Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union

Abstract

Background: nasal or oral sprays are often marketed as medical devices (MDs) in the European Union to prevent common cold (CC), with ColdZyme®/Viruprotect® (trypsin/glycerol) mouth spray claiming to prevent colds and the COVID-19 virus from infecting host cells and to shorten/reduce CC symptoms as an example. We analyzed the published (pre)-clinical evidence. Methods: preclinical: comparison of in vitro tests with validated host cell models to determine viral infectivity. Clinical: efficacy, proportion of users protected against virus (compared with non-users) and safety associated with trypsin/glycerol. Results: preclinical data showed that exogenous trypsin enhances SARSCoV2 infectivity and syncytia formation in host models, while culture passages in trypsin presence induce spike protein mutants. The manufacturer claims >98% SARSCoV2 deactivation, although clinically irrelevant as based on a tryptic viral digest, inserting trypsin inactivation before host cells exposure. Efficacy and safety were not adequately addressed in clinical studies or leaflets (no COVID-19 data). Protection was obtained among 9–39% of users, comparable to or lower than placebo-treated or non-users. Several potential safety risks (tissue digestion, bronchoconstriction) were identified. Conclusions: the current European MD regulations may result in insufficient exploration of (pre)clinical proof of action. Exogenous trypsin exposure even raises concerns (higher SARS-CoV-2 infectivity, mutations), whereas its clinical protective performance against respiratory viruses as published remains poor and substandard.

The Saliva of Probands Sucking an Iota-Carrageenan Containing Lozenge Inhibits Viral Binding and Replication of the Most Predominant Common Cold Viruses and SARS-CoV-2

“…After thorough data analysis, the authors concluded that exogenous trypsin exposure might not only be ineffective, but might even trigger adverse effects on viral transmission, susceptibility/infection and mutation. 23 In contrast, no hRV escape mutants could be detected after 10 passages in the presence of low-level iota-carrageenan. 9 As iota-carrageenan non-specifically envelops the virus, thereby preventing interaction between virus and cellular surface, development of resistance due to the occurrence of escape mutants is unlikely.…”

“…A recent review identified 14 such sprays in development; many of these sprays are already marketed as medical devices in Europe. 23 However, a closer look often reveals a lack of safety and efficacy data. Huijghebaert et al investigated a trypsin containing mouth spray (Viroprotect ® , ColdZyme ® ) for which it was claimed to prevent common cold and COVID-19.…”

Tryptase and Exogenous Trypsin: Mechanisms and Ophthalmic Applications

“…It can hydrolyse natural or denatured proteins, fibronectin and mucin into smaller peptides or amino acids. 102 This selective hydrolytic effect of trypsin is mainly related to the structure of the protein. It is said that trypsin only hydrolyses denatured protein, which can be produced under the influence of external physical or chemical factors.…”

Reply to Davison, G. Comment on “Huijghebaert et al. Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union. Int. J. Environ. Res. Public Health 2021, 18, 5066”

“…We have read the comment from Davison with great interest [1]. We are grateful that he highlighted and reported these errors on our end, and regret to inform the readership that the paper on trypsin oral spray indeed contains errors [2]. These errors relate to the misinterpretation of one study that reported on the use of ColdZyme mouth spray in endurance athletes and its impact on the duration of upper respiratory tract infection (URTI) symptoms [3].…”

“…Related to this error (we obtained the numbers the wrong-way-round), Table 2 should also be adapted. We copied the initial Table 2 from the Huighebaert et al paper [2] and have adapted the table section on the Davison study [3]. The former and adapted versions of Table 2 are provided, and the adaptations are discussed below.…”