Effect of Oral Supplement on Influenza Vaccine Long-term Response (EOSIIVE-F)

Effect of Oral Supplement Intervention on Influenza Vaccine Long-term Efficacy: a Follow-up Study

This is a follow-up study of a previously completed randomized controlled trial (NCT06827873) that investigated the effects of oral supplements on influenza vaccine response in adults aged 60-70 years. The original study was completed in April 2025, with participants receiving either TUDCA (Tauro Ursodesoxy Cholic Acid) supplementation, fatty acid supplementation, or placebo during influenza vaccination.

The primary objectives of this follow-up study are to:

1. Evaluate the durability of vaccine-induced antibody responses approximately 8 months post-vaccination
2. Assess the persistence of immune memory cells, particularly long-lived plasma cells and memory B cells
3. Compare long-term immune responses between the TUDCA supplementation group and placebo group

This observational follow-up involves a single visit where participants will:

1. Provide one blood sample for antibody and immune cell analysis
2. No intervention or vaccination will be administered

The study will specifically focus on B cell subsets through flow cytometry analysis, including total B cells, memory B cells, plasma cells, and long-lived plasma cells. This research aims to determine whether TUDCA supplementation can enhance the durability of vaccine-induced immunity in older adults.

Study Overview

• Status: Not yet recruiting
• Conditions: Influenza; Immunosenescence

Detailed Description

Influenza virus infection presents a significant global health challenge, particularly threatening the elderly population due to immunosenescence. The immune response to influenza vaccination involves a complex series of events: after vaccination, hemagglutination inhibition antibody titers peak around day 14, accompanied by the production of neutralizing antibodies and other specific antibodies. This immune response gradually stabilizes to a post-response baseline level as immune memory establishes.

The age-related decline in immune function manifests through multiple mechanisms, including: reduced production of naive T cells; decreased diversity of T cell repertoire; compromised B cell function; and altered cytokine production profiles, which all diminish vaccine response efficacy. Recent advances in immunometabolism have revealed the crucial role of specific fatty acids and bile acids in immune system modulation. Our preliminary explorations found that fatty acid intervention could significantly reduce the time required for antibody production and enhance its levels following rabies vaccination. We also noticed that serum Tauroursodeoxycholic Acid (TUDCA) was elevated in the intervention group. However, the related mechanisms remain unclear.

Besides, evidence from influenza vaccine studies reveals critical temporal dynamics: antibody titers peak at 1-1.3 months post-vaccination, decline by 3 months, yet remain elevated above baseline at 6 months. Vaccine effectiveness demonstrates time-dependent reduction from 80% at 14 days to 37% at 128 days and 46% at 180 days post-vaccination. Crucially, antibody persistence correlates with long-lived plasma cells (LLPCs), which maintain continuous antibody secretion, while memory B cells enable rapid secondary responses upon antigen re-exposure by differentiating into plasma cells and LLPCs.

Building on these findings, we hypothesized that TUDCA itself may play an active immunoregulatory role during vaccination, influencing B-cell differentiation and antibody persistence. To test this hypothesis and further characterize its potential benefits in elderly populations, we designed an extended follow-up study.

The original study (February-April 2025) demonstrated that TUDCA supplementation significantly enhanced memory B cell responses compared to placebo and fatty acid supplementation groups during the acute phase post-vaccination (Day 0-24). In this extended follow-up, conducted approximately 12 months after vaccination, participants will return for a single fasting venous blood draw (approximately 10 mL) to assess antibody titers and characterize immune-cell subsets. No further intervention or vaccination will be performed. This timepoint represents a critical window for assessing immune durability in the elderly. By quantifying long-term antibody titers and characterizing B cell subsets-particularly plasma cells and long-lived plasma cells-we will determine whether TUDCA supplementation enhances the persistence of vaccine-induced humoral and cellular immunity. This investigation addresses whether nutritional strategies can extend vaccine protection duration in older adults, where immunosenescence substantially limits both vaccine efficacy and protection longevity.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Litian Hou, Master; Phone Number: +86 17888846812; Email: hlt24@mails.tsinghua.edu.cn
• Study Contact Backup: Name: Ai Zhao, PhD; Phone Number: +86 13811131994; Email: aizhao18@mail.tsinghua.edu.cn

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100084
      • Tsinghua University
      • Contact: Litian Hou, Master; Phone Number: +86 17888846812; Email: hlt24@mails.tsinghua.edu.cn
      • Contact: Ai Zhao, PhD; Phone Number: +86 13811131994; Email: aizhao18@mail.tsinghua.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This extended follow-up study includes participants from the original randomized controlled trial (Protocol ID: THU01-20240201; NCT06827873) conducted between February and April 2025. Thirty older adults (aged 60-70 years) were previously randomized to either the TUDCA group (n=15) or placebo group (n=15). All completed the 25-day intervention, received quadrivalent influenza vaccine on Day 3, and finished all Day 24 assessments. Participants were recruited from community health centers affiliated with the Second Affiliated Hospital of Bengbu Medical College, Anhui, China, and provided written informed consent for both the original and follow-up studies.

Description

Inclusion Criteria:

1. Originally assigned to either the TUDCA supplementation group or placebo control group
2. No influenza vaccination or other vaccines received between April 2025 and December 2025
3. Willing to participate in this follow-up study and sign supplementary informed consent
4. Stable health condition

Exclusion Criteria:

1. Started using immunosuppressants or hormonal medications after the original study
2. Experienced serious illness or hospitalization within the past month, or planning surgery soon
3. Experienced fever, cold, severe diarrhea, or taken influenza antiviral medications within the past month
4. Unable or unwilling to participate in blood collection
5. Lost to follow-up or unable to contact

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
TUDCA Supplementation Group; Participants who received TUDCA supplementation (1000 mg/day) during the original study (February-April 2025). In the original trial, participants took 1000 mg of TUDCA (Tauroursodeoxycholic acid) dietary supplement capsules daily. Each capsule contained 500 mg of TUDCA (two capsules per serving). Participants maintained their usual lifestyle during the intervention: Day 0-Day 2 served as an adaptation period; on Day 3, they received a quadrivalent influenza vaccine, followed by continued supplementation until Day 24. This extended follow-up study involves no intervention, only a single fasting blood draw (20 mL) approximately 12 months post-vaccination to assess long-term immune responses.
Placebo Group; Participants who received placebo during the original study (February-April 2025). In the original trial, participants took placebo capsules identical in appearance and smell to the TUDCA capsules. Participants maintained their usual lifestyle during the intervention: Day 0-Day 2 served as an adaptation period; on Day 3, they received a quadrivalent influenza vaccine, followed by continued placebo supplementation until Day 24. This extended follow-up study involves no intervention, only a single fasting venous blood draw (approximately 20 mL) about 12 months post-vaccination to assess long-term immune responses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term Influenza-Specific Antibody Levels Post-Vaccination	Evaluate influenza virus-specific IgG antibody levels at approximately 12 months post-vaccination to assess the durability of vaccine-induced humoral immunity. Antibody levels will be measured for all four strains contained in the quadrivalent influenza vaccine (H1N1, H3N2, B/Victoria, B/Yamagata) using ELISA or hemagglutination inhibition (HI) assay.	Day 360 (approximately 12 months post-vaccination)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
B Cell Immune Memory Persistence	Assess B cell subsets through flow cytometry analysis, including Total B cells (CD19+), Memory B cells (CD19+ & CD27+), Plasma cells (CD19+, CD38+ & CD27+) and Long-lived plasma cells (CD19+, CD38+ & CD138+). Compare the persistence of these immune memory cell populations between TUDCA supplementation and placebo groups to evaluate whether TUDCA enhances long-term cellular immunity.	Day 360 (approximately 12 months post-vaccination)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Assessment	Record and monitor any adverse events related to blood collection, including pain, dizziness, bruising, or hematoma formation. In addition, participants will be asked to report any delayed or persistent adverse effects that may have occurred since completion of the original study, including those potentially associated with prior vaccination or nutritional supplementation. These events will be documented and evaluated descriptively.	Day 360 (at blood collection visit, 12 months post-vaccination)

Collaborators and Investigators

• Sponsor: Tsinghua University
• Collaborators: Second Affiliated Hospital of Bengbu Medical College
• Investigators: Study Director: Cong Tian, Master, The Second Affiliated Hospital of Bengbu Medical College

Publications and helpful links

General Publications

• Ferdinands JM, Fry AM, Reynolds S, Petrie J, Flannery B, Jackson ML, Belongia EA. Intraseason waning of influenza vaccine protection: Evidence from the US Influenza Vaccine Effectiveness Network, 2011-12 through 2014-15. Clin Infect Dis. 2017 Mar 1;64(5):544-550. doi: 10.1093/cid/ciw816. Epub 2016 Dec 29.
• Mordant FL, Price OH, Rudraraju R, Slavin MA, Marshall C, Worth LJ, Peck H, Barr IG, Sullivan SG, Subbarao K. Antibody titres elicited by the 2018 seasonal inactivated influenza vaccine decline by 3 months post-vaccination but persist for at least 6 months. Influenza Other Respir Viruses. 2023 Jan;17(1):e13072. doi: 10.1111/irv.13072. Epub 2022 Nov 30.
• Ellebedy AH. Immunizing the Immune: Can We Overcome Influenza's Most Formidable Challenge? Vaccines (Basel). 2018 Sep 22;6(4):68. doi: 10.3390/vaccines6040068.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Humoral Immunity; Antibody; Influenza Vaccine; Tauroursodeoxycholic Acid (TUDCA); Bile Acids; Elderly Adults; Memory B Cells; Long-lived Plasma Cells; Nutritional Immunomodulation
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Influenza, Human
• Other Study ID Numbers: THU01-20251109

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No