Improving Vaccine Protection for Adults

Official title

Using AS01 Adjuvant to Improve Immune Response in Older Adults Through Trained Immunity

Overview

As people grow older, their immune system - the body's natural defence against diseases - becomes weaker, making them more vulnerable to infections and less responsive to vaccines. This was clearly seen during the COVID-19 pandemic, where older adults were more likely to develop severe illness. Researchers have made an interesting discovery about AS01, an ingredient already used in successful vaccines like the shingles vaccine. They found clues that AS01 might work like a general fitness trainer for the immune system, potentially making it stronger and better at fighting off various types of infections, not just specific ones. To confirm this possibility, we are conducting this research study with adults aged 21-59 to test whether AS01 by itself can boost and train the immune system, how long this boost lasts, and if it actually helps you fight off other infections more effectively.

Detailed description

As people age, the immune system becomes less responsive, increasing susceptibility to infections and reducing vaccine responsiveness. AS01 is a liposome-based adjuvant used in licensed vaccines (e.g., shingles vaccine) that activates innate and adaptive immunity. Emerging evidence suggests AS01 may also induce trained immunity, a form of innate immune reprogramming that could enhance protection against unrelated infections. This study tests whether AS01 given alone can boost and train the immune system in healthy adults, how long these effects last, and whether this translates into better control of a heterologous viral challenge.

This will be a single-center, randomised, single-blind, placebo-controlled experimental medicine study at Singapore General Hospital (N=40; ages 21-59). Participants receive a single intramuscular dose of AS01 (0.5 mL) or saline placebo on Day 0. To model a controlled viral exposure, all participants then receive the licensed live-attenuated yellow fever vaccine (YF17D, Stamaril) either at 1 month (Day 30) or 3 months (Day 90) after AS01/placebo, per randomization. Serial blood sampling measures immune reprogramming, durability, and response to the viral challenge over \~2 or 4 months depending on assignment

Findings may clarify whether AS01 can be used as a standalone immune booster to rapidly enhance broad protection. Information that could be useful for outbreak preparedness, especially before pathogen-specific vaccines are available.

Therefore, (1) Early and durable innate immune changes after AS01 (e.g., gene expression and epigenetic markers in myeloid/innate cells); (2) YF17D viremia (RNAemia) after vaccination as an indicator of heterologous viral control; and (3) T-cell and B-cell responses to YF17D and how they relate to viremia, will be measured and analysed.

AS01 and YF17D are licensed components when used with their indicated vaccines. Common reactions include local injection-site symptoms and short-lived systemic symptoms; rare serious adverse events have been reported with YF17D. Participants are monitored and provided safety guidance and contact pathways throughout the study.

Interventions

• Biological AS01 adjuvant (0.5 mL intramuscular)
  The AS01 suspension contains 50 mcg/micrograms of 3-O-desacyl-4'monophosphoryl lipid A (MPL) and 50 mcg/micrograms of Quillaja Saponaria Molina, fraction 21 (QS21), licensed by GSK, available as a separate vial from the licensed Shingrix vaccine.
• Biological YF17D (Stamaril, Sanofi-Pasteur)
  Stamaril, the live-attenuated yellow fever vaccine, utilises the YF17D strain. Stamaril is supplied in the form of powder and solvent for suspension for injection in pre-filled syringe, Yellow fever vaccine (live).
• Other Placebo (NaCl 09%, 0.5mL)
  The placebo will consist of 0.9% saline solution in equivalent volume.

Primary outcome measures

• Host Immune Response [Time frame: Days 0, 7, 14, 28, 56, 84 (3 months)]

Secondary outcome measures (3)

• Viraemia Levels [Time frame: 7 days following yellow fever vaccine administration]
• B Cell Response [Time frame: 30 days]
• T Cell Response [Time frame: 30 days]

Eligibility criteria

Inclusion criteria

• Adults aged 21 to 59 years of age at time of screening.
• BMI 18.5 - 27.5 kg / m2 (BMI values for Asian population according to MOH guideline NIH Consensus Conference).
• Satisfactory baseline medical assessment as assessed by physical examination and a stable health status. For subjects with underlying comorbidities, the conditions must be deemed stable by the investigators, and they must not have any hospitalisation relating to these conditions in the last 6 months.
• Voluntarily participate, understand and sign an informed consent form approved by the Ethical Review Board.
• Subjects who are willing to comply with the requirements of the study protocol and scheduled visits. These requirements include completion of the subject diary, return for follow-up visits. Subjects should also be willing to make themselves available for the duration of the study, with access to a consistent means of contact.
• Accessible vein at the forearm for blood taking.
• Female subjects of non-childbearing potential due to surgical sterilisation (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Post-menopausal subjects must have had at least 12 months of natural (spontaneous) amenorrhoea.

Exclusion criteria

• Previous vaccination against yellow fever, dengue either with a registered product or from participation in a previous vaccine study.
• Previously received AS01-adjuvanted vaccines (e.g. Recombinant zoster vaccine, RTS,S/AS01, RSVPre-F3-AS01), either with a registered product or from participation in a previous vaccine study.
• Planned administration of a AS01-adjuvanted vaccine or yellow fever vaccine other than the study vaccine during the study.
• Subjects who have been unwell in the last 7 days prior to screening.
• History of documented yellow fever and / or dengue infection.
• Dengue seropositivity upon screening.
• History of smoking within the last 1 year.
• Planned travel to yellow fever endemic countries during the study.
• Known allergy to AS01 and YF17D vaccine or their components (e.g. egg products).
• Diagnosis of diabetes HBA1c > 6.5 according to American Diabetes Association criteria62.
• Any medical condition that in the judgment of the investigator will make intramuscular injection unsafe (e.g. thrombocytopenia with platelet count < 50x10\^9/L, coagulopathy, anti-coagulant therapy).
• Risk factor for live-attenuated vaccines, including any confirmed or suspected primary or acquired immunodeficiency based on history and physical examination:

• History of thymus gland disease
• Haematologic neoplasms including leukaemia, lymphoma, myelodysplastic syndromes
• Diagnosed with cancer or treatment for cancer (except for localised basal cell carcinoma) within 3 years prior to screening
• Post-transplant: solid organ and haematopoietic stem cell transplant
• Immunocompromised due to primary or acquired (including HIV/AIDS) immunodeficiency
• Other significantly immunocompromising conditions
• Administration of anti-inflammatory drugs for the past 7 days (e.g. NSAIDs, Paracetamol, aspirin).
• Use of metformin for the last 1 month.
• Use of corticosteroids within the last 6 months prior to the first vaccine dose (defined as prednisolone > 10 mg / day or equivalent for > 2 weeks, or prednisolone > 40mg / day or > 1 week). Inhaled and topical steroids are allowed.
• Received biologics (such as anti-TNF inhibitors, IL-1 inhibitors, co-stimulation blockers, B-cell depleting therapy) for the last 12 months.
• Any condition (e.g. extensive psoriasis, chronic pain syndrome, severe hearing loss, cognitive impairment, dialysis, autoimmune disorders) that in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject, or prevent completion of the study.
• Evidence of substance abuse, or previous substance abuse.
• Clinically significant anaemia (Hb < 10 g/dL).
• Blood donation exceeding > 450 ml in the past 3 months.
• Participation in a study involving administration of an investigational or non-investigational compound within the past four months or planned participation during the duration of this study.
• Administration of any licensed vaccine within 30 days before the first study vaccine dose or planned to receive such products within 30 days after the study vaccination.
• Received immunoglobulin or any blood products within the 90 days preceding the first dose of study vaccine or planned to receive such products during the study period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Singapore · 1 center

• Singapore General Hospital — Singapore

Publications

• Mok DZL, Chan KR. The Effects of Pre-Existing Antibodies on Live-Attenuated Viral Vaccines. Viruses. 2020 May 8;12(5):520. doi: 10.3390/v12050520. PMID 32397218
• Yau C, Gan ES, Kwek SS, Tan HC, Ong EZ, Hamis NZ, Rivino L, Chan KR, Watanabe S, Vasudevan SG, Ooi EE. Live vaccine infection burden elicits adaptive humoral and cellular immunity required to prevent Zika virus infection. EBioMedicine. 2020 Nov;61:103028. doi: 10.1016/j.ebiom.2020.103028. Epub 2020 Oct 9. PMID 33045466
• Tan AT, Linster M, Tan CW, Le Bert N, Chia WN, Kunasegaran K, Zhuang Y, Tham CYL, Chia A, Smith GJD, Young B, Kalimuddin S, Low JGH, Lye D, Wang LF, Bertoletti A. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021 Feb 9;34(6):108728. doi: 10.1016/j.celrep.2021.108728. Epub 2021 Jan 21. PMID 33516277
• Kalimuddin S, Tham CYL, Qui M, de Alwis R, Sim JXY, Lim JME, Tan HC, Syenina A, Zhang SL, Le Bert N, Tan AT, Leong YS, Yee JX, Ong EZ, Ooi EE, Bertoletti A, Low JG. Early T cell and binding antibody responses are associated with COVID-19 RNA vaccine efficacy onset. Med. 2021 Jun 11;2(6):682-688.e4. doi: 10.1016/j.medj.2021.04.003. Epub 2021 Apr 8. PMID 33851143
• Bollampalli VP, Harumi Yamashiro L, Feng X, Bierschenk D, Gao Y, Blom H, Henriques-Normark B, Nylen S, Rothfuchs AG. BCG Skin Infection Triggers IL-1R-MyD88-Dependent Migration of EpCAMlow CD11bhigh Skin Dendritic cells to Draining Lymph Node During CD4+ T-Cell Priming. PLoS Pathog. 2015 Oct 6;11(10):e1005206. doi: 10.1371/journal.ppat.1005206. eCollection 2015 Oct. PMID 26440518
• Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8. PMID 25516281
• Chan KR, Gan ES, Chan CYY, Liang C, Low JZH, Zhang SL, Ong EZ, Bhatta A, Wijaya L, Lee YH, Low JG, Ooi EE. Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live-attenuated yellow fever infection. Nat Med. 2019 Aug;25(8):1218-1224. doi: 10.1038/s41591-019-0510-7. Epub 2019 Jul 15. PMID 31308506
• Mok DZ, Tng DJ, Yee JX, Chew VS, Tham CY, Ooi JS, Tan HC, Zhang SL, Lin LZ, Ng WC, Jeeva LL, Murugayee R, Goh KK, Lim TP, Cui L, Cheung YB, Ong EZ, Chan KR, Ooi EE, Low JG. Electron transport chain capacity expands yellow fever vaccine immunogenicity. EMBO Mol Med. 2024 Jun;16(6):1310-1323. doi: 10.1038/s44321-024-00065-7. Epub 2024 May 14. PMID 38745062

Identifiers

NCT: NCT07527247 · AS01-YF-01 · CIRG25jan-0068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗