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Conference Report

Echinacea

Immuno-Prevention of Respiratory Tract Infections Roggwil, Switzerland 16th September, 2021

Introduction The Covid-19 pandemic demonstrated plainly the value of a healthy immune defense in coping with viral respiratory tract infections (RTIs). Impaired immunity as associated with comorbidities, age and smoking once more proved to be a valid risk factor for severe progression of illness and the associated enhanced virus spread contributing to the emergence of new mutations 1-4. Meanwhile, removal of lock-down restrictions has been a longed-for moment and represents return back to normality, but also brings back exposure to colds, flu and of course SARS-CoV-2. Vaccination against the latter is understood “best-practice” but might not offer complete protection against newly emerging variants 5,6. Reluctance in immunizing children might further attenuate herd-immunity, since they account for as much as 25% of the global population. Thus, the quest for broadly effective and safe antivirals will continue into the future together with the pursuit for effective immune defense. Echinacea purpurea is widely known as the immune-herb, recognized to inhibit viral pathogens and to modulate immune mediators according to below prevention formula 7-10. Its efficacy is greatest in infection susceptible individuals, and therefore our latest research focussed on the most susceptible segment of our population – children. They play an important role in the transmission of coronavirus infections and RTIs in general 6. This conference presents and discusses the novel evidence and medicinal value of Echinacea purpurea and its standardized preparations. Pre-clinical studies explored antiviral effects against Coronaviruses and our immune system’s ability to cope with infections. In 2021 a clinical trial was published showing a reduced need for antibiotics through prevention of RTIs by Echinacea. The same study also investigated endemic coronavirus concentrations in Echinacea-treated children, showing encouraging results.

Prevention = Antiviral + Immune Support

Echinacea Supports the Innate Antiviral Immune Defense via Interferon Prof. Wim Vanden Berghe, University Antwerp, Belgium Modulation of inflammatory cytokines (TNF-α) by Echinacea via endocannabinoid receptor CB-2 has been reported in great detail but effects on the innate antiviral immune defense so far remained unknown11. We employed newest genomic and proteomic techniques to find how Echinacea purpurea (Echinaforce®) specifically activated a group of mediators called Interferons (IFN-α or IFN-γ) in monocytes12. Interferons are early inducers of antiviral immunity and further regulate Interleukin IL-8 and CXCL-10 to enhance immune cell mobility and their ability to recognize potential pathogens (Figure 1A). Echinaforce® specifically targeted intracellular transcription factors STAT- and MAP-kinases, which have both been discovered to activate IFN-stimulated genes (ISGs). Overall, the results reveal how Echinaforce® secures innate immune system readiness via “tonic Interferon signalling”. The data present a highly relevant mode-of-action and explanation of earlier clinical findings by Ritchie13 (Figure 1B). A robust innate immune response is central in the early defense and clearance of viral infections. IFNα2

IFNγ

CXCL8 (IL8)

CXCL 10

Figure 1A: Echinaforce® treatment activates the production of various immune mediators in monocytes, which support the early antiviral immune defense: IFN-α and γ as well as chemokines IL-8, CXCL-10 in vitro.

Immuno-Prevention by Echinaforce® Percentage induction of Immune Mediators [%]

+18%

IFN-γ

+35%

IL-8

+28%

IL-10

+49%

MCP-1 0

Figure 1B: Earlier in vivo observations by Ritchie 13 on upregulation of immune factors upon Echinaforce® prevention (immuno-prevention) are herewith understood profoundly.

Echinacea’s Activity Against Respiratory Viruses Dr. Ross Walton, A-IR CLINICAL RESEARCH LIMITED, Dublin (IE) Echinaforce® is one of the few pharmaceuticals with approved indication for the prevention of respiratory tract infections (RTIs) 14, Echinaforce® can be administered in conjunction with vaccines to enhance protection from respiratory viruses, benefitting from its broad range of action 15. Latest research demonstrates that Echinacea modifies viral surface receptors, that are required for cellular attack, e.g. haemagglutinin or spike protein (Figure 2). In doing so, the extract blocks infectivity of an array of pathogens, including all enveloped viruses tested to date, like Influenza or Coronaviruses (Table 1) 7,8,16.

EF EF

Figure 2 shows how Echinacea blocks infectivity of viruses. Binding to spike protein on Coronaviruses or hemagglutinin on Influenza effectively blocks their ability to attach to host cells as shown by molecular modelling techniques.

Table 1: Minimal Inhibitory Concentrations (MIC100) indicated for individual respiratory viruses. MIC’s represent the smallest concentration that fully inactivates virus infectivity

Respiratory Viruses

Strain

Reference

Victoria/3/75

MIC100 ++++

Influenza A/H3N2 Influenza A/H5N1

Thailand/KAN-1/04

+++

Pleschka S, et al. (2009)

Influenza A/H7N7

Bratislava/79

+++

Pleschka S, et al. (2009)

Influenza A/H7N9

Anhui/1/2013

+++

Schoop R, et al. (2015)

+++

Sharma M, et al. (2009b)

Influenza B

Sharma M, et al. (2009a)

Respiratory Syncytial Virus

RSV-1

+++

Sharma M, et al. (2009a)

Parainfluenza

PI-3

+++

Sharma M, et al. (2009b)

Herpes simplex

HSV-1

++++

Sharma M, et al. (2009a)

Rhinoviruses

RV-14 / RV-1A

Sharma M, et al. (2009a)

Adenoviruses

Ad-3/-11

Sharma M, et al. (2009a)

Coronavirus

229E

+++

Engler O, et al. (2017)

Coronavirus

SARS-CoV-1

+++

Signer J, et al. (2020)

Yellow fever virus

YFV

+++

Signer J, et al. (2020)

++++ MIC100 < 1 µg/ml ; +++ MIC100 < 50 µg/ml ; ++ MIC100 < 100 µg/ml ; + MIC100 < 800 µg/ml

Latest Research on Highly Pathogenic Viruses and SARS-CoV-2 Recent experiments at the Laboratory Spiez, Switzerland and the University Giessen, Germany have shown that even highly pathogenic enveloped SARS-CoV-2, MERS-CoV or bird flu virus (H5N1 or H1N1) are inactivated by less than 50 µg/ml of Echinaforce® in vitro17. Resistance to Echinacea is not expected to develop and the activity appears robust against emerging virus mutations. The inhibition it provides is not virus strainspecific but rather very broad acting in its mode of action (Figure 2-3, Table 1).

SARS-CoV-2 (2020)

Virustiter (PFU/ml)

Virustiter (TCID50/ml)

MERS-CoV (2017)

μg/ml Echinaforce®-Extrakt

Figure 3: Echinaforce® broadly inhibits Coronaviruses in vitro

Clinical Relevance SARS-CoV-2 and other respiratory viruses are known to primarily infect and replicate in the throat (pharynx). Sucking Echinaforce® tablets or gargling the tincture applies an effective concentration, which exceeds the established antiviral concentration of 50 µg/ml by a factor of 100. In practice, clinicians found that the severity of viral illnesses (e.g. Covid-19) directly correlates with the virus concentration present 18. Thus, any reduction of the infectious virus load is beneficial not only for the prevention but also for the course of illness. Above in vitro results are further confirmed by two clinical studies on approximately 1000 subjects showing that Echinaforce® reduces enveloped virus infections (incl. Coronaviruses) by up to 50% (p < 0.05) in vivo15.

Prevention of Respiratory Tract Infections with Echinacea in Children Dr. Mercedes Ogal, Pediatric Specialist, Pediatric Clinic, Brunnen (CH) Children represent an important link in the transmission of respiratory tract infections (RTIs) because of their general susceptibility, their penchant for close contacting and substantially increased viral shedding during acute infections. Many parents rely on vitamins and food supplements with unknown efficacy and safety profile to support immune defenses in their children. The aim of this randomized, controlled and blinded study was to investigate the safety and efficacy of Echinaforce® Junior tablets when used for the long-term prevention of RTIs over 4 months 19. 203 children aged 4 – 12 years were recruited by 13 general and paediatric practices in Switzerland. N=103 were randomly allocated to take 3 x 1 Echinaforce® Junior tablet (EFJ 400mg) and N=98 to 3 x 1 vitamin C tablet (VC 50mg) for control. Nasal secretions were collected during acute infections and screened for respiratory viruses using RT-PCR (Allplex®). The majority of children using Echinaforce® remained free of RTIs and reported 32.5% fewer cold and flu episodes than the control group (odds ratio OR=0.52 [95% CI, 0.30-0.91], p = 0.021). Overall, 429 cold days occurred with EFJ in comparison to 602 days with VC (p < 0.001). Six children (5.8%) with EFJ required antibiotics on 45 days in comparison to 24 prescriptions in the VC group (24.5%) administered over 216 days, which represents a clinically highly relevant 76.3% reduction (p < 0.001, see Figure 4). The reduction in use of antibiotics was associated with a marked 65.0% prevention of RTI complications (pneumonia, tonsillitis or otitis media), where 9.7% and 20.4% of children experienced 11 and 30 events with Echinacea and control, respectively (p<0.05). A significant reduction of Influenza (3 vs. 20 detections, p<0.05) and of membranous virus infections overall (29 vs 47 detections, p<0.05) was further found for Echinacea. In those where respiratory symptoms still occurred, these were less severe and episodes shorter by 1.4 days with EFJ compared to control treatment. Fever (i.e. body core temperature ≥ 37.8°C) occurred on 1.6 vs 4.9 days on average, showing a 67.3% reduction (3.3 days) in those using Echinacea (p<0.001, Figure 4). Echinaforce® Junior was non-inferior to vitamin C with respect of safety, whereas 3 and 2 participants reported adverse drug reactions with possible causal relationship with the treatment. Allergic and hypersensitivity reactions including rash or urticaria occurred with the same frequency of 5.8 and 6.1% in both groups.

Percentage of Reduction i.c. to Control

80% –

*** ***

70% – 60% –

76.3%

67.3%

65.0%

50% – 40% –

30% –

32.5%

20% – 10% – 0% –

Colds & Flu Days with Fever Complications (RTIs)

Antibiotic Prescriptions

Figure 4: Children receiving Echinaforce® Junior benefited from prevention of multiple complaints, which are medicinally related (*p<0.05; **p<0.01; ***p<0.001).

Coronavirus Infections in Children – A Subanalysis This study was carried out before occurrence of Covid-19 (2016/17) and a total of 24 (13/11) endemic coronavirus infections occurred including CoV-229E, NL-63 and OC43, which were further analysed. Echinaforce®-treated children showed a significant 98.5% reduction of virus loads in nasal secretions with Ct-values of 31.1 [95% CI 26.3; 35.9] in comparison with 25.0 [95% CI 20.5; 29.5] for the control group (p = 0.0479; 95% CI: 0.07 – 0.47) 20. Strongly increased mean Ct-values by 5.53 and 11.92 were observed for variant NL63 and OC43, equalling a significant virus reduction by over 97.9% (p<0.05, Figure 5A). In correlation with decreased viral loads, children with Echinaforce® displayed significantly reduced respiratory symptoms during coronavirus infections as shown in figure 5B 6. The area-under-curve indicated a 64.2% reduction from 75.8 [95% CI: 39.8 – 111.7] to 27.1 [95% CI: 14.8 – 39.4] score points in children supplemented with Echinacea (p=0.0036).

Sum Score [mean+-StdErr]

CT values

15 Control 10

Echinaforce® 0 Echinaforce®

Control

1 2 3 4

Day

Figure 5: Children with Echinacea prevention reported significantly reduced viral sheddig (A) and respiratory symptoms (B) during coronavirus infections when comparing with control (vitamin C).

Conclusion The most recent research presented at this conference materially improves our understanding of how Echinaforce® supports the antiviral immune defense to prevent respiratory tract infections. Echinaforce® promotes tonic Interferon signalling to finally ensure innate immune system readiness. Broad-spectrum antiviral activity further complements the pharmacological action of Echinacea, showing an overall “Immuno-Prevention”. Clinical studies clearly demonstrate that Echinaforce® prevention over 2 – 4 months significantly reduces the occurrence of RTIs and of RTI complications in adults as well as in children. For the first time it was shown how immuno-prevention through Echinacea led to 76.3% reduction of antibiotics, which could represent a novel strategy to solve the still prevaling issue with over-prescription of the latter. Of greatest interest are data on Coronaviruses, where inhibitory effects were seen on endemic strains, as well as highly pathogenic SARS-CoV-1 and SARS-Co-2 in vitro. Newest clinical sub-analyses confirm lower endemic Coronavirus concentrations in nasal secretions of Echinaforce® treated children and reduced symptom severity in comparison with control. Considering the broad antiviral spectrum, these results strongly suggest the use of Echinaforce® for immunoprevention of RTIs, including Coronavirus infections.

Echinaforce® Extract

ü A Broad-Spectrum Antiviral ü Supports the Production of Interferon ü Ensures a Robust and Early Antiviral Defense ü Effectively Prevents Respiratory Tract Infections in Children

and Adults

ü Significantly Reduces the Need for Antibiotics ü Reduces Severity of Coronavirus Infections and Viral Shedding

Expert Panel Dr med Rainer Stange Senior Researcher at the Charité – Universitätsmedizin Berlin, Germany M.D., PhD, Internal Medicine, Natural Medicine, Physical Therapy (approval by Doctors’ Chamber). Presently Senior Researcher at Charité – Universitätsmedizin Berlin. Longterm clinical experience in Natural Medicine. Vice-president of German Society for Phytotherapy (GPT), president of German Medical Association for Natural Medicine (ZAEN). Co-editor of Lehrbuch der Naturheilverfahren (Textbook of Natural Medicine, Thieme, Germany, 2010). Appr. 45scientific publications in PubMed.

Dr. Mercedes Ogal Pediatric Specialist, Paediatric Clinic, Brunnen (CH) Mercedes Ogal has worked as a specialized integrative pediatrician for 18 years in a pediatric medical practice in Central Switzerland. She developed her deep knowledge in complementary medicine since 1991 in phytotherapy, acupuncture, homoepathy, medical hypnosis and orthomolecular medicine and owns certificates in various medicinal disciplines. Furthermore, Dr. Mercedes Ogal is author of publications and speaker on various national and international lectures and conferences.

Prof. Wim Vanden Berghe Epigenetic Signaling Lab, PPES, University Antwerp, Belgium Prof. Wim Vanden Berghe obtained his PhD in Biochemistry-Biotechnology at the University of Ghent in 1999. After postdoctoral research at University of Montpellier, Stellenbosch and Oxford, he was appointed professor of Epigenetics in 2009 at the lab for Protein chemistry, proteomics and epigenetic signaling (PPES, Universities of Antwerp and Gent, Belgium). With his current research, he is characterizing epigenetic regulation of kinase signaling pathways to modulate inflammatory disease phenotypes with phytomedicinal or pharmacological compounds in cancer, atherosclerosis, obesity, infectious disease or neurodegeneration.

Dr. Ross Walton Dr. Ross Walton, A-IR CLINICAL RESEARCH LIMITED, Dublin (IE) Ross Walton attained his PhD from Imperial College investigating mechanism of respiratory viral induced modification of allergic airway responses. He has substantial experience with complex in vivo and human models of virus infection, including rhinovirus, respiratory syncytial virus and influenza. Employing state-of-the-art analytical approaches in patient samples alongside complimentary in vivo models, he explores the cellular interactions underpinning the immunological basis of chronic respiratory diseases and viral infection.

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Victoria A, et al. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020; 183(7):1901-12.

Kemp, SA, et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021; 592:277–282.

Hopkinson NS, et al. Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people Thorax 2021;76:714–722. doi:10.1136/thoraxjnl-2020-216422

5] Gupta RK. Will SARS-CoV-2 variants of concern affect the promise of vaccines? Nature Reviews Immunology. 2021;21:340–341. 6

Laws RL, et al. Symptoms and Transmission of SARS-CoV-2 Among Children — Utah and Wisconsin, March–May Pediatrics. 2021;147(1).

Pleschka S, Stein M, Schoop R, Hudson JB. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian influenza virus (H5N1, H7N7) and swine-origin H1N1 (S-OIV). Virology Journal 2009;6:197.

8 Vimalanathan S. High-potency anti-influenza therapy by a combination of Echinacea purpurea fresh herb and root tinctures. JAPS;3(12):1-5. 9

Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial. Evidence-Based Complementary and Alternative Medicine. 2012 doi:10.1155/2012/841315.

10 Schapowal A. Efficacy and safety of Echinaforce® in respiratory tract infections. Wien Med Wochenschr. 2013;163(3-4):102-5. 11 Gertsch J, Schoop R, Kuenzle U, Suter A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett. 2004 Nov 19;577(3):563-9. 12 Declerck K, Perez Novo C, Grielens L, Van Camp G, Suter A, Vanden Berghe W. Echinacea purpurea (L.) Moench treatment of monocytes promotes tonic interferon signaling, increased innate immunity gene expression and DNA repeat hypermethylated silencing of endogenous retroviral sequences. BMC Complement Med Ther. 2021 May 12;21(1):141. 13 Ritchie MR, Gertsch J, Klein P, Schoop R. Effects of Echinaforce® treatment on ex vivo-stimulated blood cells. Phytomedicine. 2011 Jul 15;18(10):826-31. 14 Swissmedic-approved indication according to patient information retrieved from https://compendium.ch/product/1301203vogel-echinaforce-forte-tabl/mpub (2020). 15 Schapowal A. Use of Echinaforce® to Prevent Coronavirus Infections. EC Microbiology, 2020: 23-25. 16 Signer J, et al. (2020). In vitro virucidal activity of Echinaforce®, an Echinacea purpurea preparation, against coronaviruses, including common cold coronavirus 229E and SARS-CoV-2. Virology Journal. 17(1):136 17 Engler O, Suter A, Signer J, Strasser M, Schoop R. (2017). Inhibitory Potential of Echinacea purpurea on infection and dissemination of Coronaviruses including Middle-East-Respiratory Syndrome-Coronavirus (MERS-CoV). GA conference (Poster), Basel, Switzerland. 18 Bieleck M, et al. (2020). Social distancing alters the clinical course of COVID-19 in young adults: A comparative cohort study. Clinical Infectious Diseases; https://doi.org/10.1093/cid/ciaa889. 19 Ogal M, Johnston SL, Klein P, Schoop R. Echinacea reduces antibiotic usage in children through respiratory tract infection prevention: a randomized, blinded, controlled clinical trial. Eur J Med Res. 2021. Apr 8;26(1):33. 20 Nicolussi S, Gancitano G, Klein P, Stange R, Ogal M. Echinacea as a Potential Weapon aganist Coronavirus Infections?: A Mini-Review of Randomized Controlled Trials. GA conference (Poster), 2021, Bonn, Germany.

Echinaforce

Extract of freshly harvested Echinacea purpurea

Combination of 95% herba and 5% radix

Standardised ethanolic extract

Grown from own (recycled) seeds

Organically (biologically) cultivated