Tropical Influenza Control Strategies for the Elderly

Study Overview
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Brief Summary
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TROPICS1 is a randomized, observer-blind, active comparator-controlled, single-center, Phase IV trial in 200 participants aged ≥65 years. The control group will receive a standard dose licensed trivalent inactivated influenza vaccine at day 1, and an active-comparator (Tetanus-diphtheria-pertussis vaccine) at day 180. Participants in the experimental group will receive the same influenza vaccine at day 1 and day 180. Endpoints are immunological, and include measures of haemagglutination-inhibition (HI) titres, micro-neutralisation titres and cell-mediated immunity at 4 time points after the initial vaccination up to Day 360. The primary hypothesis is that participants receiving an influenza booster at day 180 will achieve superior influenza seroprotection (HI titre ≥1:40) at day 208, compared to controls. The World Health Organization (WHO) estimates the global annual burden from seasonal influenza as 1 billion infections, with 3-5 million severe cases and 300,000-500,000 deaths. The pattern and impact of these infections varies considerably with climate. In temperate countries, influenza epidemics characteristically occur during the cold winter months, while in sub-tropical countries, they coincide with the rainy seasons. Closer to the equator, influenza virus activity is more complex. In Singapore, biannual epidemics are usual, but with continuous transmission year-round. Bi-annual epidemics, tri-annual epidemics and year round virus activity have also been described in other tropical countries, from Indonesia and Malaysia to Peru and Mexico. There is no published data reporting year-round influenza vaccine effectiveness in the elderly from countries with continuous influenza virus activity. Despite numerous studies worldwide exploring the HI antibody response to influenza vaccination, the majority of these do not continue follow up beyond seroconversion (21-28 days). However, of the few available, HI antibody titres declined following influenza vaccination in the elderly, such that within 6-12 months geometric mean titres approached pre-vaccination levels. With biannual epidemics and year-round transmission in tropical regions, year-round seroprotection may be important to reduce influenza infections in this environment. A six-monthly vaccination cycle would correspond with the decline in vaccine-induced seroprotection in the elderly, and the 6-monthly periodicity of outbreaks in Singapore and other tropical countries.

Official Title
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A Single-centre, Randomised, Observer-blind, Active Comparator-controlled, Superiority Trial of the Immune Response to Six-monthly Versus Annual Standard Dose Inactivated Trivalent Influenza Vaccination in the Elderly

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: Influenza vaccine
* Biological: Influenza vaccine
* Biological: Tetanus-diphtheria-pertussis vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥65 years on the day of inclusion No influenza vaccination in the previous 10 months No tetanus, diphtheria or pertussis vaccine in the previous 1 year No virologically confirmed influenza infection in the previous 10 months Able to provide written informed consent Able to attend all scheduled visits and comply with all trial procedures Exclusion Criteria: Participation in the 4 weeks preceding the first trial vaccination or participation during the present trial period in another trial investigating a vaccine, drug, medical device, or medical procedure History of a life threatening reaction to the vaccine used in the trial, or to a vaccine containing any of the same substances Known systemic hypersensitivity to any of the vaccine components, including: Egg protein (eggs or egg products) Chicken products Formaldehyde Neomycin or kanamycin Octoxinol 9 (Triton X-100) Cetyltrimethylammonium bromide (CTAB) History of Guillain-Barré syndrome (GBS) within 6 weeks following previous influenza vaccination Acute respiratory infection on the day of enrolment Moderate or severe acute illness/infection (according to investigator judgement) on the day of vaccination, or febrile illness (temperature ≥ 37.5°C). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided. Self-reported thrombocytopenia, contraindicating Intramuscular vaccination Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding six months; or long-term systemic corticosteroid therapy (prednisolone ≥ 7.5mg/day or equivalent for more than 2 consecutive weeks within the past 3 months) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the Investigator

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Six-monthly influenza vaccine<br>Standard dose trivalent inactivated seasonal influenza vaccine will be administered at day 1 and 180 | Biological: Influenza vaccine<br>* Administered at day 1<br>Biological: Influenza vaccine<br>* Administered at day 180<br>|
| Active Comparator: Annual influenza vaccine<br>Standard dose trivalent inactivated seasonal influenza vaccine will be administered at day 1 and an active-comparator (Tetanus-diphtheria-pertussis) at day 180 | Biological: Influenza vaccine<br>* Administered at day 1<br>Biological: Tetanus-diphtheria-pertussis vaccine<br>* Administered at day 180<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroprotection (Proportion of subjects with HI titre ≥1:40 (1/dil) at day 208 post-primary vaccination for each of the influenza strains present in the administered influenza vaccine) | Proportion of subjects with HI titre ≥1:40 (1/dil) at day 208 post-primary vaccination for each of the influenza strains present in the administered influenza vaccine. | Day 208 post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean titres | Comparison by vaccination group of Geometric mean titres (GMTs) post-primary vaccination against homologous and heterologous influenza strains to those present in the administered influenza vaccine. | Day 208 to 360 post-vaccination | 
| Geometric mean ratio | Comparison by vaccination group of the Geometric mean ratio (GMR) post-primary vaccination against homologous and heterologous influenza strains to those present in the administered influenza vaccine. | Day 208 to 360 post-vaccination | 
| Seroprotection (Proportion of subjects with HI titre ≥1:40 (1/dil) at day 208 post-primary vaccination for each of the influenza strains present in the administered influenza vaccine) | Comparison by vaccination group of the proportion of subjects with HI titre ≥1:40 (1/dil) at day 360 post-primary vaccination for each of the influenza strains present in the administered influenza vaccine. | Day 360 post-vaccination | 
| Seroconversion (Proportion of subjects achieving seroconversion after vaccination for each of the influenza strains present in the administered influenza vaccine) | Comparison by vaccination group of the proportion of subjects achieving seroconversion after vaccination for each of the influenza strains present in the administered influenza vaccine. Seroconversion is defined as a pre-vaccination HI titre < 1:10 and a post vaccination titre ≥1:40, or a pre-vaccination titre > 1:10 and a minimum fourfold rise in HI titre. | Day 208 to 360 post-vaccination | 
| Micro-neutralization titres | Comparison by vaccination group of Micro-neutralization titres post-primary vaccination against strains present in the administered influenza vaccine. | Day 208 to 360 post-vaccination | 
| Influenza-like illness | Comparison by vaccination group of the number of subjects reporting an influenza-like illness | Day 208 to 360 post-vaccination | 
| Influenza infection | Comparison by vaccination group of the number of subjects with PCR confirmed influenza infection | Day 208 to 360 post-vaccination | 
| Healthcare utilization | Comparison by vaccination group of the number of subjects reporting healthcare utilization. This is defined as unscheduled physician visits, emergency room visits and hospitlizations. | Day 180 to 360 post-vaccination | 
| Solicited and unsolicited adverse events | Frequency and severity of solicited local (injection site) and systemic adverse events for 7 days post-vaccination | Day 1 to 7 and day 180 to 187 | 
| Serious adverse events | A serious adverse event is defined as any untoward medical occurrence that is an important event. | Day 1 to 28, and day 180 to 208 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seasonal Influenza, Antibody response, Influenza Vaccines, Hemagglutination Inhibition, Elderly, immunosenescence, Tropics