Immune response to the recombinant Zoster Vaccine in people living with HIV over 50 years of age compared to non-HIV age- and gender-matched controls - Shingr'HIV

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Bordeaux

Participant type

Healthy volunteers, Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

14 Dec 2023 → ongoing

Decision date (initial)

2023-07-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

GSK (financement de la partie Suisse) · GSK (fourniture du médicament expérimental pour la France) · ANRS | Maladies infectieuses émergentes (financement de la partie France)

External identifiers

EU CT number

2023-504482-23-00

ClinicalTrials.gov

NCT05575830

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

To assess the antibody response to RZV at D90 in >50 YOA PLWH under cART for more than 10 years compared to age/gender-matched non-HIV controls.

Secondary objectives 17

1. To assess the cellular immunogenicity (specific T lymphocytes) at D90 of RZV in >50 YOA PLWH under cART for more than 10 years compared to age/gender-matched non-HIV controls
2. To assess the kinetic and one-year persistence of antibody and cellular responses to RZV in >50 YOA PLWH under cART for more than 10 years compared to age/gender -matched non-HIV controls
3. To define the humoral and cellular vaccine response rate in >50 YOA PLWH under cART for more than 10 years compared to age/gender -matched non-HIV controls
4. To measure the inflammatory (innate) immune response (change in serum cytokine, change in gene expression as compared to pre-vaccination) 1 day after each dose of RZV and 1 month post dose 2 in >50 YOA PLWH under cART for more than 10 years compared to age/gender-matched non-HIV controls
5. To assess whether there is an interaction between age and HIV status on the immunogenicity (antibody, cellular and innate response) of RZV in >50 YOA patients
6. To define predictive markers of RZV immunogenicity (antibody, T cells and inflammatory markers) and/or reactogenicity among: o For all participants:  age, gender, ethnicity, gE-specific antibody response prior to vaccination, history of shingles, gamma-globulins dosage, previous zoster vaccination, leucocyte count, lymphocyte count; o Among PLWH :  HIV viral load, CD4 nadir, CD4 cell count, AIDS status, time from HIV diagnosis, time from last HIV viral load >200 copies/ml, treatment regimen
7. To compare the functionality of antibody (e.g. ADCC, Isotypes, affinity) after vaccination with RZV in all groups
8. To compare the quality of the gE-specific T cell response (e.g. memory phenotype, TcR repertoire) after vaccination with RZV in all groups
9. To evaluate the memory B cell response at baseline and after vaccination with RZV in all groups
10. To measure the ability of immune cells to response to innate stimuli in vitro (“immune fitness”) at baseline in PLWH compared to age/gender-matched non-HIV controls
11. To measure markers of biological ageing at baseline, including genetic markers, in PLWH compared to age/gender-matched non-HIV controls
12. To define predictive markers of RZV immunogenicity and/or reactogenicity among : Inflammatory markers (e.g. serum cytokines, gene expression profile including specific immune pathways) measured at baseline and post-vaccination; fitness of innate immune cells at baseline assessed in vitro; CMV seropositivity; Rockwood frailty score measured in participants > 75 YOA; Biological ageing-related biomarkers (including but not limited to cell phenotype, secretome, telomere length/activity, epigenetic marks)
13. To assess impact of vaccination on HIV reservoir at D90 and D360 by measuring HIV DNA in PLWH
14. To assess whether RZV induces functional alteration of and epigenetic changes in specific innate cells, such as monocytes, 1 month and 1 year after vaccination compared to baseline (“trained” immunity) in PLWH compared to age/gender-matched non-HIV controls
15. To monitor using samples previously bio-banked the T and B cell memory response to VZV (ie 5-10 years) and how the memory T and B cell response is recalled by vaccination and influence the magnitude of the vaccine response.
16. To assess the safety and reactogenicity (7 days for solicited events and 28 days for unsolicited events)) after each dose of RZV in >50 YOA PLWH under cART for more than 10 years compared to age/gender-matched non-HIV controls
17. To measure the HIV viral load after vaccination with RZV and explore any association with vaccine-specific immune response and/or clinical parameters in >50 YOA PLWH under cART for more than 10 years

Conditions and MedDRA coding

Human Immunodeficiency Virus (HIV)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. For PLWH: Be registered in the SHCS or in the ANRS CO3 Aquitaine Cohort
2. For PLWH + Controls : Age >50 YOA
3. For PLWH: Time since cART initiation > 10 years
4. For PLWH + Controls : Not already vaccinated with RZV
5. For PLWH: HIV viral load <50 copies/ml (within 6 months from the last blood sampling)
6. For PLWH + Controls : Informed consent as documented by signature
7. For PLWH + Controls : (France) : Person affiliated with or beneficiary of the French social security scheme

Exclusion criteria 11

1. Ongoing signs of febrile or non-febrile infection at the time of the first vaccination
2. (France) Patient governed by articles L 1121-5 to L 1121-8 (persons deprived of their liberty by a judicial or administrative decision, minors, persons of legal age who are the object of a legal protection measure or unable to express their consent).
3. Immunosuppression from the following: Current malignant neoplasm; primary immunodeficiency; recent (<2 years) solid or bone-marrow transplant or any transplant still requiring immunosuppressive therapy; Intake of drugs which suppress the immune system (e.g. glucocorticoids for a long time [an equivalent dose of prednisone >20 mg/day > 3 months], monoclonal antibodies, cytostatics, biological products, etc.) within 6 months before screening
4. Having received a vaccine in the last month or is expected to receive a vaccine in the next month
5. Having received a shingles vaccine within one year
6. Presented with herpes zoster in the previous year
7. Contra-indication to RZV due to hypersensitivity to the active substances or to any of the excipients
8. Hospitalized patients
9. Unable to provide informed consent or inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
10. Participation in another study with investigational drug within the 30 days preceding and during the present study
11. Administration of immunoglobulins or any blood products within 3 months preceding the first dose of vaccine or planned administration during the study period

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Geometric mean titer (GMT) of gE-specific total IgG measured at D90

Secondary endpoints 26

1. Incidence of solicited adverse events (AE) in the 7 days following each vaccination (reactogenicity) collected in a diary card: solicited local AE: pain at injection site, injection site swelling, injection site redness, injection site itching, axillary swelling and tenderness of the vaccination arm; solicited systemic AE: fatigue, headache, muscle ache, joint pain, chills, nausea/vomiting, diarrhea, fever, dizziness
2. Unsolicited AEs for 28 days after each RZV dose
3. Incidence of SAE throughout the study period
4. Incidence of potential immune mediated disorders (pIMDs) throughout the study period
5. In PLWH: Percentage of PLWH with viral load >50 copies/ml one month after the second RZV vaccination (D90)
6. Mean of gE-specific CD4+ T cells expressing at least 2 activation markers (i.e. CD40L, IFN-gamma, IL-2 or TNF-alpha) per million of T cells, measured at D90
7. Vaccine response rate for antibody defined as percentage of individuals with ≥4-fold increase in the anti-gE antibody concentration as compared to the prevaccination concentration (for initially seropositive participants) or as compared to the anti-gE antibody cut-off value for seropositivity (for initially seronegative participants).
8. Vaccine response rate for T cells defined as percentage of individuals with a ≥2-fold increase in the frequency of specific CD4+ T cells, as compared to prevaccination frequencies or a ≥2-fold increase above the cut-off (for participants with prevaccination frequencies below the cut-off).
9. Kinetics of GMT of gE-specific IgG measured at D0, 60, 90 and 360
10. Kinetics of the gE-specific CD4+ T cells expressing at least 2 activation markers (i.e. CD40L, IFN-gamma, IL-2 or TNF-alpha) per million of T cells measured at D0, 90, and 360
11. In the Innate subset : Change in the level of serum pro-inflammatory markers (including a panel of cytokines and CRP) between D1 and D0 (first vaccination) and between D60 and D61 (second vaccination); Differential expression of innate and adaptive immune response genes and associated pathways at D1 and D60 compared to D0 (first vaccination) and at D61 and D90 compared to D60 (second vaccination)
12. Change in the functional gE-specific antibody (e.g. ADCC function, binding to Fc receptor (FcR), isotype) at D60, D90 and D360 after RZV vaccination as compared to D0
13. Percentage of cells among gE-specific T cells expressing activation markers (such as OX-40L, 41BB, CD69), specific transcription factors (such as GATA-3, T-Bet) and other phenotypic markers (e.g naïve vs memory cells) at D0, 90 and 360
14. Change in TcR repertoire before and after vaccination
15. Number of gE-specific B cells per millions of PBMC assessed by ELISpot at D0, D90 and D360
16. Genetic markers measured in blood cells associated with the immunogenicity or reactogenicity profile of RZV
17. Percentage of innate cells (such as monocytes, dendritic cells, NK cells) expressing intracellular cytokines (e.g. IL-6, TNFa, IP-10) after restimulation in vitro with different innate stimuli, including TLR ligands and interferon-gamma measured at D0 (“innate immune cell fitness”)
18. Level of bioageing markers, such as but not limited to the level of cytosine methylation at specific gene positions in cells and specific serum markers (e.g Dehydroepiandrosterone sulphate, N-glycan, alpha-2 macroglobulin) or genetic markers at D0 (“biological ageing”)
19. Presence of CMV-specific antibodies at D0
20. Percentage of specific cell types (e.g. T-cell and B-cell subsets, unconventional T cells, NK cells) measured at D0 (“cell phenotyping”)
21. Expansion capacity and differentiation (e.g. change in expression of CD45RA, CD27, CCR7, and T bet expression) of naive and memory T cells upon stimulation with cognate antigens and innate stimuli tested at D0 (“in vitro priming and boosting”)
22. Level of soluble factors associated with ageing (e.g. inflammatory mediators, growth factors, homeostatic cytokines) measured in serum at D0 (“secretome”)
23. Telomere length and telomerase activity measured in PBMC at D0
24. Functional and epigenetic changes in isolated blood cells (such as monocytes) at D0, D90 and D360
25. Change in the quantity of HIV DNA copies in PBMC measured at D0 and D90
26. Frailty score measured at D0 in all participants aged 75 years and above

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Bordeaux

Sponsor organisation

Centre Hospitalier Universitaire De Bordeaux

Address

1 Rue Jean Burguet

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Investigatieur principal (France)

Public contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Investigatieur principal (France)

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications