigator, can and will comply with the requirements of the protocol 2. Written informed consent obtained from the participant prior to any study-specific procedure 3. Adults aged 50 years and over at the time of randomisation 4. Participants must have documented history (e.g. NHS app, GP record) or receiving their initial course (usually two doses) of any type of COVID-19 vaccinaiton, irrespective of the type of COVID-19 vaccine received. 5. Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception from 1 month prior to first vaccination continuously until 3 months after final vaccination* *A woman of childbearing potential is defined as a pre-menopausal female who is capable of becoming pregnant _____ Previous inclusion criteria: 1. Participants who, in the opinion of the investigator, can and will comply with the requirements of the protocol 2. Written informed consent obtained from the participant prior to any study-specific procedure 3. Adults aged 50 years and over at the time of randomisation 4. Participants must have documented previous COVID-19 vaccination in line with UK recommendations at the time of the study 5. Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception from 1 month prior to first vaccination continuously until 3 months after final vaccination* *A woman of childbearing potential is defined as a pre-menopausal female who is capable of becoming pregnant |
| Key exclusion criteria | Current participant exclusion criteria as of 22/10/2024: 1. Any clinical condition that in the opinion of the investigator might pose additional risk to the participant due to participation in the study. 2. History of reaction or hypersensitivity likely to be exacerbated by any component of the study intervention including allergic reaction to any component of any of the study vaccines, known reactions related to study vaccines e.g. history of myocarditis, GuillainBarre Syndrome. 3. Unstable medical condition on the day of enrolment as determined by clinical history and examination. 4. Bleeding disorders or continuous use of anticoagulation medicine, such as coumarins and related anticoagulants (i.e., warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban). Use of aspirin is allowed. 5. Any confirmed or suspected immunosuppressive, or immunodeficient condition, based on medical history and physical examination. People living with HIV that is well controlled can be included in the study.* Those with a new diagnosis or an AIDs defining illness in the past 12 months cannot be included. 6. Use of immunosuppressive medication, ongoing, long term or planned, defined as more than 14 days in total of immunosuppressant treatments. For corticosteroids this will mean more than 14 days of prednisolone >20mg/day or equivalent. Use of inhaled, intraarticular and topical steroids is allowed. 7. Use or planned use of long-acting immune modifying drugs in the 12-month period before randomisation (e.g. infliximab). 8. COVID-19 or influenza vaccination 90 days prior to the study vaccination 9. Previous vaccination with a live herpes zoster vaccine within the past 5 years. 10. Administration of monoclonal antibodies (including those targeting SARS CoV2), immunoglobulins and/or blood products during the 3 months before the first dose of the study vaccines, up to 1 month after the last dose or planned during the study period. 11. Planning to or concurrently participate in another interventional clinical study. 12. Pregnancy, lactation or willingness/intention to become pregnant within the study period. 13. Previous participation in the ZosterFluCOV trial. *Defined as less than 50 copies/ml (convert as needed from IU/ml) on the last two occasions >3 months apart, and a CD4 over 500 when last checked. Previous participant exclusion criteria as of 23/11/2023: 1. Any clinical condition that in the opinion of the investigator might pose additional risk to the participant due to participation in the study 2. History of reaction or hypersensitivity likely to be exacerbated by any component of the study intervention including allergic reaction to any component of any of the study vaccines, known reactions related to study vaccines e.g. history of myocarditis, Guillain-Barre Syndrome 3. Unstable medical condition on the day of enrolment as determined by clinical history and examination 4. Bleeding disorders 5. Any confirmed or suspected immunosuppressive, or immunodeficient condition, based on medical history and physical examination. People living with HIV that is well controlled can be included in the study.* Those with a new diagnosis or an AIDs defining illness in the past 12 months cannot be included. 6. Use of immunosuppressive medication, ongoing, long term or planned, defined as more than 14 days in total of immunosuppressant treatments. For corticosteroids this will mean more than 14 days of prednisolone >20 mg/day or equivalent. Use of inhaled, intra-articular and topical steroids is allowed. 7. Use or planned use of long-acting immune modifying drugs in the 12-month period before randomisation (e.g. infliximab) 8. COVID-19 or influenza vaccination 90 days prior to study vaccination 9. Previous vaccination with a live herpes zoster vaccine within the past 5 years 10. Administration of monoclonal antibodies (including those targeting SARS-CoV-2), immunoglobulins and/or blood products during the 3 months before the first dose of the study vaccines, up to 1 month after the last dose or planned during the study period 11. Planning to or concurrently participating in another interventional clinical study 12. Pregnancy, lactation or willingness/intention to become pregnant within the study period 13. COVID-19 or flu vaccine within 90 days, any other vaccine within 30 days of study vaccination *Defined as less than 50 copies/ml (convert as needed from IU/ml) on the last two occasions >3 months apart, and a CD4 over 500 when last checked. _____ Previous participant exclusion criteria: 1. Any clinical condition that in the opinion of the investigator might pose additional risk to the participant due to participation in the study 2. History of reaction or hypersensitivity likely to be exacerbated by any component of the study intervention including allergic reaction to any component of any of the study vaccines, known reactions related to study vaccines e.g. history of myocarditis, Guillain-Barre Syndrome 3. Unstable medical condition on the day of enrolment as determined by clinical history and examination 4. Bleeding disorders 5. Any confirmed or suspected immunosuppressive, or immunodeficient condition, based on medical history and physical examination 6. Use of immunosuppressive medication, ongoing, long term or planned, defined as more than 14 days in total of immunosuppressant treatments. For corticosteroids this will mean more than 14 days of prednisolone >20 mg/day or equivalent. Use of inhaled, intra-articular and topical steroids is allowed. 7. Use or planned use of long-acting immune modifying drugs in the 12-month period before randomisation (e.g. infliximab) 8. Planned vaccination within 30 days of study vaccination 9. Previous vaccination with a live herpes zoster vaccine within the past 5 years 10. Administration of monoclonal antibodies (including those targeting SARS-CoV-2), immunoglobulins and/or blood products during the 3 months before the first dose of the study vaccines, up to 1 month after the last dose or planned during the study period 11. Planning to or concurrently participating in another interventional clinical study 12. Pregnancy, lactation or willingness/intention to become pregnant within the study period 13. COVID-19 or flu vaccine within 90 days, any other vaccine within 30 days of study vaccination |
| Date of first enrolment | 01/10/2023 |
| Date of final enrolment | 28/02/2025 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centres
Marlborough Street
Bristol
BS1 3NU
England
Westminster Bridge Road
London
SE1 7EH
England
London
SW17 0QT
England
Bath
BA1 3NG
England
Anlaby Road
Hull
HU3 2JZ
England
Marton Road
Middlesbrough
TS4 3BW
England
2nd Floor
Cheltenham General Hospital
Cheltenham
GL53 7AN
England
Tremona Road
Southampton
SO16 6YD
England
Weston-super-mare
BS23 3HQ
England
Herries Road
Sheffield
S5 7AU
England
Orrysdale Road
West Kirby
Wirral
CH48 5AA
England
Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
England
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Published as a supplement to the results publication |
| IPD sharing plan | The datasets generated and/or analysed during the current study will be published as a supplement to the results publication. Anonymised trial data will only be made available for sharing after the publication of the main results of the trial. Thereafter, individual participant data will be made available for secondary research, conditional on assurance from the secondary researcher that the proposed use of the data is compliant with the MRC Policy on Data Sharing regarding scientific quality, ethical requirements and value for money. A minimum requirement with respect to scientific quality will be a publicly available pre-specified protocol describing the purpose, methods and analysis of the secondary research, e.g., a protocol for a Cochrane systematic review. If participants consent for the storage of samples for future research, a copy of the participant’s consent form will be shared with the licenced Research Tissue Bank. If participants consent, local sites will store their contact details so they can be contacted about future studies that may be relevant. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 20/09/2023 | No | No | ||
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Protocol file | version 4.0 | 18/09/2023 | 23/11/2023 | No | No |
| Protocol file | version 9.0 | 17/12/2024 | 03/03/2025 | No | No |
| Study website | Study website | 11/11/2025 | 11/11/2025 | No | Yes |
Additional files
- ISRCTN26495549 ZosterFluCov Protocol v4.0 18Sep2023.pdf
- Protocol file
- ISRCTN26495549 ZosterFluCov Protocol v9.0 17Dec2024.pdf
- Protocol file
Editorial Notes
18/11/2025: The study participating centres were added.
03/03/2025: The following changes were made to the trial record:
1. Uploaded protocol v9.0 (not peer-reviewed) as an additional file.
2. The total final enrolment was added.
22/10/2024: The following changes were made:
1. The overall study end date was changed from 31/01/2025 to 31/12/2025.
2. The vaccine name was changed from "Bivalent vaccine" to "COVID-19 vaccine" in the interventions, primary and secondary outcome measures.
3. The vaccine name was changed from "Comirnaty original/Omicron BA.4-5 (15/15 micrograms)/ dose dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified), adjuvanted quadrivalent influenza vaccine [influenza virus surface antigens (haemagglutinin and neuraminidase), inactivated], herpes zoster vaccine (recombinant adjuvanted) [Varicella Zoster Virus 1 glycoprotein E antigen]" to "Comirnaty JN.1(30 micrograms)/ dose dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified), adjuvanted quadrivalent influenza vaccine [influenza virus surface antigens (haemagglutinin and neuraminidase), inactivated], herpes zoster vaccine (recombinant adjuvanted) [Varicella Zoster Virus 1 glycoprotein E antigen]".
4. The target number of participants was changed from 1032 to 960.
5. The participant exclusion criteria were changed.
6. The recruitment end date was changed from 29/02/2024 to 28/02/2025.
09/01/2024: The interventions were changed.
08/01/2024: The ethics approval was added.
23/11/2023: The following changes were made to the trial record:
1. Uploaded protocol (not peer-reviewed) as an additional file.
2. The study hypothesis was updated.
3. The study website was added.
4. A link to participant information sheets was added.
5. The drug name 'Comirnaty original/Omicron BA.1 COVID-19 mRNA vaccine [tozinameran, riltozinameran]' was changed to 'Comirnaty original/Omicron BA.4-5 (15/15 micrograms)/ dose dispersion for injection COVID-19 mRNA Vaccine (nucleoside modified)'
6. The secondary outcome measures were updated.
7. The inclusion criteria were changed.
8. The exclusion criteria were changed.
9. The recruitment start date was changed from 02/01/2023 to 01/10/2023.
10. The plain English summary was updated to reflect these changes.
20/09/2023: A link to the HRA research summary was added.
05/06/2023: Internal review.
27/05/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 27/05/2023.
16/11/2022: Trial's existence confirmed by the HRA.
