Page 45 - JCTR-11-3

Journal of Clinical and
Translational Research Greek propolis use in COVID-19: Trial protocol

1. Introduction clinical validation, such products have been widely
adopted, particularly in low-resource settings and among
The COVID-19 pandemic continues to challenge global vaccine-hesitant populations. Reflecting this trend, the
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healthcare systems, despite the rapid rollout of vaccines World Health Organization (WHO) has highlighted the
and public health interventions. Vaccine inequity remains role of traditional medicine in public health, noting that
a major obstacle, particularly in low- and middle- approximately 80% of the global population uses natural
income countries, where a significant proportion of the therapies. In this context, natural agents with historical
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population still lacks access to vaccination. In addition, use and emerging antiviral evidence, such as propolis,
1,2
vaccine hesitancy has been documented among specific warrant further scientific investigation.
demographic cohorts, including healthcare workers, driven
by concerns over safety, misinformation, and distrust in Propolis is a resinous substance produced by bees
the pharmaceutical industry. 3-5 from plant exudates, widely used in traditional medicine
for its antimicrobial and wound-healing properties. 22,23 Its
These gaps underscore the urgent need for safe, effective, composition varies depending on geographic origin and
and affordable adjunctive therapies to complement botanical source, influencing its bioactivity. The poplar-
standard care, particularly those that are accessible in type propolis found in Greece is rich in flavonoids and
resource-limited settings. Propolis, a complex resinous phenolic compounds such as pinocembrin, galangin,
product collected by bees from plant exudates, has been chrysin, and caffeic acid phenethyl ester, which have
used medicinally for its antimicrobial, anti-inflammatory, been associated with antiviral, anti-inflammatory, and
and immunomodulatory properties. Contemporary immunomodulatory effects. 8,16
6,7
in vitro and in silico studies have demonstrated that
flavonoids and other polyphenolic constituents of propolis Various systematic reviews and pre-clinical studies
can inhibit viral replication and modulate immune support the potential of propolis as a candidate for
pathways. 8-11 Moreover, early-stage clinical investigations COVID-19 adjunctive therapy. A 2022 systematic review
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suggest potential benefits in symptom reduction and by Dilokthornsakul et al. summarized nine in silico
viral clearance in COVID-19; however, methodological studies showing strong binding affinities between key
limitations restrict the generalizability of these findings. 12-15 flavonoids in propolis, such as caffeic acid phenethyl ester,
chrysin, luteolin, and rutin, and SARS-CoV-2 targets,
The chemical composition and therapeutic profile of including the angiotensin-converting enzyme 2 receptor,
propolis vary by geography and botanical source. Greek main protease, papain-like protease, and RNA-dependent
poplar-type propolis, rich in polyphenols, may offer RNA polymerase. These constituents were found to
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targeted antiviral effects relevant to severe acute respiratory interact with viral entry and replication pathways, often
syndrome coronavirus 2 (SARS-CoV-2). However, no demonstrating comparable or superior docking scores to
robust placebo-controlled clinical trials have yet evaluated repurposed antiviral drugs.
its efficacy in COVID-19 treatment. Complementary in vitro investigations have further
This protocol describes a randomized, triple-blind, validated these findings. Sberna et al. reported
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placebo-controlled three-arm clinical trial investigating the that Eurasian poplar-type propolis extract inhibited
therapeutic potential of a Greek hydroalcoholic propolis SARS-CoV-2 replication in Vero E6 cells, reduced
extract, formulated into alcohol-free oral capsules, as an cytopathic effects, and modulated proinflammatory
adjunct to standard care, compared against both a placebo cytokines. Other in vitro studies with flavonoids commonly
adjunct and standard care alone. The primary outcomes found in propolis, such as rutin, hypericin, and cyanidin-3-
are time to viral clearance and duration of hospitalization, O-glucoside, have demonstrated concentration-dependent
with secondary endpoints examining symptom severity, inhibition of SARS-CoV-2 proteases. 25,26 While variability
quality of life (QoL), and safety. in composition presents a challenge, the Greek variant,
classified as poplar-type, shares a similar phytochemical
2. Background and rationale of the study profile.
Amid persistent global disparities in vaccine distribution Clinical data, though still limited, are emerging.
and uptake, there has been growing interest in accessible, A randomized controlled trial by Silveira et al. using
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safe adjuncts to conventional COVID-19 care. During Brazilian green propolis (EPP-AF ) showed reduced

the pandemic, global demand for nutraceuticals and hospital stay in COVID-19 patients. In addition, a
botanical supplements surged, driven by perceptions volunteer-based study and two case studies 12,13 have
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of immune-enhancing effects and widespread mistrust described symptom improvement, faster recovery,
toward pharmaceutical interventions. 17-19 Despite limited and possible prophylactic effects following propolis

Volume 11 Issue 3 (2025) 39 doi: 10.36922/jctr.24.00073