The Immune Response to Influenza Vaccinations in Elderly Individuals

Multi-parameter Immune Profile Associated With the Humoral Response to Influenza Vaccine, Vaxigrip® in Healthy and Frail Elderly Subjects Aged 65-90 Years in Singapore

The aim of this study is to characterize the immune profile of frail and healthy aged individuals and investigate their immune responsiveness including the response to influenza vaccine over an 18-month period. The project will include a longitudinal study to define immune signatures and multi-parameter profiles associated with frailty and may lead to the identification of predictive markers of evolution to frailty and Immunosenescence in the elderly.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Vaxigrip®

Detailed Description

With better healthcare available and improved accessibility, people are living longer. However, a majority of older persons cannot be considered to be aging well. Approximately 70% of those aged 85 years or older require frequent long hospitalizations because of their increased susceptibility to infections, cancers, dementia, and other age-related health problems, along with overall loss of function and autonomy associated with old age. Previous studies have shown that vaccination against influenza, which significantly reduces all-cause mortality in the elderly (65 years and older), was less immunogenic and effective with age. Frailty, a geriatric syndrome associated with low functional activity, weight loss, exhaustion, disability, decreased resilience to stressors, has been shown to increase risk for adverse outcomes and death. Better understanding the relationship between aging and waning immune responsiveness will enable the development of strategies to improve response to vaccination in the elderly and reduce morbidity and eventually mortality associated with age related complications and outcomes such as infectious diseases or frailty. A comprehensive analysis of the immune phenotype and function after antigenic challenge in older individuals would be a unique approach to understand (i) the potential associations between aging, impaired immune function and transition to frailty, (ii) which components of the immune system are altered with aging (innate vs adaptive immunity) and (iii) if early and/or late immune responses are preferentially altered with aging and frailty.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 4

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • National University Hospital
  • Singapore, Singapore, 090003
    • Moral Neighbourhood Link @ Telok Blangah
  • Singapore, Singapore, 150093
    • THK Seniors Activity Centre @ Henderson (Satellite 93)
  • Singapore, Singapore, 150118
    • Moral Neighbourhood Link (Bukit Merah View)
  • Singapore, Singapore, 160044
    • THK Seniors Activity Centre @ Beo Crescent
  • Singapore, Singapore, 160105
    • SARAH Senior Activity Centre
  • Singapore, Singapore, 610337
    • THK Seniors Service @ Taman Jurong
  • Singapore, Singapore, 648886
    • TaRa @ Jurong Point, Jurong West Central 2
  • Singapore, Singapore, 659674
    • Outpatient Clinic, St Luke's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged ≥ 65 years and <90 years on the day of inclusion for the elderly group, and ≥ 21-<40 for the adult group.
2. Informed consent form has been signed and dated.
3. Able to attend all scheduled visits and to comply with all trial procedures.
4. Living at home.
5. Able to walk without personal assistance and no other physical limitations that can limit participation.
6. Recruited from the cohort in Singapore Longitudinal Ageing Study-II (SLAS-II), as well as from sites in West Jurong and from Outpatient clinics at National University Hospital (NUH).

Exclusion Criteria:

1. Participation at the time of study enrollment (or in the 4 weeks preceding trial vaccination) or planned participation during the present trial period in another clinical trial investigating vaccine, drug, medical device, or medical procedure.
2. Receipt of any vaccine in the 4 weeks preceding the trial vaccination or planned receipt of any vaccine in the 4 weeks following trial vaccination, including influenza vaccination. However, 23-valent pneumococcal vaccine and tetanus vaccine will be allowed during this time window.
3. Receipt of an influenza vaccine within the 6 months preceding the trial vaccination or planned influenza vaccination during the trial.
4. Known or suspected congenital or acquired immunodeficiency or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
5. Systemic hypersensitivity to eggs, chicken proteins, or any of the vaccine components or a history of a life-threatening reaction to Vaxigrip® or to a vaccine containing any of the same substances.
6. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
7. Current alcohol or drug addiction.
8. Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion.
9. Identified as an Investigator or employee of the Investigator or study centre with direct involvement in the proposed study, or identified as an immediate family member (i.e. parent, spouse) of the Investigator or employee with direct involvement in the proposed study.
10. Severe audio-visual impairment.
11. Dementia, severe cognitive impairment (MMSE <18), major depression or other psychotic disorders.
12. Progressive, degenerative neurologic disease: e.g. Alzheimer's disease.
13. Rapidly progressive or terminal illness under palliative care with life expectancy less than 12 months.
14. Primary severely muscle/joint disorders resulting in physical disability interfering with the physical performance tests needed for the study.
15. Hospital admission in the past 6 weeks.
16. (Relevant for the healthy young adults subjects group). Subject is pregnant (or positive urine pregnancy test), or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be postmenopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to vaccination and until at least 4 weeks after vaccination).
17. Self-reported thrombocytopenia, contraindicating intramuscular vaccination
18. Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding vaccination, contraindicating intramuscular vaccination upon investigator's judgement.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Healthy Adult; Healthy adult participants aged 21-40 years will be vaccinated with Vaxigrip® influenza vaccine	Drug: Vaxigrip®; To describe the humoral immune response to Vaxigrip (IM) vaccination at Day 0 (baseline) and Day 28 according to the age and frailty status at baseline (i.e. in each study group) for each Influenza strain.
EXPERIMENTAL: Healthy Elderly; Healthy Elderly participants aged 65-90 years will be vaccinated with Vaxigrip® influenza vaccine.	Drug: Vaxigrip®; To describe the humoral immune response to Vaxigrip (IM) vaccination at Day 0 (baseline) and Day 28 according to the age and frailty status at baseline (i.e. in each study group) for each Influenza strain.
EXPERIMENTAL: Healthy Elderly Pre-Frail; Healthy Elderly participants aged 65-90 years will be vaccinated with Vaxigrip® influenza vaccine.	Drug: Vaxigrip®; To describe the humoral immune response to Vaxigrip (IM) vaccination at Day 0 (baseline) and Day 28 according to the age and frailty status at baseline (i.e. in each study group) for each Influenza strain.
EXPERIMENTAL: Healthy Elderly Frail; Healthy Elderly participants aged 65-90 years will be vaccinated with Vaxigrip® influenza vaccine.	Drug: Vaxigrip®; To describe the humoral immune response to Vaxigrip (IM) vaccination at Day 0 (baseline) and Day 28 according to the age and frailty status at baseline (i.e. in each study group) for each Influenza strain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Immune Responsiveness of Elderly Subjects when Administered Influenza Vaccination as Measured by HAI	Hemagglutination Inhibition (HAI) titer	18-month period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular Immune Response and Inflammatory Profile of elderly subjects when administered influenza vaccination - Flu-Specific T cells	% Flu-specific T cells out of total PBMCs	18 months
Flu-Specific B Cell Response	No. of flu-specific B cells quantified out of 1x105 PBMCs	18 months
Inflammatory Markers	Quantitative (pg/mL analyte, picogram of analyte per milliliter of plasma)	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Assessments of the elderly subjects - Weight	Quantitative Weight (kg, kilograms)	18 months
Clinical Assessments of the elderly subjects - Height	Quantitative Height (m, meters)	18 months
Clinical Assessments of the elderly subjects - BMI	Quantitative BMI (weight and height will be combined to report in kg/m2)	18 months
Clinical Assessments of the elderly subjects - DXA	Quantitative Dual-Energy X-Ray Absorptiometry (DXA) scan: Standardized Muscle Index (appendicular lean mass / height-squared); T-score based on Bone Mineral Density BMD (appendicular lean mass and height will be combined to report in g/cm2)	18 months

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Sanofi Pasteur, a Sanofi Company; National University, Singapore; Agency for Science, Technology and Research
• Investigators: Principal Investigator: Professor Paul Anantharajah Tambyah, MD, National University, Singapore

Publications and helpful links

General Publications

• Camous X, Visan L, Ying CTT, Abel B, Nyunt MSZ, Narang V, Poidinger M, Carre C, Sesay S, Bosco N, Burdin N, Tambyah PA, Pin NT, Larbi A. Healthy elderly Singaporeans show no age-related humoral hyporesponsiveness nor diminished plasmablast generation in response to influenza vaccine. Immun Ageing. 2018 Nov 12;15:28. doi: 10.1186/s12979-018-0137-4. eCollection 2018.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (ACTUAL): May 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: September 20, 2016
• First Submitted That Met QC Criteria: August 27, 2017
• First Posted (ACTUAL): August 30, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 30, 2017
• Last Update Submitted That Met QC Criteria: August 27, 2017
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Safety; Influenza; Immunogenicity; Aging; Respiratory Tract Infections; Frailty; Orthomyxoviridae Infections; Vaxigrip; Influenza Virus Vaccines
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human
• Other Study ID Numbers: 2012/01214

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Publication of the data in peer-reviewed journals
• IPD Sharing Time Frame: five years approx
• IPD Sharing Access Criteria: through a research agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL