key: cord-0279009-mcvrqvzy
authors: Wischmeyer, P. E.; Tang, H.; Ren, Y.; Bohannon, L.; Ramirez, Z. E.; Andermann, T. M.; Messina, J. A.; Sung, J. A.; Jensen, D.; Jung, S.-H.; Artica, A.; Britt, A.; Bush, A.; Johnson, E.; Lew, M. V.; Miller, H. M.; Pamanes, C. E.; Racioppi, A.; Zhao, A. T.; Surana, N. K.; Sung, A. D.
title: Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial
date: 2022-01-05
journal: nan
DOI: 10.1101/2022.01.04.21268275
sha: 06673a75f3d51e7080b5e604d46e230c2aad942c
doc_id: 279009
cord_uid: mcvrqvzy

Background: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, supplemental strategies to mitigate the spread and severity of COVID-19 are urgently needed. Emerging evidence suggests susceptibility to infections, including respiratory tract infections, may be reduced by probiotic interventions. Therefore, probiotics may be a low-risk, widely implementable modality to mitigate risk of COVID-19 disease, particularly in areas with low vaccine availability and/or uptake. Methods: We conducted a randomized, double-blind, placebo-controlled trial across the United States testing the probiotic Lactobacillus rhamnosus GG (LGG) as post-COVID-19-exposure prophylaxis. We enrolled individuals > 1 year of age with a household contact with a recent ([≤] 7 days) diagnosis of COVID-19. Participants were randomized to receive daily LGG or placebo for 28 days. Stool was collected to evaluate the microbiome. The primary outcome was development of symptoms of illness compatible with COVID-19 within 28 days. Findings: We enrolled 182 COVID-19-exposed participants. Intention-to-treat analysis showed that participants randomized to LGG were less likely to develop symptoms versus those randomized to placebo (26.4% vs. 42.9%, p=0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank p=0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis was not significantly different between LGG (8.8%) and placebo (15.4%) (p=0.17). LGG was well-tolerated with no increased side effects versus placebo. Interpretation: These findings suggest that LGG probiotic may protect against the development of COVID-19 infection and symptoms when used as post-exposure prophylaxis within 7 days after exposure. Funding: This work was supported by a grant from the Duke Microbiome Center to A.D.S. and P.E.W. and private philanthropic donations to A.D.S. DSM/iHealth donated the LGG and placebo for the trial but had no role in its design, conduct, analysis, or writing. Trial registration: NCT04399252

The Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, has significantly altered global public health, with over 259 million cases and 5.1 million deaths worldwide as of 29-November-2021. 1 Despite the advent of highly effective vaccines against SARS-CoV-2, widespread implementation has been slow in areas with limited vaccine availability, with reports estimating that only 3.1% of people in low-income countries have received at least one dose. 2, 3 Vaccine uptake remains limited even in developed nations: only 59% of the U.S. population is fully vaccinated against COVID-19. 1 Finally, immunity and protection provided by vaccines appears to wane over time. 4 Thus, additional safe, low-cost, rapidly implementable strategies to address the ongoing COVID-19 pandemic continue to be necessary.

One potential target for intervention is via manipulation of the gut microbiota using probiotics (ingested live bacteria), a well-described strategy to modulate the human immune system and inflammatory responses. 5 Probiotics have been shown to improve outcomes in a wide variety of infectious presentations including sepsis, ventilator-associated pneumonia, and respiratory tract infections (RTIs). 5-7 Recent studies suggest that prophylaxis with Lactobacillus species specifically can prevent the development of upper and lower RTIs; 8-11 one large randomized controlled trial of full-term healthy infants randomized to Lactobacillus synbiotic vs. placebo showed a 40% reduction in sepsis or death (9.0% vs. 5.4%, p<0.001), including a 34% reduction in lower RTIs (6.1% vs. 4.0%, p=0.002) 8 . These outcomes may be mediated by the effects of probiotics on the immune system and intestinal/lung barrier function via improved intestinal homeostasis, increased regulatory Tcells, normalization of protective mucin production, decreased pro-inflammatory cytokines, modulation of antiviral gene expression, and increased expression of TLRs. [12] [13] [14] [15] [16] These clinical and laboratory reports suggest a potent immunomodulatory role for probiotic therapies in preventing or attenuating respiratory infections, and increasing evidence suggests that gut microbiota affect COVID-19 transmission risk and symptom severity. 17 Thus, modulation of the gut microbiome via probiotics is a promising strategy for prophylaxis and mitigation of COVID-19. Since March 2020, several trials have launched investigating the benefits of probiotics in both treatment and prevention of COVID-19. 17 Among commercially-available probiotics, Lactobacillus All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 5, 2022. ; 9 rhamnosus GG (LGG) is particularly encouraging given the success of Lactobacillus strains in numerous in vivo studies and clinical trials, as discussed above. [8] [9] [10] [11] We therefore conducted a randomized, double-blind, placebo-controlled trial of

LGG as post-exposure prophylaxis in exposed household contacts (individuals living with someone recently diagnosed with COVID-19). We hypothesized that LGG prophylaxis would decrease the incidence of symptoms (primary endpoint) and incidence and time to confirmed diagnosis of COVID-19 infection.

Participants were randomized using a permuted block randomization technique to receive LGG or placebo in a 1:1 ratio.

Both subjects and study coordinators are blinded to the intervention; the randomization key was generated by the study statistician and only the pharmacist dispensing the study product had access to the key. Due to the ongoing COVID-19 pandemic, the study was designed so that all procedures could be conducted remotely. Study product was delivered by mail, and follow-up was obtained through web-based surveys and telephone calls, with stool samples shipped back to the study center. This research was conducted under Food and Drug Administration Investigational New Drug Application 24777; the research protocol was approved by the Duke University Institutional Review Board, registered on ClinicalTrials.gov (NCT04399252), and was previously published. 18 All participants provided documented informed consent.

Eligibility criteria included: age ≥ one year; exposed household contact (EHC) of someone diagnosed with COVID-19 within the past seven days; willingness to not take any other probiotic while on LGG/placebo; and access to email/internet to complete electronic consent and surveys. Exclusion criteria included: symptoms of COVID-19 at enrollment, including fever, respiratory symptoms (e.g. cough, dyspnea), GI symptoms, anosmia, ageusia; >seven days since index case of household contact had first positive COVID-19 test; taking hydroxychloroquine or remdesivir for any reason; enrolled in a COVID-19 prophylaxis study or receiving COVID-19 prophylaxis as standard of care, including vaccination; any medical condition that would prevent taking oral probiotics or increase risks associated with probiotics; unable to read and follow directions in English or Spanish; living outside of the United States of America; and prisoners and institutionalized individuals. Participants were recruited locally via telephone outreach from study coordinators who All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 5, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 5, 2022. 

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