Effect of a Multi-strain Probiotic Formulation on Immune Response to Influenza Vaccination

Study Overview
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Brief Summary
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Randomized clinical trial to determine whether a probiotic formulation containing 4 probiotic strains which belong to Lactiplantibacillus plantarum and Pediococcus acidilactici species can boost the immune response to influenza vaccination evaluated at 4 weeks in a population between 50 and 80 years of age. Secondary outcomes comprise evaluation of immune response at 8 weeks after vaccination, percentage of patients with seroconversion, incidence and duration of influenza-like infections and respiratory infections throughout a 4-month period and safety.

Detailed Description
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Double blind, randomized, placebo-controlled clinical trial to determine whether supplementation with a probiotic formulation containing 4 probiotic strains (L. plantarum CECT 30292, CECT7484, CECT7485 and P. acidilactici CECT7483) can improve immune response to seasonal influenza vaccination. Subjects with age comprised between 50 and 80 years who meet inclusion and exclusion criteria will be randomized 1:1 to one of the following study groups: one will receive probiotic formulation for 28 days (1 capsule/day) and the other will receive placebo, starting the same day of the influenza vaccination. Main study outcome will be immune response at 4 weeks after vaccination, which will be determined by analysis of specific IgG antibodies in serum against influenza A and B. Secondary outcomes comprise serum titers of specific IgG at 8 weeks after vaccination, percentage of patients with seroconversion at 4 and 8 weeks, evaluation of influenza-like infections or respiratory infections throughout a 4-month period and adverse events.

Official Title
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Efficacy and Safety of a Multistrain Probiotic Formula to Boost the Immune Response to Influenza Virus Vaccination

Conditions
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Influenza Vaccine

Intervention / Treatment
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* Dietary Supplement: Food Supplement
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects 50 - 80 years old receiving seasonal Influenza vaccine in season 2021-2022 Body mass index (BMI) 18.5-34.9 kg/m2 Willing to provide informed consent Able to follow study procedures, according to the criteria of study investigator Exclusion Criteria: Hypersensitivity to any of the components of influenza vaccine Previous influenza infection in the same season (from 01/09/2021) Having received influenza vaccination in the previous season less than 9 months before study entry (from 01/01/2021) Having received another vaccine -different from COVID19 vaccine- up to 1 month before study inclusion or planning to receive it 1 month after study inclusion Active infection at the moment of study entry as diagnosed by study physician History of severe allergic reactions (food and non-food), including severe asthma. Receiving immunosuppressant therapy, displaying neutropenia, lymphopenia, AIDS, immunoglobulin deficiency, active oncological disease. Daily ingestion of any food complement or food added with probiotics (including Actimel o similar products) 2 weeks before inclusion in the study Acute pancreatitis, short bowel syndrome or active inflammatory bowel disease Diagnosed from other pathologies that according to study physician may compromise the immunological function of the individual (such as immunodeficiencies, lupus, multiple sclerosis, among others) Having received antibiotic treatment in the previous month Exclusion criteria during the study: Withdrawal from the study as per study investigator criteria, in case that study procedures are not followed by the participant In case of adverse event that prevents them from following study procedures or complying with the treatments under study. Failure to comply with study procedures: Complete less than 70% of the days in the patient's diary and/or take less than 80% of the days of the study products. Receive any of the unauthorized treatments indicated in the selection criteria, with the exception of antibiotics that will be allowed under medical prescription.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind, randomized controlled trial in 140 subjects 50-80 years old receiving influenza vaccination, who will be allocated to receive either an experimental product containing multi-strain probiotic formula or placebo for 28 days
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Probiotic multi-strain formulation comprising L. plantarum CECT30292, CECT7484, CECT7585 and P. acidilactici and maltodextrin (E1400, qs) as excipient in hydroxymethylpropyl-cellulose (HPMC) capsules. Probiotic strains have Qualified Presumption of Safety (QPS) status by European Food Safety Authority | Dietary Supplement: Food Supplement<br>* Probiotic multistrain formulation containing Lactiplantibacillus plantarum CECT30292, CECT7484, CECT7485 and P. acidilactici CECT7483 for 28 days, starting the same day of influenza vaccination<br>* Other names: Probiotic;|
| Placebo Comparator: Placebo<br>Maltodextrin (E1400, qs) in HPMC capsules | Dietary Supplement: Placebo<br>* One maltodextrin-containing capsule/day for 28 days, starting the same day of influenza vaccination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG antibodies against vaccine influenza antigens | Titer of specific total IgG antibodies against vaccine influenza A and B antigens at day 28 | 4 weeks (day 1 and day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG antibodies against vaccine influenza antigens | Titer of specific total IgG antibodies against vaccine influenza A and B antigens at day 56 | 8 weeks (day 1 and day 56) | 
| IgM antibodies against vaccine influenza antigens | Titer of specific total IgM antibodies against vaccine influenza A and B antigens at day 28 and 56 | 8 weeks (day 1 and day 56) | 
| Seroconversion | Percentage of patients with seroconversion (defined as 4 fold change in influenza IgG antibodies concentration compared to baseline) at day 28 and 56 | 8 weeks (day 1,day 28 and 56) | 
| Incidence of influenza like infections (ILI) | Cumulative incidence of influenza like infection (ILI), according to the European Diseases Prevention and Control Center (ECDC) criteria | 16 weeks (day 1, day 56) | 
| Incidence of any other respiratory infections (including COVID-19) | Cumulative incidence of any other respiratory infections | 16 weeks (day 1, day 56) | 
| Incidence of fever | Cumulative number of days with fever (> 37.5ºC) | 16 weeks (day 1, day 56) | 
| Use of analgesics and antibiotics | Cumulative number of days using analgesics and antibiotics | 16 weeks (day 1, day 56) | 
| Duration of vaccine-related symptoms: injection-site pain, swelling, redness | Duration (in days) of symptoms after receiving the flu vaccine. | 1 week (day 1, day 7) | 
| Severity of vaccine-related symptoms: injection-site pain, swelling, redness | Severity of symptoms after receiving the flu vaccine. Measured on a 4-point scale: 0 = none , 1 = mild, 2 = moderate, and 3 = severe | 1 week (day 1, day 7) | 
| Gastrointestinal symptoms | Gastrointestinal manifestations documented through questionnaire in participants diary. Measured on a 4-point scale: 0 = none , 1 = mild, 2 = moderate, and 3 = severe. | 4 weeks (day 1, day 28) | 
| Adverse events | Frequency of adverse events reported in medical visits or patient diary | 8 weeks (day 56) | 
| Albumin | Albumin concentration in blood | 4 weeks (day 1, day 28) | 
| Alkaline phosphatase (ALP) | Alkaline phosphatase (ALP) concentration in blood | 4 weeks (day 1, day 28) | 
| Gamma-glutamil transpeptidase (GGT) | Gamma-glutamil transpeptidase (GGT) concentration in blood | 4 weeks (day 1, day 28) | 
| Aspartate aminotransferase (GOT) | Aspartate aminotransferase (AST) concentration in blood | 4 weeks (day 1, day 28) | 
| Alanine aminotransferase (AST) | Aspartate aminotransferase (AST) concentration in blood | 4 weeks (day 1, day 28) | 
| Basic hemogram | Blood cell count | 4 weeks (day 1, day 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza vaccination, probiotic