Improving Vaccine Protection for Adults

NCT07527247 | Recruiting Phase 2

• 2 other identifiers: AS01-YF-01CIRG25jan-0068
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Immune System Responses and Trained Immunity After AS01 Administration; Healthy Adult

Keywords

AS01; AS01 adjuvant; Immune durability; Immune system; Immune response modulation; Recombinant zoster vaccine adjuvant; Vaccine; Randomized; Placebo-controlled; Blinded; Healthy volunteers; Protective effects; Yellow Fever Vaccine

Outcome Measures

Primary Outcomes (1)

• Host Immune Response

  Explorative evaluation of host immune response profile (cytokines, immune cell populations, gene expression, epigenetic modifications) induced by AS01 versus placebo, using panel of validated multi-omics assay tests, over a 3-month period.

  Days 0, 7, 14, 28, 56, 84 (3 months)

Secondary Outcomes (3)

• Viraemia Levels

  7 days following yellow fever vaccine administration

• B Cell Response

  30 days

• T Cell Response

  30 days

Study Arms (4)

AS01 + YF17D at 1 Month

EXPERIMENTAL

Participants receive AS01 (0.5 mL IM on Day 0) and yellow fever vaccine YF17D on Day 30.

Biological: AS01 adjuvant (0.5 mL intramuscular); Biological: YF17D (Stamaril, Sanofi-Pasteur)

AS01 + YF17D at 3 Months

EXPERIMENTAL

Participants receive AS01 (0.5 mL IM on Day 0) and yellow fever vaccine YF17D on Day 90.

Biological: AS01 adjuvant (0.5 mL intramuscular); Biological: YF17D (Stamaril, Sanofi-Pasteur)

Placebo + YF17D at 1 Month

PLACEBO COMPARATOR

Participants receive placebo (0.9% saline, 0.5 mL IM on Day 0) and yellow fever vaccine YF17D on Day 30.

Biological: YF17D (Stamaril, Sanofi-Pasteur); Other: Placebo (NaCl 09%, 0.5mL)

Placebo + YF17D at 3 Months

PLACEBO COMPARATOR

Participants receive placebo (0.9% saline, 0.5 mL IM on Day 0) and yellow fever vaccine YF17D on Day 90.

Biological: YF17D (Stamaril, Sanofi-Pasteur); Other: Placebo (NaCl 09%, 0.5mL)

Interventions

AS01 adjuvant (0.5 mL intramuscular) BIOLOGICAL

The AS01 suspension contains 50mg of 3-O-desacyl-4'monophosphoryl lipid A (MPL) and 50mg of Quillaja Saponaria Molina, fraction 21 (QS21), licensed by GSK, available as a separate vial from the licensed Shingrix vaccine.

AS01 + YF17D at 1 Month; AS01 + YF17D at 3 Months

YF17D (Stamaril, Sanofi-Pasteur) BIOLOGICAL

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).

Also known as: YF17D, yellow fever vaccine

AS01 + YF17D at 1 Month; AS01 + YF17D at 3 Months; Placebo + YF17D at 1 Month; Placebo + YF17D at 3 Months

Placebo (NaCl 09%, 0.5mL) OTHER

The placebo will consist of 0.9% saline solution in equivalent volume.

Also known as: Placebo, Saline placebo, Saline injection

Placebo + YF17D at 1 Month; Placebo + YF17D at 3 Months

Eligibility Criteria

• Age: 21 Years - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Singapore General Hospital: lead
• A*STAR Infectious Diseases Labs: collaborator

Study Sites (1)

Singapore General Hospital

Singapore, 169608, Singapore

RECRUITING

Related Publications (74)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Chan CY, Chan KR, Chua CJ, Nur Hazirah S, Ghosh S, Ooi EE, Low JG. Early molecular correlates of adverse events following yellow fever vaccination. JCI Insight. 2017 Oct 5;2(19):e96031. doi: 10.1172/jci.insight.96031.

  PMID: 28978802 BACKGROUND

• Schep AN, Wu B, Buenrostro JD, Greenleaf WJ. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat Methods. 2017 Oct;14(10):975-978. doi: 10.1038/nmeth.4401. Epub 2017 Aug 21.

  PMID: 28825706 BACKGROUND

• Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol. 2013 Dec;13(12):875-87. doi: 10.1038/nri3547. Epub 2013 Oct 25.

  PMID: 24157572 BACKGROUND

• Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015 Apr;16(4):343-53. doi: 10.1038/ni.3123.

  PMID: 25789684 BACKGROUND

• Jo N, Hidaka Y, Kikuchi O, Fukahori M, Sawada T, Aoki M, Yamamoto M, Nagao M, Morita S, Nakajima TE, Muto M, Hamazaki Y. Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination. Nat Aging. 2023 Jan;3(1):82-92. doi: 10.1038/s43587-022-00343-4. Epub 2023 Jan 12.

  PMID: 37118516 BACKGROUND

• Hou Y, Chen M, Bian Y, Hu Y, Chuan J, Zhong L, Zhu Y, Tong R. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. NPJ Vaccines. 2024 Apr 10;9(1):77. doi: 10.1038/s41541-024-00874-4.

  PMID: 38600250 BACKGROUND

• Esmaeili ED, Azizi H, Sarbazi E, Khodamoradi F. The global case fatality rate due to COVID-19 in hospitalized elderly patients by sex, year, gross domestic product, and continent: A systematic review, meta-analysis, and meta-regression. New Microbes New Infect. 2023 Jan;51:101079. doi: 10.1016/j.nmni.2022.101079. Epub 2023 Jan 4.

  PMID: 36618974 BACKGROUND

• Stuart T, Srivastava A, Madad S, Lareau CA, Satija R. Author Correction: Single-cell chromatin state analysis with Signac. Nat Methods. 2022 Feb;19(2):257. doi: 10.1038/s41592-022-01393-7. No abstract available.

  PMID: 34997233 BACKGROUND

• Satpathy AT, Granja JM, Yost KE, Qi Y, Meschi F, McDermott GP, Olsen BN, Mumbach MR, Pierce SE, Corces MR, Shah P, Bell JC, Jhutty D, Nemec CM, Wang J, Wang L, Yin Y, Giresi PG, Chang ALS, Zheng GXY, Greenleaf WJ, Chang HY. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019 Aug;37(8):925-936. doi: 10.1038/s41587-019-0206-z. Epub 2019 Aug 2.

  PMID: 31375813 BACKGROUND

• Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, Myung P, Plikus MV, Nie Q. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021 Feb 17;12(1):1088. doi: 10.1038/s41467-021-21246-9.

  PMID: 33597522 BACKGROUND

• Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L, Fu X, Liu S, Bo X, Yu G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021 Jul 1;2(3):100141. doi: 10.1016/j.xinn.2021.100141. eCollection 2021 Aug 28.

  PMID: 34557778 BACKGROUND

• Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, Hoffman P, Stoeckius M, Papalexi E, Mimitou EP, Jain J, Srivastava A, Stuart T, Fleming LM, Yeung B, Rogers AJ, McElrath JM, Blish CA, Gottardo R, Smibert P, Satija R. Integrated analysis of multimodal single-cell data. Cell. 2021 Jun 24;184(13):3573-3587.e29. doi: 10.1016/j.cell.2021.04.048. Epub 2021 May 31.

  PMID: 34062119 BACKGROUND

• Zheng GX, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, Ziraldo SB, Wheeler TD, McDermott GP, Zhu J, Gregory MT, Shuga J, Montesclaros L, Underwood JG, Masquelier DA, Nishimura SY, Schnall-Levin M, Wyatt PW, Hindson CM, Bharadwaj R, Wong A, Ness KD, Beppu LW, Deeg HJ, McFarland C, Loeb KR, Valente WJ, Ericson NG, Stevens EA, Radich JP, Mikkelsen TS, Hindson BJ, Bielas JH. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017 Jan 16;8:14049. doi: 10.1038/ncomms14049.

  PMID: 28091601 BACKGROUND

• Ong EZ, Koh CWT, Tng DJH, Ooi JSG, Yee JX, Chew VSY, Leong YS, Gunasegaran K, Yeo CP, Oon LLE, Sim JXY, Chan KR, Low JG, Ooi EE. RNase2 is a possible trigger of acute-on-chronic inflammation leading to mRNA vaccine-associated cardiac complication. Med. 2023 Jun 9;4(6):353-360.e2. doi: 10.1016/j.medj.2023.04.001. Epub 2023 Apr 26.

  PMID: 37105176 BACKGROUND

• Lin QXX, Rajagopalan D, Gamage AM, Tan LM, Venkatesh PN, Chan WOY, Kumar D, Agrawal R, Chen Y, Fong SW, Singh A, Sun LJ, Tan SY, Chai LYA, Somani J, Lee B, Renia L, Ng LFP, Ramanathan K, Wang LF, Young B, Lye D, Singhal A, Prabhakar S. Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity. Nat Commun. 2024 Jan 18;15(1):567. doi: 10.1038/s41467-023-44524-0.

  PMID: 38238298 BACKGROUND

• Bohme J, Martinez N, Li S, Lee A, Marzuki M, Tizazu AM, Ackart D, Frenkel JH, Todd A, Lachmandas E, Lum J, Shihui F, Ng TP, Lee B, Larbi A, Netea MG, Basaraba R, van Crevel R, Newell E, Kornfeld H, Singhal A. Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits. Nat Commun. 2020 Oct 16;11(1):5225. doi: 10.1038/s41467-020-19095-z.

  PMID: 33067434 BACKGROUND

• Maleki F, Ovens K, McQuillan I, Kusalik AJ. Size matters: how sample size affects the reproducibility and specificity of gene set analysis. Hum Genomics. 2019 Oct 22;13(Suppl 1):42. doi: 10.1186/s40246-019-0226-2.

  PMID: 31639047 BACKGROUND

• de Bree LCJ, Mourits VP, Koeken VA, Moorlag SJ, Janssen R, Folkman L, Barreca D, Krausgruber T, Fife-Gernedl V, Novakovic B, Arts RJ, Dijkstra H, Lemmers H, Bock C, Joosten LA, van Crevel R, Benn CS, Netea MG. Circadian rhythm influences induction of trained immunity by BCG vaccination. J Clin Invest. 2020 Oct 1;130(10):5603-5617. doi: 10.1172/JCI133934.

  PMID: 32692732 BACKGROUND

• Kalimuddin S, Chan YFZ, Sessions OM, Chan KR, Ong EZ, Low JG, Bertoletti A, Ooi EE. An experimental medicine decipher of a minimum correlate of cellular immunity: Study protocol for a double-blind randomized controlled trial. Front Immunol. 2023 Mar 10;14:1135979. doi: 10.3389/fimmu.2023.1135979. eCollection 2023.

  PMID: 36969244 BACKGROUND

• Saucha CVV, Maia MLS, Sousa ESS, de Oliveira PMN, Xavier JR, de Castro TDM, Cruz RLS, Schwarcz WD, Pereira RC, Azevedo AS, de Filippis AMB, Ferroco CLV, Pizzini GLC, Brum RCS, Secundino L, Andrade MFS, de Oliveira RVC, Simoes M, Cerbino-Neto J, Martins-Filho OA, Campi-Azevedo AC, de Lima SMB, Camacho LAB; Collaborative Group for Yellow Fever Vaccine Studies. Immunogenicity of a single dose of the 17DD yellow fever vaccine in a cohort of adults and children in a non-endemic area, and its association with dengue and Zika seropositivity. PLoS Negl Trop Dis. 2025 Apr 9;19(4):e0012993. doi: 10.1371/journal.pntd.0012993. eCollection 2025 Apr.

  PMID: 40202994 BACKGROUND

• Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG, Sammon AB, Holland LA, Weir S, Noah TL, Beck MA. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes (Lond). 2012 Aug;36(8):1072-7. doi: 10.1038/ijo.2011.208. Epub 2011 Oct 25.

  PMID: 22024641 BACKGROUND

• Sharma NK, Das SK, Mondal AK, Hackney OG, Chu WS, Kern PA, Rasouli N, Spencer HJ, Yao-Borengasser A, Elbein SC. Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J Clin Endocrinol Metab. 2008 Nov;93(11):4532-41. doi: 10.1210/jc.2008-1001. Epub 2008 Aug 26.

  PMID: 18728164 BACKGROUND

• UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2023 Jan 6;51(D1):D523-D531. doi: 10.1093/nar/gkac1052.

  PMID: 36408920 BACKGROUND

• Syenina A, Gan ES, Toh JZN, de Alwis R, Lin LZ, Tham CYL, Yee JX, Leong YS, Sam H, Cheong C, Teh YE, Wee ILE, Ng DHL, Chan KR, Sim JXY, Kalimuddin S, Ong EZ, Low JG, Ooi EE. Adverse effects following anti-COVID-19 vaccination with mRNA-based BNT162b2 are alleviated by altering the route of administration and correlate with baseline enrichment of T and NK cell genes. PLoS Biol. 2022 May 31;20(5):e3001643. doi: 10.1371/journal.pbio.3001643. eCollection 2022 May.

  PMID: 35639676 BACKGROUND

• Izurieta HS, Wu X, Forshee R, Lu Y, Sung HM, Agger PE, Chillarige Y, Link-Gelles R, Lufkin B, Wernecke M, MaCurdy TE, Kelman J, Dooling K. Recombinant Zoster Vaccine (Shingrix): Real-World Effectiveness in the First 2 Years Post-Licensure. Clin Infect Dis. 2021 Sep 15;73(6):941-948. doi: 10.1093/cid/ciab125.

  PMID: 33580242 BACKGROUND

• Laing KJ, Ford ES, Johnson MJ, Levin MJ, Koelle DM, Weinberg A. Recruitment of naive CD4+ T cells by the recombinant zoster vaccine correlates with persistent immunity. J Clin Invest. 2023 Dec 1;133(23):e172634. doi: 10.1172/JCI172634.

  PMID: 37788096 BACKGROUND

• Laing KJ, Ouwendijk WJD, Koelle DM, Verjans GMGM. Immunobiology of Varicella-Zoster Virus Infection. J Infect Dis. 2018 Sep 22;218(suppl_2):S68-S74. doi: 10.1093/infdis/jiy403.

  PMID: 30247598 BACKGROUND

• Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D, Grose C, Hambleton S, Kennedy PG, Oxman MN, Seward JF, Yamanishi K. Varicella zoster virus infection. Nat Rev Dis Primers. 2015 Jul 2;1:15016. doi: 10.1038/nrdp.2015.16.

  PMID: 27188665 BACKGROUND

• Jeyanathan M, Vaseghi-Shanjani M, Afkhami S, Grondin JA, Kang A, D'Agostino MR, Yao Y, Jain S, Zganiacz A, Kroezen Z, Shanmuganathan M, Singh R, Dvorkin-Gheva A, Britz-McKibbin P, Khan WI, Xing Z. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis. Nat Immunol. 2022 Dec;23(12):1687-1702. doi: 10.1038/s41590-022-01354-4. Epub 2022 Dec 1.

  PMID: 36456739 BACKGROUND

• Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17537-42. doi: 10.1073/pnas.1202870109. Epub 2012 Sep 17.

  PMID: 22988082 BACKGROUND

• Lukhele S, Boukhaled GM, Brooks DG. Type I interferon signaling, regulation and gene stimulation in chronic virus infection. Semin Immunol. 2019 Jun;43:101277. doi: 10.1016/j.smim.2019.05.001. Epub 2019 May 30.

  PMID: 31155227 BACKGROUND

• Triana S, Vonficht D, Jopp-Saile L, Raffel S, Lutz R, Leonce D, Antes M, Hernandez-Malmierca P, Ordonez-Rueda D, Ramasz B, Boch T, Jann JC, Nowak D, Hofmann WK, Muller-Tidow C, Hubschmann D, Alexandrov T, Benes V, Trumpp A, Paulsen M, Velten L, Haas S. Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states. Nat Immunol. 2021 Dec;22(12):1577-1589. doi: 10.1038/s41590-021-01059-0. Epub 2021 Nov 22.

  PMID: 34811546 BACKGROUND

• Zhang X, Song B, Carlino MJ, Li G, Ferchen K, Chen M, Thompson EN, Kain BN, Schnell D, Thakkar K, Kouril M, Jin K, Hay SB, Sen S, Bernardicius D, Ma S, Bennett SN, Croteau J, Salvatori O, Lye MH, Gillen AE, Jordan CT, Singh H, Krause DS, Salomonis N, Grimes HL. An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors. Nat Immunol. 2024 Apr;25(4):703-715. doi: 10.1038/s41590-024-01782-4. Epub 2024 Mar 21.

  PMID: 38514887 BACKGROUND

• Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, Tzelepis F, Pernet E, Dumaine A, Grenier JC, Mailhot-Leonard F, Ahmed E, Belle J, Besla R, Mazer B, King IL, Nijnik A, Robbins CS, Barreiro LB, Divangahi M. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. 2018 Jan 11;172(1-2):176-190.e19. doi: 10.1016/j.cell.2017.12.031.

  PMID: 29328912 BACKGROUND

• Cirovic B, de Bree LCJ, Groh L, Blok BA, Chan J, van der Velden WJFM, Bremmers MEJ, van Crevel R, Handler K, Picelli S, Schulte-Schrepping J, Klee K, Oosting M, Koeken VACM, van Ingen J, Li Y, Benn CS, Schultze JL, Joosten LAB, Curtis N, Netea MG, Schlitzer A. BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment. Cell Host Microbe. 2020 Aug 12;28(2):322-334.e5. doi: 10.1016/j.chom.2020.05.014. Epub 2020 Jun 15.

  PMID: 32544459 BACKGROUND

• Sun SJ, Aguirre-Gamboa R, de Bree LCJ, Sanz J, Dumaine A, Joosten LAB, Divangahi M, Netea MG, Barreiro LB. BCG vaccination impacts the epigenetic landscape of progenitor cells in human bone marrow. bioRxiv [Preprint]. 2023 Nov 28:2023.11.28.569076. doi: 10.1101/2023.11.28.569076.

  PMID: 38077046 BACKGROUND

• Boutry C, Hastie A, Diez-Domingo J, Tinoco JC, Yu CJ, Andrews C, Beytout J, Caso C, Cheng HS, Cheong HJ, Choo EJ, Curiac D, Di Paolo E, Dionne M, Eckermann T, Esen M, Ferguson M, Ghesquiere W, Hwang SJ, Avelino-Silva TJ, Kosina P, Liu CS, Markkula J, Moeckesch B, Murta de Oliveira C, Park DW, Pauksens K, Pirrotta P, Plassmann G, Pretswell C, Rombo L, Salaun B, Sanmartin Berglund J, Schenkenberger I, Schwarz T, Shi M, Ukkonen B, Zahaf T, Zerbini C, Schuind A, Cunningham AL; Zoster-049 Study Group. The Adjuvanted Recombinant Zoster Vaccine Confers Long-Term Protection Against Herpes Zoster: Interim Results of an Extension Study of the Pivotal Phase 3 Clinical Trials ZOE-50 and ZOE-70. Clin Infect Dis. 2022 Apr 28;74(8):1459-1467. doi: 10.1093/cid/ciab629.

  PMID: 34283213 BACKGROUND

• Avery RK. Immunizations in adult immunocompromised patients: which to use and which to avoid. Cleve Clin J Med. 2001 Apr;68(4):337-48. doi: 10.3949/ccjm.68.4.337.

  PMID: 11326813 BACKGROUND

• Cauchi S, Locht C. Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases. Front Immunol. 2018 Dec 7;9:2872. doi: 10.3389/fimmu.2018.02872. eCollection 2018.

  PMID: 30581436 BACKGROUND

• Roring RJ, Debisarun PA, Botey-Bataller J, Suen TK, Bulut O, Kilic G, Koeken VA, Sarlea A, Bahrar H, Dijkstra H, Lemmers H, Gossling KL, Ruchel N, Ostermann PN, Muller L, Schaal H, Adams O, Borkhardt A, Ariyurek Y, de Meijer EJ, Kloet SL, Ten Oever J, Placek K, Li Y, Netea MG. MMR vaccination induces trained immunity via functional and metabolic reprogramming of gammadelta T cells. J Clin Invest. 2024 Jan 30;134(7):e170848. doi: 10.1172/JCI170848.

  PMID: 38290093 BACKGROUND

• Sorup S, Jensen AKG, Aaby P, Benn CS. Revaccination With Measles-Mumps-Rubella Vaccine and Infectious Disease Morbidity: A Danish Register-based Cohort Study. Clin Infect Dis. 2019 Jan 7;68(2):282-290. doi: 10.1093/cid/ciy433.

  PMID: 29846533 BACKGROUND

• Byberg S, Thysen SM, Rodrigues A, Martins C, Cabral C, Careme M, Aaby P, Benn CS, Fisker AB. A general measles vaccination campaign in urban Guinea-Bissau: Comparing child mortality among participants and non-participants. Vaccine. 2017 Jan 3;35(1):33-39. doi: 10.1016/j.vaccine.2016.11.049. Epub 2016 Nov 24.

  PMID: 27890397 BACKGROUND

• Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken CBEM, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018 Jan 10;23(1):89-100.e5. doi: 10.1016/j.chom.2017.12.010.

  PMID: 29324233 BACKGROUND

• Walk J, de Bree LCJ, Graumans W, Stoter R, van Gemert GJ, van de Vegte-Bolmer M, Teelen K, Hermsen CC, Arts RJW, Behet MC, Keramati F, Moorlag SJCFM, Yang ASP, van Crevel R, Aaby P, de Mast Q, van der Ven AJAM, Stabell Benn C, Netea MG, Sauerwein RW. Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun. 2019 Feb 20;10(1):874. doi: 10.1038/s41467-019-08659-3.

  PMID: 30787276 BACKGROUND

• Wardhana, Datau EA, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones. 2011 Jul;43(3):185-90.

  PMID: 21979284 BACKGROUND

• Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, Antonakos N, Kotsaki A, Dominguez-Andres J, Kyriazopoulou E, Gkavogianni T, Adami ME, Damoraki G, Koufargyris P, Karageorgos A, Bolanou A, Koenen H, van Crevel R, Droggiti DI, Renieris G, Papadopoulos A, Netea MG. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. 2020 Oct 15;183(2):315-323.e9. doi: 10.1016/j.cell.2020.08.051. Epub 2020 Sep 1.

  PMID: 32941801 BACKGROUND

• Nieminen H, Lahdenkari M, Syrjanen RK, Nohynek H, Ruokokoski E, Palmu AA. Lower incidence of hospital-treated infections in infants under 3 months of age vaccinated with BCG. Vaccine. 2022 Oct 6;40(42):6048-6054. doi: 10.1016/j.vaccine.2022.09.004. Epub 2022 Sep 9.

  PMID: 36096971 BACKGROUND

• Biering-Sorensen S, Aaby P, Lund N, Monteiro I, Jensen KJ, Eriksen HB, Schaltz-Buchholzer F, Jorgensen ASP, Rodrigues A, Fisker AB, Benn CS. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis. 2017 Oct 1;65(7):1183-1190. doi: 10.1093/cid/cix525.

  PMID: 29579158 BACKGROUND

• Baydemir I, Dulfer EA, Netea MG, Dominguez-Andres J. Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery. Clin Immunol. 2024 Apr;261:109930. doi: 10.1016/j.clim.2024.109930. Epub 2024 Feb 9.

  PMID: 38342415 BACKGROUND

• Netea MG, Latz E, Mills KH, O'Neill LA. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015 Jul;16(7):675-9. doi: 10.1038/ni.3178. No abstract available.

  PMID: 26086132 BACKGROUND

• Netea MG, Dominguez-Andres J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020 Jun;20(6):375-388. doi: 10.1038/s41577-020-0285-6. Epub 2020 Mar 4.

  PMID: 32132681 BACKGROUND

• Chumakov K, Avidan MS, Benn CS, Bertozzi SM, Blatt L, Chang AY, Jamison DT, Khader SA, Kottilil S, Netea MG, Sparrow A, Gallo RC. Old vaccines for new infections: Exploiting innate immunity to control COVID-19 and prevent future pandemics. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2101718118. doi: 10.1073/pnas.2101718118.

  PMID: 34006644 BACKGROUND

• Palacios-Pedrero MA, Jansen JM, Blume C, Stanislawski N, Jonczyk R, Molle A, Hernandez MG, Kaiser FK, Jung K, Osterhaus ADME, Rimmelzwaan GF, Saletti G. Signs of immunosenescence correlate with poor outcome of mRNA COVID-19 vaccination in older adults. Nat Aging. 2022 Oct;2(10):896-905. doi: 10.1038/s43587-022-00292-y. Epub 2022 Oct 14.

  PMID: 37118289 BACKGROUND

• Kanasi E, Ayilavarapu S, Jones J. The aging population: demographics and the biology of aging. Periodontol 2000. 2016 Oct;72(1):13-8. doi: 10.1111/prd.12126.

  PMID: 27501488 BACKGROUND

• Baker RE, Mahmud AS, Miller IF, Rajeev M, Rasambainarivo F, Rice BL, Takahashi S, Tatem AJ, Wagner CE, Wang LF, Wesolowski A, Metcalf CJE. Infectious disease in an era of global change. Nat Rev Microbiol. 2022 Apr;20(4):193-205. doi: 10.1038/s41579-021-00639-z. Epub 2021 Oct 13.

  PMID: 34646006 BACKGROUND

• Chan KR, Wang X, Saron WAA, Gan ES, Tan HC, Mok DZL, Zhang SL, Lee YH, Liang C, Wijaya L, Ghosh S, Cheung YB, Tannenbaum SR, Abraham SN, St John AL, Low JGH, Ooi EE. Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity. Nat Microbiol. 2016 Sep 19;1(12):16164. doi: 10.1038/nmicrobiol.2016.164.

  PMID: 27642668 BACKGROUND

• Bruxvoort KJ, Ackerson B, Sy LS, Bhavsar A, Tseng HF, Florea A, Luo Y, Tian Y, Solano Z, Widenmaier R, Shi M, Van Der Most R, Schmidt JE, Danier J, Breuer T, Qian L. Recombinant Adjuvanted Zoster Vaccine and Reduced Risk of Coronavirus Disease 2019 Diagnosis and Hospitalization in Older Adults. J Infect Dis. 2022 Jun 1;225(11):1915-1922. doi: 10.1093/infdis/jiab633.

  PMID: 34962997 BACKGROUND

• Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science. 2016 Apr 22;352(6284):aaf1098. doi: 10.1126/science.aaf1098. Epub 2016 Apr 21.

  PMID: 27102489 BACKGROUND

• Bechtold V, Smolen KK, Burny W, de Angelis SP, Delandre S, Essaghir A, Marchant A, Ndour C, Taton M, van der Most R, Willems F, Didierlaurent AM. Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine. Sci Transl Med. 2024 Jul 31;16(758):eadl3381. doi: 10.1126/scitranslmed.adl3381. Epub 2024 Jul 31.

  PMID: 39083587 BACKGROUND

• Didierlaurent AM, Collignon C, Bourguignon P, Wouters S, Fierens K, Fochesato M, Dendouga N, Langlet C, Malissen B, Lambrecht BN, Garcon N, Van Mechelen M, Morel S. Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells. J Immunol. 2014 Aug 15;193(4):1920-30. doi: 10.4049/jimmunol.1400948. Epub 2014 Jul 14.

  PMID: 25024381 BACKGROUND

• Smith CL, Richardson B, Rubsamen M, Cameron MJ, Cameron CM, Canaday DH. Adjuvant AS01 activates human monocytes for costimulation and systemic inflammation. Vaccine. 2024 Jan 12;42(2):229-238. doi: 10.1016/j.vaccine.2023.12.010. Epub 2023 Dec 7.

  PMID: 38065772 BACKGROUND

• Coccia M, Collignon C, Herve C, Chalon A, Welsby I, Detienne S, van Helden MJ, Dutta S, Genito CJ, Waters NC, Deun KV, Smilde AK, Berg RAVD, Franco D, Bourguignon P, Morel S, Garcon N, Lambrecht BN, Goriely S, Most RV, Didierlaurent AM. Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNgamma response promoting vaccine immunogenicity. NPJ Vaccines. 2017 Sep 8;2:25. doi: 10.1038/s41541-017-0027-3. eCollection 2017.

  PMID: 29263880 BACKGROUND

• Cunningham AL, Heineman TC, Lal H, Godeaux O, Chlibek R, Hwang SJ, McElhaney JE, Vesikari T, Andrews C, Choi WS, Esen M, Ikematsu H, Choma MK, Pauksens K, Ravault S, Salaun B, Schwarz TF, Smetana J, Abeele CV, Van den Steen P, Vastiau I, Weckx LY, Levin MJ; ZOE-50/70 Study Group. Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older. J Infect Dis. 2018 May 5;217(11):1750-1760. doi: 10.1093/infdis/jiy095.

  PMID: 29529222 BACKGROUND

• Walsh EE, Perez Marc G, Zareba AM, Falsey AR, Jiang Q, Patton M, Polack FP, Llapur C, Doreski PA, Ilangovan K, Ramet M, Fukushima Y, Hussen N, Bont LJ, Cardona J, DeHaan E, Castillo Villa G, Ingilizova M, Eiras D, Mikati T, Shah RN, Schneider K, Cooper D, Koury K, Lino MM, Anderson AS, Jansen KU, Swanson KA, Gurtman A, Gruber WC, Schmoele-Thoma B; RENOIR Clinical Trial Group. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N Engl J Med. 2023 Apr 20;388(16):1465-1477. doi: 10.1056/NEJMoa2213836. Epub 2023 Apr 5.

  PMID: 37018468 BACKGROUND

• Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barbera J, Vesikari T, Watanabe D, Weckx L, Zahaf T, Heineman TC; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015 May 28;372(22):2087-96. doi: 10.1056/NEJMoa1501184. Epub 2015 Apr 28.

  PMID: 25916341 BACKGROUND

• Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez-Domingo J, Godeaux O, Levin MJ, McElhaney JE, Puig-Barbera J, Vanden Abeele C, Vesikari T, Watanabe D, Zahaf T, Ahonen A, Athan E, Barba-Gomez JF, Campora L, de Looze F, Downey HJ, Ghesquiere W, Gorfinkel I, Korhonen T, Leung E, McNeil SA, Oostvogels L, Rombo L, Smetana J, Weckx L, Yeo W, Heineman TC; ZOE-70 Study Group. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. N Engl J Med. 2016 Sep 15;375(11):1019-32. doi: 10.1056/NEJMoa1603800.

  PMID: 27626517 BACKGROUND

MeSH Terms

Interventions

adjuvant system 01; Injections, Intramuscular; Yellow Fever Vaccine; Sodium Chloride

Intervention Hierarchy (Ancestors)

Injections; Drug Administration Routes; Drug Therapy; Therapeutics; Viral Vaccines; Vaccines; Biological Products; Complex Mixtures; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Candice Y.Y. Chan, MBChB, MRCP

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Candice Y.Y. Chan, MBChB, MRCP

CONTACT

+6563213479; candice.chan.y.y@singhealth.com.sg

Christina Titin

CONTACT

+6565762802; christina.titin@singhealth.com.sg

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants are randomized in a 1:1:1:1 parallel assignment to one of four groups defined by (1) AS01 vs placebo at Day 0 and (2) timing of yellow fever vaccine administration at Day 30 or Day 90.

Study Record Dates

• First Submitted: March 4, 2026
• First Posted: April 14, 2026
• Study Start: November 6, 2025
• Primary Completion (Estimated): February 28, 2029
• Study Completion (Estimated): February 28, 2029
• Last Updated: May 18, 2026

Record last verified: 2026-05

Locations

SG (1)