Therapeutic methods and related compositions

Abstract

The present invention relates to the use of cetyl myristate and cetyl palmitate in methods for modulating an immune response in a subject in need thereof, such as a subject exposed to or infected by a virus and / or undergoing or at risk of undergoing viral reactivation. Methods for treating or preventing a viral disease or condition, including treating or preventing one or more symptoms or sequelae of a viral disease or condition, and methods of treating or preventing viral reactivation including one or more symptoms or sequelae of viral reactivation are also contemplated. Related uses and compositions suitable for use in such methods are also provided, such as for the treatment of hypercytokinemia.

Description

[0001] THERAPEUTIC METHODS AND RELATED COMPOSITIONS

[0002] TECHNICAL FIELD

[0003] The invention relates to methods for modulating an immune response in a subject in need thereof, such as a subject exposed to or infected by a virus and / or undergoing or at risk of undergoing viral reactivation. Methods for treating or preventing a viral disease or condition, including treating or preventing one or more symptoms or sequelae of a viral disease or condition, are also contemplated. Related uses and compositions suitable for use in such methods are also provided.

[0004] BACKGROUND OF THE INVENTION

[0005] The following includes information that may be useful in understanding the present inventions. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art. Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0006] Viral diseases and conditions are among the most problematic and challenging infectious diseases to treat or prevent, at both an individual and at a population level. Human influenza virus reportedly infects between 5 % and 15 % of the global population each year, and was causative of one of the most lethal global pandemics in modern history. The recent global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in COVID19 and various sequelae, including long COVID, caused millions of deaths, widespread social disharmony, and severe economic impacts. Human immunodeficiency virus (HIV), causative of AIDS, remains prevalent in many communities, while outbreaks of virulent and usually lethal haemorrhagic diseases such as Ebola and Marburg periodically arise in West Africa causing widespread alarm in affected locales.

[0007] Reactivation of latent virus, for example following exposure to a bioactive agent, such as a chemical or environmental agent or another virus, or to some other stimuli, such as prolonged stress, can also present significant health risks.

[0008] Sequelae of viral diseases or conditions or of viral reactivation are typically challenging to treat effectively, and the ongoing health impacts associated with such sequelae may persist for many years and continue to manifest even when no appreciable viral load is present. One such example is long COVID, associated with exposure to SARS-CoV-2 and which manifests in a variety of symptoms including fatigue, fever, abdominal pain, joint and muscle pain, nausea and vomiting, diarrhoea, and weight loss. Such sequelae can be particularly debilitating for sufferors and their support, and burdensome on public health systems.

[0009] Vaccines are increasingly becoming available for various viral diseases, but given the nature of viral replication and attendant vaccine escape, many vaccines quickly become less effective at infection prevention and disease control. It is not clear how effective vaccines may be in ameliorating symptoms and sequelae of various viral diseases, such as Long Covid.

[0010] There remains a need for effective therapies to treat and prevent viral diseases, conditions, and / or one or more symptoms or sequelae of viral diseases or conditions. In particular, there is an ongoing need for therapies effective in mitigating viral reactivation and / or the symptoms or sequelae of viral reactivation. The present invention thus seeks to provide methods for treating or preventing a viral disease or condition, and / or for treating or preventing one or more symptoms or sequelae of a viral disease or condition, and / or of modulating an immune response of a subject in need thereof, wherein said subject is or has been exposed to a virus, or to at least provide a useful alternative to existing methods, or to at least provide the public with a useful choice.

[0011] SUMMARY OF THE INVENTION

[0012] In a first aspect the invention relates to a method of treating or preventing a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0013] In a second aspect the invention relates to a method of treating or preventing one or more symptoms or sequelae of a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0014] In another aspect the invention relates to a method of modulating an immune response of a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0015] In various examples, the subject has recently been exposed to or infected by the virus. In other examples, the subject has previously been exposed to or infected by the virus, including where the subject has been previously exposed to or infected by the virus and has no manifest symptoms.

[0016] In various examples, the subject is or has been determined to be at risk of viral reactivation.

[0017] In one example, the subject is suffering from viral reactivation and / or one or more consequences or sequelae thereof.

[0018] In one example, the subject is a subject in whom viral reactivation is present or is about to occur. For example, the subject is a subject in whom imminent viral reactivation or actual viral reactivation has been determined.

[0019] Accordingly, in one example the invention relates to a method of treating or preventing hypercytokinemia ("cytokine storm") in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0020] Any of the examples described herein can relate to any of the aspects presented herein.

[0021] In one example, the subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition.

[0022] In one example, the subject has previously been exposed to or infected by a virus, such as a virus capable of reactivation.

[0023] In one example, the subject is or is suspected of being at risk of viral reactivation.

[0024] In one example, the subject is suffering from viral reactivation and / or one or more consequences or sequelae thereof.

[0025] In one example, the subject has been exposed to or is infected with Epstein-Barr virus.

[0026] In one example, the subject has been exposed to or is infected with West Nile virus.

[0027] In one example, the subject has been exposed to or is infected with Varicella-zoster virus.

[0028] In one example, the subject has been exposed to or is infected with herpes virus, such as herpes simplex virus.

[0029] In one example, the subject has been exposed to or is infected with SARS-CoV-2. In one example, the subject is suffering from or at risk of Long Covid.

[0030] In still another aspect the invention relates to a method of treating or preventing viral reactivation in a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0031] In certain examples, the effective amount is an amount effective to treat or prevent hypercytokinemia in the subject.

[0032] Another aspect of the present invention relates to a composition for use in a method as contemplated herein, said composition comprising: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0033] In one example, the composition is a pharmaceutical composition. In one example, the pharmaceutical composition is unit dosage form. In various examples, the unit dosage form is a tablet or capsule.

[0034] In one example, the pharmaceutical composition comprises STIR-101, as exemplified herein.

[0035] In various examples, the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, excipients and / or diluents, such as one or more of the following: silicon dioxide, calcium phosphate, magnesium oxide and / or a trace element.

[0036] Another aspect of the present invention relates to the use of cetyl myristate, cetyl palmitate, or both cetyl myristate and cetyl palmitate in the preparation of a medicament for use in a method as contemplated herein.

[0037] Another aspect of the present invention relates to the use of cetyl myristate, cetyl palmitate, or both cetyl myristate and cetyl palmitate in a method as contemplated herein.

[0038] In still another aspect the present invention relates to cetyl myristate, cetyl palmitate, or both cetyl myristate and cetyl palmitate for:

[0039] • treating or preventing a viral disease or condition; or

[0040] • treating or preventing one or more symptoms or sequelae of a viral disease or condition; or

[0041] • modulating an immune response of a subject in need thereof; or

[0042] • treating or preventing hypercytokinemia ("cytokine storm") in a subject in need thereof; or

[0043] • treating or preventing viral reactivation in a subject in need thereof.

[0044] Other aspects, features and advantages of the present invention will become apparent from the following description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred examples of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0045] The invention is exemplified in the following non limiting examples and with reference to the accompanying figures.

[0046] BRIEF DESCRIPTION OF THE FIGURES

[0047] Figure 1 presents a graph showing the effect on TNF-a levels in 129 mice administered STIR-101 (a composition comprising cetyl myristate and cetyl palmitateas contemplated herein), as described herein in Example 1.

[0048] Figure 2 presents a graph showing the effect on RANTES levels in 129 mice administered STIR-101 as described herein in Example 1.

[0049] Figure 3 presents a graph showing the effect on MIP-ip levels in 129 mice administered STIR-101 as described herein in Example 1.

[0050] Figure 4 presents a graph showing the effect on MIP-la levels in 129 mice administered STIR-101 as described herein in Example 1.

[0051] Figure 5 presents a graph showing the effect on MCP-1 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0052] Figure 6 presents a graph showing the effect on KC levels in 129 mice administered STIR-101 as described herein in Example 1. Figure 7 presents a graph showing the effect on IFN-y levels in 129 mice administered STIR-101 as described herein in Example 1.

[0053] Figure 8 presents a graph showing the effect on GM-CSF levels in 129 mice administered STIR-101 as described herein in Example 1.

[0054] Figure 9 presents a graph showing the effect on G-CSF levels in 129 mice administered STIR-101 as described herein in Example 1.

[0055] Figure 10 presents a graph showing the effect on Eotaxin levels in 129 mice administered STIR-101 as described herein in Example 1.

[0056] Figure 11 presents a graph showing the effect on IL-17 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0057] Figure 12 presents a graph showing the effect on IL-13 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0058] Figure 13 presents a graph showing the effect on IL-12 (p70) levels in 129 mice administered STIR- 101 as described herein in Example 1.

[0059] Figure 14 presents a graph showing the effect on IL-12 (p40) levels in 129 mice administered STIR- 101 as described herein in Example 1.

[0060] Figure 15 presents a graph showing the effect on IL-la levels in 129 mice administered STIR-101 as described herein in Example 1.

[0061] Figure 16 presents a graph showing the effect on IL-ip levels in 129 mice administered STIR-101 as described herein in Example 1.

[0062] Figure 17 presents a graph showing the effect on IL-2 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0063] Figure 18 presents a graph showing the effect on IL-3 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0064] Figure 19 presents a graph showing the effect on IL-4 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0065] Figure 20 presents a graph showing the effect on IL-5 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0066] Figure 21 presents a graph showing the effect on IL-6 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0067] Figure 22 presents a graph showing the effect on IL-9 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0068] Figure 23 presents a graph showing the effect on IL-10 levels in 129 mice administered STIR-101 as described herein in Example 1.

[0069] Figure 24 presents a graph showing the effect of administration of STIR-101 on immune cell populations in whole blood samples obtained from a human subject, as described herein in Example 2.

[0070] Figure 25 presents 10 flow cytometry dot plots showing the effect of administration of STIR-101 on NK immune cell populations identified by the NK cell population markers (CD56 / CD16 or CD57), as described herein in Example 2.

[0071] Figure 26 presents 10 flow cytometry dot plots showing the effect of administration of STIR-101 on NK immune cell populations identified by the NK cell population marker CD69, as described herein in Example 2. Figure 27 presents a graph showing the effect of administration of STIR-101 on immune cell populations expressing various NK or T cell markers, as described herein in Example 2.

[0072] Figure 28 presents 5 flow cytometry dot plots showing the effect of administration of STIR-101 on myeloid / CD14+ monocyte cells (CCR2+) expressing ICAM-1, as described herein in Example 2.

[0073] Figure 29 presents a graph showing the effect of administration of STIR-101 on CD14+ myeloid cells, as described herein in Example 2.

[0074] DETAILED DESCRIPTION

[0075] The present invention relates to methods, uses, and compositions for modulating one or more immune responses of a subject who is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition, or is or is at risk of undergoing viral reactivation. The invention further relates to treating or preventing hypercytokinemia, also known as cytokine storm, in a subject, such as a subject who is or has been exposed to or infected by a virus, and particularly a subject who is or is at risk of undergoing viral reactivation.

[0076] In further aspects the invention relates to methods, uses, and compositions for treating or preventing a viral disease or condition, including one or more symptoms or sequelae of a viral disease or condition.

[0077] The methods, uses, and compositions contemplated herein utilise as therapeuctic agent cetyl myristate, and / or cetyl palmitate, and more particularly a combination of cetyl myristate and cetyl palmitate.

[0078] Selected definitions

[0079] It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7). These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

[0080] Those skilled in the art will appreciate the meaning of various terms of degree used herein. For example, as used herein in the context of referring to an amount (e.g., "about 9%"), the term "about" represents an amount close to and including the stated amount that still performs a desired function or achieves a desired result, e.g. "about 9%" can include 9% and amounts close to 9% that still perform a desired function or achieve a desired result. For example, the term "about" can refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, or within less than 0.01% of the stated amount. It is also intended that where the term "about" is used, for example with reference to a figure, concentration, amount, integer or value, the exact figure, concentration, amount, integer or value is also specifically contemplated.

[0081] The term "and / or" can mean "and" or "or".

[0082] The term "comprising" and grammatical equivalents thereof (including "comprise" and "comprises") as used in this specification means "consisting at least in part of". When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises", and the terms "including", "include" and "includes" are to be interpreted in the same manner. The term "consisting essentially of" when used in this specification refers to the features stated and allows for the presence of other features that do not materially alter the basic characteristics of the features specified.

[0083] The term "consisting" and grammatical equivalents thereof (including "consist" and "consists") as used in this specification means the specified materials or steps (for example of the claimed invention), excluding any element, step, or ingredient not specified.

[0084] The terms "co-administration" or "combined administration" as used herein is defined to encompass the administration of the selected therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0085] The term "pharmaceutical combination" is defined herein to refer to either a fixed combination in one dosage unit form, or a non-fixed combination or a kit of parts for the combined administration of two or more therapeutic agents or a prescribed therapy or treatment regimen, such as the administration of cetyl myristate or , and cetyl palmitate, which may be administered simultaneously or independently at the same time or separately within time intervals. In one example, the therapeutic agents comprising the pharmaceutical combination (i.e. , cetyl myristate or and cetyl palmitate) are administered simultaneously, independently at the same time, or separately, such as within specific time intervals that enable the therapeutic agents to provide a cooperative and / or synergistic effect.

[0086] The term "fixed pharmaceutical combination" means that the therapeutic agents comprising the pharmaceutical combination (i.e., cetyl myristate or and cetyl palmitate) are both administered to a patient simultaneously in the form of a single entity or unit dosage form.

[0087] The term "non-fixed pharmaceutical combination" means that the therapeutic agents comprising the pharmaceutical combination (i.e., cetyl myristate or and cetyl palmitate) are each administered to a subject as separate unit dosage forms, either simultaneously, separately or sequentially, optionally at specific time intervals, wherein such administration provides therapeutically effective levels of the therapeutic agents in the body of the subject.

[0088] The term "pharmaceutical composition" is defined herein to refer to a composition comprising at least one therapeutic agent to be administered to a subject in order to treat a particular disease or condition affecting the subject or to elicit a therapeutic or prophylactic response in the subject, together with one or more pharmaceutically acceptable carriers.

[0089] The term "pharmaceutically acceptable" is defined herein to refer to those compounds, carriers, materials, compositions and / or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0090] The term "pharmaceutically acceptable carrier" refers to a carrier, such as but not limited to an excipient, diluent, adjuvant or vehicle, that may be administered to a subject and will usually be administered together with the therapeutic agent. Such carriers are well known in the art, and may be as simple as water or saline, or may in certain examples comprises a number of different excipients, diluents, adjuvants and / or vehicles as may be required, for example for effective formulation.

[0091] An "effective amount" as contemplated herein is an amount sufficient to effect beneficial or desired results including clinical results. An effective amount can be administered in one or more administrations by various routes of administration. The effective amount will vary depending on, among other factors, the disease or condition indicated, the severity of the disease or condition, the age and relative health of the subject, the potency of the agent administered, the mode of administration and the treatment desired. A person skilled in the art will be able to determine appropriate dosages having regard to these any other relevant factors.

[0092] It will be appreciated that the various methods of therapy contemplated herein will typically embody the administration of an effective amount of the one or more therapeutic agents.

[0093] The term "pharmaceutically effective amount" or "clinically effective amount" or "therapeutically effective amount" of a therapeutic agent or combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.

[0094] The term "jointly therapeutically active" or "joint therapeutic effect" as used herein means that the therapeutic agents of a pharmaceutical combination may be given to the subject simultaneously or separately (e.g., in a chronologically staggered manner, for example a sequence-specific manner) in such time intervals that they show an interaction (e.g., a joint therapeutic effect, for example a synergistic effect). Whether this is the case can, inter alia, be determined by following the blood levels and showing that the combination components are present in the blood of the subject to be treated at least during certain time intervals.

[0095] A "subject" as used herein is an animal, usually a mammal, including a mammalian companion animal or a human. Representative companion animals include feline, equine, and canine. Representative agricultural animals include bovine, ovine, caprine, cervine, and porcine.

[0096] The term "treating" or "treatment" and related terms such as "treat" as used herein broadly includes any kind of treatment activity in which some desired therapeutic effect is achieved, including the amelioration, diagnosis, cure, mitigation, delay of onset or of progression, or prevention of a disease or condition in a subject, or any activity that otherwise affects the structure or any function of the body of the subject, and includes a treatment relieving, reducing or alleviating at least one symptom or sequelae in a subject or effecting a delay of onset or of progression of a disease or condition or symptom or sequelae thereof. For example, treatment can be the diminishment of one or several symptoms or sequelae of a disorder or complete eradication of a disorder. Within the meaning of the present disclosure, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment, for example, an increase in overall survival (OS) compared to a subject not receiving treatment as described herein, and / or an increase in progression-free survival (PFS) compared to a subject not receiving treatment as described herein. The term "treating" can also mean an improvement in the condition of a subject having a disease or condition, e.g., one or more of a decrease in a marker for the disease or condition in a subject, a decrease or no substantial increase in the rate of disease progression in a subject, and an improvement in one or more physiological or metabolic responses or metrics in a subject (e.g., as compared to the one or more metric(s) in a subject having a similar disease or condition receiving no treatment or a different treatment, or as compared to the one or more metric(s) in the same subject prior to treatment). Prophylactic treatments, including those in which treatment is administered before one or more indicia or symptoms of a disease or condition manifest, are particularly contemplated.

[0097] Various aspects of the invention are described in further detail in the following subsections. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions included herein, will be preferred. Although methods and materials similar or equivalent to those described herein can be used in the practice of the invention, examples of suitable methods and materials are described below. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0098] Viral diseases and conditions

[0099] The methods, uses, and compositions contemplated herein are in one aspect directed to the treatment or prevention of one or more viral disease or conditions in a subject.

[0100] In certain examples, the viral disease or condition is caused by or associated with a virus to which the subject has recently been exposed or by which the subject has recently been infected.

[0101] In other examples, the viral disease or condition is caused by or associated with a virus to which the subject has previously been exposed or by which the subject has previously been infected. In certain of such examples, the viral disease or condition is viral reactivation, for example, reactivation of a virus previously present and / or latent in the subject, including a virus causative of or associated with a viral condition or disease from which the subject has previously suffered, and also a virus causative of or associated with a viral condition or disease that has not previously manifest in the subject, or has manifest at a sub-clinical level.

[0102] In still other examples, the viral disease or condition is caused by or associated with a virus to which the subject has not yet been exposed or by which the subject has not yet been infected, whereby the methods, uses, and compositions contemplated herein are prophylactic. In certain examples, such prophylactic methods, uses and compositions are employed with or for a subject determined to be at elevated risk of exposure to the virus.

[0103] Without wishing to be bound by any theory, the applicant believes that in light of the proposed mode of action for the therapeutic agents contemplated herein, the type of viral disease or condition amenable to treatment as contemplated herein is not particularly limited. Examples of possible viral diseases or conditions amenable to treatment as contemplated herein include, but are not limited to viral diseases which are caused by or associated with Poxyiridae, Herpesviridae, Adenoviridae, Papillomaviridae, Polyomaviridae, Parvoviridae, Hepadnaviridae, Retroviridae, Reoviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae, Caliciviridae, Astroviridae, Togaviridae, Flaviviridae, Deltavirus, and Bornaviridae.

[0104] Examples of various viruses are given in the following table. Without wishing to be bound by any theory, the applicant believes that a disease or condition caused by or associated with any of the viruses identified in this table are amenable to treatment as contemplated herein.

[0105]

[0106] In various examples, the viral disease or condition is caused by or associated with a virus selected from the group consisting of Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, and Flaviviridae.

[0107] Examples of viruses causing or associated with disease or conditions amenable to treatment as contemplated herein include coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), influenza viruses such as H1N1 and H5N1, haemorrhagic viruses such as flaviviruses including West Nile, Dengue, Yellow Fever, Japanese encephalitis, and Zika, arenaviruses such as Chapere, Guanarito, Lassa, Lujo, and Lymphocytic choriomeningitis, bunyavirales viruses such as Rift Valley fever, Crimean-Congo, and various hantaviruses, filoviruses such as Marburg and Ebola, cytomegalovirus, Epstein-Barr virus, and variola virus.

[0108] Certain viruses have been reported to trigger hypercytokinemia, also known as a "cytokine storm", in which the immune system of the subject infected by the virus becomes over-stimulated. Various inflammatory cytokines are produced at a much higher rate than normal, and this overproduction causes positive feedback on other immune cells, prompting more immune cells to be recruited to the site of injury which can lead to organ damage. In severe cases, the over-stimulation of the immune system can result in death, for example from acute respiratory distress syndrome (ARDS).

[0109] Examples of viruses causing or associated with disease or conditions amenable to treatment as contemplated herein that are associated with cytokine storm include coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East Respiratory Syndrome coronavirus (MERS-CoV); influenza viruses such as H1N1 and H5N1; haemorrhagic viruses such as West Nile, Dengue, and Ebola; herpesviruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus (such as herpes simplex types 1 and 2), human herpesvirus 6 (variants A and B), human herpesvirus 7, and human herpesvirus 8; and pox viruses such as Varicella virus and Variola virus. Specifically contemplated viral diseases or conditions (including viral disorders or pathologies) to be treated include those that would benefit from the modulation of immune responses in the subject. Accordingly, in one aspect the methods contemplated herein relate to a method of modulating an immune response in a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition.

[0110] Further examples of viruses causing or associated with disease or conditions amenable to treatment as contemplated herein are those associated with viral reactivation (for example reactivation of latent virus present in the subject) include herpesviruses such as Epstein-Barr virus, herpes simplex virus (such as herpes simplex types 1 and 2), Varicella-zoster virus, and B virus; human immunodeficiency virus (HIV); hepatitis, and measles.

[0111] Herpesviruses are a group of viruses that can cause a variety of diseases, including glandular fever / infectious mono (EBV / CMV), cold sores (HSV), and shingles (VZV). As discussed herein, these viruses can lie dormant in the body for long periods of time, but can be reactivated by stressor events, including infection with SARS-CoV-2. There is mounting evidence to suggest that the reactivation of herpesviruses may be a leading cause or driver of long COVID. Therefore, without wishing to be bound by any theory, the applicant believes that the compositions and methods contemplated herein have the potential to improve quality of life, and indeed, encourage a full recovery from long COVID.

[0112] The methods and compositions of the invention thus have particular application to the treatment or prevention of long COVID and other associated post-viral illnesses such as Myalgic Encephalomyelitis / Chronic fatigue syndrome (ME / CFS). Long COVID is a complex condition that is thought to be triggered or driven at least in part by the reactivation of latent viruses. Without wishing to be bound by any theory, the inventor believes that administration of the compositions contemplated herein (and the immunomodulatory effect mediated thereby including but not limited to the prevention or mitigation of hypercytokinemia (cytokine storm) in a subject) is effective in preventing or mitigating viral reactivation and / or long COVID.

[0113] Accordingly, in one example the invention relates to a method of treating or preventing one or more symptoms or sequelae of long COVID, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

[0114] Immune responses

[0115] Inflammation is the body's initial response to pathogenic insult and results in the infiltration of immune cells. Infiltration and activation of immune cells leads to heat, pain, redness, and swelling of tissues. Cytokines play an essential role in the orchestration of the host's defense against the infection and must be regulated very closely. When this regulation goes awry, the immune response is detrimental to the host. Cytokines such as IL-1, IL-6, IL-11, IL-17, and TNF-a are thought to be responsible for many acute and chronic inflammatory diseases (10). Therapies targetig these and other cytokines to regulate the inflammation response may reduce pain and lead to a better quality of life.

[0116] As described above, certain viral infections are associated with inflammation and with hypercytokinemia (cytokine storm), in which the immune system becomes over-stimulated with elevated expression of many different cytokines that leads to significant morbidity, and some mortality in patients (31).

[0117] As shown herein, administration of cetyl myristate in combination with cetyl palmitate modulates cytokine production and immune responses in a variety of cell types. Without wishing to be bound by any theory, the applicant believes that administration of these agents will be effective in treating or preventing one or more viral diseases or conditions, and / or one or more symptoms or sequelae thereof.

[0118] For example, as shown herein, administration of cetyl myristate in combination with cetyl palmitate downregulates Intercellular Adhesion Molecule 1 (ICAM-1) expression. In another example presented herein, administration of cetyl myristate in combination with cetyl palmitate downregulates Monocyte Chemoattractant Protein-1 (MCP-1) expression.

[0119] In further examples shown herein, administration of cetyl myristate in combination with cetyl palmitate upregulates each of IFN, IL-10 and IL-13.

[0120] In further examples shown herein, administration of cetyl myristate in combination with cetyl palmitate downregulates each of IL-1, IL-6, IL-11, IL-17, and TNF-a.

[0121] Therapeuatitic compositions and methods

[0122] The therapeutic methods contemplated herein comprise the administraton of cetyl myristate, and / or the administration of cetyl palmitate, for the treatment or prevention of a viral disease or condition (including a viral disorder or a viral pathology) in a subject in need thereof.

[0123] In particular, the therapeutic methods contemplated herein comprise the administraton of cetyl myristate in conjunction with the administration of cetyl palmitate.

[0124] In various examples, the therapeutic methods contemplated herein comprise the administration to a subject of from about 10 mg / kg to about 200 mg / kg of a combination of cetyl myristate and cetyl palmitate, for example a mixture comprising at least 50% w / w cetyl myristate and cetyl palmitate.

[0125] In certain examples, the administration is of from about 10 mg / kg to about 150 mg / kg, from about 10 mg / kg to about 140 mg / kg, from about 10 mg / kg to about 130 mg / kg, from about 10 mg / kg to about 120 mg / kg, from about 10 mg / kg to about 110 mg / kg, from about 10 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 90 mg / kg, from about 10 mg / kg to about 80 mg / kg, from about 10 mg / kg to about 70 mg / kg, from about 10 mg / kg to about 60 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 10 mg / kg to about 40 mg / kg, or from about 10 mg / kg to about 30 mg / kg of a composition as herein described, such as a composition comprising a combination of cetyl myristate and cetyl palmitate.

[0126] In certain particularly contemplated examples, the administration is from about 10 mg / kg / day to about 200 mg / kg / day of a composition as herein described, such as a composition comprising a combination of cetyl myristate and cetyl palmitate, such as from about 20 mg / kg / day to about 150 mg / kg / day . In certain examples, such as are exemplified herein in the Examples, the administration is of about 28 mg / kg / day, or is of about 70 mg / kg / day, or is of about 140 mg / kg / day, of a composition as herein described, such as a composition comprising a combination of cetyl myristate and cetyl palmitate.

[0127] Compositions, and particularly pharmaceutical compositions comprising cetyl myristate, or pharmaceutical compositions comprising cetyl palmitate, are thus also contemplated herein. More particularly, pharmaceutical compositions comprising both cetyl myristate and cetyl palmitate, together with one or more pharmaceutically acceptable carriers, are contemplated for use in the methods disclosed herein.

[0128] Cetyl myristate and cetyl palmitate are both known compounds and are available from commercial sources. Methods of preparing these compounds, and of preparing pharmaceutical compositions suitable for administration to a subject are also known.

[0129] By way of representative example, a mixture of cetyl myristate and cetyl palmitate suitable for use in the methods and compositions contemplated herein is synthesised from starting materials utilising the procedures disclosed in PCT International Patent Publication No. WO 2003 / 018731 (PCT International Application No. PCT / NZ2001 / 000179). The disclosure of WO 2003 / 018731 is incorporated herein by reference in its entirety.

[0130] Briefly, the synthetic methods described in WO 2003 / 018731 involve reacting both myristic acid and palmitic acid with cetyl alcohol at an elevated temperature in the presence of at least one acid catalyst and at least one aromatic hydrocarbon. The aromatic hydrocarbon fraction then contains the mixture of cetyl myristate and cetyl palmitate from which it can be crystallised.

[0131] In one particularly contemplated example of a synthetic method described in WO 2003 / 018731, cetyl alcohol is reacted with a mixture of myristic acid and palmitic acid in an aromatic liquid hydrocarbon such as toluene or xylene, in the presence of phosphoric acid catalyst, at an elevated temperature (for example between 65° C. and 140° C.) and for a period of time (for example about 8 to about 45 hours).

[0132] Following crystallisation of the mixture of cetyl myristate and cetyl palmitate, the crystallised form can then be ground up, dissolved and mixed with a pharmaceutical carrier suitable for administration to a subject. The crystals may conveniently be dissolved in hot water before adding to a pharmaceutical carrier, which may conveniently be sugar syrup available from most pharmaceutical companies. The liquid may be made up to a concentration of about 70% w / v.

[0133] Alternatively, the crystals may be ground up into a powder and combined with one or more pharmaceutically acceptable carriers, such as an excipient or diluent, such as magnesium oxide, silicon oxide or fine dicalcium phosphate. This powder can then be transferred into capsules for oral ingestion into the body. Suitable capsules, such as non-gelatin capsules such as VEGICAP™ or the like, are well known in the art.

[0134] In other examples, a medicament suitable for use herein and comprising cetyl myristate, and / or cetyl palmitate, such as a medicament comprising cetyl myristate and cetyl palmitate can be obtained using cetyl myristate and cetyl palmitate separately available from commercial sources and handled as described above.

[0135] In certain particularly contemplated examples, the pharmaceutical composition comprises a mixture of cetyl myristate and cetyl palmitate, said mixture comprising at least 50% w / w cetyl myristate, such as about 50% to about 98% w / w cetyl myristate (such as about 60% to about 98% w / w, such as about 70% to about 98% w / w, such as about 80% to about 98% w / w, such as about 90% to about 98% w / w, such as about 92% to about 97% w / w, such as about 93% to about 96% w / w).

[0136] In certain preferred examples, the ratio of cetyl myristate to cetyl palmitate to be administered to the patient, either serially or in admixture, may be from about 80:20 to 99: 1 w / w, such as from about 85: 15 to about 97:3 w / w, such as about 95:5 w / w cetyl myristate:cetyl palmitate. In one example, the pharmaceutical composition is STIR-101, comprising 4: 1 w / w cetyl myristate: cetyl palmitate and magnesium stearate.

[0137] In certain examples, the pharmaceutical composition comprises a mixture of cetyl myristate and cetyl palmitate, and one or more other fatty acids. In certain examples, the pharmaceutical composition additionally comprises linolate, such as cetyl linolate, and / or stearate, such cetyl stearate.

[0138] Pharmaceutically acceptable carriers that may be used in the compositions contemplated herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0139] Cyclodextrins such as a-, £-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-3-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery. Oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.

[0140] The compositions are formulated to allow for administration to a subject by any chosen route, including but not limited to oral or parenteral (including topical, subcutaneous, intramuscular and intravenous) administration.

[0141] For example, the compositions may be formulated with an appropriate pharmaceutically acceptable carrier (including excipients, diluents, auxiliaries, vehicles, and combinations thereof) selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compositions may be administered orally as a powder, liquid, tablet or capsule, or topically as an ointment, cream or lotion. Suitable formulations may contain additional agents as required, including emulsifying, antioxidant, flavouring or colouring agents, and may be adapted for immediate-release, delayed-release, modified-release, sustained-release, pulsed-release, or controlled-release.

[0142] The compositions may be formulated to optimize bioavailability, immunogenicity, or to maintain plasma, blood, or tissue concentrations within the therapeutic range, including for extended periods. Controlled delivery preparations may also be used to optimize concentration, for example at the site of action, for example.

[0143] The compositions may be formulated for periodic administration, for example to provide continued exposure. Strategies to elicit a beneficial immunological response, for example those that employ one or more follow-up administrations, are well known in the art, and such strategies may be adopted.

[0144] Examples of dosage forms suitable for oral administration include, but are not limited to tablets, capsules, lozenges, or like forms, or any liquid forms such as syrups, aqueous solutions, emulsions and the like, capable of providing a therapeutically effective amount of the composition. Capsules can contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets can be formulated in accordance with conventional procedures by compressing mixtures of the active ingredients with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. Active ingredients can also be administered in a form of a hard-shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tabletting agent.

[0145] The compositions may be administered via the parenteral route. Examples of parenteral dosage forms include aqueous solutions, isotonic saline or 5% glucose of the active agent, or other well- known pharmaceutically acceptable excipients. Those familiar with the art will understand that a variety of excipients, solubilizing agents, buffers, and the like can be utilized as pharmaceutical carriers for delivery of the therapeutic agent.

[0146] Examples of dosage of forms suitable for injection of the compositions include delivery via bolus such as single or multiple administrations by intravenous injection, subcutaneous, subdermal, and intramuscular administration or oral administration.

[0147] Examples of dosage forms suitable for depot administration of the compositions and include pellets of the peptide or solid forms wherein the peptide is entrapped in a matrix of biodegradable polymers, microemulsions, liposomes or are microencapsulated.

[0148] Examples of infusion devices for the compositions include infusion pumps for providing a desired number of doses or steady state administration, and include implantable drug pumps.

[0149] Examples of implantable infusion devices for compositions include any solid form in which the one or more therapeutic agent is encapsulated within or dispersed throughout a biodegradable polymer or synthetic, polymer such as silicone, silicone rubber, silastic or similar polymer.

[0150] Examples of dosage forms suitable for transmucosal delivery of the compositions include depositories solutions for enemas, pessaries, tampons, creams, gels, pastes, foams, nebulised solutions, powders and similar formulations containing in addition to the active ingredients such carriers as are known in the art to be appropriate. Such dosage forms include forms suitable for inhalation or insufflation of the compositions, including compositions comprising solutions and / or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixture thereof and / or powders. Transmucosal administration of the compositions may utilize any mucosal membrane but commonly utilizes the nasal, buccal, vaginal and rectal tissues. Formulations suitable for nasal administration of the compositions may be administered in a liquid form, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, including aqueous or oily solutions of the polymer particles. Formulations may be prepared as aqueous solutions for example in saline, solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilising or dispersing agents known in the art.

[0151] Examples of dosage forms suitable for buccal or sublingual administration of the compositions include lozenges, tablets and the like. Examples of dosage forms suitable for opthalmic administration of the compositions include inserts and / or compositions comprising solutions and / or suspensions in pharmaceutically acceptable, aqueous, or organic solvents.

[0152] Examples of dosage forms suitable for transdermal administration include, but are not limited, to transdermal patches, transdermal bandages, and the like.

[0153] Examples of dosage forms suitable for topical administration of the compositions include any lotion, stick, spray, ointment, paste, cream, gel, etc., whether applied directly to the skin or via an intermediary such as a pad, patch or the like. Examples of dosage forms suitable for suppository administration of the compositions include any solid dosage form inserted into a bodily orifice particularly those inserted rectally, vaginally and ureth rally.

[0154] Examples of formulations of compositions may be found in, for example, Sweetman, S. C. (Ed.). Martindale. The Complete Drug Reference, 33rd Edition, Pharmaceutical Press, Chicago, 2002, 2483 pp.; Aulton, M. E. (Ed.) Pharmaceutics. The Science of Dosage Form Design. Churchill Livingstone, Edinburgh, 2000, 734 pp.; and, Ansel, H. C, Allen, L. V. and Popovich, N. G. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, 676 pp..

[0155] Excipients employed in the manufacture of drug delivery systems are described in various publications known to those skilled in the art including, for example, Kibbe, E. H. Handbook of Pharmaceutical Excipients, 3rd Ed., American Pharmaceutical Association, Washington, 2000, 665 pp. The USP also provides examples of modified-release oral dosage forms, including those formulated as tablets or capsules. See, for example, The United States Pharmacopeia 23 / National Formulary 18, The United States Pharmacopeial Convention, Inc., Rockville MD, 1995 (hereinafter "the USP"), which also describes specific tests to determine the drug release capabilities of extended-release and delayed- release tablets and capsules. The USP test for drug release for extended-release and delayed-release articles is based on drug dissolution from the dosage unit against elapsed test time. Descriptions of various test apparatus and procedures may be found in the USP. Further guidance concerning the analysis of extended-release dosage forms has been provided by the F.D.A. (See Guidance for Industry. Extended-release oral dosage forms: development, evaluation, and application of in vitro / in vivo correlations. Rockville, MD: Center for Drug Evaluation and Research, Food and Drug Administration, 1997).

[0156] In particularly contemplated examples, the mode of administration is oral.

[0157] In further particularly contemplated examples, administration is via oral administration of a fixed pharmaceutical combination, such as a fixed pharmaceutical combination comprising cetyl myristate and cetyl palmitate in the form of a unit dosage form.

[0158] The oral unit dosage form may conveniently be either a tablet or capsule.

[0159] In other examples, the fixed pharmaceutical combination is an orally-consumable liquid composition, for example, a liquid composition comprising a general pharmacy type carrier such as methyl cellulose.

[0160] In other particularly contemplated examples, the administration is via oral administration of a non-fixed pharmaceutical combination, such as a non-fixed pharmaceutical combination comprising a unit dosage form comprising cetyl myristate or and a unit dosage form comprising cetyl palmitate.

[0161] Again, the oral unit dosage form may conveniently be either a tablet or capsule.

[0162] In other examples, the non-fixed pharmaceutical combination comprises an orally-consumable liquid composition comprising cetyl myristate, and an orally consumable liquid composition comprising cetyl palmitate. Again, examples of liquid carriers for use in such combinations include a general pharmacy type carrier such as methyl cellulose.

[0163] Non-fixed pharmaceutical combinations comprising solid unit dosage forms, such as a tablet, in combination with a liquid dosage form, are also contemplated.

[0164] Other modes of administration can include transdermal and suppository delivery. The administration process may involve either orally ingesting the composition, such as ingesting one or more tablets or capsules, or ingesting a liquid formulation containing cetyl myristate or a mixture of cetyl myristate and cetyl palmitate.

[0165] The number of tablets or capsules ingested or the amount of liquid taken will of course depend on a range of factors, including the formulation of the dosage form to be administered, the desired dose to be administered, the characteristics of the subject (including, for example, age and weight), and on the nature and severity of the subject's disease or condition.

[0166] In certain examples, a dosage unit comprising cetyl myristate, cetyl palmitate, or a mixture of cetyl myristate and cetyl palmitate for use as contemplated herein may contain between about 5 and 400 mg (such as from 20 to 380 mg, such as from 30 to 370 mg, such as from 40 to 360 mg, such as from 50 to 350 mg, such as from 100 to 350 mg, such as from 200 to 350 mg, such as from 300 to 350 mg) of either cetyl myristate alone, of cetyl palmitate alone, or of a mixture of cetyl myristate and cetyl palmitate, conveniently in the proportions described above.

[0167] The methods contemplated herein will in certain examples comprise the administration of therapy in accordance with a dosage regimen. An example of a dosage regimen suitable for an adult suffering from a viral disease or condition comprises administering (including self-administering) from 1 - 4 tablets or capsules comprising a preferred dosage unit as herein described 2 to 3 times daily for a period of at least one to eight weeks.

[0168] Over this treatment period and after, the dosage can be reduced or increased to suit the individual subject and to accommodate changes in the disease or condition, such as decreased disease progression, on the symptoms of the subject, and the like.

[0169] In certain examples, such as in the treatment of long COVID and / or conditions associated therewith, a dosage regimen in which a high dosage, for example a dosage of from about 70 mg / kg / day to about 140 mg / kg / day or higher, is initially delivered for a period, and then a decreased or decreasing dosage is administered. In certain examples, the dosage regimen comprises administering a high dosage, for example of about 140 mg / kg / day, for an initial perios of about 5 - 10 days, followed by decreased dosage thereafter.

[0170] Comparable dosages of a liquid formulation such as a liquid formulation as described herein can readily be administered.

[0171] As described above the various methods of therapy contemplated herein will typically embody the administration of an effective amount of the one or more therapeutic agents, for example, an effective amount of cetyl myristate, an effective amount of cetyl palmitate, or more particularly an effective amount of a combination of cetyl myristate and cetyl palmitate.

[0172] The effective amount will vary depending on, among other factors, the disease or symptom(s) indicated, the severity of the disease or symptom(s), the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired. A person skilled in the art will be able to determine appropriate dosages having regard to these any other relevant factors.

[0173] The efficacy of a composition can be evaluated both in vitro and in vivo. For example, the composition can be tested in vitro or in vivo for its ability to induce, up-regulate, down regulate, or otherwise modulate an immune response, such as a cell-mediated immune response or a humoral response. For in vivo studies, the composition can be fed to or injected into an animal (e.g., a mouse) and its effects on eliciting and / or modulating an immune response are then assessed. Based on the results, an appropriate dosage range and administration route can be determined.

[0174] The composition may be administered as a single dose or a multiple dose schedule. Multiple doses may be used in a primary immunomodulatory schedule and / or in subsequent immunomodulatory schedule(s).

[0175] A method of eliciting and / or modulating an immune response in a subject comprising administering to the subject an effective amount of a pharmaceutical composition as herein described is particularly contemplated. Further, the use of a pharmaceutical composition as herein described for eliciting and / or modulating an immune response in a subject, and the use of one or more therapeutic agents as described herein and combinations thereof in the manufacture of a medicament for eliciting and / or modulating an immune response in a subject are also contemplated.

[0176] In one specific example, the method of eliciting and / or modulating an immune response in a subject comprises administering to the subject an effective amount of cetyl myristate, an effective amount of cetyl palmitate, or more particularly an effective amount of a combination of cetyl myristate and cetyl palmitate, and / or a composition comprising same, as herein described.

[0177] The use of a therapeutic agent as described herein for eliciting and / or modulating an immune response in a subject, and the use of a therapeutic agent as described herein in the manufacture of a medicament for eliciting and / or modulating an immune response in a subject, are also contemplated.

[0178] In certain examples, eliciting an immune response comprises raising or enhancing an immune response. In exemplary examples, eliciting an immune response comprises eliciting a humoral and a cell mediated response. In certain examples, eliciting an immune response comprises raising or enhancing an anti-inflammatory response.

[0179] In certain examples, eliciting an immune response provides improved inflammatory response.

[0180] The immune response is elicited for treating a viral disease or condition, or ameliorating one or more symptoms or sequelae of or associated with a viral disease or condition. A person skilled in the art will appreciate that the therapeutic agents, combinations thereof, and compositions comprising same as described herein are useful for treating or preventing viral infection and / or a disease or condition associated with viral infection, including viral reactivation.

[0181] In certain examples, the compositions are used to elicit an anti-inflammatory response. An antiinflammatory response may be reflected in upregulation or downregulation of, or increased or decreased expression, production, amount, or concentration of one or more immunomodulators and / or markers selected from the group consisting of: IFN, IL-1, IL-6, IL-10, IL-11, IL-13, IL-17, ICAM-1, MCP-1, and TNF-a.

[0182] In certain examples, the anti-inflammatory immune response comprises an upregulation of or an increase in the expression, production, amount, or concentration of one or more anti-inflammatory immunomodulators and / or markers, such as an upregulation of or an increase in the expression, production, amount, or concentration of one or more immunomodulators, markers, or cytokines selected from the group consisting of IFN, IL-10 and IL-13.

[0183] In certain examples, the anti-inflammatory immune response comprises a downregulation of or a decrease in the expression, production, amount, or concentration of one or more pro-inflammatory immunomodulators and / or markers, such as a downregulation of or a decrease in the expression, production, amount, or concentration of one or more immunomodulators, markers, or cytokines selected from the group consisting of IL-1, IL-6, IL-11, IL-17, ICAM-1, MCP-1, and TNF-a. The invention is further described with reference to the following examples. It will be appreciated that the invention as claimed is not intended to be limited in any way by these examples.

[0184] EXAMPLES

[0185] Example 1: Immunomodulation in a murine model

[0186] This example presents an assessment of the effect of administration of STIR-101, a combination of cetyl myristate and cetyl palmitate, on viral reactivation and immunological responses in a murine model of viral infection.

[0187] Here, a murine model was employed to test the effect of STIR-101 administration on a ubiquitous human pathogen with high human seroprevalance, herpes simplex virus 1 (HSV-1) (26). Briefly, a corneal scarification model was used to infect strain 129 mice with a lethal dose of HSV-1 strain 17. Survival and global cytokine profiles of the mice following STIR-101 treatment and viral infection was assessed.

[0188] It has been reported that in the HSV-1 corneal model, strain 129 mice succumb to viral infection due to a cytokine storm (23). After treatment with STIR-101, the death of 129 mice was either delayed or prevented. Further, STIR-101 modulated the immune response of mice to which it was administered.

[0189] The data presented in this Example shows that STIR-101 is an effective immune modulator affecting the cytokine profiles following treatment with the drug and following HSV-1 infection. This Example supports the applicant's view that cetyl myristate, cetyl palmitate, and combinations thereof are effective in treating inflammatory diseases by controlling the often harmful cytokine responses elicited by immune cells.

[0190] Material and Methods

[0191] Cells, virus, and mice. Vero cells were used to prepare virus stocks and determine in vivo viral tissue titers as previously described (30). HSV-1 wild-type strain 17 from the same stock was used in all studies. Mice were purchased from Taconic at 3 weeks of age, housed 5 per cage, and separated by sex in the Washington University School of Medicine barrier facility. Mice were housed and treated in accordance with all federal and university policies.

[0192] Mouse food production. Supplemented mouse feed was produced through Ralston Purina (Test Diet, Richmond, IN). The mouse feed was formulated to different doses of STIR-101 corresponding to a different feed color. The daily dose of STIR-101 was calculated assuming a 22.5 gram mouse eating 3 grams of food per day. The feed was pre-irradiated and air dried to assure no changes in the chemical make-up of STIR-101. Feeds were formulated containing doses of 7mg / kg, 28mg / kg, 70mg / kg, and 140mg / kg. A control feed containing no STIR-101 was also manufactured. The food was stored at 4°C.

[0193] Feeding protocol. All purchased mice arrived in the barrier facility and were allowed to acclimate to their new environment for 5 days. A cohort of 50 mice were then separated into 5 groups of 10 and placed on the formulated feed. The experimental doses were control (Omg / kg), 7mg / kg, 28mg / kg, 70mg / kg, or 140mg / kg of STIR-101. The mice were left on the feed for 14 days until experimentation occurred. The feed was either changed or added to each week until termination of the experiment. Mouse weights were followed during feeding to assure the feed was being eaten and normal weight gains were being made. Animal infection procedure. After 2 weeks on STIR-101 diets, the mice were anesthetized and corneas were bilaterally scarified with a 25G needle. Immediately following scarification, WT HSV- 1 strain 17 with a titer of 2xlOA6 pfu / eye was inoculated directly on the cornea in a volume of 5pl.

[0194] Tissue harvests. On days 1 and 3 post-infection, corneas were swabbed to assess viral titers. On day 3, 2 mice were sacrificed for periocular skin and trigeminal ganglion. These tissues were harvested to assess viral titers as well. The remaining five mice were monitored for survival. Viral titers were found using a standard plaque assay as previously described (30) and are displayed as pfu per milliliter (pfu / ml).

[0195] Reactivation Assay, (experiments 1 and 2) On day 28 post-infection, the surviving mice were sacrificed for reactivation assays. Vero cells were plated one day prior to harvest in a 24-well plate. Trigeminal ganglion were harvested, cut in half, and placed in the well with ~lmL of cell media. For the next 7 consecutive days, 110 pL of media was harvested from each well and frozen at -80°C. Vero cells were then plated in a 48-well plate and lOOpi of each harvested supernatant was placed in each well. Reactivation was measure by CPE and followed for 10 successive days.

[0196] Cytokine study procedure, (experiments 3 - 5) Fifty (50) 3 week old 129 mice were purchased from Taconic (5 mice housed per cage). After the mice were allowed to acclimate to their new environment (5 days), 10 mice were bled via the mandibular vein. The blood was collected in a serum separator tube, placed on ice, allowed to clot for ~30 minutes, and centrifuged at 14,000RPM for 4 minutes. The serum was collected and stored at -20°C In a 1.5 mL eppendorf tube. Immediately following this initial bleed, 10 mice (2 cages) were given each of the 5 doses of formulated feed: control, 7mg / kg, 28mg / kg, 70mg / kg or 140mg / kg. For 2 weeks, the mice were given this feed and the food was changed once a week. Following the 2 weeks treatment, the mice were then bled again in the same fashion previously described. On the day of the second bleed, the mice were anesthetized and their corneas were scarified and inoculated as described above. Following 4 days post infection, the mice were again bled via the mandibular vein, serum was collected, and stored at -20°C.

[0197] Bio-plex cytokine analysis. Serum was thawed on ice and diluted 1:4 with Bio-Rad serum diluent in accordance with the kit protocol. Cytokine concentrations are reported in pg / ml and a new standard curve was generated for each experiment. A two-tailed, unpaired Student's t-test was done and independently compared back to control for each time point. Two experiments used a standard 23-plex and 1 experiment used a custom 10-plex.

[0198] Graphs and Statistics. All data was graphed using Graphpad Prism software. All statistics were done using Microsoft Excel.

[0199] Results

[0200] To examine the effects of STIR-101 on viral tissue titers, the protocol in the Materials and Methods section was used. In brief, a group of 50 129 mice were divided into groups of 10 (5 males and 5 females). Each group of 10 was placed on the varying doses of STIR-101 formulated feed or control feed for 2 weeks. After 2 weeks of treatment, each mouse was bilaterally scarified and inoculated with 2xlOA6 pfu / eye. On days 1 and 3 post-infection, a subset of mice were eye swabbed to measure corneal viral titers. Two mice on day 3 were sacrificed for periocular skin and trigeminal ganglia. Viral titers were determined on Vero cells. The remaining mice were followed to assess survival.

[0201] Body Weight Changes To confirm the fact that the addition of STIR-101 to the diet did not change the health of the mice, body weight was measured before and after infection. Body weight of mice loosely correlates to the overall health of the animal. There were no real, significant differences among any of the treated groups compared to the control group post infection (data not shown). The weights of the animals on day of infection were the same (within 3% of each other). This weight was measured after 2 weeks on the formulated or control feed. No significant difference was observed between the control and the STIR-101 feed. This data indicates that mice ate the manufactured food in the same way as the control feed and that the addition of STIR-101 does not change the overall bodyweight of the mouse. No differences were seen between males and females.

[0202] Survival / Titer Experiment 1

[0203] This experiment was performed to investigate the hypothesis that STIR-101 has anti-viral activity. Following the protocol from Materials and Methods, titers of the mice were found using a plaque assay. Day 1 eye swabs showed no significant differences among any groups. Day 3 eye swabs showed a possible reduction in viral replication in-vivo. Periocular skin and the trigeminal ganglion were also titered. Day 3 trigeminal ganglion showed no difference among any groups while periocular skin presented a possible slight reduction as well (data not shown). These data showed that STIR-101 may have an impact in viral replication during infection.

[0204] Survival was followed for 21 days following infection. All treated groups survived at a greater rate than the control groups (Figure 2). The results showed an inverse dose dependent response with 7mg / kg having the greatest survival and 140mg / kg having the lowest survival compared to the untreated group. When the groups are separated by sex, it is clear that any dose of STIR-101 was beneficial to females more than males (Figure 2).

[0205] Survival / Titer Experiment 2

[0206] A further investigation of viral replication was performed using the same system in another experiment. Again, there were no differences in viral titers in any of the tissues measured, suggesting that STIR-101 may not have a direct effect against HSV-1 replication.

[0207] The survival data gave similar results as in experiment #1 (data not shown). The treated groups tended to survive the lethal infection better than the untreated groups. Furthermore, two treated groups went on to survive the infection (28mg / kg and 140mg / kg). When the data is separated by sex, again a greater effect of STIR-101 administration was observed in females than males. In fact, all survival was seen in female treated groups only. This could be due to the reported overall greater female resistance to HSV-1 viral infection (15).

[0208] Survival / Titer Experiment 3

[0209] A further experiment following replication and survival again revealed a clear trend. Again, there was no difference in viral titers in any tissue at any day (data not shown). This was consistent through all experiments supporting the view that STIR-101 does not have an impact on HSV-1 replication.

[0210] The survival data replicated that observed in experiments 1 and 2 reported above. The treated groups (7mg / kg and 28mg / kg) survived the infection, or death was delayed by a day to four days. Males had a slightly delayed death (28mg / kg and 70mg / kg) as compared to control. Females also saw a delay in death (70mg / kg and 140mg / kg) or overcame the lethal infection (7mg / kg and 28mg / kg).

[0211] These data indicate that STIR-101 had an effect on lethality, but it appears to be independent of an effect on viral replication.

[0212] Reactivation Assay One of the hallmarks of herpes infections is the establishment of latency. This is a state where the viral genome lies dormant until a stimulus reactivates the virus and replication ensues. To examine the effects of STIR-101 on latency, an ex vivo transplant co-cultivation experiment was performed as described in the Materials and Methods section.

[0213] Briefly, on day 28 post-infection, the surviving mice were sacrificed, trigeminal ganglion were harvested, cut in half, and placed on Vero cells in a 24 well tissue culture plate. For the next 7 days, HOpI of supernatant was collected and stored at -80°C. Vero cells were then plated in 96 well dishes and lOOpI of the supernatant was added. Reactivation was measured by CPE and was followed for 10 days.

[0214] The results show that STIR-101 did not affect the establishment of HSV-1 latency (data not shown). These results are consistent with the tissue viral titer data.

[0215] Cvtokine Experiment 1

[0216] This experiment was performed to assess whether infected 129 mice succumb to corneal infection with HSV-1 strain 17 not from acute viral replication, but rather a cytokine storm.

[0217] The global cytokine profile of the mice before treatment, two weeks after treatment, and 4 days post infection was assessed, as described in the Materials and Methods above. Briefly, serum was collected at the indicated time points and cytokines were analyzed. A total of 23 different cytokines were analyzed in 2 separate experiments (a third experiment was performed looking at 10 cytokines). This experiment used only females.

[0218] The first experiment showed a nearly across the board reduction of pro-inflammatory and antiinflammatory cytokines at higher doses of STIR-101 (70mg / kg and 140mg / kg) following treatment alone. Cytokines which induce inflammation such as IL-1 a and 8, IL-6, and TNF- a were suppressed, as well as anti-inflammatory cytokines such as IL-10 and IL-13 (data not shown).

[0219] The cytokine profile at four days post infection showed an induction of the pro-inflammation (IL- 1 a and IL-6) and anti-inflammatory cytokines (IL-10 for example) compared to the control group. This induction was seen at the higher doses of 70mg / kg and 140mg / kg.

[0220] Many of the cytokines and chemokines followed a dose dependent response curve at both preinfection and post-infection time points. This experiment clearly showed that many different classes of cytokines were down regulated following treatment alone.

[0221] Further studies were done to check and validate the four days post infection data, as reported below.

[0222] Cvtokine Experiment 2

[0223] The second set of cytokine experiments shed light into the true mechanism of how STIR-101 was conferring survival to the mice. This experiment was done with an equal number of males and females (5 males and 5 females per group). Following 2 weeks of treatment with the STIR-101, a slight reduction of global cytokines was again seen compared to untreated mice including IL-la, IL-5, IL-10, IL-12 (p70), and IL-17. This reduction continued following infection. A dampening of all classes of cytokines (inflammatory, anti inflammatory, chemokines, growth factors, and T cell associated cytokines) was seen at higher doses (70mg / kg and 140mg / kg) compared to control groups, including IL-la, IL-4, IL-9, IL-10, IL-12, IL-13, GM-CSF, MIP-la, and RANTES (CCL5), (data not shown).

[0224] The applicant believes, without wishing to be bound by any theory, that this observed attenuation of cytokines following infection may be the mechanism by which STIR-101 prevents a cytokine storm, since all classes of cytokines seem to be down regulated following infection. Cvtokine Experiment 3

[0225] A third cytokine profile experiment was done using 10 selected cytokines with the same ratio of males and females as in cytokine experiment 2 above.

[0226] Following two weeks of treatment, in higher dosed animals there were noted reductions (70mg / kg and 140mg / kg) of IL-2, IL-6, IL-10, IL-13, IL-17, IFNy, and TNF-a (data not shown). Many of the 70mg / kg animals in this experiment did not follow the dose dependent response.

[0227] Similar results to those observed in experiment 2 were observed at four days following infection. There was a noted total dampening of cytokines in higher treated groups (70mg / kg and 140mg / kg) (Figure 10). There was a noted attenuation in IL-2, IL-6, IL-10, and KC (IL-8) following infection with HSV-1 (Figure 10).

[0228] Again without wishing to be bound by any theory, the applicant believes these data support their view that an HSV-1 initiated cytokine storm was being delayed or halted completely by treatment with STIR-101.

[0229] Summary of cytokine experiments

[0230] TNF-a

[0231] TNF-a is a major pro-inflammatory cytokine produced mainly by macrophages and numerous other immune cells. It is part of the acute phase response along with IL-1, IL-6, and IL-8. It has been termed the 'master regulator' of the inflammatory response (9). Local inductions of TNF-a are found primary at sites of redness and swelling. TNF-a inhibitors have been used to treat many diseases including Rheumatoid arthritis, Crohn's Disease, psoriasis, and refractory asthma. Since TNF-a is crucial to the inflammatory response, inhibitors of this cytokine can lead to the increase of opportunistic infections.

[0232] Again, although this cytokine is down regulated on administration of STIR-101, there have been no reported cases of a secondary viral infection arising.

[0233] • TNF-a is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as depicted in Figure 1.

[0234] RANTES

[0235] RANTES is also known as CCL5. It is a chemokine responsible for recruiting T cells, monocytes, basophils, and eosinophils to sites of inflammation. CCL5 has been reported to also activate and recruit NK cells (24). Like CCL3 and CCL4, CCL5 is generally considered in terms of viral infection, specifically HIV.

[0236] • RANTES is down regulated at 140mg / kg following STIR-101 treatment, as depicted in Figure 2.

[0237] MIP-1B

[0238] MIP-ip is also known as CCL4. It reportedly primarily recruits NK cells and monocytes to the site of infection to aid in the host's defense (4), and again is generally considered with respect to viral infection.

[0239] Although MIP-ip is down regulated on administration of STIR-101, there have been no clinical instances of increased susceptibility to viral infection.

[0240] • MIP-ip is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR- 101 treatment, as depicted in Figure 3. MIP-la

[0241] MIP-la is more commonly known as CCL3, and is secreted mainly by macrophages. It is an early inducer of inflammation and attracts activated leukocytes to the site of infection (38). Inductions of MIP-la are reported very early in infection and lead to the accumulation of other immune cells. After its secretion, it activates many other pro-inflammatory cytokines.

[0242] • MIP-la is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR- 101 treatment, as shown in Figure 4.

[0243] MCP-1

[0244] MCP-1 (Monocyte Chemoattractant Protein-1, also known as CCL2), is another chemokine reportedly responsible for recruiting memory T cells and monocytes to sites of infection (5). It has been proposed this chemokine mainly works by inducing large amounts of monocytic infiltrates to the site. Disease caused by an influx of MCP-1 has been linked to Rheumatoid Arthritis, atherosclerosis, and psoriasis. Anti-CCL2 antibodies have been reported to decrease the symptoms of RA in rats leading to less macrophage and cytokine accumulation (33).

[0245] • MCP-1 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR- 101 treatment, as shown in Figure 5.

[0246] KC fIL-8)

[0247] IL-8, a chemokine, is primarily produced by macrophages and endothelial cells. It is stored within endothelial cells in storage vesicles known as Weibel-Palade bodies (37). Increased levels of IL- 8 have been reported to correlate with inflammation. As a chemokine, IL-8 recruits other inflammatory cells to the site of insult and further increases inflammation. Increases in IL-8 have been reported to be responsible for the inflammation seen in psoriasis (29). Also, high levels of IL-8 have been reported to be responsible for some types of lung inflammation (22).

[0248] • IL-8 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 6.

[0249] IFN-v

[0250] Interferon gamma is a type 2 interferon involved in the immunological response to viral and bacterial infections. It is mainly produced by active NK cells during the innate immune response and CTLs mainly during the adaptive immune response. It has been reported that IFN- y controls up to 30 genes in response to an infection to activate NK cells, suppress Th2 activity, increase antigen presentation to macrophages, and activate APC's (32). IFN-y inhibitors have been hypothesized to treat symptoms of MS, IBS, and possibly psoriasis (29).

[0251] • IFN-y is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 7.

[0252] GM-CSF

[0253] GM-CSF acts to stimulate stem cells to produce many types of white blood cells including neutrophils, basophils, and eosinophils. Supplemental GM-CSF is currently being used to increase the number of white blood cells in patients with cancer and organ transplants (35). It has been suggested that the levels of GM-CSF must remain at a relatively normal level to allow WBC's to recognize infection.

[0254] • GM-CSF is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR- 101 treatment, as shown in Figure 8.

[0255] G-CSF G-CSF targets stem cells in bone marrow to stimulate granulocyte production. It is released from fibroblasts, endothelium, and macrophages in response to an insult, and acts to stimulate and activate neutrophils to help fight infections. G-CSF is currently being used to treat patients during chemotherapy and with neutropenia.

[0256] • G-CSF is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR- 101 treatment, as shown in Figure 9.

[0257] Eotaxin

[0258] Eotaxin is an esoniphil attractant that brings eosinophils to sites of infection via chemotaxis. Eosinophils are implicated in many allergic diseases such as asthma and respiratory inflammation (19). Eosinophils are reportedly responsible for much of the inflammation seen in patients.

[0259] • Eotaxin is downregulated at all experimental doses following STIR-101 treatment, as shown in Figure 10.

[0260] IL-17

[0261] IL-17 is an important mediator of the pro-inflammatory response. It is reportedly responsible for the regulation of many other cytokines such as IL-6, TNF-a, MCP-1, and IL-8 (10). It is also reportedly secreted by many different types of cell lines including macrophages, endothelial cells, and fibroblasts among others. IL-17 is considered to be important in many autoimmune and inflammatory diseases due to the subset of CD4+ cells reported in the Thl7 system (10). IL-17 has been linked to many diseases such as rheumatoid arthritis, psoriasis, asthma, and lupus (1). The overexpression of IL-17 has been reported to lead to inflammation causing these diseases. The inhibition of IL-17 has been reported to have positive effects on animals with arthritis and helps alleviate its symptoms (21).

[0262] • IL-17 is down regulated at 140mg / kg following STIR-101 treatment, as shown in Figure 11.

[0263] IL-13

[0264] IL-4 and IL-13 are closely related ligands that reportedly help induce the allergic response via the activation of STAT6. IL-13 is reportedly secreted mainly by Th2 cells and upregulates MHC class II expression (39) and to possess anti-inflammatory activity. IL-13 is considered a major mediator of allergic asthma by regulating eosinophilic inflammation and mucus secretion (39). Antibodies against IL-13 have been proposed to help patients by increasing type I associated anti-tumor defenses. IL-13 is a good target to help patients with respiratory inflammatory diseases.

[0265] • IL-13 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 12.

[0266] IL-12 fp40) and IL-12 fp70)

[0267] IL-12 is reported to be produced by dendritic cells, macrophages, and B cells, and to comprise two covalently linked glycosylated subunits, p40 and p70. It is a potent activator of Natural Killer (NK) cells which are believed to be important for the innate immune response and the production of interferon gamma. The administration of IL-12 has been reported to worsen autoimmunity in animal models (15). Increased IL-12 has been reported to be responsible for the inflammatory bowel disease Crohn's Disease. Anti-IL-12 treatment has been reported to help the symptoms of patients with this disease (25).

[0268] IL-12 (p70) and IL-12 (p40) are down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 13, and Figure 14, respsectively. IL-la and IL-1B

[0269] IL-la and IL- 1 [3 are the two closely related ligands of IL-1 that bind its receptor, IL-1RI. These pro-inflammatory cytokines are produced by monocytes, macrophages, and dendritic cells in response to an infection. Both have been reported to be crucial in the regulation of hematopoiesis, especially in the differentiation of myeloid and lymphoid cells. Induction of IL-1 has been reported to induce fever, thus leading to IL-1 mediated T-cell proliferation to the infection site (7). IL-1 is a member of the acute phase response.

[0270] Polymorphisms of IL-1 have been implicated in diseases such as Rheumatoid Arthritis and Alzheimer's disease. Current data suggests that IL-1 signaling is crucial in many cardiovascular diseases (3). Also, IL-1 a has been reported to be essential for the maintenance and regeneration of skin epithelial cells (2). IL-1 antagonists are currently being used for the treatment of Rheumatoid Arthritis (RA) and Sepsis (20). This therapy has been reported to greatly reduce the disease progression of RA and give the patient a greater quality of life. The many diverse roles of IL-1 have made it and its receptor a good target for novel therapy.

[0271] • IL-la and IL- 1 [3 are down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 15, and Figure 16, respectively.

[0272] IL-2

[0273] IL-2 is a cytokine believed to be responsible for the growth and differentiation of cytotoxic T cells during an immune response (34). It has also been reported to be crucial in the recognition of self versus non-self antigens through the maturation of T-regulatory cells - cells that are responsible for suppressing the immune response (36). Furthermore, IL-2 can reportedly both induce and suppress the inflammatory response via Fas ligand mediated cell death and the inhibition of Thl7 cells (16). Normal, regulated levels of IL-2 are generally considered to be essential.

[0274] • IL-2 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 17.

[0275] IL-3

[0276] IL-3 is a growth factor reported to be responsible for the differentiation and proliferation of hematopoietic cells. It is reportedly secreted by activated T cells and monocytes / macrophages to aid in the differentiation of other T cells from bone marrow. IL-3 has been reported to have many of the same biological functions as GM-CSF.

[0277] • IL-3 is down regulated at higher doses (28mg / kg, 70mg / kg, and 140mg / kg) following STIR-101 treatment, as shown in Figure 18.

[0278] IL-4

[0279] IL-4 is considered a necessary and critical cytokine for adaptive immunity. IL-4 is a cytokine essential for the differentiation of ThO cells into Th2 cells. It is also reportedly responsible for the proliferation of B and T cells as well as upregulation of MHC class II production.

[0280] Elevated levels of IL-4 and IL-13 have been linked to atopy, the underlying cause of asthma and eczema (18).

[0281] • IL-4 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 19.

[0282] IL-5

[0283] IL-5 is reportedly secreted from Th2 cells and mast cells. It is considered to be responsible for the activation of eosinophils, thereby reportedly leading to many allergic conditions such as asthma and rhinitis. Activated eosinophils also secrete IL-5 and have been reported to stimulate B cell growth and immunoglobulin secretion.

[0284] Increased levels of IL-5 may be one of the causative agents of allergic asthma and rhinitis due to high levels of infiltrating eosinophils. Studies have reported that the RNAi knockdown of IL-5 in mouse models decreased the amount of infiltrating cells and could possibly be a treatment for asthma (6). Also, anti-IL-5 antibodies have been proposed as treatments for asthma patients and have shown clinical relevance (12).

[0285] • IL-5 is down regulated at 140mg / kg following STIR-101 treatment, as shown in Figure 20.

[0286] IL-6

[0287] IL-6 is both a pro-inflammatory and anti-inflammatory cytokine that is believed to be an important mediator of fever and the acute phase response. It is reportedly secreted by T cells and macrophages in response to some foreign antigens. IL-6 can reportedly act as an anti inflammatory cytokine by inhibiting IL-1 and TNF-a as well as activating IL-10 and the IL-lra (40).

[0288] Increased levels of IL-6 are reported in diseases such as rheumatoid arthritis (RA), systemiconset juvenile chronic arthritis (JCA), osteoporosis, and psoriasis (17). The diseases involving IL-6 are extremely prevalent throughout the world.

[0289] Without wishing to be bound by any theory, the applicant believes that IL-6 may be a good target therapy for STIR-101 due to its repeated decrease of the cytokine in all animal trials at higher doses (70mg / kg and 140mg / kg).

[0290] • IL-6 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 21.

[0291] IL-9

[0292] IL-9 is a cytokine reportedly produced mainly by CD4+ T cells (31). IL-9 reportedly regulates many hematopoietic cell types, aids in proliferation of eosinophils (11), and prevent apoptosis. IL-9 signals mainly through the JAK / STAT pathways and has many implications in inflammatory disease.

[0293] IL-9 is considered a candidate gene for asthma (27). Increases in IL-9 and the disregulation of eosinphils have been reported to produce asthma in animal models. IL-5 shows the same type of disorder, but via a different mechanism. Reductions of IL-9 could possibly serve as a treatment to alleviate this allergic condition.

[0294] • IL-9 is down regulated at all experimental doses following treatment with STIR-101, as shown in Figure 22.

[0295] IL-1O

[0296] IL-10 is probably the most studied anti-inflammatory cytokine. IL-10 is a very potent cytokine reportedly responsible for inhibiting synthesis of the major inflammatory Thl cytokines such as IL-1, IL-2, IL-3, TNF-a, and IFN-y. T regulatory cells reportedly act by producing IL-10 to suppress the response to an insult. It is also reportedly responsible for suppressing the presentation of antigen to APC's. IL-10 also reportedly aids in the stimulation of B and T cells.

[0297] Since IL-10 is believed to be necessary for the suppression of the inflammatory response, it is likewise believed that regulated levels of IL-10 are required for normal physiologic function. The administration of IL-10 to patients with Crohn's disease has been reported to have minimal effects in vivo (14). A deficiency of IL-10 can possibly lead to an unchecked immune response and uncontrollable inflammation. • IL-10 is down regulated at higher doses (70mg / kg and 140mg / kg) following STIR-101 treatment, as shown in Figure 23.

[0298] Discussion

[0299] The data presented in this Example show that a composition comprising a combination of cetyl myristate and cetyl palmitate, STIR-101, was an effective immune modulator affecting cytokine levels of subjects exposed to HSV-1 infection. Treatment dampens the global cytokine profile in vivo, and based on the survival data lessens the effect of the viral infection. This global inhibition of cytokines seen in the serum of treated mice was clearly beneficial and prolonged the lives of a significant number of animals.

[0300] This Example supports the applicant's view that cetyl myristate and cetyl palmitate are effective in suppressing cytokine storm and modulating the immune response during inflammation reaction. Without wishing to be bound by any theory, the applicant believes these data support the utility of compositions contemplated herein in the treatment or prevention of the unwanted effects of an over- zealous immune response to infectious diseases, and in treating viral diseases and / or their sequelae by controlling the often-harmful immune responses elicited by the immune system in response to viral challenge.

[0301] Example 2: Immunomodulation in human cells

[0302] This example presents an assessment of the use of STIR-101 to modulate immune cell function as a possible agent to influence the immune dysfunction associated with Long Covid.

[0303] More particularly, this example explores the immunomodulatory and / or anti-inflammatory effects of the mixture of esterified fatty acids comprising STIR-101, and the potential therapeutic benefits to inflammatory diseases, including long covid and other associated post-viral illnesses such as Myalgic Encephalomyelitis / Chronic fatigue syndrome (ME / CFS).

[0304] Of particular interest is the role of NK cells in the control of herpesviruses (41, 42), and indeed, whether SAR-CoV-2 infection leads to a loss of immune control, or immune dysfunction in these cells. Patients with identified NK cell deficiencies have been reported to be predisposed to particularly severe, recurrent viral infections (43). NK cell dysfunction has been reported in both ME / CFS (44, 45) and Long Covid (46, 47). NK cells are important players in the immune response against viruses, however, very little is known about their metabolic requirements during acute infections.

[0305] This study presents various investigations conducted using STIR-101. Whole blood samples were used in these assays to provide a general overview of the impacts of viral stimulation (via exposure to spike peptides) in the presence or absence of STIR-101 treatment. A 38 colour spectral cytometry panel was developed to include markers to identify all main immune cell populations, and some functional markers, as described in more detail below.

[0306] Materials and Methods

[0307] Sample Collection and Preparation

[0308] 2 healthy controls (vaccinated / recovered) and 1 patient (twice vaccinated / Long Covid) were initially used to establish in vitro conditions to monitor immunological changes when exposed to STIR- 101.

[0309] The conditions investigated included: Control (DMSO), R848 (viral mimic), Spike protein peptide, STIR-101, and MCL (control reagent for comparison). Triggering cells (whole blood samples) was done with viral stimuli - i.e., spike protein or a viral mimic (R848) both before and after treatment with STIR-101 to investigate prophylactic and protective changes in immunological responses. Duplicate samples were prepared for each condition.

[0310] The experimental plan is shown in Table 1 below.

[0311] Table 1: Experimental plan

[0312] Immunological Assays

[0313] Flow Cytometry: Spectral cytometry was selected to measure immunological changes in response to STIR-101. This technique allowed for the identification and quantification of specific cell populations based on their surface markers.

[0314] A panel of 38 fluorescently labelled antibodies was chosen to assess different immune cell subsets and functional cell surface markers. The panel included antibodies targeting myeloid, T cells, B cells, natural killer cells and other relevant markers. The antibody panel was designed to capture a comprehensive profile of the immune response. Importantly, markers such as ICAM-1, CD62L, CDllb, CD69, CD39 were included to establish whether they were altered during the in vitro stimulation assay.

[0315] Results

[0316] Potential immunological changes in response to STIR-101 were observed in experiment 1. Specific immune cell subsets, such as NK, T cells and monocytes showed alterations in their frequency or activation status.

[0317] A higher-level overview of the complex data set revealed a number of observations. These include:

[0318] • 3 samples were used to screen for effects - 2 x recovered covid, and 1 x suspected Long Long Covid (LCS062). Data from LCS062 are displayed in Figure 24 and are representative of data obtained in each sample, as no distinctive differences were noted between these 3 samples. • Addition of STIR-101 (labelled LYP) did not induce any major changes - either via activation or death indicating that the product is well tolerated in whole blood samples and didn't cause any obvious stimulation to any of the main immune cell populations.

[0319] However, subtle changes in cell populations were noted when analysing the percentage of cells in each sample. For example, when analysing all samples across 2 donors in duplicate, spike + LYP post appears to lead to an increase in CD14+ monocytes and a drop in CD3 T cells. This may be due to a loss of CD3 T cells, or retention of CD14 monocytes.

[0320] No changes in NK cell population markers (CD56 / CD16 or CD57, a late-stage marker on NK cells) or activation markers were seen across the conditions as shown in Figure 25, although donors had different proportions. (LCS062 = LC patient).

[0321] No distinctive NK or T cell activation markers (CD69) were different across the key conditions highlighted when assessing the flow cytometry dot plots (see Figure 26 and Figure 27). However, analyses based on the median fluorescent intensity of each marker showed some subtle differences, potentially indicating a slight upregulation in CD69 and CD25 when stimulated with spike and LYP.

[0322] T cells also did not seem to show obvious signs of activation (data not shown).

[0323] Spike peptide induced activation - and a notable upregulation of ICAM-1 on myeloid / CD14+ monocyte cells (CCR2+) was observed (see Figure 28), indicating the stimulation of an inflammatory signal. Spike + STIR-101 (post L+ spike) led to a higher percentage of myeloid cell survival / upregulation of ICAM-1 when compared to pre-treatment with STIR-101. This was not observed when pre-treated with STIR-101, or at least, it was similar to spike alone. This phenomenon aligns with the observation that under these conditions, there are more CD14+ cells and less CD3 cells.

[0324] Other activation markers were also interrogated on these CD14+ myeloid cells. Other observations included a possible drop in CD39 and a slight increase in CD25 and CD38 and CCR2, as seen in Figure 29.

[0325] Conclusions

[0326] These data show that administration of STIR-101 is neither significantly stimulatory nor toxic to cells or to human subjects, and elicits a variety of immunomodulatory effects on various immune cell populations.

[0327] Example 3: Immunomodulation in human subjects

[0328] This example presents an assessment of the use of STIR-101 in human subjects to modulate immune cell function and to influence the immune dysfunction associated with Long Covid.

[0329] Mitochondrial Membrane Potential Recovery Analysis

[0330] Human subjects volunteered to take STIR-101 (140 mg / kg / day) as case studies under observation with their health care provider. Baseline bloods, and then weekly samples were taken for a period of four weeks and stored for subsequent analyses.

[0331] Blood samples from eight human subjects (one healthy control and seven long covid sufferers) were treated as described above in Example 2. Blood samples were collected at the same timepoints. All samples were carried out in duplicate.

[0332] The healthy control subject had normal mitochondrial membrane potential, which was protected in the presence of spike protein by STIR-101. Of the seven long covid subjects, the spike protein-induced immunological reaction in blood samples from two subjects were so severe that the addition of spike protein resulted in cell death greater than 50%. The other five long covid subjects showed varying degrees of mitochondrial membrane protection in the presence of spike protein when STIR-101 was used as a pretreatment. One subject (DP 62) had 20% cell death as their baseline, with some protection against further death observed by the addition of STIR-101. Another subject (CM 80) showed improved mitochondrial function when blood cells were treated with STIR-101, with enhanced protection against spike protein when pretreated.

[0333] Clinical Efficacy Testing

[0334] Two subjects (DP 62 and CM 80) subsequently volunteered to take STIR-101, with baseline bloods collected and blood samples taken again at 4 and 24 hours, and then weekly for four weeks.

[0335] Initial analysis has shown that within 4 hours mitochondrial membrane potential and cell death rates were improving, and by 24 hours were significantly improved, following treatment with STIR- 101. An increase in monocytes was also detected.

[0336] Equivalent changes with increase in NK cells, monocytes, CD69, and ICAM occurred in the first week and then stabilized over the other timepoints. Subject DP 62 matched their in vitro blood results above, indicating that the in vitro assay was equivalent to the clinical assay. Cell death also decreased in DP62 from 12% to 3 % over the time period.

[0337] Challenge of the blood samples with spike protein showed equivalent protection to that observed in vitro, indicative of an immune modulation benefit being mediated in vivo.

[0338] Conclusions

[0339] These results support the applicant's hypothesis that T cells are activated on STIR-101 administration, evidenced by increased IL-10 expression following STIR-101 administration. This results in an increase of NFkappa B leading to an increase in ICAM.

[0340] Without wishing to be bound by any theory, the applicant believes that although ICAM can be a signal of inflammation, these data show that STIR101 induces an increase in IL-10 when triggered by viral protein which results in the observed increase in ICAM. The applicant further believes (again without wishing to be bound by any theory) that these ICAM+ cells will then self convert into an innate immune response thereby protecting immune function, rather than mediating a proinflammatory response which would result in apoptosis.

[0341] These data show that administration of STIR-101 is well-tolerated by human subjects including Long Covid sufferers and elicits beneficial immunomodulatory effects in vivo when administered to human subjects, including those suffering from Long Covid and associated symptoms and sequelae.

[0342] Publications

[0343] 1. Aggarwal, S., and A. L. Gurney. 2002. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71:1-8.

[0344] 2. Barland, C. O., E. Zettersten, B. S. Brown, J. Ye, P. M. Elias, and R. Ghadially. 2004. Imiquimod-induced interleukin-1 alpha stimulation improves barrier homeostasis in aged murine epidermis. J Invest Dermatol 122:330-6.

[0345] 3. Bujak, M., and N. G. Frangogiannis. 2009. The role of IL-1 in the pathogenesis of heart disease. Arch Immunol Ther Exp (Warsz).

[0346] 4. Bystry, R. S., V. Aluvihare, K. A. Welch, M. Kallikourdis, and A. G. Betz. 2001. B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2:1126-32.

[0347] 5. Carr, M. W., S. J. Roth, E. Luther, S. S. Rose, and T. A. Springer. 1994. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A 91:3652-6. 6. Chen, S. X., F. Y. Huang, G. H. Tan, C. C. Wang, Y. H. Huang, H. Wang, S. L. Zhou, F. Chen, Y. Y. Lin, and J. B. Liu. 2009. RNA interference against interleukin-5 attenuates airway inflammation and hyperresponsiveness in an asthma model. J Zhejiang Univ Sci B 10:22-8.

[0348] 7. Duff, G. W., and S. K. Durum. 1982. Fever and immunoregulation: hyperthermia, interleukins 1 and 2, and T-cell proliferation. Yale J Biol Med 55:437-42.

[0349] 8. Feghali, C. A., and T. M. Wright. 1997. Cytokines in acute and chronic inflammation. Front Biosci 2:dl2- 26.

[0350] 9. Feldmann, M., and R. N. Maini. 2003. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 9:1245-50.

[0351] 10. Gaffen, S. L. 2008. An overview of IL-17 function and signaling. Cytokine 43:402-7.

[0352] 11. Gounni, A. S., B. Gregory, E. Nutku, F. Aris, K. Latifa, E. Minshall, J. North, J. Tavernier, R. Levit, N. Nicolaides, D. Robinson, and Q. Hamid. 2000. Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96:2163-71.

[0353] 12. Haidar, P., C. E. Brightling, B. Hargadon, S. Gupta, W. Monteiro, A. Sousa, R. P. Marshall, P. Bradding, R. H. Green, A. J. Wardlaw, and I. D. Pavord. 2009. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360:973-84.

[0354] 13. Han, X., P. Lundberg, B. Tanamachi, H. Openshaw, J. Longmate, and E. Cantin. 2001. Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice. J Virol 75:3048-52.

[0355] 14. Herfarth, H., and J. Scholmerich. 2002. IL-10 therapy in Crohn's disease: at the crossroads. Treatment of Crohn's disease with the anti-inflammatory cytokine interleukin 10. Gut 50:146-7.

[0356] 15. Holz, A., K. Brett, and M. B. Oldstone. 2001. Constitutive beta cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. J Clin Invest 108:1749-58.

[0357] 16. Hoyer, K. K., H. Dooms, L. Barron, and A. K. Abbas. 2008. Interleukin-2 in the development and control of inflammatory disease. Immunol Rev 226:19-28.

[0358] 17. Ishihara, K., and T. Hirano. 2002. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 13:357-68.

[0359] 18. Izuhara, K., and T. Shirakawa. 1999. Signal transduction via the interleukin-4 receptor and its correlation with atopy. Int J Mol Med 3:3-10.

[0360] 19. Jahnz-Ro yk, K., T. Plusa, and J. Mierzejewska. 2000. Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function. Mediators Inflamm 9:175-9.

[0361] 20. Kavanaugh, A. 2006. Anakinra (interleukin-1 receptor antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis. Adv Ther 23:208-17.

[0362] 21. Koenders, M. I., E. Lubberts, B. Oppers-Walgreen, L. van den Bersselaar, M. M. Helsen, F. E. Di Padova, A. M. Boots, H. Gram, L. A. Joosten, and W. B. van den Berg. 2005. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol 167:141-9.

[0363] 22. Krupa, A., M. J. Walencka, V. Shrivastava, T. Loyd, R. Fudala, C. W. Frevert, T. R. Martin, and A. K. Kurdowska. 2007. Anti-KC autoantibody:KC complexes cause severe lung inflammation in mice via IgG receptors. Am J Respir Cell Mol Biol 37:532-43.

[0364] 23. Lundberg, P., C. Ramakrishna, J. Brown, J. M. Tyszka, M. Hamamura, D. R. Hinton, S. Kovats, O. Nalcioglu, K. Weinberg, H. Openshaw, and E. M. Cantin. 2008. The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol 82:7078-88.

[0365] 24. Maghazachi, A. A., A. Al-Aoukaty, and T. J. Schall. 1996. CC chemokines induce the generation of killer cells from CD56+ cells. Eur J Immunol 26:315-9.

[0366] 25. Mannon, P. J., I. J. Fuss, L. Mayer, C. O. Elson, W. J. Sandborn, D. Present, B. Dolin, N. Goodman, C. Groden, R. L. Hornung, M. Quezado, Z. Yang, M. F. Neurath, J. Salfeld, G. M. Veldman, U. Schwertschlag, and W. Strober. 2004. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 351:2069-79.

[0367] 26. Morris, M. C., W. J. Edmunds, L. M. Hesketh, A. J. Vyse, E. Miller, P. Morgan-Capner, and D. W. Brown. 2002. Sero-epidemiological patterns of Epstein-Barr and herpes simplex (HSV-1 and HSV-2) viruses in England and Wales. J Med Virol 67:522-7.

[0368] 27. Nicolaides, N. C., K. J. Holroyd, S. L. Ewart, S. M. Eleff, M. B. Kiser, C. R. Dragwa, C. D. Sullivan, L. Grasso, L. Y. Zhang, C. J. Messier, T. Zhou, S. R. Kleeberger, K. H. Buetow, and R. C. Levitt. 1997. Interleukin 9: a candidate gene for asthma. Proc Natl Acad Sci U S A 94:13175-80.

[0369] 28. Osterholm, M. T. 2005. Preparing for the next pandemic. N Engl J Med 352:1839-42.

[0370] 29. Pietrzak, A. T., A. Zalewska, G. Chodorowska, D. Krasowska, A. Michalak-Stoma, P. Nockowski, P. Osemlak, T. Paszkowski, and J. M. Rolinski. 2008. Cytokines and anticytokines in psoriasis. Clin Chim Acta 394:7-21.

[0371] 30. Rader, K. A., C. E. Ackland-Berglund, J. K. Miller, J. S. Pepose, and D. A. Leib. 1993. In vivo characterization of site-directed mutations in the promoter of the herpes simplex virus type 1 latency- associated transcripts. J Gen Virol 74 ( Pt 9):1859-69.

[0372] 31. Renauld, J. C., A. Goethals, F. Houssiau, H. Merz, E. Van Roost, and J. Van Snick. 1990. Human P40 / IL- 9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene. J Immunol 144:4235-41.

[0373] 32. Schoenborn, J. R., and C. B. Wilson. 2007. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41-101.

[0374] 33. Shahrara, S., A. E. Proudfoot, C. C. Park, M. V. Volin, G. K. Haines, J. M. Woods, C. H. Aikens, T. M. Handel, and R. M. Pope. 2008. Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant- induced arthritis. J Immunol 180:3447-56. 34. Stern, J. B., and K. A. Smith. 1986. Interleukin-2 induction of T-cell G1 progression and c-myb expression. Science 233:203-6.

[0375] 35. Tayal, V., and B. S. Kalra. 2008. Cytokines and anti-cytokines as therapeutics— an update. Eur J Pharmacol 579:1-12.

[0376] 36. Thornton, A. M., E. E. Donovan, C. A. Piccirillo, and E. M. Shevach. 2004. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 172:6519-23.

[0377] 37. Wolff, B., A. R. Burns, J. Middleton, and A. Rot. 1998. Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies. J Exp Med 188:1757- 62.

[0378] 38. Wolpe, S. D., G. Davatelis, B. Sherry, B. Beutler, D. G. Hesse, H. T. Nguyen, L. L. Moldawer, C. F. Nathan, S. F. Lowry, and A. Cerami. 1988. Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J Exp Med 167:570-81.

[0379] 39. Wynn, T. A. 2003. IL-13 effector functions. Annu Rev Immunol 21:425-56.

[0380] 40. Xing, Z., J. Gauldie, G. Cox, H. Baumann, M. Jordana, X. F. Lei, and M. K. Achong. 1998. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101:311-20.

[0381] 41. Dai H-S, Caligiuri MA. Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. 2018;9.

[0382] 42. Della Chiesa M, De Maria A, Muccio L, Bozzano F, Sivori S, Moretta L. Human NK Cells and Herpesviruses: Mechanisms of Recognition, Response and Adaptation. 2019;10.

[0383] 43. Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes and infection. 2002;4(15): 1545-58.

[0384] 44. Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. 2023;24(15):11937.

[0385] 45. Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis / chronic fatigue syndrome. Systematic Reviews. 2019;8(l):279.

[0386] 46. Di Vito C, Calcaterra F, Coianiz N, Terzoli S, Voza A, Mikulak J, et al. Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications. Front Immunol. 2022;13:888248.

[0387] 47. Zafarani A, Razizadeh MH, Pashangzadeh S, Amirzargar MR, Taghavi-Farahabadi M, Mahmoudi M. Natural killer cells in COVID-19: from infection, to vaccination and therapy. Future Virol. 2023.

[0388] 48. Arguello RJ, Combes AJ, Char R, Gigan JP, Baaziz Al, Bousiquot E, et al. SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution. Cell Metab. 2020;32(6): 1063-75 e7.

[0389] 49. Wang P-y, Ma J, Kim Y-C, Son AY, Syed AM, Liu C, et al. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis / chronic fatigue syndrome. 2023;120(34):e2302738120.

[0390] 50. Guarnieri JW, Dybas JM, Fazelinia H, Kim MS, Frere J, Zhang Y, et al. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. 2023;15(708):eabql533.

[0391] The entire disclosures of all applications, patents and publications cited above are herein incorporated by reference in their entirety.

[0392] Where in the foregoing description reference has been made to integers or components having known equivalents thereof, those integers are herein incorporated as if individually set forth.

[0393] It should be noted that various changes and modifications to the presently preferred examples described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be included within the present invention.

[0394] The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features.

[0395] Aspects of the invention have been described by way of example only, and it should be appreciated that variations, modifications and additions may be made without departing from the scope of the invention, for example when present the invention as defined in the indicative claims. Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred in this specification.

Claims

CLAIMS1. A method of treating or preventing hypercytokinemia in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

2. A method of treating or preventing a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

3. A method of treating or preventing one or more symptoms or sequelae of a viral disease or condition, the method comprising administering to a subject in need thereof an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

4. A method of modulating an immune response of a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition, the method comprising administering to the subject an effective amount of: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

5. The method according to any one of claims 1 to 4, wherein the subject is or has been determined to be at risk of viral reactivation.

6. The method according to any one of claims 1 to 5, wherein the subject is suffering from or has been determined to be at risk of hypercytokinemia.

7. The method according to any one of claims 1 to 6, wherein the subject is or is at elevated risk of suffering from one or more of the following: myalgic encephalymyelitis / chronic fatigue syndrome, COVID, long COVID, shingles, herpes or herpes simplex infection, or a retroviral disease or condition.

8. The method according to any one of the preceding claims, wherein when both cetyl myristate and cetyl palmitate are administered the cetyl myristate and cetyl palmitate are administered separately, simultaneously, or sequentially.

9. The method according to any one of the preceding claims, wherein when both cetyl myristate and cetyl palmitate are administered, the w / w ratio of cetyl myristate to cetyl palmitate administered is in the range of between 4: 1 to 100: 1.

10. The method according to any one of the preceding claims, wherein when both cetyl myristate and cetyl palmitate are administered the cetyl myristate and cetyl palmitate are administered together as a pharmaceutical composition.

11. The method according to claim 10, wherein the w / w ratio of cetyl myristate to cetyl palmitate in the pharmaceutical composition is in the range of between 4: 1 to 100:

1. w / w.

12. The method according to any one of the preceding claims, wherein the cetyl myristate is administered as a unit dosage form and wherein said unit dosage form comprises from about 5 mg to 400 mg of cetyl myristate.

13. The method according to any one of the preceding claims, wherein the cetyl palmitate is administered as a unit dosage form and wherein said unit dosage form comprises from about 1 mg to 400 mg of cetyl palmitate.

14. The method according to claim 12 wherein the unit dosage form comprises from about 1 mg to 400 mg of cetyl palmitate.

15. A pharmaceutical composition for use in a method as contemplated herein, said pharmaceutical composition comprising: a) cetyl myristate; or b) cetyl palmitate; or c) cetyl myristate and cetyl palmitate; or d) a pharmaceutical composition comprising any one of a) to c) above.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is a unit dosage form.

17. The pharmaceutical composition according to claim 15 or 16 wherein the pharmaceutical composition comprises [define composition / components of STIR-101].

18. Use of cetyl myristate in the preparation of a medicament for treating or preventing a viral disease or condition or treating or preventing one or more symptoms or sequelae of a viral disease or condition.

19. Use of cetyl myristate in the preparation of a medicament for modulating an immune response of a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition.

20. The use according to claim 18 or 19, wherein the medicament additionally comprises cetyl palmitate.

21. Use of cetyl palmitate in the preparation of a medicament for treating or preventing a viral disease or condition or treating or preventing one or more symptoms or sequelae of a viral disease or condition.

22. Use of cetyl palmitate in the preparation of a medicament for modulating an immune response of a subject in need thereof, wherein said subject is or has been exposed to or infected by a virus, and / or is or is suspected of suffering from a viral disease or condition.

23. The use according to claim 21 or 22, wherein the medicament additionally comprises cetyl myristate.

Images