WO2021195011A1

WO2021195011A1 - Immunomodulatory oligosaccharides for the treatment of viral respiratory infection

Info

Publication number: WO2021195011A1
Application number: PCT/US2021/023561
Authority: WO
Inventors: Alexander Martinez; Jason FERRONE
Original assignee: Intrinsic Medicine, Inc.
Priority date: 2020-03-24
Filing date: 2021-03-23
Publication date: 2021-09-30

Abstract

The disclosure provides for methods of treating respiratory infections with certain oligosaccharides.

Description

IMMUNOMODULATORY OLIGOSACCHARIDES FOR THE TREATMENT OF VIRAL RESPIRATORY INFECTION

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 62/993,766, filed March 2, 2020; U.S. Provisional Application Serial No. 63/011,416 filed April 17, 2020; U.S. Provisional Application Serial No. 63/058,248 filed July 29, 2020; and U.S. Provisional Application Serial No. 63/137,406 filed January 14, 2021. The entire contents of each of is the above applications are incorporated by reference herein.

TECHNICAL FIELD

The disclosure provides for immunomodulatory oligosaccharides, and therapeutic uses thereof for the treatment of flu-like symptoms, including aches, fever and inflammation associated with respiratory infections caused by pathogens.

BACKGROUND

The pathology of multiple severe respiratory infections - (i) viral, including influenza and coronaviruses, (ii) bacterial pathogens and (iii) fungal infections, lead to critical compromise of patients’ respiratory function. Many of these manifestations are caused by cytokine storms where the immune system increases activity to a point where it becomes pathogenic to the host. Cytokine storms are related to the pathogenesis of severe acute respiratory syndrome (SARS) and acute respiratory distress syndrome (ARDS). As a result, many efforts to develop host directed therapies (HDTs) to prevent cytokine storms from occurring in infected patients are underway to treat the current SARS-CoV2, COVID-19 pandemic.

An unregulated cytokine storm caused by both increases in pro-inflammatory cytokines and chemokines have led to the suggestions that single-cytokine targeting agents could play a therapeutic role in preventing or treating SARS and or ARDS in patients infected with a virus such as SARS-CoV, SARS-CoV2 or other respiratory viral infections. Single-cytokine targeting agents, however, all carry with them black box warnings related to the immunosuppressive properties of these agents which compromise all immunity in such patients potentially exposing such patients to increased risk of secondary infections. While SARS-CoV (referring to both SARS-CoV and SARS-CoV2 herein) productively infects airway and alveolar epithelial cells, infection of hematopoietic cells such as dendritic cells (DCs), monocyte-macrophages, and other PBMC derived cells is abortive. SARS-CoV infection of DCs induces low-level expression of antiviral cytokines IFN-ab, moderate up- regulation of pro-inflammatory cytokines TNF and IL-6, and a significant up-regulation of inflammatory chemokines CCL3, CCL5, CCL2, and CXCL10. Similarly, SARS-CoV- infected macrophages show delayed but elevated levels of IFN and other pro-inflammatory cytokines. Additionally, SARS-CoV-infected airway epithelial cells (AECs) also produce large amounts of CCL3, CCL5, CCL2, and CXCL10. The delayed but excessive production of these cytokines and chemokines is thought to induce a dysregulated innate immune response to SARS-CoV infection. High serum levels of pro-inflammatory cytokines (IFN-g, IL-1, IL-6, IL-12, and TGFp) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) were found in SARS patients with severe disease compared to individuals with uncomplicated SARS. Conversely, SARS patients with severe disease had very low levels of the anti inflammatory cytokine, IL-10. In addition to pro-inflammatory cytokines and chemokines, individuals with lethal SARS showed elevated levels of IFN (IFN-a and IFN-g) and IFN- stimulated genes (ISGs) (CXCL10 and CCL-2) compared to healthy controls or individuals with mild-moderate disease. These results were the first to suggest a possible role for IFNs and ISGs in the immunopathogenesis of SARS in humans. Thus, it appears from these studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV- infected AECs, DCs, and macrophages could play an important role in SARS pathogenesis. Channappanavar, R., Perlman, S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and imraunopathology. Semin hnmiinopaihol 39, 529-539 (2017).

SUMMARY OF THE INVENTION

The invention includes methods for the treatment of a respiratory pathogen infection as well as methods for the treatment of COVID-19 or a SARS-CoV2 infection in a subject or patient in need therefore comprising administering a composition comprising one or more oligosaccharides or one or more human milk oligosaccharides (HMOs).

The invention encompasses a method for treating a patient diagnosed with or suffering from a respiratory pathogen infection, wherein the method comprises administering to the patient a composition comprising one or more oligosaccharides or HMOs, optionally in combination with one or more anti-viral compounds. The invention includes, for example, a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of sialyllactose or a pharmaceutically acceptable salt thereof. The invention additionally encompasses a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of sialyllactose or a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compound. In certain aspects, the sialyllactose is 3’SL or 6’SL. In further aspects, the sialyllactose is a compound selected from Formula (I), (la), or (II) (described below).

The invention also includes a method of treating a patient diagnosed with or suffering from a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition consisting of fucosyllactose a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compound. In certain aspects the fucosyllactose is 3’FL.

The invention also includes a method of treating a patient suffering from COVID-19 or a SARS-CoV2 infection comprising administering to said patient a composition comprising one or more oligosaccharides or one or more human milk oligosaccharides (HMOs). The invention includes a method of treating a patient hospitalized with moderate COVID-19, wherein said patient has (a) a confirmed positive RT-PCR test for SARS-CoV2 infection, (b) a Sp02 >94% on ambient air and (c) has signs of lower respiratory disease, comprising administering to said patient a composition consisting of an effective amount of 3’ sialyllactose, 6’ sialyllactose or 2’fucosyllactose. The invention also encompasses a method of treating a subject with active SARS-CoV2 infection comprising administering to such subject a composition comprising one or more human milk oligosaccharides. In certain aspects the HMO is selected from 3’ sialyllactose,

6’ sialyllactose or 2’fucosyllactose, or a combination of any of thereof. In further aspects, the sialyllactose is a compound selected from Formula (I), (la), or (II) (described below).

Sialyllactose is a class of human milk oligosaccharides (HMOs) that appear in two different forms in human milk, 3’ -sialyllactose and 6’-sialyllactose:

2,3 Sialyllactose (3 -SL) 2,6 Sialyllactose (6-SL)

Sialyllactose, an oligosaccharide found in human milk, has been shown to modulate acute and chronic immune responses in both murine and human derived macrophages stimulated with LPS and various pro-inflammatory cytokines. Both forms of sialyllactose have shown reductions in interleukin (IL)-ip, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a in vitro , with 3’-SL exhibiting more significant reductions.

In addition, 3’SL has been shown to reduce other key components that contribute to the critical nature of respiratory infections, including PDL1, COX2 and select chemokines, such as CCL2 (also known as monocyte chemoattractant protein 1 (MCP1) and CCL5. An embodiment of the invention is to reduce plasma levels of proinflammatory cytokines and chemokines in subjects with respiratory pathogen disease, including viral, fungal and bacterial pneumonias. In another embodiment, viral infections that can be treated with sialyllactose include influenza and coronavirus, including influenza A and B, H1N1, SARS-CoV, and SARS-CoV2.

In vivo data in mouse models of rheumatoid arthritis, which include an LPS challenge, sialyllactose has shown benefit in clinical assessments of disease when administered orally.

Another class of HMOs are fucosylated oligosaccharides. The primary fucosylated HMO is 2’-fuscosyllactose or 2’FL.

2’fucosyllactose has been gained generally regarded as safe status in the U.S. and Europe to be included in infant formula. 2’fucosyllactose has been shown to have many beneficial properties, such as affecting gut health through modulation of the gut microbiome as well as affection local gut inflammation in models of necrotizing enterocolitis and other inflammatory bowel diseases. In addition, 2Tucosyllactose has been shown to have positive effects on gut epithelial barrier function and also independent anti-inflammatory effects through the reduction in TNFa and IL-8.

Of note also is the glycosylation of the putative binding receptor of respiratory viruses which have been shown to be predominantly a combination of fucosylated and sialylated moieties. Analysis of the glycosylation of the ACE2 receptor, the receptor to which the SARS-CoV virus, both CoV and CoV2, shows that the primary glycosylation is fucosylation and the secondary is sialylation with a preference for a.2->3 attachment.

The invention encompasses a method of treating a patient with COVID-19, comprising administering a composition comprising one or more human milk oligosaccharides. In one embodiment, the invention is a method of treating a patient with COVID-19, comprising administering a composition consisting of 2’fucosyllactose, 3’sialyllactose or 6’sialyllactose.

The invention encompasses a method for treating a respiratory infection or treating a subject diagnosed with a respirator pathogen infection comprising administering to the subject an effective amount of an oligosaccharide or a human milk oligosaccharide (HMO). In a particular embodiment, the disclosure provides a method for treating a respiratory infection or treating a subject diagnosed with a respiratory pathogen infection comprising administering to the subject an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide comprises crhas a structure of Formula 1. 1(a) or II:

5 Formula 1(a)

Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R1_R18 _are independently selected from H, D, a halo, an unsubstituted or substituted (Cl-C6)alkyl, an unsubstituted or substituted (Cl-C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR', -RN(R')2, -RSSR', - SH, - RSOR', -RS02R', -RS02H, -RSO3H, -RC(=S)-R, -ROH, -RC(=0)R, -RNO2, - RSR', -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, -RC(=0)H, -RC(=0)0H, - RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -RONO2, -RNO, -R0P(=0)(0H)2, and - RB(OH)2;

R is absent or a (C 1 -C5)alkyl; and R' is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl-C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl.

In another embodiment, the disclosure also provides a method for treating a respiratory infection in patient in need thereof or treating a patient diagnosed with a respiratory pathogen infection, comprising administering to the subject an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide comprises or has a structure of Formula 1(b) or 1(c):

Formula 1(b)

Formula 1(c) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R1-R are independently selected from H, D, a halo, an unsubstituted or substituted (Cl- C6)alkyl, an unsubstituted or substituted(Cl-C6)heteroalkyl, an unsubstituted or substituted (C2-C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR, -RN(R')2, -RSSR, - SH, - RSOR, -RS02R', -RS02H, -RS03H, -RC(=S)-R, -ROH, -RC(=0)R, -RN02, - RSR, -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, -RC(=0)H, -RC(=0)0H, - RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -R0N02, -RNO, -R0P(=0)(0H)2, and - RB(0H)2;

R is absent or a (C 1 -C5)alkyl; and

R is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl-C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl.

In yet another embodiment, the disclosure further provides a method for treating respiratory infection in patient in need thereof or treating patient diagnosed with a respiratory pathogen infection, comprising administering to the subject an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide comprises or has a structure of Formula 1(d), 1(e) or 11(a):

Formula 1(d)

Formula 1(e)

Formula 11(a) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In yet another embodiment, the disclosure further provides a method for treating respiratory infection in patient in need thereof or treating patient diagnosed with a respiratory pathogen infection, comprising administering to the subject an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide has the structure of Formula (Ilia):

Formula Ilia or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

1 18

R -R are each independently selected from H, D, a halo, an unsubstituted or substituted (Ci-C₆)alkyl, an unsubstituted or substituted (Ci-C₆)heteroalkyl, an unsubstituted or substituted (C₂- C₆)alkenyl, an unsubstituted or substituted (C₂- C₆)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (Ch-Cxjcycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR, - RN(R)₂, -RSSR, -SH, - RSOR, -RS0₂R, -RS0₂H, -RS0₃H, -RC(=S)-R, -ROH, - RC(=0)R', -RN0₂, -RSR, -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, - RC(=0)H, -RC(=0)0H, -RC(=0)N(R)₂, -RN₃, -ROCN, -RNCO, -R0N0₂, -RNO, - R0P(=0)(0H)₂, and -RB(OH)₂;

R is absent or a (Ci-C₅)alkyl;

R' is independently selected from H, D, an unsubstituted or substituted (Ci-Cr,) alkyl, an unsubstituted or substituted (Ci-C₆)heteroalkyl, an unsubstituted or substituted (C₂-C₆) alkenyl, an unsubstituted or substituted (C₂-C₆)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an un substituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C-rCxjcycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl; and

R²⁹ is an unsubstituted or substituted (Ci-C₆)alkyl.

In yet another embodiment, the disclosure further provides a method for treating respiratory infection in patient in need thereof or treating patient diagnosed with a respiratory pathogen infection, comprising administering to the subject an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide has the structure of Formula (Illb):

Formula Illb wherein: one, two or three of R¹⁹-R²⁸ are each independently selected from the group consisting of hydrogen, an unsubstituted or substituted C1-C6 alkyl (including, but not limited to, methyl and ethyl) and N(R’)2 (wherein R’ is as defined above), the remainder or R19-R28 are - OH, and R²⁹ is substituted or unsubstituted C1-C⁶ alkyl; or one, two or three of R¹⁹-R²⁹ are each independently selected from NHC(0)R”, wherein R” is unsubstituted or substituted (Ci-C₆) alkyl (including, but not limited to, methyl), the remainder or R19-R28 are -OH, and R²⁹ is substituted or unsubstituted C1-C⁶ alkyl. In certain aspects, R²⁶ is NHC(0)CH3 and R¹⁹-R²⁵ and R²⁷-R²⁸ are -OH, and R²⁹ is methyl.

In a certain embodiment, a method disclosed herein comprises orally administering an oligosaccharide or HMO of the disclosure or a pharmaceutical composition comprising an oligosaccharide of the disclosure to a subject.

In yet a further embodiment, a method disclosed herein comprises orally administering to a subject a nutritional composition comprising at least one oligosaccharide of the disclosure.

In certain embodiments, the nutritional composition comprises or consists of 3’SL, 6’SL or a combination of 3 ’ SL and 6’ SL. In other embodiments, the nutritional composition comprise or consists of 3’SL, 6’SL or combination thereof at 145 mg/L or greater of 3 ’ SL, 6’ SL or a combination of 3 ’ SL and 6’ SL.In another embodiment, the nutritional composition comprises at least 9% (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%; or any value between any of the foregoing) 3’SL, 6’SL or a combination thereof of the total oligosaccharides in the composition. In another embodiment, a pharmaceutical composition comprising the oligosaccharide of the disclosure is formulated as a tablet ora capsule.

In certain aspects, the oligosaccharide or HMO is co-administered with one or more non steroidal anti-inflammatory drugs.

Examples of nonsteroidal anti-inflammatory drugs include, but are not limited to, Aminophenazone, Ampyrone, Azapropazone, Clofezone, Difenamizole, Famprofazone, Feprazone, Kebuzone, Metamizole, Mofebutazone, Morazone, Nifenazone, Oxyphenbutazone, Phenazone, Phenylbutazone, Propyphenazone, Sulfinpyrazone, Suxibuzone, Aspirin, Aloxiprin, Benorylate, Carbasalate, calcium Diflunisal,

Dipyrocetyl, Ethenzamide, Guacetisal, Magnesium salicylate, Methyl salicylate,

Salsalate, Salicin, Salicylamide, Salicylic acid (salicylate), Sodium salicylate, Aceclofenac, Acemetacin, Alclofenac, Amfenac, Bendazac, Bromfenac, Bumadizone, Bufexamac, Diclofenac, Difenpiramide, Etodolac, Felbinac, Fenclozic acid, Fentiazac, Indomethacin, Indomethacin farnesil, Isoxepac, Ketorolac, Lonazolac, Oxametacin, Prodolic acid, Proglumetacin, Sulindac, Tiopinac, Tolmetin, Zomepirac, Ampiroxicam, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, Tenoxicam, Alminoprofen, Benoxaprofen, Carprofen, Dexibuprofen, Dexketoprofen, Fenbufen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen,

Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Pirprofen, Suprofen, Tarenflurbil, Tepoxalin, Tiaprofenic acid, Vedaprofen, Naproxcinod, Azapropazone, Clonixin, Etofenamate, Flufenamic acid, Flunixin, Meclofenamic acid, Mefenamic acid, Momiflumate, Niflumic acid, Tolfenamic acid, Flutiazin, Apricoxib, Celecoxib, Cimicoxib, Deracoxib, Etoricoxib, Firocoxib, Lumiracoxib, Mavacoxib, Parecoxib, Robenacoxib, Rofecoxib, Valdecoxib, Aminopropionitrile, Benzydamine, Chondroitin sulfate, Diacerein, Fluproquazone, Glucosamine, Glycosaminoglycan, Hyperforin,Nabumetone, Nimesulide, Oxaceprol, Proquazone, Superoxide dismutase/Orgotein, and Tenidap. Examples of glucocorticoids include but are limited to betamethasone and prednisone. Examples of biological response modifiers include but are not limited to hydroxychloroquine, leflunomide, methotrexate, tofacitinib, abatacept, adalimumab, adalimumab-atto, anakinra, etanercept, etanercept-szzs, rituximab, infliximab-dyyb,golimumab,certolizumab pegol, tocilizumab,and sarilumab. Example of opioidsinclude but are not limited to tramadol, oxycontin, oxycodone, fentanyl, morphine, codeine, dihydrocodeine, and actiq.

In a particular embodiment, the disclosure provides for a method to attenuate macrophage inflammation and/or suppress the secretion of pro-inflammatory cytokines in a subject suffering from a respiratory infection, comprising administering to the subj ect an effective amount of an oligosaccharide, or a pharmaceutical composition comprising the oligosaccharide, wherein the oligosaccharide comprises or has a structure of Formula I, 1(a), (lb), (Ic), (Id), (Ie), (II), (Ha), (Ilia), or (Illb). In certain aspect, the oligosaccharide has the structure of Formula (I), (la), or (II). In yet a further embodiment, the pro- inflammatory cytokines comprise interleukin (IL)-ipand IL-6.

In certain embodiments, for a method disclosed herein, an oligosaccharide or a pharmaceutical composition comprising the oligosaccharide is administered to a human subject that is 5 years of age or older ( e.g ., 6, 7, 8, 9, 10, 11, 12 years of age or older). In an alternative embodiment, the composition comprising the oligosaccharide(s) are administered to a subj ect less than 5 years of age. In a further embodiment, for a method disclosed herein, an oligosaccharide or a pharmaceutical composition comprising the oligosaccharide, is administered to a human subj ect that is 18 years of age or older.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGs. 1A and IB demonstratethat3^,-sialyllactose(3^,SL) reduces IL-6 (FIG. lA)andIL-ip (FIG. lB)mRNA expression in LPS-activated macrophages. RAW246.7 cells were exposed to LPS either alone or in combination with either pooled human milk oligosaccharides (HMOs), or 3’- sialyllactose (3’SL) or 2^,-fucosyllactose(2’FL). After 6 hours, IL-6 and IL-Ib mRNA levels (FIGs. 1A and IB, respectively) were measured by RT-PCR and are plotted as mean ± standard deviation (n=8) relative the respective mRNA levels in cells that were exposed to LPS alone (**p<0.01; ***p<0.001).

FIG. 1C is a drawing depicting the building blocks of different HMOs. HMOs are a group of more than 150 different structurally distinct oligosaccharides and their composition follows a basic structural blueprint, containing five monosaccharide building blocks: glucose (dark gray circle), galactose (light gray circle), N- acetylglucosamine (dark gray square), fucose (gray triangle) and sialic acid (gray diamond). 3’SL contains lactose with sialic acid at the terminal end; 2’FL contains lactose with fucose at the terminal end.

DETAILED DE SCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an oligosaccharide" includes a plurality of such oligosaccharides and reference to "the therapeutic agent" includes reference to one or more therapeutic agents and equivalents thereof known to those skilled in the art, and so forth.

Also, the use of "or" means "and/or" unless stated otherwise. Similarly, "comprise," "comprises," "comprising" "include," "includes," and "including" are interchangeable and not intended to be limiting.

It is to be further understood that where descriptions of various embodiments use the term "comprising," those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language "consisting essentially of' or "consisting of."

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

Although many methods and reagents are similar or equivalent to those described herein, the exemplary methods and materials are disclosedherein. All publications mentioned herein are incorporated herein by reference in full for the purpose of describing and disclosing the methodologies, which might be used in connection with the description herein. Moreover, for terms expressly defmedin this disclosure, the definition of the term as expressly provided in this disclosure will control in all respects, even if the term has been given a different meaning in a publication, dictionary, treatise, and the like.

The term “about” as used herein, in reference to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, within 5%, or within 4%, or within 2% of the value or range. The term "alkyl" refers to an organic group that is comprised of carbon and hydrogen atoms that contains single covalent bonds between carbons. Typically, an "alkyl" as used in this disclosure, refers to an organic group that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of the foregoing values. Where if there is more than 1 carbon, the carbons may be connected in a linear manner, or alternatively if there are more than 2 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, orquaternary carbons. An alkyl may be substituted or unsubstituted, unless stated otherwise.

The term "alkenyl" refers to an organic group that is comprised of carbon and hydrogen atoms that contains at least one double covalent bond betweentwo carbons. Typically, an "alkenyl" as used in this disclosure, refers to organic group that contains 2, 3, 4, 5, 6, 7, 8,

9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of theforegoing values. While a C2-alkenyl canform a double bond to a carbon of a parent chain, an alkenyl group of three or more carbons can contain more than one double bond. In certain instances the alkenyl group will be conjugated, in other cases an alkenyl group will not be conjugated, and yet other cases the alkenyl group may have stretches of conjugation and stretches of non-conjugation. Additionally, if there is more than 2 carbon, the carbons may be connected in a linear manner, or alternatively if there are more than 3 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, orquaternary carbons. An alkenyl may be substituted or unsubstituted, unless stated otherwise.

The term "alkynyl" refers to an organic group that is comprised of carbon and hydrogen atoms that contains a triple covalent bond betweentwo carbons. Typically, an "alkynyl "as used in this disclosure, refers to organic group that contains that contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, or 30 carbon atoms, or any range of carbon atoms between or including any two of theforegoing values. While aC2-alkynyl can form a triple bond to a carbon of a parent chain, an alkynyl group of three or more carbons can contain more than one triple bond. Where if there is more than 3 carbon, the carbons may be connected in a linear manner, or alternatively if there are more than 4 carbons then the carbons may also be linked in a branched fashion so that the parent chain contains one or more secondary, tertiary, or quaternary carbons. An alkynyl may be substituted or un substituted, unless stated otherwise.

The term "aryl", as used in this disclosure, refers to a conjugated planar ring system with delocalized pi electron clouds that contain only carbon asring atoms. An "aryl" forthe purposes of this disclosure encompass from 1 to 4 aryl rings wherein when the aryl is greater than 1 ring the aryl rings are j oined so that they are linked, fused, or a combination thereof. An aryl may be substituted or unsubstituted, or in the case of more than one aryl ring, one or more rings may be unsubstituted, one or more rings may be substituted, or a combination thereof.

The term "cycloalkyl", as used in this disclosure, refers to an alkyl that contains at least 3 carbon atoms but no more than 12 carbon atoms connected so that it forms a ring. A "cycloalkyl" for the purposes of this disclosure encompasses from 1 to 4 cycloalkyl rings, wherein when the cycloalkyl is greater than 1 ring, then the cycloalkyl rings are joined so that they are linked, fused, or acombinati on thereof. A cycloalkyl may besubstituted or un substituted, or in the case of more than one cycloalkyl ring, one or more rings may be un substituted, one or more rings may be substituted, or a combination thereof.

The term "hetero-" when used as a prefix, such as, hetero-alkyl, hetero-alkenyl, hetero- alkynyl, or hetero-hydrocarbon, for the purpose of this disclosure refers to the specified hydrocarbon having one or more carbon atoms replaced by non-carbon atoms as part of the parent chain. Examples of such non-carbon atoms include, but are not limited to, N, O, S, Si, Al, B, and P. If there is more than one non-carbon atom in the hetero-based parent chain then this atom may be the same element or may be a combination of different elements, such as Nand O. In aparticular embodiment, a "hetero"-hydrocarbon (e.g, alkyl, alkenyl, alkynyl) refers to a hydrocarbon that has from 1 to 3 C, N and/or S atoms as part of the parent chain.

The term "heterocycle," as used herein, refers to ring structures that contain at least 1 noncarbon ring atom. A "heterocycle" for the purposes of this disclosure encompass from 1 to 4 heterocycle rings, wherein when the heterocycle is greater than 1 ring the heterocycle rings are joined so that they are linked, fused, or a combination thereof. A heterocycle may be aromatic or nonaromatic, or in the case of more than one heterocycle ring, one or more rings may be nonaromatic, one or more rings may be aromatic, or a combination thereof. A heterocycle may be substituted or unsubstituted, or in the case of more than one heterocycle ring one or more rings may be un substituted, one or more rings may be substituted, or acombinati on thereof. Typically, the noncarbon ring atom is N, O, S, Si, Al, B, or P. In the case where there is more than one noncarbon ring atom, these noncarbon ring atoms can either be the same element, or combination of different elements, such as N and O.

Examples of heterocycles include, but are not limited to: a monocyclic heterocycle such as, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3- dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, l,3-dioxane,dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopiperazine, 1,3- dioxepane, 4,7-dihydro-l,3- dioxepin, and hexamethylene oxide; and polycyclic heterocycles such as, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran,2,3- dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptaneand7- oxabicyclo[2.2. ljheptane. Theterms "heterocyclic group", "heterocyclic moiety", "heterocyclic", or "heterocyclo" used alone or as a suffix or prefix, refers to a heterocycle that has had one or more hydrogens removedtherefrom.

The term "hydrocarbons" refers to groups of atoms that contain only carbonand hydrogen. Examples of hydrocarbons that can be used in this disclosure include, but are not limited to, alkanes, alkenes, alkynes, arenes, and benzyls.

The term “optionally substituted” means independent replacement of one or more hydrogen atoms with a substituent. The term "optionally substituted" alsoreferstoa functional group, typically a hydrocarbon or heterocycle, where one or more hydrogen atoms may be replaced with a substituent. Accordingly, "optionally substituted" refers to a functional group that is substituted, in that one or more hydrogen atoms are replaced with a substituent, or unsubstituted, in that the hydrogen atoms are not replaced with a substituent. For example, an optionally substituted hydrocarbon group refers to an unsubstituted hydrocarbon group or a substituted hydrocarbon group.

The term "substituent" refers to an atom or group of atoms substituted in place of a hydrogen atom. For purposes of this invention, a substituent would include deuterium atoms.

The term "substituted" with respect to hydrocarbons, heterocycles, and the like, refers to structures wherein the parent chain contains one or more substituents.

The term "unsubstituted" with respect to hydrocarbons, heterocycles, and the like, refers to structures wherein the parent chain contains nosubstituents. The term "non-release controlling excipient" as used herein, refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" as used herein, refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. Examples of "pharmaceutically acceptable carriers" and "pharmaceutically acceptable excipients" can be found in the following, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe etal ., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004.

The term "release controlling excipient" as used herein, refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

The term "subject" as used herein, refers to an animal, including, but not limited to, a primate ( e.g ., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g, pig, miniature pig), equine, canine, feline, and the like. The terms "subject" and "patient" are used interchangeably herein. For example, a mammalian subject can refer to a human patient. In preferred aspects, the subject is a human patient. The terms “subject” and “patient” are used interchangeably herein.

The term "substantially pure" as used herein in reference to a given oligosaccharide means that the oligosaccharide is substantially free from other biological macromolecules. The substantially pure oligosaccharide is at least 75% (e.g, at least 80, 85, 95, or 99%) pure by dry weight. Purity can be measured by any appropriate standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenecity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The terms "treat", "treating" and "treatment", as used herein, refers to ameliorating symptoms associated with a disease or disorder ( e.g . , arthritis or a respiratory infection), including inhibiting the progress of the disease or disorder (e.g., arthritis or a respiratory infection), reducing the severity of the disease or disorder (e.g., arthritis or a respiratory infection), preventing or delaying the onset of the disease or disorder symptoms, and/or lessening the severity or frequency of symptoms of the disease or disorder.

The terms “active ingredient” and “active substance” and “active agent” refer to an oligosaccharide or other compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients and/or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

The terms “drug,” or “therapeutic agent,” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of adisorder.

The term “disorder” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disease,” “syndrome” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.

An "oligosaccharide" is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides). A “human milk oligosaccharide” is an oligosaccharide found in human milk. As used herein, the term “human milk oligosaccharide” includes natural or native oligosaccharides found in human milk, as well as pharmaceutically acceptable salts, derivatives, prodrugs, and solvates thereof. The term “natural human milk oligosaccharide” or “natural HMO” refers to human milk oligosaccharides naturally found in human milk. Natural human milk oligosaccharides (HMOs) are separated into different classes including, for example, sialylated human milk oligosaccharides (which include sialyllactoses; sialyllactoses are sialylated oligosaccharides that comprise a lactose) and fucosylated oligosaccharides (which include “fucosyllactoses”; fucosyllactoses are fucosylated oligosaccharides that comprise a lactose). HMOs include natural sialylated human milk oligosaccharides and fucosylated oligosaccharides, as well as non-naturally occurring derivatives thereof. Non-limiting examples of sialyllactoses are 3’-SL and 6’-SL. A non-limiting example of a Fucosyllactose is 2’-FL.

The terms “3’-SL” and “3’SL” are used interchangeably herein. Similarly, the terms “6’- SL” and “6’SL” are used interchangeably herein. Sialyllactoses have been shown to modulate acute and chronic immune responses in both murine and human derived macrophages stimulated with LPS and various pro-inflammatory cytokines. Both 3’SL and 6’SL have shown reductions in interleukin (IL)-ip, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a in vitro , with 3’-SL exhibiting more significant reductions. In addition, 3’SL has been shown to reduce other key target proteins, including PDL1, COX2 and select chemokines, such as CCL2 (also known as monocyte chemoattractant protein 1 (MCP1)) and CCL5. In vivo data in mouse models of rheumatoid arthritis, which include an LPS challenge, sialyllactose has shown benefit in clinical assessments of disease when administered orally.

Fucosylated oligosaccharides are a class of human milk oligosaccharides (HMOs) that have been associated with the production of anti-inflammatory short-chain fatty acids. Fucosylated oligosaccharides include, for example, 2'-fucosyllactose, 3-fucosyllactose, difucosyllactose, lacto-N-fucopentaoses (that is to say lacto-N-fucopentaose I, lacto-N- fucopentaose II, lacto-N-fucopentaose III and lacto-N-fucopentaose V), lacto-N- difucohexaose I, fucosyllacto-N-hexaose, Difucosyllacto-N-hexaose I and Difucosyllacto-N- neohexaose II. In certain aspects, the fucosylated non-digestible oligosaccharide is T- fucosyllactose (2’-FL). In certain aspects, the fucosylated oligosaccharide is 2'- fucosyllactose (2'-FL), 3-fucosyllactose (3’-FL), difucosyllactose (DFL). In yet further aspects, the fucosylated oligosaccharide is 2’-FL. As used herein, a “fucosylated oligosaccharide” is an oligosaccharide having the three sugar unit backbone, wherein each of the sugar units (fucose (Fuc), galactose (Gal), and glucose (Glc)) can be independently either in its native form or in a modified form. For example, the modified form of a sugar unit can be a sugar unit, in which at least one or more (e.g., 1, 2, 3, or more) of the hydroxyl groups is replaced with hydrogen, alkyl or a functional group; such as, for example, hydrogen, substituted or unsubstituted C1-C6 alkyl (e.g., methyl, ethyl), or substituted or unsubstituted amine group.

The terms 2’-fucosyllactose or “2’-FL” and “2’FL” are used interchangeably herein.

Derivatives of natural HMOs can be chemically modified as compared to the natural HMO. HMOs include, but are not limited to, compounds having a structure of Formula I, 1(a), 1(b), 1(c), 1(d), 1(e), II, 11(a), 111(a) or 111(b). i. Treatment of respiratory pathogen infections

As discussed above, the invention encompasses a method for treating a patient diagnosed with or suffering from a respiratory pathogen infection, wherein the method comprises administering to the patient a composition comprising one or more oligosaccharides or HMOs, optionally in combination with one or more anti-viral compounds. The invention includes, for example, a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of a sialyllactose or a pharmaceutically acceptable salt thereof. The invention additionally encompasses a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of a sialyllactose or a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compound. In certain aspects, the sialyllactose is 3’ -sialyllactose or 6’- sialyllactose. In yet further aspects, the sialyllactose is 3’-sialyllactose. In yet further aspects, the sialyllactose is a combination of 3’ -sialyllactose and 6’-sialyllactose.

The invention additionally encompasses a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of a fucosylated oligosaccharide or a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compounds. The invention also includes a method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition comprising or consisting of a fucosyllactose or a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compounds. In certain aspects, the fucosylated oligosaccharide or fucosyllactose is selected from the group consisting of 2'-fucosyllactose, 3-fucosyllactose, difucosyllactose, lacto-N-fucopentaoses (that is to say lacto-N-fucopentaose I, lacto-N- fucopentaose II, lacto-N-fucopentaose III and lacto-N-fucopentaose V), lacto-N- difucohexaose I, fucosyllacto-N-hexaose, Difucosyllacto-N-hexaose I and Difucosyllacto-N- neohexaose II. In yet further aspects, the fucosyllactose is 3’FL.

A “respiratory pathogen” is a pathogen that can cause infection of the respiratory tract. The respiratory pathogen can, for example, be a bacterial pathogen, a viral pathogen, a fungal pathogen, or a combination thereof. Non-limiting examples of respiratory pathogens include, but are not limited to, a coronavirus, influenza A, influenza B, Haemophilus influenza, and Streptococcus pneumoniae. In certain aspects, the patient is diagnosed with more than one respiratory pathogen; for example, the patient is diagnosed with two or more pathogens selected from coronavirus, influenza A, influenza B, Haemophilus influenza or Streptococcus pneumoniae. Coronavirus includes, for example, MERS-CoV, or SARS-CoVl, and SARS-CoV2. In certain aspects, the patient is diagnosed with SARS-CoV2; for example, the patient is diagnosed with mild to moderate COVID-19. Symptoms of a respiratory infection can include, for example, fever, cough, and/or myalgias with or without shortness of breath. In certain aspects, the patient is diagnosed as presumptively having a pathogen based upon presentation of fever, cough, and/or myalgias with or without shortness of breath.

In certain aspects, the method described herein results in one or more of the following: reduction in the severity of fever associated with the respiratory pathogen infection, wherein the patient does not require hospitalization; wherein hospitalization is delayed or prevented; and/or wherein ventilation is delayed or prevented.

In yet further aspects, the method described herein prevents or delays the onset of a cytokine storm in said patient. In yet additional aspects, the patient experiences a reduction in the plasma level of one or more pro-inflammatory cytokines or chemokines after administration of the HMO or the sialyllactose. The proinflammatory cytokine can be selected from the group consisting of interleukin (IL)- 1 b, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a. The proinflammatory chemokine can, for example, be selected from CCL2 (MCP-1), CCL5, CCL7, CXCL1, CXCL2, or CXCL5. In certain aspects, administration of the HMO or sialyllactose reduces plasma levels of CCL2 (MCP-1) or CCL5.

In yet additional aspects, the treatment results in a reduction of COX2 and/or prostaglandin E2 levels.

In yet further aspects, the method reduces the incidence of severe acute respiratory syndrome (SARS), acute respiratory distress syndrome (ARDS) or coronavirus disease- 19 (COVID-19).

In additional aspects, the patient to be treated is a patient contraindicated for non steroidal anti-inflammatory drugs (NSAIDs). Such contraindication can include gastrointestinal intolerance, liver impairment or renal impairment. The patient can also be contraindicated for NSAID treatment due to due to hypertension, cardiovascular disease, ulcers, platelet disorders, impending surgery, concomitant anti-clotting medications, concomitant cyclosporin, fluid retention, kidney disease, liver function impairment, a history of urticaria, pregnancy, or breastfeeding.

The methods can optionally comprise co-administration of an anti-viral agent to the subject or patient. Non-limiting examples of an antiviral compound are remdesivir, convalescent plasma, hydroxychloroquine, chloroquine, favipiravir or lopinavir-ritonavir, or a combination of any of thereof. In certain aspects, the antiviral compound is administered with interferon beta. In other aspect, the antiviral compounds is administered without interferon beta.

In further aspects, the composition comprises a mixture of one neutral core and one neutral fucosylated human milk oligosaccharide. In additional embodiments, the composition comprises a mixture of one neutral and one acidic human milk oligosaccharide.

The method can further comprise a step of determining where on the 8-point National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment. In certain aspects, the method further comprises a step of determining where on the 8-point (NIAID) ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient is not designated higher than 5 on the 8-point NIAID ordinal scale. In yet additional aspects, the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient has an improvement on the ordinal scale during treatment.

The National Institute of Allergy and Infectious Disease (NIAID) initiated the COVID Adaptive COVID-19 Treatment Trial (ACTT) wherein the following 8 point ordinal scale: The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID- 19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

In certain embodiments, during treatment days 1 through 21, the patient does not require hospitalization and/or respiratory therapy for shortness of breath. In yet further aspects, the patient does not present with symptoms of kidney or liver injury after recovery from the respiratory pathogen infection and/or does not present with a secondary infection after sialyllactose treatment. The treatment can also, for example, decrease the duration and severity of myalgias during day 1 to 21 of treatment and/or decreases the number and severity of fevers during day 1 to 21 of treatment. In yet further aspect, the treated patient maintains a blood oxygen level above 60 mm Hg or >94% SpCk.

The method can further comprise administering an antibiotic compound. Non-limiting examples of antibiotic compounds are penicillin, erythromycin, azithromycin, amoxicillin, augmentin, doxycycline, clarithromycin, levofloxacin, moxifloxacin or Gemifloxacin.

In certain aspects, the composition is not a mammalian milk. In further aspects, the composition is not derived from human milk. In certain embodiments, the one or more human milk oligosaccharides is selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N-neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3’FL), lacto-difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N-fucopentaose I (LNFP I), lacto-N-difuco-hexaose I (LNDFH I), lacto-N- difuco-hexaose II (LNDFH II), difucosyl-para-lacto-N-neohexaose (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS- tetrasaccharide a (LSTa), LS-tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'- sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or disialyllacto- N-tetraose (DSLNT). For example, the human milk oligosaccharide can be selected from 2’FL, 3’FL, 3’SL, 6’SL, LNT, or LNnT. In certain aspects, the one or more human milk oligosaccharides are selected from 2’fucosyllactose, 3’sialyllactose or 6’sialyllactose. The composition can, for example, comprise 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharides. The composition can additionally comprise a mixture of two, three, four or five human milk oligosaccharides; for example, the composition can comprise a mixture selected from: i. 2’FL and LNT; ii. 2’FL and LNnT; iii. 2’FL, 3’FL, 3’SL, 6’SL and LNT; iv. 3’SL and 6’SL; or v. 6’ SL and LNT.

In additional aspects, the composition comprises a mixture of one neutral core and one neutral fucosylated human milk oligosaccharide or a mixture of one neutral and one acidic human milk oligosaccharide or a mixture of one neutral fucosylated and one acidic human milk oligosaccharide. For example, the composition can comprise a mixture of 4:1 2’FL:LNnT.

In yet further aspects, the oligosaccharide or HMO administered to the patient is a compound having a structure of Formula 1, 1(a), 1(b), 1(c), 1(d), 1(e), II, 11(a), 111(a) or 111(b). In additional aspects, the sialyllactose compound is a compound selected from a compound of Formula 1, 1(a) and/or II. ii. Treatment of COVID-19 or SARS-CoV2 infection

As discussed above, the present invention also specifically includes a method of treating a patient suffering from COVID-19 or a SARS-CoV2 infection comprising administering to said patient a composition comprising one or more oligosaccharides or human milk oligosaccharides (HMOs). The patient can, for example, be suffering from mild to moderate COVID-19. The invention includes, for example, a method of treating a patient hospitalized with moderate COVID-19, wherein said patient has (a) a confirmed positive RT-PCR test for SARS-CoV2 infection, (b) a Sp02 >94% on ambient air and (c) has signs of lower respiratory disease, comprising administering to said patient a composition consisting of an effective amount of 3’sialyllactose, 6’sialyllactose or 2’fucosyllactose. The invention additionally encompasses a method of treating a subject with active SARS-CoV2 infection comprising administering to such subject a composition comprising one or more human milk oligosaccharides. In certain aspects the HMO is selected from 3’sialyllactose, 6’sialyllactose or 2’fucosyllactose, or a combination of any of thereof.

Signs of lower respiratory disease are determined by clinical examination or by imaging. In certain aspects, the patient has one or more symptoms selected from myalgia, headache, persistent cough, fever, diarrhea, nausea, abdominal pain, fatigue, skin sensitivity, ageusia, anosmia, and joint pain. In yet additional embodiments, the patient has one or more COVID-19 risk factors selected from >65 years of age, hypertension, type 2 diabetes, obesity, and heart disease.

The HMO can, for example, be administered orally; for example, once daily oral administration, twice daily oral administration or three-times daily oral administration. Non-limiting examples of daily doses of HMOs are 2.5g, 5g, lOg, 15g or 20g.

The treatment can result in one or more of the following outcomes: stabilization or improvement of the patient’s clinical status along the 8-point NIAID COVID-19 ordinal scale; shortening of the patient’s time to discharge as measured by hospital days; reducing the patient’s fever incidence and severity, wherein the severity is assessed with a Likert 7-point scale; reduction of the patient’s myalgia incidence and severity, wherein the severity is assessed with a Likert 7-point scale; reduction of the patient’s gastrointestinal symptom incidence and severity, wherein the severity is assessed with a Likert 7-point scale (such gastrointestinal symptoms can include nausea, vomiting, diarrhea and abdominal pain); reduction in the severity of overall COVID-19 symptomology, wherein the severity is assessed with a Likert 7-point scale; reduction in the viral load in said patient (for example, in respiratory and fecal samples); reduction in the incidence of secondary respiratory infections in said patient, decrease in time to SARS-CoV2 seroconversion in said patient; increases in the levels of IgG and IgM antibodies to SARS-CoV2 after said treatment ends; decreases in all-cause mortality (e.g. a decrease in all-cause mortality is decreased from 1 to 12 months after said treatment); and/or reduction in the amount of gut microbiome amounts of Bifidobacterium in said patient.

In certain aspects, the treated subject does not experience signs and symptoms of long haul COVID-19 after recovering from active SARS-CoV2 infection.

In additional aspects, the subject’s gut microbiome improves after said administering a composition comprising one or more human milk oligosaccharides. For example, the improvement in the subject’s gut microbiome improvement is measured by fecal 16S ribosomal sequencing. For example, the sequencing can indicate an increase in one or more of Bifidobacterium spp., Faecalbacterium spp., Eubacterium spp. or Roseburium spp; or the fecal 16S ribosomal sequencing indicates an increase in one or more of Bifobacterium longum or Faecalbacterium prausnitzi.

In certain aspects, the composition is not a mammalian milk. In further aspects, the composition is not derived from human milk.

In certain embodiments, the one or more human milk oligosaccharides is selected from the group consisting of lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N-neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3’FL), lacto- difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N-fucopentaose I (LNFP I), lacto-N-difuco-hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), difucosyl-para-lacto-N-neohexaose (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS- tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N-acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT). For example, the human milk oligosaccharide can be selected from 2’FL, 3’FL, 3’SL, 6’SL,

LNT, or LNnT. In certain aspects, the one or more human milk oligosaccharides are selected from 2’fucosyllactose, 3’sialyllactose or 6’sialyllactose. The composition can, for example, comprise 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharides. The composition can additionally comprise a mixture of two, three, four or five human milk oligosaccharides; for example, the composition can comprise a mixture selected from: i. 2’FL and LNT; ii. 2’FL and LNnT; iii. 2’FL, 3’FL, 3’SL, 6’SL and LNT; iv. 3’SL and 6’SL; or v. 6’ SL and LNT.

The methods described herein can further comprise administration of an antibiotic compound. Exemplary antibiotic compounds are penicillin, erythromycin, azithromycin, amoxicillin, augmentin, doxycycline, clarithromycin, levofloxacin, moxifloxacin or Gemifloxacin.

In certain aspect, the composition comprising one or more oligosaccharides or HMOs can comprise or consist of an effective amount of 3’sialyllactose. In additional embodiments, the composition comprise one or more oligosaccharides or HMOs can comprise or consist of an effective amount of 6’sialyllactose. In yet further aspects, the composition can comprise or consist of an effective amount of 2’fucosyllactose.

In yet further aspects, the oligosaccharide or HMO administered to the patient is a compound having a structure of Formula 1, 1(a), 1(b), 1(c), 1(d), 1(e), II, 11(a), 111(a) or 111(b). In additional aspects, the sialyllactose compound is a compound selected from a compound of Formula 1, 1(a) and/or II. iii. Oligosaccharides including HMOs

As described herein, the subject is administered a composition comprising one or more oligosaccharides or human milk oligosaccharides. The composition can comprise 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharide. In certain aspects, the composition is not human milk. In additional aspects, the composition is not derived from human milk.

In certain aspects, the one or more human milk oligosaccharides are selected from lacto-N- tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N-neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3’FL), lacto-difucotetraose (LDFT), lacto- N-fucopenaose II/III (LNFP I I/I II), lactose-N-fucopentaose I (LNFP I), lacto-N-difuco- hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), difucosyl-para-lacto-N- neohexaose (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’ sialyllactose (3’SL),

6’ sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS-tetrasaccharide b (LST b), LS- tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N- acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT), or a combination of any of thereof. In yet other aspects, the one or more human milk oligosaccharides are selected from 2’FL, 3’FL, 3’SL, 6’SL, LNT, or LNnT, or a combination of any of thereof.

The composition administered to the subject can comprise one HMO or can comprise a mixture of two, three, four, five or more HMOs. In certain aspects, the composition comprises one HMO and the HMO is selected from the group consisting of 2’FL, 3’FL, 3’SL, 6’SL, LNT, or LNnT.

In further aspects, the composition comprises a mixture of 2’FL and at least one other HMO. In certain aspects, the composition comprises 2’FL and LNT; 2’FL and LNnT; 2’FL, 3’FL, 3’SL, 6’SL and LNT. The composition comprising 2’FL and LNT includes a 4:1 mixture of 2’FL and LNT; such a composition is GRAS (generally regarded as safe) and is available from Glycom, Lyngby, Denmark. A composition comprising 2’FL, 3’FL, 3’SL, 6’SL and LNT is sold by Jennewein Biotechnologie and is GRAS. Rheumatoid arthritis (RA) is a lifelong, systemic autoimmune disease that affects women three times more frequently than men, often in their most productive and childbearing years. Pregnancy in women with RA poses a therapeutic challenge. Some anti -rheumatic drugs can cross the placenta and harm the fetus and/or are transferred into breast milk and harm the breastfed baby. Teratogenic compounds like methotrexate and leflunamide are to be avoided and high dose steroids may be associated with a premature rupture of the membranes. The high risk of drugtransfer into breast milk often leads to the recommendation for women to cease breastfeeding. Pregnant patients can experience an improvement in symptoms of RA or even go into complete remission. There are several mechanisms that have been attributed to this phenomenon including paternal HLA type, hormones and switches in T cell subtypes.

The disclosure demonstrates that 3’- and/or 6-sialyllactose have anti-inflammatory effects in macrophages and alleviates paw swelling and cartilage damage in mice. 3’-and/or6’- sialyllactose (3’SL and 6’SL, respectively) were found to be an anti-inflammatory agent that reduced pro-inflammatory cytokine expression in activated macrophages in vitro and when given orally, alleviate paw swelling and cartilage damage in the collagen antibody- induced arthritis (CAIA) mouse model in vivo.

Oral administration of the oligosaccharides of the disclosure provide for systemic circulation of the oligosaccharides both in infants and adults. Unlike other drug products approved by the FDA, the oligosaccharides described herein can not only be administered to treat a disease or disorder in an adult subj ect, but can also be administered to pregnant females, infants, and subjects who have impaired organ function (e.g., liver disfunction, kidney failure). The efficacy of oligosaccharides of disclosure as therapy for treating viral pneumonia, especially that caused by. Due to the oligosaccharides of the disclosure having little to no adverse effects in humans, this form of therapy could be used as a preventive, as a first line therapy option, or as an adjunct to existing therapies that would be well tolerated by patients of either sex.

In a particular embodiment, the disclosure provides for an oligosaccharide having the structure of Formula 1, 1(a) or II:

Formula 1(a)

Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R!-R1 are independently selected from H, D, a halo, an unsubstituted or substituted

(Cl-C6)alkyl, an unsubstituted or substituted (Cl -C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR', -RN(R')2, -RSSR', - SH, - RSOR, -RS02R', -RS02H, -RS03H, -RC(=S)-R, -ROH, -RC(=0)R, -RN02, - RSR', -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, -RC(=0)H, RC(=0)0H, - RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -R0N02, -RNO, - R0P(=0)(0H)2, and- RB(OH)2; R is absent or a(Cl-C5)alkyl;

R' is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl- C6)heteroalkyl, an unsubstituted or substituted (2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl. In a certain additional embodiments, the disclosure provides for an oligosaccharide having the structure of Formula 1(b) or 1(c):

Formula 1(c) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R1-R are independently selected from H, D, a halo, an unsubstituted or substituted (Cl- C6)alkyl, an unsubstituted or substituted(Cl-C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR, -RN(R')2, -RSSR, - SH, - RSOR, -RS02R', -RS02H, -RS03H, -RC(=S)-R, -ROH, -RC(=0)R, -RN02, - RSR, -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, -RC(=0)H, -RC(=0)0H, - RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -R0N02, -RNO, - R0P(=0)(0H)2, and- RB(OH)2; R is absent or a(Cl-C5)alkyl; R’ is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl- C6)heteroalkyl, an unsubstituted or substituted (C2-C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4- C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl.

In a particular embodiment, the disclosure provides for a method disclosed herein which comprises administering a 3’- sialyllactose (3’SL)-based oligosaccharide disclosed herein or a pharmaceutical composition comprising a 3’ -sialyllactose (3’SL)- based oligosaccharide disclosed herein.

In another embodiment, the disclosure also provides for a method disclosed herein which comprises administering one or more oligosaccharides having the structure of Formula I, 1(a) and/or II:

Formula 1(a)

5

Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein,

R1_R18 _are independently selected from H, D, a halo, an unsubstituted or substituted (Cl-C6)alkyl, an un substituted or substituted (Cl -C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2- C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR', - RN(R')2, -RSSR, -SH, - RSOR, -RS02R', -RS02H, -RS03H, -RC(=S)-R, -ROH, -

RC(=0)R', -RN02, -RSR', -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, - RC(=0)H, -RC(=0)0H, -RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -R0N02, -RNO, - R0P(=0)(0H)2, and-RB(OH)2;

R is absent or a(Cl-C5)alkyl; R is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl- C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl. In an alternate embodiment, the disclosure further provides for a method disclosed herein which comprises administering a pharmaceutical composition which comprises one or more oligosaccharides having the structures of Formula 1, 1(a) and/or II or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, the disclosure also provides for a method disclosed herein which comprises administering one or more oligosaccharides having the structure of Formula 1(b) and/or 1(c):

Formula 1(b)

Formula 1(c) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein,

R -R are independently selected from H, D, a halo, an unsubstituted or substituted (Cl- C6)alkyl, an unsubstituted or substituted (Cl -C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, -ROR, -RN(R')2, -RSSR, - SH, - RSOR, -RS02R', -RS02H, -RS03H, -RC(=S)-R, -ROH, -RC(=0)R, -RN02, - RSR, -RCN, -RNC, -RNNR', -RC(=0)0R, -R0C(=0)R, -RC(=0)H, -RC(=0)0H, - RC(=0)N(R')2, -RN3, -ROCN, -RNCO, -R0N02, -RNO, - R0P(=0)(0H)2, and- RB(OH)2;

R is absent or a(Cl-C5)alkyl;

R is independently selected from H, D, an unsubstituted or substituted (C1-C6) alkyl, an unsubstituted or substituted (Cl- C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl.

In an alternate embodiment, the disclosure further provides for a method disclosed herein which comprises administering a pharmaceutical composition which comprises one or more oligosaccharides having the structure of Formula 1(b) and/or 1(c) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In yet another embodiment, the disclosure provides for a method disclosed herein which comprises administering one or more oligosaccharide having the structures of Formula 1(d), 1(e) and/or 11(a):

Formula 1(d)

Formula 1(e)

In an alternate embodiment, the disclosure also provides for a method disclosed herein which comprises administering a pharmaceutical composition which comprises one or more oligosaccharides of Formula 1(d), 1(e) and/or 11(a) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In a further embodiment, said oligosaccharide is substantially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)- enantiomer and about 10% or less by weight of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

The oligosaccharides disclosed hereinmay be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, a racemic mixture, or a diastereomeric mixture. As such, one of skill in the art will recognize that administration of an oligosaccharide in its (R) form is equivalent, for oligosaccharides that undergo epimerization in vivo , to administration of the oligosaccharide in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

When the oligosaccharide disclosed herein contains an acidic or basic moiety, it may also be disclosed as a pharmaceutically acceptable salt (See, Berge etal._^J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(lS)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2- disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL- mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1- hydroxy-2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L- arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole,L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1 -(2-hydroxy ethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D- glucamine, 2-amino-2- (hydroxymethyl)-l, 3 -propanediol, and tromethamine.

The oligosaccharide as disclosed herein may also be designed as a prodrug, which is a functional derivative of the oligosaccharide as disclosed herein and is readily convertible into the parent oligosaccharide/// vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent oligosaccharide. They may, for instance, be bioavailable by oral administration whereas the parent oligosaccharide is not.

The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent oligosaccharide. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in “Design of Biopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal, Pharm. Biotech. 1998, 11, 345-365; Gaignault et al, Pract. Med. Chem. 1996, 671- 696; Asghamej ad in “Transport Processes in Pharmaceutical Systems,” Amidon et al, Ed., Marcell Dekker, 185-218, 2000; Balant et al, Eur. J DrugMetab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al, Methods Enzymol. 1985, 112, 360-381; Farquhar et al, J. Pharm. Sci. 1983, 72,324-325; Freeman et al, J. Chem. Soc., Chem. Commun. 1991, 875- 877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409- 421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al, Drugs 1985, 29, 455-73; Tan etal, Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, A dv. Drug Delivery Rev. 1996, 19, 131- 148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Waller et al.,Br. J. Clin. Pharmac. 1989, 28, 497-507.

The oligosaccharide may be produced by biotechnological means using enzyme-based fermentation technology (recombinant or natural enzymes) or microbialfermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures and/or mixed cultures may be used. Alternatively, the oligosaccharides may be produced by chemical synthesis from lactose and other substrates.

Biotechnological approaches have made it possible for the large scale, cost-efficient production of target oligosaccharides.

Precisely, the oligosaccharides disclosed herein can be produced in high yields in aqueous media by fermentation of genetically modified bacteria, yeasts or other microorganisms. See, for example, W0200104341; W02007101862,W02010070104; W02010142305; WO20121 12777; Priem etal. , Glycobiology 12:235 (2002); Drouillard etal.,Angew.

Chem. Int. Ed. 45: 1778 (2006); Han et al.,Biotechnol. Adv. 30: 1268 (2012); Lee etal. , Microb. Cell Fact. 11:48 (2012); Baumgartner et al., Microb. Cell Fact. 12:40 (2013); and WO 2014135167A1.

Alternatively, the oligosaccharides of the disclosure can be synthesized based upon methods described in WO2011100980A1; W02012007588A1; W02012127410A1; WO20 12155916 A 1 ; WO2013044928 A 1 ; and US9102966B2. LNT can be synthesized as described in WO 2012/155916 and WO 2013/044928, a mixture of LNT and LNnT can be made as described in WO 2013/091660, 2'-FL can be made as described in WO 2010/115934 and WO 2010/115935, 3-FL can be made as described in WO 2013/139344, 6'-SL and salts thereof can be made as described in WO 2010/100979, sialylated oligosaccharides can be made as described in WO 2012/113404 and mixtures of human milk oligosaccharides can be made as described inWO 2012/113405. As examples of enzymatic production, sialylated oligosaccharides can be made as described in WO 2012/007588, fucosylated oligosaccharides can be made as described inWO 2012/127410. With regard to biotechnological methods, WO 2001/04341 and WO 2007/101862 describe howto make oligosaccharides optionally substituted by fucose or sialic acid using genetically modified E.coli.

In a certain embodiment, the disclosure provides for a nutritional composition that comprises one or more oligosaccharides ( e.g ., 3’SL and/or 6’SL or derivatives thereof) disclosed herein along with one or more foodgrade agents. In certain embodiments, the nutritional composition comprises or consists of 3’SL, 6’SL or a combination of 3’SLand 6’SL. In other embodiments, the nutritional composition comprise or consists of 3’SL, 6’SL or a combination thereof at 145 mg/L or greater of 3’SL, 6’SL or a combination of 3’SL and 6’SL.

In another embodiment, the nutritional composition comprises atleast9% {e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%; or any value between any of the foregoing) 3’SL, 6’SL or a combination thereof of the total oligosaccharides inthe composition. Examples of foodgrade agents that can be used with the oligosaccharides disclosed herein, include, but are not limited to, milk {e.g., cow's milk, almond milk, soy milk), yogurt, maltodextrin, milk protein concentrate, Sucromalt, glycerine, cocoa powder, soy protein isolate, fructose, vegetable or animal oils {e.g., high oleic safflower oil, soy oil, canola oil), plant sterol esters, HMSs/HMOs, soy lecithin, carrageenan, taurine, L-camitine, vitamins and/or minerals {e.g., sodium ascorbate, potassium citrate, sodium phosphate, calcium citrate, choline chloride, potassium chloride, sodium citrate, magnesium oxide, alpha-tocopheryl acetate, zinc sulfate, ferrous sulfate, niacinamide, calcium pantothenate, vitamin A palmitate, citric acid, manganese sulfate, pyridoxine hydrochloride, vitamin D3, copper sulfate, thiamine mononitrate, riboflavin, beta carotene, folic acid, biotin, potassium iodide, chromium chloride, sodium selenate, sodium molybdate, phytonadione, vitamin B 12, magnesium chloride, calciumphosphate).

Disclosed herein arepharmaceutical compositions comprising one or more oligosaccharides of the disclosure {e.g., 3’SL and/or 6’SL or derivatives thereof), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as an active ingredient, combined with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof; in combination with one or more pharmaceutically acceptable excipients or earners. Disclosed herein are pharmaceutical compositions in modified release dosage forms, which comprise one or more oligosaccharides (e.g., 3’SL and/or 6’SL or derivatives thereof) of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers as described herein. Suitable modifiedrelease dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical compositionsmay also comprise non-release controlling excipients or carriers.

Further disclosed herein are pharmaceutical compositions in enteric coated dosage forms, which comprise one or more oligosaccharides (e.g., 3’SL and/or 6’SL or derivatives thereof) as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers for use in an enteric coated dosage form. The pharmaceutical compositions may also comprise non-release controlling excipients or carriers.

Further disclosed herein are pharmaceutical compositions in effervescent dosage forms, which comprise one or more oligosaccharides (e.g., 3’SL and/or 6’SL or derivatives thereof) as disclosed herein in substantially pure form (e.g, lacking other oligosaccharides found in milk), or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers for use in an effervescent dosage form. The pharmaceutical compositions may also comprise non release controlling excipients or carriers.

Additionally, disclosed are pharmaceutical compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of one or more oligosaccharides (e.g., 3’SL and/or 6’ SL or derivatives thereof) disclosed herein in the form of at least two consecutive pulses separated in time (e.g, separated in time from 0.1 up to 24 hours or a few days). The pharmaceutical compositions comprise an oligosaccharide as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling and non-release controlling excipients or carriers, such as those excipients or carriers suitable for a disruptable semi-permeable membrane and as swellable substances. Disclosed herein also are pharmaceutical compositions in a dosage form for oral administration to a subject, which comprise one or more oligosaccharides (e.g., 3’SL and/or 6’SL or derivative thereof) as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.

Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg or up to 2000 mg or up to 3000 mg (or any value between 0.1 - 3000 mg), about 1 to about 500 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg of one or more oligosaccharides as disclosed herein, in the form of immediate release tablets for oral administration. The pharmaceutical compositions further comprise inactive ingredients such as flavoring agents, copovidone, ethylcellulose, magnesium stearate, mannitol, and silicondioxide.

Provided herein are pharmaceutical compositions that comprise about 0. 1 to about 1000 mg or up to 2000 mg or up to 3000 mg (or any value there between), about 1 to about 500 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg of one or more oligosaccharides as disclosed herein, in the form of extended release tablets for oral administration. The pharmaceutical compositions further comprise inactive ingredients such as ethylcellulose, dibutyl sebacate, polyvinyl pyrroliodone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinylalcohol.

The pharmaceutical compositions disclosed herein may be disclosed in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the oligosaccharide sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged to capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple- dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

The oligosaccharides as disclosed herein may be administered alone, or in combination with one or more other oligosaccharides disclosed herein, and/or one or more other active ingredients. The pharmaceutical compositions that comprise an oligosaccharide disclosed herein may be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.

These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone el al. , Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126).

The pharmaceutical compositions disclosed herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of the oligosaccharides may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the oligosaccharides may be given continuously or temporarily suspended for a certain length of time (i.e., a “drug holiday”).

Once improvement of the patient's condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence ofsymptoms.

The pharmaceutical compositions disclosed herein may be formulated in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastimes, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the oligosaccharides, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.

Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as com starch, potato starch, and pre-gelatinized starch ( e.g ., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, suchas AVICEL-PH-101, AVICEL-PH-103, AVICELRC- 581, AVICEL-PH-105(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions disclosed herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross- linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions disclosed herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof. The pharmaceutical compositions disclosed herein may contain about 0. 1 to about 5% by weight of alubricant. Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.

Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.

Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylenelauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non- aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve several functions, even within the same formulation. The pharmaceutical compositions disclosed herein may be formulated as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.

Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment ofthe stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up obj ectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets andlozenges.

The pharmaceutical compositions disclosed herein may be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, orcalcium alginate.

The hard gelatin capsule, also known as the dry -filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) isa soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated in a capsule. Suitable liquid andsemisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

The pharmaceutical compositions disclosed herein may be formulated in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in-oil. Emulsions may includea pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.

Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholicsolutionsmay include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. , water, to be measured conveniently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) disclosed herein, and a dialkylated mono- or poly alky lene glycol.

The pharmaceutical compositions disclosed herein for oral administration may be also formulated in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions disclosed herein may be formulated as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.

Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions disclosed herein can be formulated as an oralnutritional composition. An oral nutritional composition can contain sources of protein, lipids and/or digestible carbohydrates and can be in solid, powdered or liquid forms. The composition can be designed to be the sole source of nutrition or a nutritional supplement. Suitable protein sourcesinclude intact, hydrolyzed, and partially hydrolyzed protein, which can be derived from any suitable source such as milk ( e.g ., casin, whey), animal (e.g., meat, fish), cereal (e.g, rice, com), and vegetable (e.g., soy, potato, pea), insect (e.g., locust) and combinations of these sources. Examples of the source of protein include whey protein concentrates, whey protein isolates, whey protein hydrolysates, and acid.

The pharmaceutical compositions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed- releaseforms.

The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action.

The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. The pharmaceutical compositions disclosed herein may be formulated for single or multiple dosage administration. The single dosage formulations are packaged in an ampule, a vial, or a syringe. The multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

The pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.

The pharmaceutical compositions disclosed herein may be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, include (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, ureteral, respiratory, and rectal administration.

The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches. The topical formulation of the pharmaceutical compositions disclosed herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions disclosed herein may be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be formulated in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1, 1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may also be formulated as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

The pharmaceutical compositions disclosed herein may be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.

Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion- exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).

The pharmaceutical compositions disclosed herein in a modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.

Provided herein are immunomodulatory oligosaccharides that provide for the modulation of a subj ecf s immune system. In particular, the oligosaccharides as disclosed herein can be used for immunotherapy. Immunotherapy is the treatment of disease, disorder, or medical condition by either inducing, enhancing, or suppressing an immune response in a respiratory pathogen infection. Immunomodulatory regimens often havefewer side effects than existing drugs, including less potential for creating resistance when treating microbial disease. In particular, ithas been found herein that components of human breast milk, human milk oligosaccharides, can be an effective modulation of inflammatory cytokines, therefore these compounds and derivatives thereof have the potential to treat respiratory pathogen infections and delay or prevent severe acute respiratory syndrome (SARS), acute respiratory distress syndrome (ARDS) or coronavirus disease- 19 (COVID-19) in patients.

Generally, the amount of an oligosaccharide disclosed herein required to be administered to the person can vary depending upon factors such as the risk and condition severity, the age of the person, the form of the composition, and other medications being administered to the person. It would be expected that an oligosaccharide described herein should be well tolerated irrespective of the age and condition of the subj ect. The dosage of oligosaccharide to be administered can readily be set by a medical practitioner and would generally be in the range from about 10 mg to about 20 g per day, in certain embodiments from about 10 mg to about 15 g per day, from about 100 mg to about 10 g per day, in certain embodiments from about 500 mg to about 10 g per day, in certain embodiments from about 1 g to about 7.5 g per day. An appropriate dose can be determined based on several factors, including, for example, the body weight and/or condition of the patient being treated, the severity of the condition, being treated, other ailments and/or diseases of the person, the incidence and/or severity of side effects and the manner of administration. Appropriate dose ranges can be determined by methods known to those skilled in the art. During an initial treatment phase, the dosing can be higher (for example 200 mg to 20 g per day, preferably 500 mg to 15 g per day, more preferably 1 g to 10 g per day, in certain embodiments 2.5 g to 7.5 g per day). During a maintenance phase, the dosing can be reduced (for example, 10 mg to 10 g per day, preferably 100 mg to 7.5 g per day, more preferably 500 mg to 5 g per day, in certain embodiments 1 g to 2.5 g per day).

Depending on the disorder to be treated and the inj ection in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

The dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day. The dose or sub-doses can be administered in the form of dosage units containing from about 0.01 to about 2 grams, from about 0.05 to about 1 gram, or from about 10 to about 500 milligrams active ingredient(s) per dosage unit.

In certain embodiments, an appropriate dosage level is about 0.01 to about 5 g/kg patient body weight per day (mg/kg per day), about 0.01 to about 1 g/kg per day, about 0.01 to about .5 g/kg per day, or about 0.1 to about 500 mg/kg per day, which may be administered in single ormultiple doses. A suitable dosage level may be about 0.1 to about 500 mg/kg per day, about 0.1 to about 250 mg/kg per day, or about 0.1 to about 100 mg/kg per day. Within this range the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 100 mg/kg per day.

The oligosaccharides disclosed herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of an autoimmune disorder and/or inflammatory disorder. Or, by way of example only, the therapeutic effectiveness of one of the oligosaccharides described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with an oligosaccharide as disclosed herein. When an oligosaccharide as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to an oligosaccharide disclosed herein may be utilized, but is not required. Accordingly, the pharmaceutical compositions disclosed herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to an oligosaccharide disclosedherein.

In certain embodiments, an oligosaccharide disclosed herein can be combined with one or more anti-inflammatories known in the art, including, but not limited to, nonsteroidal anti- inflammatory drugs ( e.g ., Aminophenazone, Ampyrone, Azapropazone, Clofezone, Difenamizole, Famprofazone, Feprazone, Kebuzone, Metamizole, Mofebutazone, Morazone, Nifenazone, Oxyphenbutazone, Phenazone, Phenylbutazone, Propyphenazone, Sulfinpyrazone, Suxibuzone, Aspirin, Aloxiprin, Benorylate, Carbasalate, calcium Diflunisal, Dipyrocetyl, Ethenzamide, Guacetisal, Magnesium salicylate, Methyl salicylate, Salsalate, Salicin, Salicylamide, Salicylic acid (salicylate), Sodium salicylate, Aceclofenac, Acemetacin, Alclofenac, Amfenac, Bendazac, Bromfenac, Bumadizone, Bufexamac, Diclofenac, Difenpiramide, Etodolac, Felbinac, Fenclozic acid, Fentiazac, Indomethacin, Indomethacin farnesil, Isoxepac, Ketorolac, Lonazolac, Oxametacin, Prodolic acid, Proglumetacin, Sulindac, Tiopinac, Tolmetin, Zomepirac, Ampiroxicam, Droxicam, Isoxicam, Lomoxicam, Meloxicam, Piroxicam, Tenoxicam, Alminoprofen, Benoxaprofen, Carprofen, Dexibuprofen, Dexketoprofen, Fenbufen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Pirprofen, Suprofen, Tarenflurbil, Tepoxalin, Tiaprofenic acid, Vedaprofen, Naproxcinod, Azapropazone, Clonixin, Etofenamate, Flufenamic acid, Flunixin, Meclofenamic acid, Mefenamic acid, Momiflumate, Niflumic acid, Tolfenamic acid, Flutiazin, Apricoxib, Celecoxib, Cimicoxib, Deracoxib, Etoricoxib, Firocoxib, Lumiracoxib, Mavacoxib, Parecoxib, Robenacoxib, Rofecoxib, Valdecoxib, Aminopropionitrile, Benzydamine, Chondroitin sulfate, Diacerein, Fluproquazone, Glucosamine, Glycosaminoglycan, Hyperforin, Nabumetone, Nimesulide, Oxaceprol, Proquazone, Superoxide dismutase/Orgotein, and Tenidap); glucocorticoids ( e.g ., betamethasone, prednisone); biologic response modifiers ( e.g ., hydroxychloroquine, lefhmomide, methotrexate, tofacitinib, abatacept, adalimumab, adalimumab-atto, anakinra, etanercept, etanercept-szzs, rituximab, infliximab-dyyb,golimumab,certolizumab pegol, tocilizumab, and sarilumab); and opioids {e.g., tramadol, oxycontin, oxycodone, fentanyl, morphine, codeine, dihydrocodeine, actiq).

In another embodiment of the invention, a sialyllactose can be administered to a patient that is contraindicated for NSAID treatment either in place of an NSAID described herein or to reduce the dose of NSAIDs used to treat such patient’s signs and symptoms of inflammatory pain. Examples of patients who are contraindicated for NSAID treatment are patients with hypertension, cardiovascular disease, ulcers, platelet disorders (von Willebrand disease, abnormal platelet function from uremia and thrombocytopenia), patients preparing for surgery, patients on anti-clotting medications (warfarin, heparin), cyclosporin, patients who have fluid retention, kidney disease, a history of urticaria, or patients who are pregnant or breastfeeding. For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass orplastic.

For example, the container(s) can comprise one or more oligosaccharides described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic inj ection needle). Such kits optionally comprise an oligosaccharide with an identifying description or label or instructions relating to its use in the methods described herein.

In certain embodiments, a container consists of 3’SL, 6’SL or a combination of 3’SLand 6’SL. In other embodiments, the container comprises or consists of3’SL, 6’SL ora combination thereof at 145 mg/L or greater. In another embodiment, the container comprises a composition that is at least 9% ( e.g ., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%; or any value between any ofthe foregoing) 3 ’ SL,

6’ SL or a combination thereof of the total oligosaccharides in the composition.

A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of an oligosaccharide described herein. Non-limiti ng examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package insert with instructions for use. A set of instructions will also typically be included.

A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein. These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

The following examples are intended to illustrate but not limit the disclosure. While they are typical of those that might be used, other procedures known to those skilled in the art may alternatively beused.

EXAMPLES

Oligosaccharides Reduce Pro-Inflammatory Cytokine mRN A Expression inStimulated Macrophages. HMOs were firstisolated and purified from pooled human donor milk (pHMO) by using polymixin B affinity chromatography to remove any lipopolysaccharide (LPS) contamination. RAW 264.7 cells, a murine macrophage cell line, were then incubated with LPS (10 ng/mL) and pHMO (500 pg/inL) for 6 hours. RT- PCR was used to measure cytokine mRNA expression. Compared to cells that received LPS alone, cells that were exposed to both LPS and pHMO had significantly reduced mRNA levels for both IL-6 (see FIG. 1A) and IL-Ib (see FIG. IB), two pro- inflammatory cytokines that are of major etiological importance in chronic inflammatory disorders like rheumatic arthritis (RA).

Identification of an Oligosaccharide That Significantly Reduces Pro-Inflammatory Cytokine mRNA Expression in Stimulated Macrophages.

A multi-dimensional chromatography approach was used that separates pHMO first by charge and then by size. A specific oligosaccharide, 3’ sialyllactose (3’ SL), was identified as being the most effective in reducing IL-6 and IL-Ib mRNA expression. To exclude that the observed effect was due to impurities or contaminations from the isolation process, the results were confirmed with synthetized and commercially available 3’SL. Dose- range finding studies identified IC50 values for 3’SL of around 15 pg/inL_. Other oligosaccharides like 2’-fucosyllactose(2’FL), where the terminal monosaccharide is fucose instead of sialic acid (see FIG. 1C), had no effect, emphasizing that the anti inflammatory effect of 3’SL in macrophages is specific to the structure of 3'SL.

3 ’ SL reduced pro-inflammatory cytokine expression not only in the murine cell line (RAW 264.7), but also in primary mouse cells (bone marrow derived macrophages) and notably in the human THP-1 monocytic cell line, indicating that the effects are not merely a mouse cell line artifact. Accordingly, the results with 3'SL translate to primary cells as well as to human macrophages.

Human Whole Blood Inflammatory Challenge Experimental conduct

Blood from each subject was collected at two different time points (two visits);

- First visit: 3’SL endotoxin screening experiment and modulation of TLR (2 and 4) responses

Second visit: Modulation of inflammasome responses

The entire study was divided in a series of five different experiments in five days;

TLR2 and TLR4 responses: Three groups of two people each (3 days)

- Inflammasome responses: Two groups of three people each (2 days)

3’SL endotoxin screening

- Healthy donors

- Whole blood incubation of 24 hours, conditions: o Untreated (PBS) o 3’SL (500 pg/mL)

- Readout cytokine: o MSD: IL-Ib, IL-6, IFN-g, TNF-a

Modulation of TLR responses

- Healthy donors

- Whole blood incubation of 30 minutes, conditions: o Untreated (PBS) o 3’SL (1, 10, 100, 500 pg/mL)

Followed by 5h30m or 23h30m incubation, conditions: o Untreated (PBS) o Pam3CSK4 (TLR1/2; 100 ng/mL) o LPS (TLR4; 2 ng/mL)

- Readouts: o MSD: IL-Ib, IL-6, IFN-g, TNF-a Results:

* Data set based only on 2 patients, other 4 where BLOQ ** Stat Sig

It will be understood that various modifications may be made without departing from the spirit and scope of this disclosure. Accordingly, other embodiments are within the scope of the following claims. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition consisting of a sialyllactose or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the respiratory pathogen is a bacterial pathogen, a viral pathogen, a fungal pathogen or a combination thereof.

3. The method of any one of claims 1 and 2, wherein the patient is diagnosed as presumptively having a pathogen based upon presentation of fever, cough, and/or myalgias with or without shortness of breath.

4. The method of claim 2, wherein the respiratory pathogen is a coronavirus, influenza A, influenza B, Haemophilus influenza or Streptococcus pneumoniae.

5. The method of claim 1, wherein the patient is diagnosed with two or more pathogens selected from coronavirus, influenza A, influenza B, Haemophilus influenza or Streptococcus pneumoniae.

6. The method of any one of claims 4 and 5, wherein the coronavirus is MERS-CoV, or SARS-CoVl, SARS-CoV2.

7. The method of claim 1, wherein the administering of the sialyllactose reduces the severity of fever associated with the respiratory pathogen infection.

8. The method of claim 1, wherein the patient does not require hospitalization.

9. The method of claim 1, wherein the treating delays or prevents hospitalization.

10. The method of claim 1, wherein the treatment delays or prevents ventilation in said patient.

11. The method of claim 1, wherein the administering of the sialyllactose prevents the onset of a cytokine storm in said patient.

12. The method of claim 1, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory cytokine.

13. The method of claim 1, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory chemokine.

14. The method of claim 11, wherein the administering of the sialyllactose reduces plasma levels of one or more proinflammatory cytokines selected from interleukin (IL)-ip, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a in said patient.

15. The method of claim 13, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory chemokines selected from CCL2 (MCP-1), CCL5, CCL7, CXCL1, CXCL2, or CXCL5.

16. The method of claim 13, wherein the administering of the sialyllactose reduces plasma levels of CCL2 (MCP-1) or CCL5.

17. The method of any one of claims 1 to 5, wherein the administering of the sialyllactose reduces COX2.

18. The method of any one of claims 1 to 5, wherein the administering of the sialyllactose reduces prostaglandin E2 levels.

19. The methods of any one of claims 1 to 5, wherein the administering of the sialyllactose reduces the incidence of severe acute respiratory syndrome (SARS), acute respiratory distress syndrome(ARDS) or coronavirus disease-19 (COVID- 19).

20. The methods of any of the previous claims wherein the sialyllactose is 3’- sialyllactose or 6’ -sialyllactose.

21. The method of claim 20, wherein the sialyllactose is 3’ -sialyllactose.

22. The method of any one of claims 1 to 5, wherein the patient contraindicated for non-steroidal anti-inflammatory drugs (NSAIDs), and wherein the method comprises administering an effective amount of sialyllactose.

23. The method of claim 22, wherein the contraindication for is selected from gastrointestinal intolerance, liver impairment or renal impairment.

24. The method of claim 22, wherein the patient is contraindicated for NSAIDs due to hypertension, cardiovascular disease, ulcers, a platelet disorders, impending surgery, concomitant anti-clotting medications, concomitant cyclosporin, fluid retention, kidney disease, liver function impairment, a history of urticaria, pregnancy or breastfeeding.

25. The method of any of claims 1 to 5 and 19, wherein the effective amount of the sialyllactose is administered intranasally, orally, subcutaneously or intravenously.

26. The method of claim 19, wherein the effective amount of the sialyllactose achieves a steady-state plasma concentration of between 0.01 and 100 mi crogram s/ mL .

27. The method of claim 19, wherein the effective amount of the sialyllactose achieves a steady-state plasma concentration of between 0.1 and 100 mi crogram s/ mL .

28. The method of claim 19, wherein the effective amount of the sialyllactose achieves a steady-state plasma concentration of between 0.1 and 75 mi crogram s/ mL .

29. The method of any of the previous claims, wherein the sialyllactose is selected from 3’ sialyllactose, 6’ -sialyllactose or a combination thereof.

30. The method of any one of the previous claims, wherein the sialyllactose compound is a compound selected from a compound of Formula 1, 1(a) and/or II:

Formula 1(a)

Formula II or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R!-R18 are independently selected from H, D, a halo, an unsubstituted or substituted (Cl- C6)alkyl, an unsubstituted or substituted (Cl-C6)heteroalkyl, an unsubstituted or substituted (C2- C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C3-C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, an unsubstituted or substituted aryl, - ROR, -RN(R)2, -RSSR, -SH, - RSOR, -RSO2R, -RS02H, -RSO3H, -RC(=S)-

R, -ROH, -RC(=0)R, -RNO2, -RSR, -RCN, -RNC, -RNNR’, -RC(=0)0R, - R0C(=0)R, -RC(=0)H, -RC(=0)0H, -RC(=0)N(R)2, -RN3, -ROCN, -RNCO, - R0N02, -RNO, -R0P(=0)(0H)2, and -RB(OH)2; R is absent or a (C 1-C5)alkyl; and is independently selected from H, D, an unsubstituted or substituted (Cl- C6) alkyl, an unsubstituted or substituted (C 1 -C6)heteroalkyl, an unsubstituted or substituted (C2-C6)alkenyl, an unsubstituted or substituted (C2-C6)heteroalkenyl, an unsubstituted or substituted (C3-C6)alkynyl, an unsubstituted or substituted (C 3- C6)heteroalkynyl, an unsubstituted or substituted (C4-C8)cycloalkyl, an unsubstituted or substituted heterocycle, and an unsubstituted or substituted aryl.

31. A method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition consisting of a sialyllactose or a pharmaceutically acceptable salt thereof optionally in combination with one or more antiviral compound.

32. The method of claim 31, wherein the respiratory pathogen is a bacterial pathogen, a viral pathogen, a fungal pathogen or a combination thereof.

33. The method of any one of claims 31 and 32, wherein the patient is diagnosed as presumptively having a viral pathogen based upon presentation of fever, cough, and/or myalgias without shortness of breath.

34. The method of any one of claims 31 and 32, wherein the antiviral compound is selected from remdesivir, convalescent plasma, hydroxychloroquine, chloroquine, favipiravir or lopinavir-ritonavir.

35. The method of claim 34, wherein the antiviral compound is administered with or without interferon beta.

36. The method of any one of claims 31 and 32, wherein the administering of the sialyllactose reduces the severity of fever associated with the respiratory pathogen infection.

37. The method of any one of claims 31 to 35, wherein the patient does not require hospitalization.

38. The method of any one of claims 31 to 35, wherein the treating delays or prevents hospitalization.

39. The method of any one of claims 31 to 35, wherein the treatment delays or prevents ventilation in said patient.

40. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose prevents the onset of a cytokine storm in said patient.

41. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory cytokine.

42. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory chemokine.

43. The method of any one of claims 31 to 41, wherein the administering of the sialyllactose reduces plasma levels of one or more proinflammatory cytokines selected from interleukin ( I L) - 1 b, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a in said patient.

44. The method of claim 42, wherein the administering of the sialyllactose reduces plasma levels of one or more pro-inflammatory chemokines selected from CCL2 (MCP-1), CCL5, CCL7, CXCL1, CXCL2, or CXCL5.

45. The method of claim 44, wherein the administering of the sialyllactose reduces plasma levels of CCL2 (MCP-1) or CCL5.

46. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose reduces COX2.

47. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose reduces prostaglandin E2 levels.

48. The method of any one of claims 31 to 35, wherein the administering of the sialyllactose reduces the incidence of severe acute respiratory syndrome (SARS), acute respiratory distress (ARDS) or coronavirus disease- 19 (COVID-19).

49. The methods of any one of claims 31 to 48, wherein the sialyllactose is 3’- sialyllactose or 6’ -sialyllactose.

50. The method of claim 49, wherein the sialyllactose is 3 -sialyllactose.

51. The method of any one of claims 31 to 35, wherein the patient contraindicated for non-steroidal anti-inflammatory drugs (NSAIDs), comprising administering an effective amount of the sialyllactose.

52. The method of claim 51, wherein the contraindication for is selected from gastrointestinal intolerance, liver impairment or renal impairment.

53. The method of claim 51, wherein the patient is contraindicated for NSAIDs due to hypertension, cardiovascular disease, ulcers, a platelet disorders, impending surgery, concomitant anti-clotting medications, concomitant cyclosporin, fluid retention, kidney disease, liver function impairment, a history of urticaria, pregnancy or breastfeeding.

54. The method of any one of claims 31 to 53, wherein the effective amount of the sialyllactose is administered intranasally, orally, subcutaneously or intravenously.

55. The method of any one of claims 1 to 54, wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment.

56. The method of any one of claims 1 to 54, wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient is not designated higher than 5 on the 8-point NIAID ordinal scale.

57. The method of any one of claims 1 to 54, wherein the method further comprises wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient has an improvement on the ordinal scale during treatment.

58. The method of any one of claims 1 to 54, wherein during treatment days 1 through 21, the patient does not require hospitalization for shortness of breath.

59. The method of any one of claims 1 to 54, wherein during treatment days 1 through 21, the patient does not require respiratory therapy for shortness of breath.

60. The method of any one of claims 1 to 54, wherein the patient is diagnosed with SARS-CoV2 and diagnosed with mild to moderate COVID-19 symptoms.

61. The method of any one of claims 1 to 54, wherein the patient does not present with symptoms of kidney or liver injury after recovery from the respiratory pathogen infection.

62. The method of any one of claims 1 to 54, wherein the patient does not present with a secondary infection after the sialyllactose treatment.

63. The method of any one of claims 1 to 54, wherein the treatment decreases the duration and severity of myalgias during day 1 to 21 of treatment.

64. The method of any one of claims 1 to 54, wherein the treatment decreases the number and severity of fevers during day 1 to 21 of treatment.

65. The method of any one of claims 1 to 54, wherein the patient maintains a blood oxygen level above 60 mm Hg or >94% SpC .

66. The method of any one of the previous claims, wherein the method further comprises administering an antibiotic compound.

67. The method of claim 66, wherein the antibiotic compound is penicillin, erythromycin, azithromycin, amoxicillin, augmentin, doxycycline, clarithromycin, levofloxacin, moxifloxacin or Gemifloxacin.

68. A method of treating a patient hospitalized with moderate COVID-19, wherein said patient has (a) a confirmed positive RT-PCR test for SARS-CoV2 infection, (b) a Sp0₂ >94% on ambient air and (c) has signs of lower respiratory disease, comprising administering to said patient a composition consisting of an effective amount of 3’ sialyllactose, 6’ sialyllactose or 2’fucosyllactose.

69. The method of claim 68, wherein the signs of lower respiratory disease are determined by clinical examination or by imaging.

70. The method of claim 68, wherein said patient has one or more symptoms selected from myalgia, headache, persistent cough, fever, diarrhea, nausea, abdominal pain, fatigue, skin sensitivity, ageusia, anosmia, or joint pain.

71. The method of claim 68, wherein said patient has one or more COVID-19 risk factor selected from >65 years of age, hypertension, type 2 diabetes, obesity, or heart disease.

72. The method of claim 68, wherein said administration is once daily oral administration, twice daily oral administration or three-times daily oral administration.

73. The method of claim 72, wherein said administration is a 2.5g, 5g, lOg, 15g or 20g daily dose.

74. The method of any one of claims 68 to 73, wherein the treatment stabilizes or improves said patient’s clinical status along the 8-point NIAID COVID-19 ordinal scale.

75. The method of any one of claims 68 to 73, wherein the treatment shortens the patient’s time to discharge as measured by hospital days.

76. The method of any one of claims 68 to 73, wherein the treatment reduces the patient’s fever incidence and severity, wherein the severity is assessed with a Likert 7-point scale.

77. The method of any one of claims 68 to 73, wherein the treatment reduces the patient’s myalgia incidence and severity, wherein the severity is assessed with a Likert 7-point scale.

78. The method of any one of claims 68 to 73, wherein the treatment reduces the patient’s gastrointestinal symptom incidence and severity, wherein the severity is assessed with a Likert 7-point scale.

79. The method of claim 78, wherein the gastrointestinal symptoms are nausea, vomiting, diarrhea and abdominal pain.

80. The method of any one of claims 68 to 73, wherein the treatment reduces the severity of overall COVID-19 symptomology, wherein the severity is assessed with a Likert 7-point scale.

81. The method of any one of claims 68 to 73, wherein the treatment reduces viral load in said patient.

82. The method of claim 81, wherein the viral load is reduced in respiratory and fecal samples.

83. The method of any one of claims 68 to 73, wherein the treatment reduces the incidence of secondary respiratory infections in said patient.

84. The method of any one claims 68 to 73, wherein the treatment decreases time to SARS-CoV2 seroconversion in said patient.

85. The method of any one claims 68 to 73, wherein the treatment increases the levels of IgG and IgM antibodies to SARS-CoV2 after said treatment ends.

86. The method of any one claims 68 to 73, wherein the treatment decreases all-cause mortality.

87. The method of any one claims 68 to 73, wherein the all-cause mortality is decreased at from 1 to 12 months after said treatment.

88. The method of any one of claims 68 to 73, wherein the treatment increases the amount of gut microbiome amounts of Bifidobacterium in said patient.

89. The method of any one of claims 68 to 88, wherein the composition consists of an effective amount of 3’sialyllactose.

90. The method of any one of claims 68 to 88, wherein the composition consists of an effective amount of 6’sialyllactose.

91. The method of any one of claims 68 to 88, wherein the composition consists of an effective amount of 2’fucosyllactose.

92. A method of treating a patient diagnosed with a respiratory pathogen infection, comprising administering to said patient an effective amount of a composition consisting of a fucosyllactose or a pharmaceutically acceptable salt thereof, optionally in combination with one or more antiviral compound.

93. The method of claim 92, wherein the respiratory pathogen is a bacterial pathogen, a viral pathogen, a fungal pathogen or a combination thereof.

94. The method of any one of claims 92 and 93, wherein the patient is diagnosed as presumptively having a viral pathogen based upon presentation of fever, cough, and/or myalgias without shortness of breath.

95. The method of any one of claims 92 and 93, wherein the antiviral compound is selected from remdesivir, convalescent plasma, hydroxychloroquine, chloroquine, favipiravir or lopinavir-ritonavir.

96. The method of claim 94, wherein the antiviral compound is administered with or without interferon beta.

97. The method of any one of claims 92 and 93, wherein the administering of the fucosyllactose reduces the severity of fever associated with the respiratory pathogen infection.

98. The method of any one of claims 92 to 96, wherein the patient does not require hospitalization.

99. The method of any one of claims 92 to 96, wherein the treating delays or prevents hospitalization.

100. The method of any one of claims 92 to 96, wherein the treatment delays or prevents ventilation in said patient.

101. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose prevents the onset of a cytokine storm in said patient.

102. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose reduces plasma levels of one or more pro-inflammatory cytokine.

103. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose reduces plasma levels of one or more pro-inflammatory chemokine.

104. The method of claim 103, wherein the administering of the fucosyllactose reduces plasma levels of one or more proinflammatory cytokines selected from interleukin (IL)-ip, IL-2, IL-4, IL-6, IL-12, interferon (IFN) g or TNF-a in said patient.

105. The method of claim 104, wherein the administering of the fucosyllactose reduces plasma levels of one or more pro-inflammatory chemokines selected from CCL2 (MCP-1), CCL5, CCL7, CXCL1, CXCL2, or CXCL5.

106. The method of claim 105, wherein the administering of the fucosyllactose reduces plasma levels of CCL2 (MCP-1) or CCL5.

107. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose reduces COX2.

108. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose reduces prostaglandin E2 levels.

109. The method of any one of claims 92 to 96, wherein the administering of the fucosyllactose reduces the incidence of severe acute respiratory syndrome (SARS), acute respiratory distress (ARDS) or coronavirus disease- 19 (COVID- 19).

110. The method of any one of claims 92 to 109, wherein the effective amount of the fucosyllactose is administered intranasally, orally, subcutaneously or intravenously.

111. The method of any one of claims 92 to 110, wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment.

112. The method of any one of claims 92 to 110, wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient is not designated higher than 5 on the 8-point NIAID ordinal scale.

113. The method of any one of claims 92 to 110, wherein the method further comprises wherein the method further comprises a step of determining where on the 8-point NIAID ordinal scale designation of disease for each patient before treatment and after 5-21 days of treatment, wherein the patient has an improvement on the ordinal scale during treatment.

114. The method of any one of claims 92 to 110, wherein during treatment days 1 through 21, the patient does not require hospitalization for shortness of breath.

115. The method of any one of claims 92 to 110, wherein during treatment days 1 through 21, the patient does not require respiratory therapy for shortness of breath.

116. The method of any one of claims 92 to 110, wherein the patient is diagnosed with SARS-CoV2 and diagnosed with mild to moderate COVID-19 symptoms.

117. The method of any one of claims 92 to 110, wherein the patient does not present with symptoms of kidney or liver injury after recovery from the respiratory pathogen infection.

118. The method of any one of claims 92 to 110, wherein the patient does not present with a secondary infection after the fucosyllactose treatment.

119. The method of any one of claims 92 to 110, wherein the treatment decreases the duration and severity of myalgias during day 1 to 21 of treatment.

120. The method of any one of claims 92 to 110, wherein the treatment decreases the number and severity of fevers during day 1 to 21 of treatment.

121. The method of any one of claims 92 to 110, wherein the patient maintains a blood oxygen level above >94% SpCk.

122. The method of any one of claims 92 to 121, wherein the method further comprises administering an antibiotic compound.

123. The method of claim 122, wherein the antibiotic compound is penicillin, erythromycin, azithromycin, amoxicillin, augmentin, doxycycline, clarithromycin, levofloxacin, moxifloxacin or Gemifloxacin.

124. A method of treating a subject with active SARS-CoV2 infection comprising administering to such subject a composition comprising one or more human milk oligosaccharides.

125. The method of claim 124, wherein the one or more human milk oligosaccharides is selected from 2’fucosyllactose, 3’sialyllactose or 6’sialyllactose.

126. The method of claim 124, wherein the composition is not a mammalian milk.

127. The method of claim 124, wherein the composition is not derived from mammalian milk.

128. The method of claim 124, wherein the composition comprises 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more by mass one or more human milk oligosaccharides.

129. The method of any one of claims 124 to 128, wherein the one or more human milk oligosaccharide is selected from lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-hexaose (LNH), lacto-N-neohexaose (LNnH), 2’fucosyllactose (2’FL), 3’fucosyllacose (3’FL), lacto-difucotetraose (LDFT), lacto-N-fucopenaose II/III (LNFP II/III), lactose-N-fucopentaose I (LNFP I), lacto-N-difuco-hexaose I (LNDFH I), lacto-N-difuco-hexaose II (LNDFH II), difucosyl-para-lacto-N-neohexaose (DFpLNnH), difucosyllacto-N-hexaose c (DFLNH c), 3’sialyllactose (3’SL), 6’sialyllactose (6’SL), LS-tetrasaccharide a (LSTa), LS-tetrasaccharide b (LST b), LS-tetrasaccharide c (LST c), 3'-sialyl-N-acetyllactosamine (3’SLN), 6'-sialyl-N- acetyllactosamine (6’SLN), or disialyllacto-N-tetraose (DSLNT).

130. The method of any one of claims 124 to 128, wherein the one or more human milk oligosaccharide selected from 2’FL, 3’FL, 3’SL, 6’SL, LNT, or LNnT.

131. The method of claim 124, wherein the composition comprising one or more human milk oligosaccharides contains a mixture of two, three, four or five human milk oligosaccharides.

132. The method of claim 130, wherein the composition comprises a mixture selected from: i. 2’FL and LNT; ii. 2’FL and LNnT; iii. 2’FL, 3’FL, 3’SL, 6’SL and LNT; iv. 3’SL and 6’SL; or v. 6’ SL and LNT.

133. The method of claim 130, wherein the composition comprises a mixture of one neutral core and one neutral fucosylated human milk oligosaccharide.

134. The method of claim 130, wherein the composition comprises a mixture of one neutral and one acidic human milk oligosaccharide.

135. The method of claim 130, wherein the composition comprises a mixture of one neutral fucosylated and one acidic human milk oligosaccharide.

136. The method of claim 130, wherein the composition comprises a mixture of 4: 1 2’FL:LNnT.

137. The method of any one of claims 124 to 136, wherein the method further comprises administering an antibiotic compound.

138. The method of any one of the previous claims, wherein the subject does not experience signs and symptoms of long haul COVID-19 after recovering from active SARS-CoV2 infection.

139. The method of claim 137, wherein the antibiotic compound is penicillin, erythromycin, azithromycin, amoxicillin, augmentin, doxycycline, clarithromycin, levofloxacin, moxifloxacin or Gemifloxacin.

140. The method of any one of the previous claims, wherein the subject’s gut microbiome improves after said administering a composition comprising one or more human milk oligosaccharides.

141. The method of claim 139, wherein the subject’s gut microbiome improvement is measured by fecal 16S ribosomal sequencing.

142. The method of claim 140, wherein the fecal 16S ribosomal sequencing indicates an increase in one or more of Bifidobacterium spp., Faecalbacterium spp., Eubacterium spp. or Roseburium spp.

143. The method of claim 141, wherein the fecal 16S ribosomal sequencing indicates an increase in one or more of Bifobacterium longum or Faecalbacterium prausnitzi.