scientific evaluation of viiral nasal spray · viiral nasal spray contains 1 mg sialic acid/ml. a...

Scientific Evaluation of

Viiral Nasal Spray

Avia Pharma AB

Project: Viiral Nasal Spray

June 14th 2019

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Svärdvägen 23, SE-182 33 Danderyd, Sweden, Phone +46 (0)8-755 80 80

Overall assessment of Viiral Nasal Spray

Product and safety

Viiral Nasal Spray is a CE-labelled class I medical device. This report evaluates the safety and efficacy of Viiral Nasal Spray and is based on a safety and toxicity study plus a separate clinical study conducted in Norway where the product was tested on SAS cabin crew. Viiral Nasal Spray contains sialic acid, a naturally occurring type of sugar molecule. The mechanism of action for sialic acid with regard to the prevention viral infections is not detailed but is probably related to the fact that sialic acid prevents viruses from binding to cell surface receptors and thereby prevents viruses from entering cells, where it replicates and causes infection.

Clinical documentation

The role of Viiral Nasal Spray in preventing viral infections (colds) has been documented in a 4-week study on a total of 127 participants. Of the 111 participants who successfully completed the study, 68 received Viiral Nasal Spray and 43 participants received placebo. The study evaluated several different parameters, including sick days away from work (the main parameter), moistness in the nose, unblocked nose, problems affecting the nose and everyday life energy levels. This report focuses exclusively on the main efficacy variable: the number of sick days away from work. Regarding the main efficacy variable, the question was designed as follows: Primary variable:

From a methodological perspective, the phrasing of the question may underestimate the number of sick days taken (and of any effect of treatment) because if the question is strictly answered, a sick day is only counted if it was taken on a scheduled workday. Since it can be assumed that cabin crews maintain irregular working schedules with days off work during a week, it is likely that there are unrecorded sick days - simply because such days occurred on a day off work. However, since the study was randomized and controlled, it means that the same possible underreporting is present in both treatments and that a comparison between the groups is, after all, valid. The results of the study show that treatment with Viiral Nasal Spray can likely reduce the risk of contracting upper respiratory diseases and also reduce the number of sick days taken by those who do fall ill. Overall, the number of sick days taken by those treated with Viiral Nasal Spray is estimated at 0.58 per 4-week period compared to 1.37 per 4-week period for those treated with a placebo, which is a reduction of over 50%.

Have you been home from work and been on sick leave during the past week due to an upper

respiratory tract disease? If so, for how many days?

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The reduction in morbidity is estimated in two steps: the risk of becoming ill and the reduction in the number of sick days for those who do fall ill. In a model that estimates only the number of sick days for those who fall ill, the p-value is 0.047. In a more complicated model that simultaneously estimates both the risk of illness and the number of sick days for those who fall ill, the p-values are 0.084 and 0.051 respectively (a p-value for each parameter). An overall assessment of these two p-values, which are both close to 0.05, gives a p-value of less than 0.05 when simultaneously interpreting both variables. The p-value cannot be calculated exactly because of the variables are not independent (one-sided test, H0: Viiral better than a placebo, statistical method: zero-inflated Poisson). In summary, the clinical study shows that Viiral Nasal Spray, when used as a prophylactic, reduces morbidity related to upper respiratory tract infections. Danderyd, June 14th 2019 Anna Törner PhD, Regulatory Expert, SDS Niclas Sjögren Med Lic, Senior Statistician, SDS Ann-Kristin Spiik Med Lic, Medical Writer, SDS

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Content Overall assessment of Viiral Nasal Spray....................................................................................................... 2

Product and safety .................................................................................................................................... 2 Clinical documentation.............................................................................................................................. 2

1. Introduction ........................................................................................................................................... 5 2. Background ............................................................................................................................................ 5

2.1 Sialic acid ....................................................................................................................................... 5 2.2 Viiral nasal spray ............................................................................................................................ 6

2.2.1 Viiral nasal spray product ...................................................................................................... 6 2.2.2 Viiral nasal spray mechanism of action ................................................................................. 6

3. Safety, sialic acid in Viiral nasal spray ................................................................................................... 9 4. Clinical study with Viiral nasal spray ..................................................................................................... 9

4.1 Study background .......................................................................................................................... 9 4.2 Study design ................................................................................................................................ 10 4.3 Population ................................................................................................................................... 10

4.3.1 Inclusion- and exclusion criteria .......................................................................................... 10 4.4 Conduct of study ......................................................................................................................... 10 4.5 Test products ............................................................................................................................... 11

4.5.1 Production of test product Viiral nasal spray ...................................................................... 12 4.5.2 Produktion av test product, Placebo ................................................................................... 12

4.6 Treatment .................................................................................................................................... 12 4.7 Questionnaire .............................................................................................................................. 12 4.8 Study results ................................................................................................................................ 13

4.8.1 Participation and completion of the study program ........................................................... 13 4.9 Statistical methods and analysis ................................................................................................. 14 4.10 Conclusions .................................................................................................................................. 14

5. References ........................................................................................................................................... 15

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1. Introduction

This report describes the benefits and safety of Viiral Nasal Spray when used to avoid colds. Viiral Nasal Spray contains the sialic acid N-acetylneuramic acid (Neu5Ac). Sialic acid is a natural substance (a type of sugar molecule) found in many common foods and is an important part of all cell surfaces and membranes. When coupled to larger sugar molecules and to proteins and/or lipids, sialic acid can function, inter alia, as a receptor for viruses and a virus must bind to a receptor in the nasal mucosa in order to initiate an infection. Once bound to a receptor, the virus particle can then enter the cell for replication (propagation). Research shows that mechanisms for both receptor binding and viral cell penetration can be inhibited by sialic acid and its mechanism of action is probably related to its effects on the cell membrane, possibly by masking sialic acid binding sites on the virus particle itself, or by blocking receptors on the cell membrane. The addition of soluble sialic acid in saline solution can also help moisturize dry and sore mucous membranes. Together, the molecular and physiological properties of sialic acid likely provide protection against colds. The mechanism of action is physiological, and the product is classified as medical device class I (CE marking according to MDD).

2. Background

2.1 Sialic acid

Sialic acid is the generic name for N- or O-substituted derivatives of neuraminic acid, a monosaccharide with nine carbon atoms. The substance was first described in saliva, and the term sialic acid was derived from the Greek word for saliva: sialon. Sialic acids are found naturally at the end of dense and complex braids of sugar molecules, proteins and lipids on cell surfaces - and on many soluble proteins. Sialic acid naturally occurs on the surface of all eukaryotic cells in plants, animals and humans. Sialic acid is present in large amounts in human breast milk and foods. Foods such as wild salmon, caviar and mozzarella cheese contain particularly high levels of sialic acid. According to Schalcter (2017), Neu5Ac is rapidly absorbed into the body after ingestion. It is also rapidly excreted again via urine. Animal studies show that up to 98% of Neu5Ac may be recovered in the urine after six hours and translated to humans, this indicates about eight hours after ingestion. The highest concentration of sialic acid is found in saliva, urine and the human brain. Molecular, cellular and genetic studies show that sialic acids participate in the control of cell to cell and cell matrix interactions, intermolecular cell surface interactions and in interactions between other molecules in the cell's immediate extracellular environment. The figures below show that N-acetylneuramic acid = Neu5Ac and N-glycolylneuramic acid = Neu5Gc. Neu5Ac can be converted to Neu5Gc using the enzyme CMAH (cytidine monophosphate-N-acetylneuramic acid hydroxylase). However, this enzyme is not found in humans due to a deletion in the gene coding for it. It is believed that humans in prehistoric times lost the functionality of this gene and

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thus the ability to convert Neu5Ac to Neu5Gc. In contrast to animals and some other organisms, humans can only synthesize Neu5Gc (Sprenger and Duncan, 2012).

2.2 Viiral nasal spray

Viiral Nasal Spray is a product developed by the Norwegian company Viiral AS. The common cold is often caused by a virus. Viiral increases the amount of Sinalin™ in the nasal mucosa. Sinalin™ is a neuraminic acid that occurs naturally in breast milk and can prevent a cold virus infection by stopping the virus from penetrating through the mucosa. Viiral also moisturizes the mucosa, which helps reduce nasal breathing problems.

2.2.1 Viiral nasal spray product

Viiral Nasal Spray contains 1 mg sialic acid/ml. A 20 ml bottle delivers 130 doses or puffs, with each puff containing about 0.154 mg of sialic acid. The recommended dose of Viiral Nasal Spray is two puffs sprayed into each nostril twice daily - a total of 8 doses per day. This corresponds to the inhalation of 1.23 mg of sialic acid.

2.2.2 Viiral nasal spray mechanism of action

Sialic acids cover the epithelium of the respiratory tract and can act as receptors for viruses. Recent research using glycan microarrays and other sophisticated methods shows the complexity of the

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interactions between sialic acid-containing receptors on cell surfaces and viral proteins. This provides opportunities to study how viruses attach to cell surfaces in the airway epithelium (Neu, Bauer, & Stehle, 2011). A virus has either DNA or RNA as its genetic material and is dependent on a host cell for replication causing infection. The first step in an infection cycle is when a virus particle binds itself to an epithelial cell via specific receptors. These receptors are often glycans with bound sialic acid. Different types of viruses have varying structures in their surface proteins that recognize the respective receptors. After binding, they use different mechanisms to enter the cell. Influenza viruses, for example, enter the cell with their own enzyme (neuraminidase). The enzyme breaks bonds between the sialic acid and the sugar molecules and the virus particle is absorbed into the cell via endocytosis. Other viruses use different mechanisms. The rhinovirus (HRV) is the most common cause of upper airway colds. HRV uses an intercellular molecule - ICAM-12 - in the host cell as its receptor. This is found on the surface of the ciliated nasal epithelium. The structure of the receptor has been known for a long time and contains sialic acid as part of the binding mechanism. Like the influenza virus, rhinovirus also enters the cell via endocytosis. From a treatability perspective, substances that stop a virus’s ability to infect at an early stage are of interest. The most effective approach is to block the binding of the virus’s surface or surface protein with the nasal epithelium. If the virus does not bind definitively to its receptor, it will not fuse with the cell membrane or be absorbed into the cell via endocytosis. Studies show that small changes in either the receptor or the chemical relationship with the mucosa, such as an altered ionic composition or pH, have an effect on virus activity. The unique structure of Neu5Ac provides a molecule with several important functional groups: carboxyl; hydroxyl; N - acetyl; and glycerol functions. These groups give the Neu5Ac molecule many possibilities for hydrogen binding, salt bridges and non-polar interactions when compared to individual monosaccharides (Schnaar et al., 2014). For the virus to reproduce and create an infection, the virus must not only attach itself to the epithelial surface but also penetrate enzymatically within the cell in order to utilize its own replication mechanism. Furthermore, new virus particles must be able to leave the cell. Breaching of cell membranes can occur via a neuraminidase enzyme, an enzyme that cuts the sialic acid from glycoconjugate. The viral enzyme thus facilitates the further spread of new virus particles. Studies have shown that they are also able to neutralize silanic acid containing soluble proteins that would otherwise interfere with the surface of viral binding (Varki, 2018 and Stehle, 2014). The theory behind how Viiral Nasal Spray functions is that its supply of sialic acids can clear and possibly also block the binding of viruses to cell surfaces so that virus replication is inhibited. Studies show that sialic acids must be bound to glycoconjugates in order for them to function as receptors for the virus particles. In order for this to occur, the sialic acid must first be absorbed in the cell via pinocytosis and then transported in an activated state in the cell nucleus and also conjugated in the Golgi apparatus before the conjugates are transported onto the cell surface. Neu et al. (2011) has conducted extensive studies of the conditions required for binding between different types of virus and the sialic acid in the glycan coating. No matter which virus protein the sialic acid binds to, the sialic acid molecule has the same three-dimensional structure. This particular form

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provides exposure to two important functional groups on the sialic acid molecule providing a possible cause for virus recognition of the sialic acid of other monosaccharides. Studies of the receptor's contact points (Neu et al., 2011) between the virus and the cell, claim that these are not particularly strong, so-called low affinity bonds. According to Neu et al. (2011), the sialic acid that is found in Viiral Nasal Spray can affect the contact points and thus the binding between the virus and the epithelial cell. This prevents the virus from entering the cell and can be a potential mechanism of action for Viiral Nasal Spray. Sialic acid is, as the name implies, an acid. In solution, sialic acid can dissociate and bind to other active groups having opposite charge. It is therefore conceivable that unbound sialic acid can camouflage the binding sites on the virus particle itself before it binds to the glycan bound sialic acid. It provides a competitive bond between bound and free sialic acid to viral proteins. The figure below shows the chemistry of the binding area between the viral protein and sialic acid bound to the host cell receptor. It illustrates chemical bonds between receptor-bound sialic acid (yellow molecule) and amino acids that are part of the virus's coat protein. This protein contains specific regions where amino acids are indicated by their name codes and their location in the protein chain (ex v Tyr98). The bonds between the saline acid and groups on the amino acids are dashed in most cases, indicating relatively weak bond. Ref Cross et al 2001. Exp Reviews In Molecular Medicine.

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3. Safety, sialic acid in Viiral nasal spray

Sialic acid is found naturally in foods. Sialic acid and its glycoconjugates have been used by humans for a long time. Extensive work to describe sialic acid's safety profile has been undertaken through searches in databases of publicly available information (Reference: Safety of Sialic acid, Anne Bjørnebye Vik, Aug 27, 2018). The above referenced report described the molecular structures and function of sialic acid in cells. The dose of free sialic acid in Viiral Nasal Spray was compared with the daily intake of sialic acid via certain foods, where wild-caught salmon clearly had the highest proportion of sialic acid. The report also includes results from toxicity studies, reproductive toxicity studies, mutagenicity and genotoxicity studies. The NOAEL for Neu5Ac is determined in rats at 974 mg/kg body weight per day. The report summarized that no information could be identified that shows, or indicates, any safety issues arising from sialic acid present in a spray for human use.

4. Clinical study with Viiral nasal spray

4.1 Study background

The airline SAS has long experienced high staff absence due to sickness. In the spring of 2017, SAS contacted Viiral AS to discuss the possibility of conducting a study to investigate if distributing Viiral Nasal Spray to its cabin crew could reduce sick leave. During flights, cabin crews are exposed to bacteria and viruses from different geographical areas and to individuals of varying health statuses. Furthermore, they are exposed to time differences, large variations in temperature, air pollution, changed circadian rhythms and various atmospheric pressures. As a result, it can be argued that cabin crews are a group particularly vulnerable to airborne infection, so-called drop infection, which is a common way both viruses and bacteria spreads. The purpose of the study was to test whether Viiral Nasal Spray had a soothing and/or preventive/inhibitory effect on respiratory ailments such as colds and dry nasal membranes. The study was conducted over a 4-week period. Participants were instructed to take the Nasal Spray twice daily - (2 sprays per nostril/day). The study was conducted on healthy volunteers with the hypothesis that daily treatment with Viiral Nasal Spray could prevent and/or alleviate upper respiratory tract infections. All participation was based on written information about the study, voluntary and with written consent. Participants could withdraw from the study at any time. Anonymized data was collected via an online solution once a week. The data processing took place independently of both Viiral AS and at SAS at the department for health and safety.

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4.2 Study design

The study was a blind, placebo-controlled randomized study. Viiral Nasal Spray contains the sialic acid N-acetylneuramic acid (Neu5Ac).

4.3 Population

127 people participated in the study. Due to logistical challenges related to placebo production, 78 people were given the active product (Viiral Nasal Spray) - study product A, and 49 a placebo - study product B. The participants answered 127 x 4 questionnaires = 508 forms in aggregate. A total of 445 forms were satisfactorily answered and returned, a rate of 87.6%. Of these, 271 came from group A and 174 from group B. A total of 69 participants in group A and 43 participants in group B completed the study. In total, 88% of the participants took 8 sprays daily for 4 weeks. The study was conducted on healthy individuals during the period October to November 2017. All study participants signed consent forms.

4.3.1 Inclusion- and exclusion criteria

Inclusion criteria People over the age of 18 and of either sex. Cabin crew at SAS. Exclusion criteria Asthmatics. People with respiratory allergies. People with chronic lung diseases. People taking medications for chronic diseases. Cancer patients. People who had received a flu vaccine during the previous 6-12 months. Pregnant and nursing women.

4.4 Conduct of study

A trial protocol was prepared by Viiral AS, which was subsequently approved by the HR department and the occupational health service of SAS July 2017.

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SAS took responsibility for recruiting a selection of voluntary participants for the survey from among the approximately 1,300 employees in the organization. The recruitment took place during the period July to

August 2017. The employees were informed of the study plans via SAS's internal network, where those who were interested in participating in the study were asked to contact the HR department. The participants in the study received information about the study and trial and they also signed a consent form in accordance with applicable regulations. The consent form was signed by all participants before the start of study. A total of 127 employees participated in the study, which was physically carried out during the period 29th October 29th to November 26th, 2017. The study was double-blind and randomized. SAS's HR department distributed two types of study material: nasal spray bottles of labelled A and nasal spray bottles of labelled B. Those who distributed the study material did not know which spray bottle (A or B) contained Viiral Nasal Spray. The HR department randomly distributed the spray bottles to the study participants at the national border office at Gardemoen. Study participants were each given 2 nasal spray bottles and also information about how to use the nasal spray (2 sprays in each nostril twice daily) plus instructions and access to a 6-question questionnaire to be answered electronically after 1, 2, 3 and 4 weeks. • The independent consulting company eSTEP was selected to set up the questionnaires electronically via an app and to collect data. The data processing was also anonymous to this company.

4.5 Test products

Viiral Nasal Spray and Viiral Placebo (0.9% Saline/NaCl) Viiral Nasal Spray (20 ml) contained a total of 20 mg of neuraminic acid (Neu5Ac) dissolved in isotonic saline (0.9% NaCl). A 20 ml spray bottle contained 140 spray doses. Viiral Placebo contained 20 ml of isotonic saline. Comment: It is important to note that the composition of the placebo substance (identical to the known pharmacy product with 0.9% NaCl) is recommended as "therapy" for stuffy nose and colds (ref: physicians and pharmacists). This is why Viiral AS chose to use a 0.9% NaCl spray as a control. A possible difference in effect between Viiral Nasal Spray and Viiral Placebo spray can therefore be attributed to the neuraminic acid in Viiral Nasal Spray. Since the placebo can also be expected to have an effect on colds and stuffy noses, the study will therefore investigate which potential additional effects are observed by the addition of neuraminic acid.

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4.5.1 Production of test product Viiral nasal spray

Viiral Nasal Spray was manufactured by the Norwegian company Pharmatech AS; Valley Hills 4; 1664 Rolvsøy. Pharmatech is GMP certified, ref. EU Directive 91/356 / EEC and has approval from the Norwegian Food Safety Authority (Norwegian Food Administration), which contains HACCP and ØF number. Viiral Nasal Spray was prepared under these conditions and with Neu5Ac in a 0.9% NaCl aqueous solution. The spray bottle was a standard 20 ml spray bottle. Each spray bottle contained 150 mg of sialic acid/Neu5Ac per 20 ml, i.e. 7.5 mg/ml. Pure Neu5Ac supplied by SigmaAldrich was used as the sialic acid ingredient.

4.5.2 Produktion av test product, Placebo

The Placebo product was produced in the same way as the Viiral nasal spary with Neu5Ac, but without Neu5Ac, ie. placebo was 0.9% NaCl in water solution. All spray bottles in the study, Viiral and placebo, was marked so that the participants could not identify the content.

4.6 Treatment

Each study participant was to take 2 x 2 x 2 x 28 sprays (224 in total) during a 4-week period. Each study participant therefore received 2 spray bottles at the start of the study.

4.7 Questionnaire

Electronic questionnaires which were sent to eSTEP after weeks 1, 2, 3 and 4, included the following 6 questions: 1. Have you taken 2 x 4 spray doses daily during the past week? 2. Have you noticed an increasingly moist nose during the past week? 3. Have you noticed that your nose feels less blocked during the past week? 4. Have you noticed increased dryness, colds or other upper respiratory problems during the past week? 5. Have you noticed increased energy during the past week? 6. Have you been home from work and been on sick leave during the past week due to upper respiratory tract diseases? If so, for how many days?

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4.8 Study results

A total of 127 participants successfully completed the study. 78 participants received the active study substance, Viiral Nasal Spray (A), and 49 participants received the placebo substance (B). Despite a small number of participants in the placebo group (due to production technical issues), the study was judged to be large enough to evaluate the effect of Viiral Nasal Spray.

4.8.1 Participation and completion of the study program

The total number of questionnaires sent to 127 the test participants was 508 (127 x 4 questionnaires). Of these, 445 were returned with satisfactory answers; a response rate of 87.6% with respect to approved returned forms. Of these, 271 (61%) were responses from group A (active substance); and 174 (39%) from group B (placebo). A total of 68 participants in group A and 43 participants in group B completed the study. The result from question 1 (compliance) “Have you taken all doses given in the protocol?” was that overall, 88% of the study participants had taken 8 Nasal Spray doses daily for 4 weeks.

4.8.1.1 Answers to questions 2 – 5

Question 2: Have you experienced a moister nose during the past week? Approximately 50% of the study participants in both groups experienced a moister nose during the study period. Question 3: Have you noticed that your nose feels less blocked during the past week? As per question 2 - approximately 50% of study participants in both groups experienced a slightly less blocked nose during the study period. Therefore, no significant difference in the answers for questions 2 and 3 was found for the active substance Viiral Nasal Spray and the placebo 0.9% NaCl solution. Question 4: Have you noticed increased dryness, cold symptoms or other upper respiratory problems during the past week? The responses showed that this question was interpreted very differently by the participants. The same type of treatment response was experienced as with the other questions and therefore also gave no meaningful feedback or differences between the study products. Question 5: Have you noticed increased energy during the past week? Here the answers were the same for participants who received Viiral Nasal Spray or the placebo. Question 6: Have you been home from work and been on sick leave during the past week due to upper airway problems? If so, for how many days?

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Here, the answers present the major difference between group A and B. Of the 68 participants who completed the study with the Viiral Nasal Spray sample, 41 days of sick leave were registered, which represents 2.23% sick leave. For the 43 people who completed the study in the placebo group, 63 had sick days, representing an absence rate of 5.29%. These figures are based on the total number of sick days.

4.9 Statistical methods and analysis

The primary effect variable, the number of sick days, has been analysed using a zero-inflated Poisson model. The model takes into account that a large number of people reported zero days of sick leave and that the number of sick days for those who did report sick days is Possion distributed. The null hypothesis tested was: H0: Upper respiratory tract morbidity Viiral > Upper respiratory tract morbidity Placebo Ha: Upper respiratory tract morbidity Viiral < Upper respiratory tract morbidity Placebo The objective is to be able to reject the null hypothesis and show that the morbidity is lower for the participants who received product A, Viiral Nasal Spray.

4.10 Conclusions

The objective of the clinical study was to evaluate whether the use of Viiral Nasal Spray, which contains neuraminic acid dissolved in saline solution, can prevent the onset of upper respiratory tract infections and thereby reduce sick leave among cabin crew at SAS. The study was double-blind and randomized. This means that neither the participants nor those who were practically involved in administering the study and distributing the trial product had knowledge whether individual participants received the Viiral Nasal Spray product or the placebo. The study involved approximately 10% of SAS’s cabin crew over a 4-week period when the incidence of colds and flu in Norway is normally low to moderate. The results for this group, who are among the most exposed to viruses and bacteria affecting the upper respiratory tract, show that the number of sick days is reduced by approximately 50%. The results indicate that Viiral Nasal Spray can help reduce the risk of contracting upper respiratory tract infections when given prophylactically. The results can be evaluated from two standpoints; firstly, it is possible to estimate the risk of getting sick at all and secondly it is possible to estimate the number of sick days for those who do fall ill. Overall, the number of sick days taken by those treated with Viiral Nasal Spray is estimated at 0.58 per 4-week period compared to 1.37 per 4-week period for those treated with a placebo, which is a reduction of over 50%.

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The reduction in morbidity is estimated in two steps: the risk of becoming ill and the reduction in the number of sick days for those who do fall ill. In a model that estimates only the number of sick days for those who fall ill, the p-value is 0.047. In a more complicated model that simultaneously estimates both the risk of illness and the number of sick days for those who fall ill, the p-values are 0.084 and 0.051 respectively (a p-value for each parameter). An overall assessment of these two p-values, which are both close to 0.05 gives a total risk for type I errors, i.e. estimation of p-value, well below 5%, that is a p-value for simultaneous interpretation of both variables much less than 0.05. The p-value cannot be calculated precisely because the variables are not independent (one-sided test, H0: Viiral Nasal Spray better than placebo, statistical method: zero-inflated Poisson).

5. References

Bella. J., Kolatkar, P.R., Marlor, C.W., Greve, J.Y., Rossmann, M.G. (1998). The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand. Proc. Natl. Acad. Sci., 95 (8). 4140 – 4145. doi 10.1073/pnas.95.8.4140. Benton, D.J., Wharton, S.A., Martin, S.R., McCauley, J.W. (2017). Role of neuraminidase in influenza A(H7N9) virus receptor binding. Journal of Virology, 91 (11). 1 – 10. doi.org/10.1128/ JVI.02293-16. Bjørnebye Vik, A. (2018). Safety of Sialic acid Casanovas, J.M., Bickford, J.K., Springer, T.A. (1998). The Domain Structure of ICAM-1 and the Kinetics of Binding to Rhinovirus. Journal of Virology, 72 (7). 6244 – 6246. Cross et al 2001. Exp Reviews In Molecular Medicine. Neu, U., Bauer, J., Stehle, T. (2011). Viruses and Sialic Acids: Rules of Engagement. Curr Opin Struct Biol 21 (5). 610 – 618. Doi 10.1016/j.sbi.2011.08.009 Schalcter, M: N-Acetylneuraminic Acid (Neu5Ac). http://www.glyconutritionforlife.org/Science_of_Glyconutrients/N- Acetylneuraminic_Acid_(Neu5Ac).php Schnaar, R.L., Gerardy-Schahn, R., Hildebrandt; H. (2014). Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration. Physiological Review 94(2). 461 – 518. doi: 10.1152/physrev.00033.2013 Sprenger, N., Duncan, P.I. (2012). Sialic Acid Utilization. American Society for Nutrition 3(3) 392S–397S. doi:10.3945/an.111.001479.

http://www.glyconutritionforlife.org/Science_of_Glyconutrients/N-‐

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Stehle, T., Khan, Z. (2014). Rules and Exceptions: Sialic Acid Variants and Their Role in Determining Viral Tropism. Journal of Virology 88(14) 7696–7699 Varki, A. (2008) Sialic acids in human health and disease. Trends Mol Med. 14(8). 351– 360. doi:10.1016/j.molmed.2008.06.002.

scientific evaluation of viiral nasal spray · viiral nasal spray contains 1 mg sialic acid/ml. a...

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