The objective of this study is to evaluate the effects of the consumption of L coryniformis K8 on the incidence and severity of symptomatic infection by SARS-CoV-2 and the severity of COVID-19 in HCWs who carry out their professional work among patients with infection or suspected infection by SARS-CoV-2 at 2 referral hospitals that treat individuals with COVID-19 in the province of Granada (Andalusia, Spain).

The administration of the experimental product and the placebo will be carried out in the form of a gelatin capsule that will have the same weight, consistency, and color.

The Experimental Group will receive hard gelatin capsules that will contain 3×10⁹ colony forming units of L coryniformis K8 (120 mg), 10 mg magnesium stearate, and 120 mg maltodextrin.

The control group will receive hard gelatin capsules that will contain magnesium stearate (10 mg) and maltodextrin (220 mg). Individuals from both groups will take 1 capsule a day (preferably with dinner).

Capsules for the probiotic and placebo will be provided by Biosearch Life (Granada, Spain).

The study is a nutritional, randomized, double-blind, controlled, and parallel-group observational prospective cohort study. Volunteers will be distributed into 2 groups: a control group and an experimental group. The study will be performed as shown in Figure 1.

The trial has been registered on ClinicalTrials.gov (NCT04366180).

This clinical research protocol has been prepared with full understanding and in accordance with the standards of Good Clinical Practice in accordance with CPMP/ICH/135/95, the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, October 2013), ISO 14155, and all relevant national guidelines. All investigators participating in the study are appropriately qualified. The protocol was approved by the Research Ethics Committee for the province of Granada (3/2020_P_054; CEIM/CEI Province of Granada). Volunteers will be included in the study after informed written consent is obtained.

Withdrawal will be allowed at any time during the trial. Investigators may recommend discontinuing the trial if, in their opinion, staying in the study would be detrimental to the participant’s well-being. This decision must be based on the appearance of an adverse effect that will be duly included in the case report form.

Volunteers will return the unconsumed capsules. Compliance ≤80% of the total will be considered a violation of the protocol and will be considered dropouts.

L coryniformis species are included in the Qualified Presumption of Safety list published by the EFSA, which guarantees safety for consumption [30]. On each visit, it will be monitored for adverse effects, which will be recorded in the patient’s medical history and evaluated by the principal investigator. In the event of serious adverse events considered related to the experimental product, the researcher will inform the health authorities and the Clinical Research Ethics Committee involved in the clinical trial.

Given that the current rates of infection among health professionals worldwide are very different, the sample size has been based on the comparison of 2 independent proportions for the use of the chi-square test. For an α of 5% and a power of 80%, taking a percentage of affected individuals in the control group of 15% and 10% as the minimum meaningful difference to be detected, a sample of 157 per branch would be necessary, taking into account a loss of 10% of participants.

Due to the urgency of the circumstances of the pandemic, the statistical methods have not been fully planned. A statistical analysis plan will be prepared during the execution of the study and before the closure of the database. The statistical methods to be used, the strategy to be followed in the case of missing values, and the tables and figures to include in the statistical report will be described in detail.

The sample size has been calculated assuming 10% dropouts. It is not planned to replace withdrawal participants. Intention-to-treat analysis will be carried out, taking into account all the data of the recruited volunteers, even if they have not completed the intervention.

In general, the data will be presented as absolute frequencies and percentages in the case of qualitative variables. For the quantitative variables, central tendency statistics, such as the mean and median, and dispersion statistics, such as the SD, IQR, minimum and maximum values, and to indicate the shape of the distribution, shape measures such as coefficients of skewness and kurtosis, will be used. In the case of ordinal variables, depending on the number of categories, one form or another of description will be used. In all cases, a column that includes the number of volunteers with available data must be added to the data presentation table. The analyses will be divided by randomization group.

To analyze the comparisons between groups, parametric tests (Student t test or ANOVA) and nonparametric tests (Mann-Whitney U or Kruskal-Wallis) will be used for continuous variables according to the characteristics of the study variables (assumption normality), while for categorical variables, chi-square tests or Fisher exact tests will be used.

In the case of between-visit comparisons of continuous variables, parametric tests (Student t test for paired data or repeated measures ANOVA) and nonparametric tests (Wilcoxon or Friedman) will be used, as appropriate, according to the characteristics of the study variables (assumption of normality) and the number of visits to be compared, while the categorical variables will be compared using the McNemar test. The effect size will be estimated using CIs.

The significance level of the statistical tests used will be .05. All calculations will be performed with the SPSS statistical software package (version 26; IBM Corp).

For the analysis of adverse events, a descriptive analysis (frequencies and percentages) will be carried out throughout the study, presenting a list of the adverse events grouped according to severity. These events will be listed by volunteer and randomization groups.

Adverse events and concomitant medication will be coded using a standardization system. In the case of adverse events, the most current version of the MedDRA system will be used, and for concomitant medication, the ATC code will be used.

To further ensure the accuracy and reliability of the collected data, a thorough process of data cleansing will be implemented before computerization at the coordinating center in Granada, Spain. Any errors or inconsistencies identified during this process will be rectified or clarified with the relevant source documents or database managers. The source documents and databases will also be subjected to regular data cleansing procedures to maintain their integrity throughout the minimum 5-year retention period after the study’s conclusion. Additionally, any personal information will be carefully screened and removed as part of the data cleansing process to guarantee anonymity and confidentiality.

Communications and scientific reports that emerge from this study will be carried out under the responsibility of the principal investigator in agreement with the associated investigators. Publication rules will follow international recommendations. The findings will also be shared with national health authorities.

Authorship will follow the guidelines established by the International Committee of Medical Journal Editors [31], which require substantive contributions to the design, conduct, interpretation, and reporting of a trial.

This study is conducted to evaluate the efficacy of the effects of L coryniformis K8 consumption on the incidence and severity of COVID-19 in HCWs working with SARS-CoV-2–infected or suspected patients in referral hospitals for patients with COVID-19 in the province of Granada. This randomized controlled trial aims to study whether the consumption of L coryniformis K8 will reduce the incidence of SARS-CoV-2 infection in the staff caring for patients with suspected or confirmed COVID-19 disease at the San Cecilio University Hospital and Virgen de las Nieves University Hospital. For this purpose, the incidence of hospital admissions caused by SARS-CoV-2 infection, both in the general hospitalization area and in the ICU area, will be studied in HCWs caring for SARS-CoV-2–infected patients.

It is important to determine the prevalence of pneumonia caused by SARS-CoV-2 infection and the need for oxygen supply to these patients. The presence of fever will be studied, and the number of days will be quantified, as well as the persistence of cough and feeling of fatigue. On the other hand, it will also be assessed whether these workers have needed pharmacological treatment.

This intervention aims to shed light on the use of probiotics to enhance the immune effect against SARS-CoV-2. In addition, this intervention study aims to contribute to the understanding of the effect of taking probiotics to improve the immune response to vaccines against SARS-CoV-2. An article published in March 2020 shows how the immune response to the COVID-19 virus is similar to the response generated by the influenza virus [18]. When the immune system works properly, the first barrier to SARS-CoV-2 is the innate response. This innate response, characterized by interferon and cytokines, which are small proteins responsible for symptoms such as fever, headaches, and muscle pain, has 2 functions: to slow down the replication and spread of the virus until the specific immune response (which, when it is a virus that has not been previously contacted, takes approximately 2 to 3 weeks) is activated. The specific immune response is what will stop and ultimately eliminate the infection. This specific response also controls the innate response in order to prevent excessive activity from damaging the tissues. When this response works in a correct and coordinated manner, the infection is overcome, showing symptoms more or less similar to those of the flu. However, in an older population experiencing dysfunction of the age-related immune response, called immunosenescence, or in a population in which the response appears to be poorly coordinated, the innate response occurs later or is ineffective, giving the virus time to replicate and spread and delaying the activation of the specific response. Before the massive invasion of tissues, the innate response exaggeratedly damages tissues, causing respiratory failure and failure in other organs, such as the kidney. Given this situation, some authors speak of 3 disease states that require different approaches: an asymptomatic state, a second state with nonsevere symptoms, and a third state with severe respiratory symptoms and a high viral load. During the first 2 states, a specific immune response is required to eliminate the virus and prevent the disease from progressing to state 3. In this phase, strategies to enhance the immune response are important. However, in state 3, when the immune system has failed and the virus has spread, the damage to the tissues causes a massive inflammatory response; the strategy should be aimed at controlling that inflammation [27]. Several clinical trials have evidenced the positive effects of certain probiotic strains on the prevention of respiratory tract infections. In fact, some authors propose the use of probiotics as a strategy to mitigate the effects of SARS-CoV-2 [19]. Mechanisms that would be involved in a positive effect of probiotic treatments on respiratory viruses include enhancement of the intestinal epithelial barrier, competition with pathogens for nutrients and adhesion to the intestinal epithelium, production of antimicrobial substances, and modulation of the host immune system [19]. L coryniformis K8 CECT5711 has immunomodulatory properties that could be useful for COVID-19 management. On the one hand, we have previously discussed its ability to improve the immune response against viral antigens, leading to the production of specific antibodies [14,15]. On the other hand, the strain has been shown in animal experiments to have anti-inflammatory capacity in models of inflammation [3,27]. This anti-inflammatory activity would also be of interest in the case of COVID-19, as it could help prevent uncontrolled inflammatory processes from leading to respiratory and other organ failure.

The working hypothesis is that the administration of L coryniformis K8 will stimulate the immune response of people exposed to COVID-19, acting as an adjuvant that contributes to developing an effective response against the virus, and therefore fewer infectious cases are presented due to this virus or, in the event of an occurrence, the disease is milder among the participants taking the probiotic strain.

The high degree of exposure among HCWs puts them at high risk of contracting the virus. If we add to this situation the fact that the stress and physical overexertion caused by the pandemic can affect the immune response, the risk increases even more. The study has been designed to demonstrate if the consumption of these probiotic bacteria might contribute to reducing the level of incidence, or at least the severity of infection, in this population.

Further knowledge in this area could lead to an improvement in the immune response of HCWs to noninfection with SARS-CoV-2 or to a reduction of symptoms in cases of infection. This would ensure that HCW workforces are not impaired in their ability to cope with SARS-CoV-2 and that those infected with SARS-CoV-2 are able to return to work more quickly than those who do not take probiotic supplements.