WO2021245365A1

WO2021245365A1 - Improved immunomodulator compositions and viral pathogen treatments

Info

Publication number: WO2021245365A1
Application number: PCT/GB2020/000058
Authority: WO
Inventors: Stephen Spaulding Hickok
Original assignee: Remedy Research Limited
Priority date: 2020-06-04
Filing date: 2020-06-04
Publication date: 2021-12-09

Abstract

An aqueous ionic concentrate composition comprising zinc ions, ammonium ions, sulphur-containing ions, which concentrate composition has a pH of less than 3 and an electrolytic potential of at least 100 millivolts, for dilution prior to administration to a patient or patient group as a medicament for prophylaxis against infection by a viral pathogen and/or for treatment of an infection caused by such a viral pathogen. The pathogenic virus may be, for example, selected from the group consisting of HIV-AIDS, Haemorrhagic virus that can develop into serious disease such as such as Ebolavirus, Yellow Fever and Lassa Fever; other virus such as Hantavirus; Coronavirus that can develop into serious respiratory disease such as SARS-CoV, SARS-CoV-2 or MERS-Cov, seasonal and Avian influenza; and Flavivirus that can develop into serious neurological viral disease selected from Dengue Fever and Zika virus, and virus causing lymphocytic choriomeningitis, Marburgvirus, measles and mumps.

Description

Improved immunomodulator compositions and viral pathogen treatments

This invention is concerned with improved immunomodulator compositions and viral pathogen treatments.

One of the most important dietary metallic mineral elements is zinc, and in the bloodstream it is present as the zinc ion, principally bound to numerous large molecule proteins.

Globally, there are issues with zinc deficiency in the human diet and many health problems arise from zinc deficiency where serum or plasma zinc is below minimum recommended levels. Effects of zinc deficiency, especially in the elderly, include depressed immune functionality. This leads to enhanced susceptibility to infections, for example decreased immunity to infection by viral pathogens which may infect and attack the body. It is also known that zinc deficiency arising from decline of serum or plasma zinc leads to dysregulation of immunity, in that for example, viral infection in a subject can result in over production of inflammatory cytokines, giving rise to serious inflammation that prolongs disease and can be life-threatening. Levels of plasma/serum zinc decline with increasing age, and even marginal deficiency can impair multiple aspects of both the innate and adaptive immune systems.

An initial consequence of zinc deficiency is an impairment of immunological functions. The wide involvement of zinc in the immune system includes an ability to influence the production and signalling of numerous inflammatory cytokines in a variety of cell types.

Zinc may affect the generation of cytokines by influencing the normal development and function of immune cells. Cytokines are produced by a variety of cells, but most typically from T-lymphocytes and macrophages.

Several investigations report that zinc may influence the function of polymorphonuclear neutrophils (PMN's). These are an important component of the acute inflammatory response, providing the primary cellular defense against bacteria in humans. Beyond their role as professional phagocytes, neutrophils can be induced to express a variety of cytokines and chemokines.

In vitro zinc deficiency studies indicated that zinc depletion disrupts cell membrane barrier integrity and induces increases in the secretion of the chemokine IL-8 and neutrophil transmigration. Zinc may also modulate the ovxidative burst.

Zinc has also been shown to be both a negative and positive regulator of NF- kappaB. The classical NF-kappaB pathway regulates the induction of most pro- inflammatory cytokines.

Mineral zinc supplementation is recommended in certain circumstances by various health bodies, authorities and practitioners, where levels are below limits, particularly amongst the elderly population, whose innate immune cells will already show reduced functionality.

This important metallic mineral element/ion is known to comprise part of the structure of over 3,000 proteins in the human circulatory system. In its ionic water- soluble form it exhibits remarkable stability. What is not so well known is how zinc deficiency leads to specific disorders and disease of the human body. Whilst inadequate dietary zinc uptake has been loosely associated with impaired immune system performance, the mechanisms by which lack of adequate bio-available zinc affects the immune performance is less well understood.

Zinc in the human bloodstream is mostly found, as foreshadowed above, bound to proteins, as in the case of some 300 or so enzymes and transcription factors. But the human body needs ionic zinc continuously since given limited available stores for zinc, which are all too readily depleted. In the human body, variations in uptake, retention and sequestration of zinc can rapidly develop into clinical deficiency in the bloodstream. In turn, this can equally rapidly adversely affect zinc-dependent cellular functions within practically all tissue, however especially so within the innate and adaptive immune systems. Here there can be rapid proliferation and differentiation of immune cells, for which a constantly replenished supply of soluble zinc in the bloodstream is needed.

Further light has been shed on the importance of zinc to immune functionality, the zinc ion being a signalling ion involved in immune cell signal transduction and inflammatory response signalling. It is known to stimulate PKC-kinase activity, phosphatases and transcription factors. It mediates desirable interferon expression from T-cells and moderates other T-cell dependent immune response. Zinc supplementation has been shown under conditions of pathogenic viral challenge to suppress formation of pro-inflammatory cytokines and/or chemokines especially interleukin-1 (ILN-1) and TNF alpha.

Zinc deficiency, can unfavourably alter the balance of T-helper cells towards TH-2 with concomitant reduction of, for example, TH-1 cytokines I FN-alpha and increasing ILN-10. Several chronic diseases are linked to reduced T-cell response and to shifts favouring Th2-type cytokine T-cell responses. Low levels of serum zinc have been implicated in such chronic diseases. Adequate and replenished, but bioavailable, zinc is critical to proper T-cell function and desirable Thl-type immune responses.

It is therefore desirable to develop an improved zinc composition for administration by oral ingestion, to raise serum or plasma zinc, where the zinc ions in solution are enhanced by the presence of supplementary soluble components to demonstrate sustained bio-availability with minimal wastage of the zinc component through excretion.

Oral ingestion of enhanced zinc ion is therefore proposed herein as prophylactic immunomodulator against potential pathogenic viral challenge, and/or as a therapeutic treatment to combat the viral infection.

The innate immune system has developed a host of sub-systems to detect invading infective viral pathogens, including signal transduction pathways focussed upon an initial containment of the infection within the body. Virus replication induced expression of cytokine within, for example, the airway epithelium recruits innate immune cells to the site of infection. These are predominantly leukocytes, namely neutrophils, monocytes, macrophages, dendritic cells, eosinophils, natural killer cells, lymphoid cells and T-helper cells which become activated in response to the viral infection, to contain the virus and in the case of respiratory viruses, protect the airway epithelium while triggering the adaptive arm of the immune system.

Whilst the present invention has application in prophylaxis or therapeutic treatment, or both, of viral pathogens in general, for example but without limitation the HIV virus that leads to AIDS as will be subsequently elaborated, there is currently much focus and attention upon how to prevent and treat infective RNA viruses as cause serious respiratory disease, in particular, the group of coronaviruses MERS, SARS and SARS-CoV-2 the latter of which has been declared pandemic by the WHO. These are troublesome and difficult to treat seriously pathogenic respiratory viruses which can lead to acute respiratory distress syndrome (ARDS/ARDA), pneumonia and fatalities. The more so in patients and patient groups who are elderly or have underlying health conditions such as diabetes, obesity, hypertension, heart failure and/or renal compromise, and in subjects with auto-immune disorders receiving immunosuppression medication, such as, for example, sufferers of rheumatoid arthritis, Crohn's disease and ulcerative colitis.

Of these coronaviruses, there is much attention in the novel coronavirus SARS- CoV-2 which can lead to the serious and difficult to treat disease known as Covid-19. That is because of the WHO declared pandemic with significant numbers in many different countries of cases of infection, serious illness, hospitalisation, requirement for oxygen therapy, intensive care treatment with intubation and ventilation and high intensive care patient morbidity.

Accordingly, we further consider this recent novel respiratory coronavirus in more detail and how aspects of the present invention are particularly beneficial in the armoury of available medicaments to tackle the current pandemic respiratory disease Covid-19 both from a prophylactic and therapeutic treatment viewpoint.

It is suggested that the positive sense, single strand, RNA pathogenic viruses of the coronavirus type, but especially SARS-Cov-2, exhibit pathogenicity by an inherent ability to bypass the initial innate immune system response, primarily IFN-expression response to the invading infective virus, so this characteristic is a type of dysregulation of the body's innate immune system. It is also suggested that with or following such initial dysregulation, with concomitant compromise of otherwise normal IFN-expression response, the signalling between innate immune cells, NK (natural killer) cells, dendritic cells, monocytes and macrophages is impeded. The impeded signalling responses create a defensive time gap useful to the virus, in that the normally encountered contact of the viral antigen with B- and T-cells of the adaptive immune system is delayed. In consequence, as the innate and the adaptive immune defence mechanisms become overtaken by rapidly spreading and replicating pathogenic virus, the body is signalled to express more and more pro-inflammatory cytokine and/or chemokine. This is the well- known 'cytokine storm' immensely damaging to healthy tissue in the lungs, and can lead to pneumonia, acute respiratory distress both of which necessitate oxygen therapy, and can be fatal.

It appears that, for example, of the serious respiratory pathogenic viruses mentioned, the SARS-CoV-2 virus giving rise to Covid-19 has a relatively high human to human transmissibility by airborne droplets, and susceptibility to infection. This may stem partly from dysregulation of the innate response by the invading and massively replicating coronaviral challenge. The human population, having been unprotected against the virus for sufficient time, has now been infected in large and growing numbers. Hence what was a local epidemic soon developed into a pandemic outbreak of the novel coronavirus SARS CoV-2. This may well derive from its apparent ability massively to disrupt not only the innate immune defence mechanisms but also delay and interfere with the adaptive immune response.

As cells are invaded by e.g. the SARS Cov-2 virus, they release cytokine messaging proteins to warn surrounding cells. As the volume of expressed cytokines rise, a positive feedback loop is established that releases more and more cytokine and/or chemokine of the tissue damaging pro-inflammatory type. Thus, the cytokine storm develops which summons other components of the adaptive system such as killer T-cells to destroy viral infected human cells. But the cytokine storm, if it develops and persists, causes much inflammation in surrounding otherwise healthy tissue, which is harmful, troublesome to treat and in a certain proportion of cases can be fatal.

ACE-2 receptors, abundant in the lung epithelia, and in some other organs, are especially vulnerable to attachment of the aforesaid virus, because the viral protein case spikes target and attach to these receptors in the lung epithelia after penetrating the over-lying mucus membrane. The cytokine storm if generated by the adaptive immune response thereby causes severe inflammation in the lungs, the epithelia and the alveolar sacs and membranes through which there is oxygen and carbon dioxide exchange with neighbouring blood vessels. This can lead to pneumonia, ARDA/ARDS, requirement for applied oxygen therapy, possible requirement for intubation and ventilation using valuable and potentially scarce intensive care and even then in a proportion of cases ultimately the patient may not recover.

In addition to the above, the SARS CoV-2 virus exhibits another mode of action to dysregulate and so downgrade the body's defensive immune system. It has been shown that this virus can neutralise T-lymphocytes by means of a CD147 protein, to merge with the T-cell. Whilst unable to replicate within the T-cell, this modification of T-Cells impairs one of the body's adaptive immune responses.

Given that the novel coronavirus infection SARS CoV-2 is proving to be more susceptible to and severe in the elderly, and in those with underlying health conditions, this is putting a great strain on health services, particularly within hospitals and their intensive treatment facilities. It is highly desirable and important therefore to provide safe and effective medical treatments to boost immune function as a prophylaxis against the viral infection, and as a safe and effective therapeutic treatment to treat those already exposed and infected, at whatever may be their stage or severity of infection. It is even more desirable to provide one such treatment, such as a medicament composition that can act as both such a prophylaxis and a therapeutic treatment. For instance it is desirable to provide a medicament composition that can be administered initially as a prophylactic immunomodulator to a patient or patient group at risk of exposure to the viral pathogen and then the same medicament composition being available, if necessary, for sequential administration by oral ingestion as a treatment therapy against viral infection should symptoms of a viral infection manifest.

One established way of treating viral infections is to try and find one single chemical compound, in the nature of a small molecule, that impedes or prevents viral replication, by interfering with viral protein expression or their mechanistic pathways. Hence the existence of a few antivirals. They can however be expensive to produce, very expensive and time consuming to test, and may have unpleasant, even debilitating, side effects. However, it is widely accepted that as many as 99% of potential such small molecules fail with the associated waste in resource of research and development. It is therefore a very risky and potentially expensive proposition to develop a new single compound antiviral medicament, and with no guarantee of success. It is even less likely that any candidate single compound medicament will have the twin utility of being useful both as prophylactic immunomodulator to boost immune function before exposure to the viral pathogen, and as a therapeutic treatment to combat the infection directly and so relieve the adverse effects and symptoms associated with the corresponding disease in a person infected by the virus, which prophylactic and therapeutic treatments could be administered if required sequentially with an interval between.

It is further and even still less likely that any such candidate medicament that might now be developed for use as a prophylactic and/or therapeutic treatment of viral pathogenic disease, such as of a highly pathogenic human virus such as a respiratory coronavirus, for example SARS CoV-2 but without excluding other viral pathogens, would simultaneously demonstrate an ability to restore bio-available serum zinc levels in a patient identified as deficient in serum zinc to any significant extent.

We have now developed a medicament composition in the form of an aqueous ionic concentrate, suitable for dilution immediately before oral ingestion by the patient or patient group and that is surprisingly useful in one, more or preferably all of the following scenarios:

(i) as an innate system immunomodulator in a primary sense that it can increase beneficial activity of the innate immune system, which may be referred herein to 'upregulation',

(ii) as an adaptive system immunomodulator in a secondary sense in that it can decrease over-reaction of the adaptive immune system by capacity to suppress, dampen, lessen and potentially arrest expression of the cytokine and/or chemokine storm that ordinarily proliferates within lung tissue when subjected to viral pathogenic attack, and which can lead to, and has lead to pneumonia and/or ARDS , which decrease of over-reaction may be referred to herein as 'down-regulation', (iii) as a prophylactic treatment to provide a measure of protection against such a pathogenic viral attack,

(iv) as a therapeutic treatment in a patient already infected by such a pathogenic virus, in that the composition concentrate (in its diluted form suitable for administration by oral ingestion immediately post-dilution) may be beneficial in limiting ability of the virus to replicate by interfering with its replication systems,

(v) as a mineral zinc supplementation in sustained bio-available form, and

(vi) optionally as an adjunct or adjuvant in the prophylactic and/or therapeutic treatment of a viral pathogenic risk, challenge or attack, with one or more other useful such treatment agents.

Moreover the aforesaid medicament compositions contemplated herein can preferably be produced from multiple components each of which is readily available in commercial quantities at economic prices, and which components have been designated GRAS (generally regarded as safe ) in the US FDA codex and within corresponding medical directives within the UK and European Union, such as the EFSA.

Moreover, we have observed that medicament compositions of the present invention may have the particular advantage of avoiding significant side effects in subjects receiving it as prophylaxis or therapeutic treatment, and that where the present medicament composition is provided in the form of a concentrate to be diluted with a carrier, excipient or diluent such as water, then that concentrate may exhibit a shelf-life of more than one year, preferably more than two years, or more than three years, or more than four years.

Moreover, we have observed that the problem of potential resistance to the present antiviral compositions, in the familiar sense of 'resistance' comparable with well- known problems of bacterial antibiotic resistance, may be lessened, reduced and potentially practically eliminated, with use of the present compositions as prophylactic and/or therapeutic antiviral treatments.

According to a first aspect of this invention there is provided an aqueous ionic concentrate composition comprising zinc ions, ammonium ions, sulphur- containing ions, which concentrate composition has a pH of less than 3 and an electrolytic potential of at least 100 millivolts, for dilution and administration as a medicament for prophylaxis against infection by a viral pathogen and/or for treatment of an infection by said viral pathogen.

The sulphur-containing ions may be sulphate. The concentrate preferably consists of the aforesaid components, any preferred optional components, acid and de-ionised water.

The pathogenic virus is preferably selected from the group consisting of HIV- AIDS, Haemorrhagic virus that can develop into serious disease such as such as Ebolavirus, Yellow Fever, and Lassa Fever; other virus such as Hantavirus; highly pathogenic human Coronavirus that can develop into serious respiratory disease such as SARS-CoV, SARS-CoV-2 or MERS-Cov, seasonal and Avian influenza; and Flavivirus that can develop into serious neurological viral disease selected from Dengue Fever and Zika virus. Additionally the compositions can be used as a prophylactic or therapeutic treatment of Lymphocytic choriomeningitis virus, Marburgvirus, measles and mumps viruses.

More preferably, in one embodiment of the present invention, the virus to be treated in a subject, or use of the present compositions as a prophylactic, is in relation to highly pathogenic respiratory coronavirus.

In a preferred aspect, such a coronavirus is a SARS coronavirus, such as SARS - CoV-2.

In a preferred aspect the composition is to be administered as a prophylactic immunomodulator in a daily dosage in the region of the daily RDA (recommended daily amount) of zinc, where the RDA is that in force in the country of administration. For example in the UK the RDA of zinc is 12.55 mg, so for use as prophylaxis we prefer to administer a dose of the diluted concentrate in which the patent or patient group receives about 12.55 mg of zinc. However if the patient is showing symptoms of viral infection, such as from influenza or Coronavirus, then as a therapeutic treatment we prefer to administer on a daily basis, three times the RDA of zinc where the RDA corresponds to the RDA of zinc in the country of administration. So in the UK the daily dosage of the diluted concentrate for therapeutic treatment would be an amount of some 37.65 mg, so three doses of the zinc RDA per day. This can be continued for some 6 to 9 days to reinvigorate the immune system and to dampen and suppress the cytokine storm. This neither long term nor excessive levels of zinc. The total treatment regime for a viral infected patient or patient group is thus in the UK some 37.65 mg of elemental zinc.

However dosage regimes can be adjusted to take account of the weight and body mass of the patient.

This is well below accepted toxicity starting levels at 50mg per day, and less than other groups using chelated zinc. For example, there are reports in the literature of use of HCQ. plus chelated zinc where the zinc was dosed at 200mg twice daily, apparently due to the poor bio-availability of zinc in chelated form.

In a secondary aspect the invention provides an aqueous ionic concentrate composition as defined in said first aspect above, for dilution and administration as an immunomodulator medicament, capable of modulating response of both innate and adaptive immune systems to challenge by a viral pathogen, preferably a viral pathogen as also is specified hereinabove.

The aforesaid immunomodulator preferably has capacity to modulate immune function by enhancing zinc signalling, transportation or catalysis of zinc- dependent proteins expressed during response of the innate and/or adaptive immune systems to pathogenic viral challenge, wherein the viral challenge derives from one of the aforesaid viruses.

The immune system to be modulated may be that of a patient or patient group at risk of exposure to the pathogenic viral challenge or having been exposed to and/or infected by that pathogenic virus.

The patient or patient group may have previously received other medication for prophylaxis or treatment of infection by the said viral challenge, which other medication was ceased or reduced by the patient or patient group due to one or more adverse side effects experienced by the patient or patient group and attributed to that other medication.

The immunomodulator effect may enhance and sustain responses of the innate and adaptive immune systems to pathogenic viral challenge. The innate immune system preferably becomes up-regulated to become hyper-responsive to said pathogenic viral challenge, whereas the response by the adaptive system to express pro-inflammatory cytokine and/or chemokine preferably becomes down-regulated, in the sense that the adaptive immune system becomes moderated in its response to pathogenic viral challenge

Viral effected dysregulation of the immune systems intracellular signalling pathways may be moderated by the immunomodulator medicament.

The ZIP 8 (zinc importer protein) receptor of lung tissue may be moderated.

The immunomodulator preferably impairs viral replication of the pathogenic viral challenge, for example this may be effected by blocking production or use of RNA dependant RNA polymerase by providing abundant intercellular Zn2+ ions, a necessary component and function in replication of RNA viruses. Moreover, we postulate that, without being bound by theoretical considerations, this blocking may result at least in part from a relative excess of enhanced soluble zinc ion in the cellular fluids in the vicinity of such viral replication.

The said viral replication may be impaired through inhibition of viral RNA synthesis within the replication and transcription complex of cells infected by the virus or which may become infected by the virus subject of the viral challenge.

The modulating may restore a balance between TH1 and TH2 T-helper cells in favour of TH2 such cells.

The virus may be enveloped single stranded RNA positive sense Coronavirus SARS-Cov-2 and which upon exposure to the patient or patient group can develop into the serious respiratory disease Covid -19.

The treatment may further comprise combined, separate or sequential administration of one or more adjuvants, optionally as another said component or components of the composition.

An adjuvant can be present for example one or more extracellular zinc ionophores. Said ionophore(s) may exhibit immunomodulatory activity. Such ionophore(s) preferably act to suppress expression of cytokines/chemokines, preferably at least expression of TNF-alpha and IL - 6.

The zinc ionophore can be, for example, selected from one or more of the following: chloroquine, hydroxychloroquine, dithiocarbamate, pyrrthione, 8- hydroxyquinoline, zincophorin and quercetin. In preferred embodiments the ionophores included are chloroquine and/or hydroxychloroquine.

In a yet further aspect of the present invention, there is provided use of a concentrate composition as defined hereinabove within said first aspect, in the manufacture of a medicament for prophylaxis against infection by a viral pathogen, such as a pathogenic virus as described hereinabove, and/or for treatment of an infection by such a viral pathogen.

In an even further aspect of the present invention there is provided use of a concentrate composition as defined hereinabove within said first aspect, in the manufacture of a medicament for use as an immunomodulator capable of modulating response of both innate and adaptive immune systems to challenge by a viral pathogen, such as a pathogenic virus as has been defined herein above.

In order to make up suitable ionic aqueous concentrate compositions, the following preparative procedure was deployed.

The compositions preferably essentially consist of the aforesaid components, together with any optional components if required, more preferably the compositions consist of such components, any required additive(s) if present, the balance being distilled water with any inevitable impurities.

(i) a water- soluble zinc compound, such as a zinc salt, preferably zinc sulphate is provided, as a source of zinc ions. It is dissolved in distilled water, either of, or to make up to 1 litre of composition, by mixing the zinc compound into the water with stirring to completely dissolve it, at ambient room temperature.

(ii) following dissolution of the zinc compound, a water -soluble ammonium compound is added into the solution, for example an ammonium salt like ammonium sulphate. Where the zinc compound used to generate zinc ions is zinc sulphate, it is preferred for the ammonium compound also to be sulphate. This is to avoid other anionic species unless intentionally wanted and present. In some embodiments, other ionic species can be present.

(iii) an acid is then added, such as sulphuric acid, to lower the pH and increase electrolytic potential. As sulphate anions are already present from the zinc and ammonium sulphate, we prefer to deploy sulphuric acid, in concentrated form, about 98% by volume. This avoids yet another anionic species, although in some instances we incorporate additives which may dissociate into ions. The acid is used to alter and control both pH and electrolytic potential of the aqueous ionic concentrate composition. Adding more acid lowers the pH but increases the millivolts. It is preferred to reach a pH of not more than 2, such as in the range of 0.5 to 2. It is preferred to reach a potential of more than 100 millivolts, more preferably more than 200 millivolts, most preferably more than 300 millivolts, such as about 320 to 340 mV. The pH can be measured by pH meter, the electrolytic potential may be measured by milli-voltmeter. The volume of sulphuric acid is controlled until the desired levels of pH and mV are reached.

At this point or beforehand, any optional preferred additives may be incorporated, such as other medicament(s) or zinc ionophore(s).

This then forms the concentrate, which may be put into containers and has attractive shelf-life stability, but which must be diluted immediately before administration by oral ingestion.

The concentrate compositions according to the invention apparently function as an overall cationic solution in which positively charged cations, of or including the zinc and/or ammonium ions seem to outnumber the negatively charged anions in the aqueous composition.

At the point of administration, the concentrate needs dilution by a substantial extent. It is preferred to dilute with more water as the diluent, although at this point that need not be distilled or deionised as tap water can suffice. In order that the invention may be further elucidated, several non-limiting examples will now be described of suitable aqueous ionic concentrate compositions. The preparative procedure -was as just described in paragraphs (i) to (iii), to make up 1 litre of concentrate composition.

Example 1

Zinc sulphate 150 to 200 g; Distilled water to make up to 1 litre of concentrate composition; Ammonium sulphate 75 g; Sulphuric acid cone 98% [by vol] variable; pH adjusted by the acid to reach 0.5 to 2; mV adjusted by the acid to reach in excess of 300 mV.

Examples 2 to 7

Example 1 was repeated but with other added optional water- soluble components

Ex 2 including a zinc ionophore - variable amounts Ex 3 including another zinc ionophore - variable amounts Ex 4 including another zinc ionophore - variable amounts Ex 5 including another zinc ionophore - variable amounts Ex 6 including another zinc ionophore - variable amounts Ex 7 including another zinc ionophore - variable amounts

Example 8

The concentrate of Example 1 was diluted with more water (tap water) as a diluent to form a daily dosage of an aqueous ionic composition ready for use as prophylactic immune system immunomodulator, against viral challenge, for oral ingestion. In diluted form the level of zinc was measured and found to be equal to the UK RDA.

Example 9

The diluted composition of Example 8 was prepared for use as a medicament to treat seasonal influenza, a viral respiratory infection, to a subject who received the composition as an out-patient. The diluted composition was orally ingested 3 times a day, so the total overall daily dosage was three times the UK RDA of zinc. Anecdotal evidence indicated that after 6 to 9 days at that daily dosage the infection improved, cleared up and the patient made a full recovery.

Example 10

AIDS having its usual meaning of acquired immune deficiency syndrome. The HIV virus infects and takes over CD4 T-cells, macrophage and dendritic cells Thereby protecting itself against the body's immune response. By pirating key elements of the human immune system, the body's ability to fight other opportunistic is greatly reduced.

The present compositions, particularly of Example 1, have been used to treat drug naive HIV patients with effective results:

Within the first two weeks opportunistic infections such as molluscum, herpes and Human Papilloma Virus disappeared or were greatly reduced. The patient, who was thin and wasted, gained weight after taking the composition of Example 1. The patient's blood test results from an HIV/AIDS clinic in a major London Hospital revealed that after 60 days taking the composition of example 1, massively diluted in tap water immediately prior to oral ingestion, the patient's HIV viral load had decreased by 70% and the CD4 cell count had increased froml80 to 420.

The present aqueous compositions are unique, highly charged zinc ion electrolytic compositions, requiring aqueous dilution prior to administration, and of delivering in a subject zinc ions more efficiently and in more bio- available form than other orally administered zinc preparations.

Zinc ions are critical to many mechanisms involved in zinc homeostatsis, including those involved in signalling and transportation. They are essential for effective and sustained operation of many aspects of the human innate and adaptive immune systems. The cytokine storm syndrome, a form of systemic inflammatory response, is an example of a runaway, positive feedback loop which escalates a cascade of immune factors such as pro-inflammatory cytokines and chemokines and can result in hyper inflammatory conditions in which such an immune response attacks otherwise healthy tissue of the host at the site or in the region of infection. This can and does result in increased morbidity and mortality.

Suppressor of cytokine signalling family of proteins (SOCS) is a family of proteins that interact with activated cytokine receptors and signalling components. They are able to suppress cytokine-signalling and can dampen or suppress a cytokine/chemokine storm. The expression of SOCS-3 as an example is regulated (enhanced) by zinc. This effect is driven by the zinc transporter SLC39A14. The present compositions can enhance and activate SOCS proteins and hence disrupt cytokine signalling pathways or arrest the cytokine storm.

The present compositions may also have an effect upon NF-KappaB modulation in their prophylactic immunomodulator role and/or therapeutic treatment role. This transcription factor plays a central role in multiple cellular events. It functions as a regulator of the expression of inflammatory cytokines, chemokines, immunoreceptors and adhesion molecules and this has been shown at least in relation to infection by the respiratory virus H5N1 Influenza A infection in murine models.

Use of the present ionic aqueous concentrates, in diluted form, has been found to enhance zinc ion mobility aswell as its intracellular bioavailability.

The present compositions can regenerate normal immune responses in HIV/AIDS patients allowing them to fight off opportunistic infections. They represent highly charged, zinc ion electrolytes which can rebalance zinc homeostasis and re-align the entire innate and adaptive immune systems. The compositions can promote the activity of the Th-1 helper cell production of interferon-gamma and interleukin-2. The compositions provide a particularly effective zinc delivery system, with its electrolytic charged ion formulation optimising the Th-1 stimulus. By promoting Thl helper cells, the present compositions promote rebalancing of Thl against Th-2 helper cells. The present compositions can increase Thl efficiency, whilst inversely Th2 activity can be reduced. Th2 controls production of IL-4, IL-6, IL-10 and TNF. The present compositions are particularly effective at inhibiting production of tumour necrosis factor TNF, which is implicated in the pathophysiology of cachexia and wasting in AIDS. An increase in TNF levels has been reported as the H IV infection progresses to AIDS.

Claims

CLAIMS (Amended 11^th Aug '20)

1) An aqueous ionic concentrate composition comprising zinc ions, ammonium ions, sulphur-containing ions, which concentrate composition has a pH of less than 3 and an electrolytic potential of at least 100 millivolts, for dilution prior to administration to a patient or patient group as a medicament for prophylaxis against infection by a viral pathogen and/or for treatment of an infection caused by such a viral pathogen.

2) A composition as claimed in claim 1, wherein the sulphur-containing ions comprise sulphate.

3) A composition as claimed in either preceding claim, wherein apart from any inevitable impurities the concentrate composition consists of the aforesaid components, any required optional component(s), acid and de-ionised water.

4) A composition as claimed in any preceding claim, wherein the viral challenge arises from an RNA virus.

5) A composition as claimed in claim 4, wherein the virus is enveloped single strand.

6) A composition as claimed in claim 4 or 5, wherein the virus is positive sense.

7) A composition as claimed in any preceding claim, wherein the pathogenic virus is selected from the group consisting of HIV-AIDS, Haemorrhagic virus that can develop into serious disease such as such as Ebolavirus, Yellow Fever and Lassa Fever; other virus such as Hantavirus; Coronavirus that can develop into serious respiratory disease such as SARS-CoV, SARS-CoV-2 or MERS-Cov, seasonal and Avian influenza; and Flavivirus that can develop into serious neurological viral disease selected from Dengue Fever and Zika virus, and virus causing lymphocytic choriomeningitis, Marburgvirus, measles and mumps.

8) A composition as claimed in any preceding claim, in which the virus is a respiratory coronavirus.

9) A composition as claimed in claim 8, wherein the coronavirus is a SARS coronavirus, such as SARS -CoV-2.

10) A composition as claimed in any preceding claim, for use as a prophylactic immunomodulator, to be administered in a daily dosage of the daily amount of the RDA for zinc in the country of administration; or for use as a medicament for treatment of such an infection to be administered in a daily dosage of three times the daily RDA of zinc in the country of administration, preferably for a period of 6 to 9 days.

11) An aqueous ionic concentrate composition as defined in claim 1, for dilution prior to administration to a patient or patient group as an immunomodulator medicament, capable of modulating response of the innate and the adaptive immune systems to challenge by a viral pathogen, preferably a viral pathogen as specified in claim 7.

12) A composition as claimed in claim 11, in which the immunomodulator has capacity to modulate immune function by enhancing zinc signalling, transportation or catalysis of zinc-dependent proteins expressed during response of the innate and/or adaptive immune systems to pathogenic viral challenge, wherein the viral challenge derives from one of the aforesaid viruses.

13) A composition as claimed in claim 11 or 12, in which the immune system to be modulated is that of a patient or patient group at risk of exposure to the pathogenic viral challenge, or having been exposed to and/or infected by that pathogenic virus.

14) A composition as claimed in claim 13, in which the patient or patient group previously received other medication for prophylaxis or treatment of infection by the said viral challenge, which other medication was ceased or reduced by the patient or patient group due to one or more adverse side effects experienced by the patient or patient group and attributed to that other medication.

15) A composition as claimed in any of claims 11 to 14, wherein the immunomodulator effect enhances and sustains responses of the patient or patient group innate and adaptive immune systems to pathogenic viral challenge.

16) A composition as claimed in claim 15, in which the innate immune system becomes up-regulated to become hyper-responsive to said pathogenic viral challenge, whereas response by the adaptive system to express pro- inflammatory cytokine and/or chemokine becomes down-regulated to reduce such expression.

17) A composition as claimed in any preceding claim, in which dysregulation of the immune systems intracellular signalling pathways is modulated. 18) A composition as claimed in any of claims 11 to 17, in which the immunomodulator has capacity to moderate that immune response component which expresses pro-inflammatory cytokine and/or chemokine.

19) A composition as claimed in claim 18, in which the ZIP 8 (zinc importer protein) receptor of lung tissue is moderated.

20) A composition as claimed in any of claims 11 to 19, in which the immunomodulator impairs viral replication of the pathogenic viral challenge, such as by interference with the production and/or use of RNA polymerase required by the virus.

21) A composition as claimed in claim 20, in which in the presence of a relative excess of zinc ions, said viral replication is impaired through inhibition of viral RNA synthesis within the replication and transcription complex of cells infected by the virus or which may become infected by the virus subject of the viral challenge.

22) A composition as claimed in any of claims 11 to 21, in which the modulating restores a balance between Thl and Th2 T-helper cells in favour of Th2 such cells.

23) A composition as claimed in any preceding claim, in which the virus is enveloped single stranded RNA positive sense, such as SARS-Cov-2 which upon exposure to the patient or patient group can develop into the serious respiratory disease Covid -19.

24) A composition as claimed in any preceding claim, in which the treatment further comprises combined, separate or sequential administration of one or more adjuvants, optionally as another said component or components of the composition.

25) A composition as claimed in claim 24, in which one or more extracellular zinc ionophores are present as an adjuvant.

26) A composition as claimed in claim 25, in which said ionophore(s) exhibit(s) immunomodulatory activity.

27) A composition as claimed in claim 26, in which such ionophore(s) act to suppress expression of cytokines/chemokines, preferably at least of TNF-alpha and IL - 6. 28) A composition as claimed in claim 27, in which the zinc ionophore is selected from one or more of the following: chloroquine, hydroxychloroquine, dithiocarbamate, pyrrthione, , 8-hydroxyquinoline, zincophorin and quercetin.

29) A composition as claimed in claim 28, in which the ionophores included are chloroquine and/or hydroxychloroquine, with or without quercetin.

30) Use of a concentrate composition as defined in any preceding claim, in the manufacture of a medicament for prophylaxis against infection by a viral pathogen, such as a pathogenic virus as defined in claim 7, and/or for treatment of an infection by such a viral pathogen.

31) Use of a concentrate composition as defined in any preceding claim, in the manufacture of a medicament for use as an immunomodulator capable of modulating response of both innate and adaptive immune systems to challenge by a viral pathogen, such as a pathogenic virus as defined in claim 7.