Efficacy and Tolerability of ABBC1 in Volunteers Receiving the Influenza or Covid-19 Vaccine

Study Overview
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Brief Summary
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The immune system response needs to be forceful but also balanced for a rapid recovery from infection which avoids harmful overreactions. Innate immunity can adapt and respond more efficiently to secondary exposures, thanks to epigenetic and metabolic reprogramming, namely trained immunity. ABBC1 is a combination of beta-1,3/1,6-glucan with inactivated Saccharomyces cerevisae rich in selenium and zinc for training immunity. ABBC1 includes repurposed synergistic yeast-based ingredients: a unique ß-1,3/1,6-glucan complex and a consortium of probiotic Saccharomyces cerevisiae, rich in Selenium and Zinc. ABBC1 induces trained immunity due to its specific chemical and tridimensional structure: its ß-glucan complex interacts with specific receptors in immune cells, provoking a release of cytokines and priming phagocytosis. Simultaneous activation of these pathways activates innate immunity and counteracts cytokine storm. ABBC1 provides highly bioavailable selenium and zinc, micronutrients with a critical role in an optimal immune responsiveness to allergy, infection, and vaccines. ABBC1 possesses proven microbiome modulating properties, which revert in immune training. Due to its high tolerance, safety and immediate availability, ABBC1 is an ideal candidate for complementary management of geriatric patients with seasonal influenza viruses or COVID-19, or to improve the immune response in the general population receiving the influenza or Covid-19 vaccines. The absence of drug interactions in ABBC1 allows a dosage that is fully compatible with the medication prescribed for all types of patients, including the elderly who are frequently polymedicated, and allows adding an additional therapeutic tool in the fight against the pandemic. This study assesses the benefits of a nutritional supplementation with ABBC1 in volunteers receiving the influenza vaccine during autumn 2020 and the Covid-10 vaccine during winter 2021.

Detailed Description
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On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) as a pandemic. The Covid-19 pandemic is evolving throughout the world and is associated with high mortality and morbidity. According to Salem ML et al. 2020, the influenza vaccine may have an adjuvant effect to minimize the severity of COVID-19, since the correlation of Covid-19-related mortality and morbidity and the influenza vaccination situation appears to be protective. The trend of the correlation could be explained in parameters of incidence and recovery of cases. Vaccination against influenza (H1N1) is cost-effective and safe. Given that the influenza virus shares some common epitopes and mechanisms with the SARS-CoV-2 virus, there is the possibility of partial protection for reduce severity related to Covid-19 through flu vaccination. The influenza viruses and the SARS-CoV-2 viruses have an evolutionary proximity. Since this vaccination is not mandatory for routine clinical practice, various countries adopt different policies, and vaccination rates differ considerably among them. For this reason, the WHO in February 2020 published a recommendation on the composition of vaccines against influenza virus for use in the 2020-2021 northern hemisphere influenza season. Under this situation, it has been identified that older adults and people suffering from serious chronic conditions such as heart disease, lung disease or kidney disease have a higher risk of suffering from severe COVID-19. Older people are twice as likely to have severe COVID-19. This is probably because as people age, their immune systems change, making it harder to fight off disease and infection, and for this reason age is considered a risk factor for the disease. After several months of the global impact of the pandemic, specific vaccines for Covid-19 will begin to be available by end 2020. In Spain, the Ministry of Health designed a vaccination plan that will begin immediately. Specifically, in Catalonia this plan foresees classifying the population into various risk groups, based on highest priority and immediacy. Older adults make up one of the groups that will receive the vaccine as a priority. At the same time, they represent a population group whose immune response after the administration of other vaccines has been found to be less effective or optimal than in healthy adults under 65 years of age. For example, the influenza vaccine has an efficacy of 70-90% in the general population, while this efficacy is reduced to 17-53% in adults older than 65 years. In the same line, preliminary results with Covid-19 vaccines observe a better efficacy (> 90%) in groups of people under 55 years of age compared to those over 55 years of age (62%), results that suggest that the efficacy could decrease with age. The reduced efficacy of vaccines in the elderly may be because the geriatric population frequently presents immunosenescence (or a decline in immune function due to aging), but also to a possible poor nutritional status, in which it is not achieved to reach an optimal supply of essential oligonutrients for an effective antiviral immune response. Specifically, the efficacy data for the BNT162b2 vaccine in people older than 65 years considered a risk population point to a slightly lower efficacy (91.7% versus 94.8% in the general population). However, the results point to less protection after the administration of a single dose of the vaccine (82.0% efficacy just after the administration of the first dose and 52.4% between doses 1 and 2, compared to 94.8% 7 Days after the second dose), regardless of age. This requires a long administration schedule that does not make protection effective until a month after the first administration, slowing down access to the vaccine to a greater part of the population and leaving around 18-48% of unprotected vaccinated population until the administration of the second dose. The benefits of increasing efficacy after the first dose could be of great importance for Public Health since it would allow a more immediate immunization of the vaccinated population even before the administration of the second dose. A higher and faster immune response to the vaccine could benefit not only the elderly population, but also any other type of sub-population to be vaccinated. The group of medical staff workers represents a population subject to constant exposure to the virus, and for this reason it is considered another priority group to receive the vaccine. This group will be exposed to infection during the window of time that passes between the administration of the first and the second dose, so the possibility of improving the immune response immediately could have a huge benefit. Over the past 10 years, a wide range of pleiotropic effects of selenium have been discovered, ranging from antioxidant and anti-inflammatory effects to the production of active thyroid hormone, which has drawn attention to the relevance of selenoproteins for health. Low selenium level has been associated with an increased risk of mortality, poor immune function, and cognitive decline. An increased level of selenium or selenium supplementation has antiviral effects, is essential for the success of male and female reproduction and reduces the risk of autoimmune thyroid diseases. Older adults with insufficient selenium intake are at increased risk for a poorer clinical outcome after viral exposure due to a response sub-optimal antiviral response. Results from an intervention clinical trials have shown that daily supplementation of older adults with 100 ug of high selenium yeast can raise plasma selenium levels to 150 ug / L, which is within the proposed target range of selenium status. High selenium yeast has demonstrated its safety and clinical efficacy in human supplementation trials. On the other hand, the low to moderate zinc deficiency that is highly prevalent in elderly persons mimics many of the features of the immunosenescence of aging. Therefore, some of the deficits in immune regulation seen among the elderly could be ameliorated or reversed through daily zinc supplementation. It has been demonstrated that low zinc status is associated with increased risk of respiratory disease, including pneumonia, and inflammation. Research indicates that zinc supplementation can restore serum zinc levels in some elderly persons with low zinc status. Zinc supplementation of 15 per day that may increase immune readiness and favor regulated immune response. This protective approach may be particularly important in individuals who may be prone to cytokine-driven immune overreaction during the COVID-19 epidemic. Finally, the immunostimulatory effect of beta-glucan is widely known. Specifically, yeast or fungal beta-1,3/1,6-glucans interact with specific receptors (dectin-1, TLR2 and 6 or CR3) in different cells of the immune system, such as macrophages, neutrophils, granulocytes, Natural Killer cells or dendritic cells. This interaction stimulates the production of antibodies and primes phagocytosis, strengthening defense mechanisms against infections. It is important to note that not all beta-glucans have the same mechanisms of action: while other linear beta-glucans only bind to Dectin-1 and promote a reduction of phagocytosis and cytokine secretion, beta-1,3/1,6-glucans, branched polymers that simultaneously stimulate Dectin-1 and TLR4 receptors, stimulate phagocytosis, activate innate immunity and prevent or counteract exacerbated immune reactions, allergy or inflammation. In addition, these effects are improved in combination with selenium. ABBC1 is a combination of beta-1,3/1,6-glucan with inactivated Saccharomyces cerevisae rich in selenium and zinc for immunity enhancement. Due to its high tolerance, safety and immediate availability, ABBC1 is an ideal candidate for complementary management for geriatric patients with seasonal influenza viruses or COVID-19, or to improve the immune response in the general population receiving the influenza or Covid-19 vaccines. The absence of drug interactions in ABBC1 allows a dosage that is fully compatible with the medication prescribed for all types of patients, including the elderly who are frequently polymedicated, and allows adding an additional therapeutic tool in the fight against the pandemic. In this study we propose to determine the benefits of supplementation with ABBC1 in volunteers receiving the influenza vaccine at a first stage and the Covid-19 vaccine when available, to study if their immune response to the vaccine improves and/or leads to a better clinical outcome.

Official Title
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Efficacy and Tolerability of a Nutritional Supplementation With ABBC-1, a Symbiotic Combination of Beta-glucans and Selenium and Zinc Enriched Probiotics, in Volunteers Receiving the Influenza or the Covid-19 Vaccines

Conditions
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Immunity, Vaccine Reaction, Influenza, Covid19, Cytokine Storm, Immunologic Deficiency Syndromes

Intervention / Treatment
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* Dietary Supplement: ABBC1 Immunoessential
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COMMON CRITERIA: Subjects with the ability to take the study product orally Ability to understand the study, the information about the symptoms and to comply with the treatment shots. Subject or legal guardian / representative willing to give informed consent in writing. INFLUENZA VACCINE GROUPS: Subjects who require hospitalization or external follow-up (outpatients or PADES) Subjects over 60 years old who will receive the influenza vaccine COVID-19 VACCINE GROUPS Subjects from long-stay centres attached to the Hospital Mare de Déu de la Mercè, and meet the following inclusion criteria: Groups: Subjects over 18 years of age who receive the Covid-19 vaccine, in a stable clinical situation, at the discretion of the researcher, or Healthcare workers of the study centers, over 18 years of age who receive the Covid-19 vaccine Availability to attend clinical visits. Exclusion Criteria: COMMON CRITERIA: Need for assisted ventilation that makes oral consumption of the product under study impossible History of allergy, idiosyncrasy, hypersensitivity or adverse reactions to the active principle or to any of the excipients. History or evidence of any medical conditions or medication use that, in the opinion of the principal investigator, could affect the safety of the subjects or interfere with the study evaluations Subjects in situation of last days COVID-19 VACCINE GROUPS: Subjects in whom the Covid-19 vaccine is contraindicated. A history of frailty or comorbidity that indicates a situation of clinical instability. History or evidence of any medical conditions or drug use that, in the opinion of the principal investigator, could affect the safety of subjects or interfere with study evaluations.

Ages Eligible for Study
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Minimum Age: 18 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: Single-center, randomized, double-blinded, placebo-controlled clinical study. Multicomponent intervention (clinical and nutritional) resulting from the administration of influenza or Covid-19 vaccine and supplementation with ABBC-1.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Influenza vaccine + intervention with beta-glucan complex and Saccharomyces cerevisiae consortium<br>Influenza vaccine followed by 30 days of supplementation with a beta-glucan complex and Saccharomyces consortium rich in selenium and zinc | Dietary Supplement: ABBC1 Immunoessential<br>* Powder for dissolution in water, based on a yeast beta-glucan complex and a consortium of Saccharomyces cerevisiae rich in selenium and zinc + excipents. Lemon flavor<br>|
| Placebo Comparator: Influenza vaccine + placebo<br>Influenza vaccine followed by 30 days of supplementation with a placebo, similar en aspect, flavor and odour to the intervention product | Dietary Supplement: Placebo<br>* Powder for dissolution in water, excipents. Lemon flavor<br>|
| Experimental: Covid-19 vaccine + intervention with beta-glucan complex and Saccharomyces cerevisiae consortium<br>Covid-19 vaccine followed by 35 days of supplementation with a beta-glucan complex and Saccharomyces consortium rich in selenium and zinc | Dietary Supplement: ABBC1 Immunoessential<br>* Powder for dissolution in water, based on a yeast beta-glucan complex and a consortium of Saccharomyces cerevisiae rich in selenium and zinc + excipents. Lemon flavor<br>|
| Placebo Comparator: Covid-19 vaccine + placebo<br>Covid-19 vaccine followed by 30 days of supplementation with a placebo, similar en aspect, flavor and odour to the intervention product | Dietary Supplement: Placebo<br>* Powder for dissolution in water, excipents. Lemon flavor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the acute immune response to the influenza vaccine after supplementation (influenza vaccine groups) | Generation of T-cells (TCD8, TCD3 and TCCD4) | 30 days (Days 1, 7 and 30) | 
| Change in the delayed immune response to the influenza vaccine after supplementation (influenza vaccine groups) | Generation of influenza-specific antibodies (IgM, IgG influenza A and B) | 30 days (Days 1, 7 and 30) | 
| Change in the acute immune response to the Covid-19 vaccine after supplementation (Covid-19 vaccine groups) | Generation of T-cells (TCD8, TCD3 and TCCD4) | 35 days (Days 1, 7, 21 and 35) | 
| Change in the delayed immune response to the Covid-19 vaccine after supplementation (Covid-19 vaccine groups) | Generation of influenza-specific antibodies (IgM, IgG influenza A and B) | 35 days (Days 1, 7, 21 and 35) | 
| Change in blood levels of selenium and zinc | Variation of selenium and zinc levels measured in plasma | 30 days (Days 1, 7 and 30) for influenza vaccine groups. 35 days (Days 1, 7, 21 and 35) for Covi-19 groups. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of influenza (only for influenza vaccine groups) | Number of volunteers presenting influenza as measured by clinical diagnostic | 30 days | 
| Incidence of Covid-19 | Number of volunteers presenting Covid-19 as measured by clinical diagnostic and/or PCR or antigen test | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Mean Change in the Ordinal Scale WHO R&D Blueprint novel Coronavirus | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. A positive change indicates a worsening and a negative change is an improvement. | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Number of subjects with fever during the study | Variation on body temperature (ºC) | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Number of subjects with cough during the study | Clinical assessment | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Number of subjects with myalgia during the study | Clinical assessment | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Number of subjects with dyspnea during the study | Clinical assessment | 30 days for influenza groups, 35 days for Covid-19 groups | 
| Number of subjects with anosmia / ageusia during the study | Clinical assessment | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Hospital readmission rate during the study and the additional follow-up period | percentage of patients readmitted to the hospital during the study and the addition follow-up period | 60 days | 
| Changes in blood glucose | measured in blood samples | 30 days for influenza groups, 35 days for Covid-19 groups | 
| Incidence of adverse effects of the study product | reporting of adverse events (if any) | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 
| Dietary history | Record of the dietary history during the study | 30 days for influenza vaccine groups, 35 days for Covid-19 vaccine groups | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trained immunity, Vaccine adjuvant, Influenza, Covid-19, beta-glucans, Saccharomyces cerevisiae, microbiota, ABBC1