Therapeutic combinations and methods for treating long COVID

Abstract

The present disclosure relates, in some aspects, to methods of treating subjects suffering from COVID-19 post-acute sequelae (PASC), sometimes also referred to as "long COVID". Also provided are pharmaceutical combinations for treating a subject suffering from PASC, for example with one or more antiviral agents and one or more antibodies, as well as kits for use with the disclosed pharmaceutical combinations and in the disclosed methods.

Description

[0001] Cross-references

[0002] Priority is claimed under PCT Section 8(1) and Rule 4.10 to U.S. Provisional Application No. 63 / 414,662, filed on October 10, 2022, which is incorporated by reference for all purposes as if fully set forth herein. Technical Field

[0003] The present disclosure as a whole relates to medical treatments for viral infections. In some aspects, the present disclosure relates to methods for treating subjects suffering from post-acute sequelae (PASC) of COVID-19. In some aspects, the present disclosure also relates to drug combinations and kits thereof that can be used for the disclosed methods. Background Art

[0004] COVID-19 is a contagious viral disease caused by infection with the SARS-CoV-2 virus. The number of cases of infection with the SARS-CoV-2 virus and the number of deaths related to COVID-19 complications have exceeded the millions, and COVID-19 has become a major global problem. Post-acute syndrome of COVID-19 (PASC), sometimes also called "long COVID-19" or "long COVID," is the persistence or development of symptoms several weeks or longer after the initial SARS-CoV-2 infection. These symptoms can include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, body aches, headache, loss of taste, loss of smell, sore throat, nasal congestion, runny nose, nausea, vomiting, diarrhea, difficulty thinking or concentrating (i.e., brain fog), sleep problems (e.g., insomnia), dizziness, neuropathic pain, nerve sensitivity, changes in taste, changes in smell, depression, anxiety, palpitations, joint pain, chest pain, stomach pain, and others.

[0005] Due to the recent nature of COVID-19, the onset, diagnosis, and prognosis of PASC have not been well studied. More importantly, effective treatments for the sequelae of COVID-19 after the acute phase remain elusive, and the ongoing prevalence of PASC creates an unmet need for the prevention and treatment of its symptoms.

[0006] Incorporated by reference

[0007] Each of the cited patents, publications, and non-patent documents is hereby incorporated by reference in its entirety, as if each were individually incorporated by reference and fully set forth herein. However, no such citation should be construed as an admission that the citation is from similar art or is directly applicable to the present invention, nor should any citation be construed as an admission that the document or any underlying information is prior art or part of the common general knowledge in the art in any jurisdiction. Summary of the Invention

[0008] The following is a brief summary of some embodiments of the present invention to provide a basic understanding of these embodiments. It is not an exhaustive overview, nor is it intended to identify every key or important element of the present invention or to describe the full scope of the invention. Its sole purpose is to provide some exemplary embodiments in a simplified form as a prelude to the more detailed description below.

[0009] In a first aspect, a method of treating a subject having post-acute sequelae (PASC) of COVID-19 is provided, comprising administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; iii) a first antibody; and iv) optionally, a second antibody.

[0010] In another aspect, a pharmaceutical kit for treating a subject with post-acute sequelae (PASC) of COVID-19 is provided, comprising: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; iii) a first antibody; and iv) optionally, a second antibody.

[0011] In embodiments, the first antiviral agent is a protease inhibitor. In embodiments, the first antiviral agent is selected from the group consisting of ritonavir, nirmatrelvir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, pranavir), asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, molnupiravir, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, favipiravir favir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, Dolutegravir, olsetamivir, ensitrelvir (Xocova), simnotrelvir, bemnifosbuvir (AT-527), deuremidevir (VV116), azvudine, sofosbuvir, obeldesivir (GS-5245), acyclovir, and pharmaceutically acceptable salts thereof.

[0012] In an embodiment, the first antibody is a monoclonal antibody. In an embodiment, the first antibody is an immunoglobulin G (IgG) antibody. In embodiments, the first antibody is selected from the group consisting of tixagevimab, cilgavimab, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumab, rituximab, basiliximab, ibritumomab tiuxetan), cetuximab, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, raxibacumab, obinutuzumab, siltuximab, ramucirumab, vedolizumab, alemtuzumab, necitumomab tumumab), dinutuximab, elotuzumab, reslizumab, bezlotoxumab, obiltoxaximab, avelumab, sotrovimab, bebtelovimab, casivirimab, imdevimab, etesevimab, bamlanivimab, amubarvimab, regdanvimab, romlusevimab,Adintrevimab, 002-S21F2, AZD3152, lenzilumab, ravulizumab, canakinumab, adalimumab, sarilumab, ronapreve, vilobelimab, casirivimab, sarilumab, leronlimab, golimumab, tabalumab, veltuzumab, mepolizumab, secukinumab, evolocumab, blinatumomab, adotrastuzumab ), brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, toitumomab-1131, palivizumab, basilixumab, daclizumab, abciximab, murononomab, certolizumab, benralizumab, dupilumab, omalizumab, muromonab-CD3, anti-endothelin receptor B antibody (AER002), and durvalumab. 、

[0013] In embodiments, the second antiviral agent is a protease inhibitor. In embodiments, the second antiviral agent is selected from the group consisting of ritonavir, namatevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, monovaccin, GC376, umifenovir, SSAA09E2, ribavirin, favipiravir, osprevir, sirolimus ... Tasvir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), sennotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), acyclovir and pharmaceutically acceptable salts thereof.

[0014] In embodiments, the second antibody is a monoclonal antibody. In embodiments, the second antibody is an IgG antibody. In embodiments, the second antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, panitumumab, Monoclonal antibody, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, resibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dextrostatin, elotuzumab, reslizumab, bezoloxetine, obituximumab, avelumab, sotovir, bectetuzumab, casiruzumab, idevumab, Etesuvir, barenvir, ambavir, radanvir, romisvir, edinvir, 002-S21F2, AZD3152, lenzlumab, ravulizumab, canakinumab, adalimumab, salizumab, lonaprivir, velolimab, casirizumab, salizumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, Evolumab, blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, AER002, and durvalumab.

[0015] In embodiments, the disclosed methods further comprise administering an effective amount of an additional active agent. In embodiments, the disclosed pharmaceutical kits further comprise an additional active agent. In embodiments, the additional active agent is any of an amino acid, an antioxidant, an anti-inflammatory, an analgesic, an anti-neurotropic and anti-nociceptive, an anti-migraine, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, an immunostimulant, an anticancer, an antiemetic, an anorectic, an antiulcer, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotectant, a monoamine oxidase inhibitor, an empathy-inducing agent, a soothing agent, a hallucinogen, a dissociative, a nootropic, a euphoric, a sedative, a stimulant, and a vitamin.

[0016] In embodiments, the additional active agent is any of an uncoating inhibitor, an entry inhibitor, a protease inhibitor, an immunostimulant, a latency reversal agent, a reverse transcriptase, a reverse transcriptase inhibitor, an integration inhibitor, a nucleoside analog, an RNA polymerase inhibitor, a viral uncapping agent, a neuraminidase inhibitor, a fusion inhibitor, an interferon, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor. In embodiments, the additional active agent is an immunostimulant, a COVID-19 vaccine, an additional agent with antiviral activity, or an additional antibody. In embodiments, the additional active agent is an additional agent with antiviral activity. In embodiments, the additional agent with antiviral activity is a MIR (siR-7-EM / KK-46), baicalin, pegylated interferon λ, metformin, ursodeoxycholic acid (UCDA), TVGN-489, LAU-7b, sabizabulin, azithromycin, ivermectin, opanganib, baricitinib, mycophenolate mofetil, APN01, epigallocatechin gallate (EGCG), diphenhydramine, quercetin, Qingfei Paidu Decoction (QFPDT), Lianhua Qingwen (LQ), Qingguan No. 1 (NRICM101), Jingsi Bencao Yin (JSHD), nicotine, lactoferrin, nattokinase, or ubiquinone.

[0017] In an embodiment, the first antiviral agent is nematevir, sofosbuvir, or ritonavir, including any of which are pharmaceutically acceptable salts thereof. In an embodiment, the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof. In an embodiment, the first antiviral agent is nematevir and the second antiviral agent is ritonavir, including any of which are pharmaceutically acceptable salts thereof, or both.

[0018] In an embodiment, the first antibody is tesagvir or celegavir. In an embodiment, the first antibody is tesagvir and the second antibody is celegavir.

[0019] In an embodiment, the first antiviral agent is namatevir, or a pharmaceutically acceptable salt thereof; and the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir monoclonal antibody; and the second antibody is segavir monoclonal antibody. In an embodiment, the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir monoclonal antibody; and the second antibody is segavir monoclonal antibody.

[0020] In embodiments, the first antibody and the second antibody are in the same composition, i.e., administered in a single pharmaceutical composition (i.e., co-formulated as a single pharmaceutical composition). In embodiments, the first antibody and the second antibody are contained in the same composition, i.e., as a single pharmaceutical composition comprising both the first and second antibodies. In other embodiments, the first antiviral agent and the second antiviral agent are administered in the same composition. In other embodiments, the first antiviral agent and the second antiviral agent are contained in the same composition. In embodiments, generally, any one or more of the disclosed agents are administered in the same composition, or are contained in the same composition.

[0021] In embodiments, the method reduces the incidence or severity of at least one symptom of PASC. In embodiments, the symptom of PASC is a neurologic symptom, a cardiovascular symptom, a pulmonary symptom, a musculoskeletal symptom, an endocrine symptom, a skin symptom, or a renal symptom.

[0022] In the embodiment, the neurological symptoms are selected from the group consisting of sleep disorders, chronic headaches, smell disorders, taste disorders, brain fog, memory loss, decreased concentration, depression, anxiety, post-traumatic stress disorder (PTSD), dizziness, vertigo, tinnitus, hearing loss, balance disorders, delirium, hallucinations, small fiber neuropathy, postural tremor, chronic pain, neurodegeneration and myalgia.

[0023] In embodiments, the cardiovascular symptoms are selected from the group consisting of nonspecific chest pain, chest tightness, palpitations, tachycardia, conduction disturbances, arrhythmias, orthostatic hypotension, vasovagal syncope, postural orthostatic tachycardia syndrome (POTS), phlebitis, and thrombophlebitis.

[0024] In an embodiment, the pulmonary symptoms are selected from the group consisting of dyspnea, persistent cough, wheezing, worsening asthma, decreased lung diffusion capacity, persistent abnormal imaging findings, pleurisy, cough, sleep apnea, and sore throat.

[0025] In embodiments, the musculoskeletal symptoms are selected from the group consisting of arthritis, back pain, gait abnormalities, and joint pain.

[0026] In an embodiment, the endocrine symptom is selected from the group consisting of impaired glucose metabolism, subacute thyrotoxicosis, Hashimoto's disease, Graves' disease, and dyslipidemia.

[0027] In an embodiment, the skin symptoms are selected from the group consisting of rash, hives, skin lesions, telogen effluvium, nail changes, erythema, and scalp pain.

[0028] In embodiments, the renal symptom is selected from the group consisting of decreased glomerular filtration rate, urinary incontinence, and microscopic hematuria.

[0029] In embodiments, the symptoms of PASC are selected from the group consisting of fever, chills, muscle aches, body aches, chest pain, stomach pain, nausea, vomiting, diarrhea, gastroesophageal reflux, stress, swelling, bleeding, weight loss, weight gain, abdominal pain, constipation, pain in the extremities, paresthesia, peripheral edema, pruritus, lymphadenopathy, and edema.

[0030] In embodiments, the incidence of a PASC symptom is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% compared to the incidence of the symptom prior to treatment with the method.

[0031] In embodiments, the severity of the PASC symptoms is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% compared to the severity of the PASC symptoms prior to treatment with the method.

[0032] In embodiments, the method restores the serum concentration of a PASC biomarker to within about 50%, 40%, 30%, 20%, 10%, 5%, or 1% of the baseline concentration.

[0033] In embodiments, the PASC biomarker is a nervous system biomarker. In embodiments, the nervous system biomarker is GDNF, GFAP, NGF-β, NFL, NT-3, or pGFAP / pNFL.

[0034] In embodiments, the PASC biomarker is a cardiovascular biomarker. In embodiments, the cardiovascular biomarker is Ang-2, Col1A2, Col3A1, D-dimer, ESR, ET-1, Factor VIII:C, hemoglobin, MMP-1, MMP-9, MPO, NO, PDGF-BB, sICAM-1, sTM, sVEGFR, sVCAM-1, VEGF, VWF:Ag, or VWF:pp.

[0035] Also provided is the use of a pharmaceutical kit according to any one of the preceding embodiments for treating PASC. Also provided is the use of a pharmaceutical kit according to any one of the preceding embodiments for the manufacture of a medicament for treating PASC.

[0036] The above has broadly outlined some relevant features of certain exemplary embodiments of the present disclosure so that the specific embodiments of the invention that follow may be better understood and the contribution of the present invention to the art may be more fully appreciated. Additional features of the present invention will be described below, which form the subject of the claims of the present invention. It will be understood by those skilled in the art that the concepts and the specific formulations and methods disclosed can be easily used as a basis for modifying or designing other formulations and methods for achieving the same purposes as the present disclosure. It will also be recognized that such equivalent formulations and methods do not depart from the spirit and scope of the invention as set forth in the claims. Therefore, this summary is made with the understanding that the summary will be regarded as merely a brief and general summary of some of the purposes and embodiments of this document, provided only for the benefit and convenience of the reader, and is not intended to limit in any way the scope or equivalent scope of the claims to which they are legally entitled. It will also be understood that the titles herein are intended only to expedite the reader's review; they should not be construed as limiting the present invention in any way. DETAILED DESCRIPTION

[0037] The present disclosure relates to methods of treating subjects suffering from post-acute syndrome of COVID-19 (abbreviated as PASC, sometimes also referred to under the umbrella term "long COVID").

[0038] In other aspects, the present disclosure also relates to methods of preventing or treating symptoms of PASC. In some other aspects, the present disclosure also relates to pharmaceutical combinations used in the disclosed methods, and pharmaceutical kits comprising the disclosed combinations.

[0039] While various aspects and features of certain embodiments have been summarized above, this detailed description presents several exemplary embodiments in greater detail to enable those skilled in the art to practice such embodiments and to make and use the full scope of the invention. However, the described embodiments and examples are for illustrative purposes only and are not intended to limit the scope of the invention. It should be understood that those skilled in the art may make many modifications, substitutions, variations, and changes to the described embodiments, examples, details, and applications of the invention without departing from the spirit of the invention or the scope of the invention as described in the claims.

[0040] A. General Definitions and Terminology

[0041] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" include plural referents. Thus, for example, reference to an "active agent" includes reference to a combination of two or more active agents, and reference to an "excipient" includes reference to a combination of two or more excipients. Although the term "one or more" can be used, not using this term (or replacing it with the singular) does not merely indicate the singular, but simply emphasizes the possibility that there are multiple agents or ingredients in a particular embodiment. The terms "comprising", "including", "such as" and "having" are inclusive and not exclusive (i.e., in addition to the listed elements, other elements may also be present). Thus, as used herein, the term "comprising" means the phrase "including but not limited to" and can be used interchangeably with the phrase "including but not limited to". Unless the context clearly indicates otherwise, the term "or" is used herein to refer to the term "and / or" and can be used interchangeably with the term "and / or".

[0042] Unless otherwise indicated, all numbers representing quantities of ingredients, properties (such as concentrations, reaction conditions, etc.) used to describe and claim certain embodiments of the present invention are to be understood as being modified in some cases by the term "about". Thus, in embodiments, the numerical parameters set forth in the written description and the appended claims are approximate values ​​that may vary depending on the desired properties sought to be obtained by a particular embodiment. In embodiments, "about" means plus or minus five percent (±5%) of the recited unit of measure. When the term "substantially" is applied to modify a feature or limitation herein, it should be interpreted in the context of the present invention and in accordance with the knowledge in the art to provide appropriate certainty, for example, by measuring the meaning of "substantially" as a term of degree using standards recognized in the art, or by determining the range that can be determined by one skilled in the art.

[0043] In some embodiments (equivalent to simply "in embodiments"), numerical parameters should be interpreted in light of the number of reported significant figures and by applying ordinary rounding techniques. Although the numerical ranges and parameters setting forth the broad scope of some embodiments of the present invention are approximate, the numerical values ​​set forth in the specific examples are reported as precisely as possible. The numerical values ​​provided in the embodiments may contain certain errors due to the standard deviation found in their respective testing measurements.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art (hereinafter referred to as "technician") to which this invention belongs. Other definitions that may assist the reader in understanding the disclosed embodiments are as follows; however, it should be understood that these definitions are not intended to limit the scope of the invention, which should be appropriately interpreted and understood by reference to the entire specification (and any plain meaning known to a skilled person) and in conjunction with the language used in the claims. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0045] In general, the nomenclature used herein and the procedures performed are those known in the art (such as medicine, biology, molecular biology, pharmacology, chemistry, biochemistry, biotechnology, virology, immunology, infectious diseases, statistics, etc.) relevant to one or more aspects of the present invention and are well known and commonly used in these fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0046] As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably and refer to humans, mammals, or any other animals (e.g., poultry) susceptible to COVID-19 infection. The animal may be a domesticated animal (e.g., a cat, a dog). The animal may be a livestock or farm animal (e.g., a horse, a cow, a pig, a chicken). Preferably, the subject is a human. The subject may be a human infant, a human child, a human adult, or a human elderly person. Such terms should be understood to include people with indications for which the methods described herein can be effectively treated, or people who may benefit from the present invention. In general, although individual differences are to be expected, all disclosed methods are understood to be applicable to all individuals and are understandable. The disclosed methods of treatment may also be modified to treat multiple patients, including couples or families, simultaneously. Therefore, these terms will also be understood to mean two or more individuals.

[0047] As used herein, an "effective amount," "therapeutically effective amount," or "pharmacologically effective amount" refers to an amount of an active agent (e.g., an antiviral agent or monoclonal antibody) that is non-toxic and sufficient to provide the desired therapeutic effect and is suitable for any medical treatment at a reasonable benefit / risk ratio. The effective amount will vary depending on the subject, the subject's weight and age, the severity of the symptoms or degree of health benefit sought, the mode of administration, and the like, all of which can be readily determined by one skilled in the art.

[0048] As used herein, "therapeutic effect" or "therapeutic efficacy" refers to the response of a subject (preferably a human) following treatment that is judged to be desirable and beneficial. Thus, these responses will vary depending on the condition being treated, or the improvement in health or function being sought, as well as on the particular composition of the disclosed method under consideration, but will be readily understood by those skilled in the art.

[0049] As used herein, "treating" or "treatment" of a condition, such as PASC, includes any treatment of a condition in a mammal, preferably a human, and includes: (a) inhibiting the condition, i.e., arresting its development; (b) relieving the condition, i.e., causing regression of the condition or its symptoms; (c) preventing or alleviating symptoms or pathology caused by or associated with the condition; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or pathology associated with the condition; and (f) preventing or inhibiting worsening or progression of symptoms or pathology associated with the condition.

[0050] In preferred usage, the term "treating" or "treatment" refers to reducing, eliminating or alleviating one or more symptoms of PASC in a subject.

[0051] In embodiments, treatment will be directed towards PASC symptoms that are the same as any of the symptoms of the original SARS-CoV-2 infection and that persist after the original SARS-CoV-2 infection.

[0052] In embodiments, treatment is for PASC symptoms that are distinct from any of the symptoms of the original SARS-CoV-2 infection. In embodiments, treatment is for PASC symptoms that are distinct from all symptoms of the original SARS-CoV-2 infection and that arise after the original SARS-CoV-2 infection.

[0053] Those skilled in the art will be aware of appropriate symptoms associated with symptoms of PASC and corresponding clinically measurable indicators and / or other diagnostic criteria. Reduction or alleviation of symptoms includes reducing the incidence or severity of a particular symptom. For example, certain PASC symptoms include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, body aches, headache, loss of taste, loss of smell, sore throat, nasal congestion, runny nose, nausea, vomiting, diarrhea, difficulty thinking or concentrating (i.e., brain fog), sleep problems (e.g., insomnia), dizziness, neuropathic pain, nervousness, altered taste, altered smell, depression, anxiety, palpitations, joint pain, chest pain, and stomach pain. PASC symptoms also typically include fatigue, headache, sleep problems (e.g., insomnia), dizziness, difficulty thinking or concentrating (i.e., brain fog), altered or lost sense of smell or taste, depression, and anxiety. Those skilled in the art can understand other such symptoms and clinically measurable indicators (alone or in combination) based on the teachings of this article and the general knowledge in the art, for example, by referring to the "PASCLex" PASC symptoms described in Wang L et al. J Biomed Inform. 2022 Jan;125:103951, which is incorporated by reference as if fully set forth herein.

[0054] As used herein, “COVID” refers to an infectious disease caused by an RNA virus of the coronavirus group and present in humans, mammals, or any other animal. “COVID-19” refers to the COVID viral infectious disease that is derived from the coronavirus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and present in humans, mammals, or any other animal. COVID-19 also refers to a viral disease that is derived from a variant of SARS-CoV-2. A variant refers to a change in the genetic code of a virus, wherein the variant has multiple mutations that distinguish it from other variants of the common ancestral virus. Variants of SARS-CoV-2 include, but are not limited to, alpha (α), beta (β), gamma (γ), delta (δ), omicron (ο), epsilon (ε), zeta (ζ), eta (η), theta (θ), iota (ι), kappa (κ), lambda (λ), muon (μ), Cluster 5, and any future variants not yet defined, the determination and identification of which should be within the skill of one of ordinary skill in the art.

[0055] SARS-CoV-2 can also be classified as A.1-A.30, AA.1-AA.8, AB.1, AC.1, AD.1, AD.2. AE.1-AE.8、AF.1、AG.1、AH.1-AH.3、AJ.1、AK.1、AK.2、ON.1、AM.1-AM.4、AN. 1、AP.1、AQ.1、AQ.2、AT.1、AS.1、AS.2、AU.1-AU.3、AV.1、AW.1、AY.1-AY.13 4、AZ.1-AZ.6、B、B.1-B.61、BA.1-BA.5、BB.2、BC.1、BC.2、BD.1、BE.1-BE.13 、BF.1-BF.42、BG.1-BG.7、BH.1、BJ.1、BK.1、BL.1-BL.6、BM.1-BM.6、BN.1- BN.6、BP.1、BQ.1、BR.1-BR.5、BS.1、BT.1、BT.2、BU.1-BU.3、BV.1、BV.2、BW. 1、BY.1、BZ.1、BZ.2、C.1-C.40、CA.1-CA.7、CB.1、CC.1、CD.1、CD.2、CE.1、C F.1、CG.1、CH.1-CH.3、CJ.1、CK.1-CK.3、CL.1、CM.1-CM.12、CN.1、CN.2、CP. 1-CP.8、CQ.1、CQ.2、CR.1、CR.2、CS.1、CT.1、CV.1、CV.2、CW.1、CY.1、CY.2、 CZ.1、CZ.2、D.1-D.5、DA.1、DB.1-DB.3、DC.1、DD.1、DE.1、DE.2、DF.1、DG.1、 DH.1、DJ.1、DK.1、DL.1、DM.1、DN.1-DN.3、DP.1、DQ.1、DR.1、DR.2、DS.1-DS .3、DT.1-DT.3、DU.1、DV.1-DV.8、DW.1、DY.1-DY.4、DZ.1、DZ.2、EA.1、EA.2、 EB.1、EC.1、ED.1-ED.3、E.1-E.5、EF.1-EF.3、EG.1-EG.14、EH.1、EJ.1-E J.3、Ex.1-Ex.4、EL.1、EM.1、EN.1、EP.1-EP.2、EQ.1、ER.1、ET.1、ES.1、EU.1 、EW.1-EW.3、EV.1、EY.1、EZ.1、FA.1、FA.2、FB.1、FB.2、FC.1、FD.1-FD.4、F E.1、FF.1、FG.1-FG.3、FH.1、FJ.1、FK.1、FL.1-FL.36、FM.1、FM.2、FN.1、FP.1-FP.4、FQ.1、FR.1、FR.2、FS.1、FT.1-FT.4、FU.1-FU.5、FV.1、FW.1-FW.3、 FY.1-FY.7、FZ.1、FZ.2、G.1、GA.1-GA.6、GB.1、GB.2、GC.1、GC.2、GD.1-GD.3 、GE.1、GF.1、GG.1、GH.1、GJ.1-GJ.5、GK.1-GK.4、GL.1、GM.1-GM.3、GN.1-G N.5、GO.1、GP.1-GP.3、GR.1、GS.1-GS.5、GT.1、GU.1、GV.1、GW.1-GW.5、GY.1 -GY.8、GZ.1、HA.1、HA.2、HB.1、HC.1-HC.4、HD.1、HE.1、HF.1、HG.1,HG.2、H H.1、HH.2、HJ.1、HK.1-HK.9、HK.11、HL.1、HL.2、HM.1、HN.1、HP.1、HQ.1、HR. 1、HS.1、HT.1、HT.2、HU.1、HU.2、HV.1、HW.1、HY.1、HZ.1-HZ.3、JA.1、JB.1、 JB.2、JC.1、JD.1、JD.2、JE.1、JF.1、JF.2、JG.1-JG.3、JH.1、JH.2、JJ.1、JK. 1、JL.1、JM.1、JM.2、JN.1、JP.1、K.1-K.3、L.1-L.4、M.1-M.3、N.1-N.10、P. 1-P.7, Q.1-Q.8, R.1, R.2, S.1, XA, XB, XC, XG, XH, XJ, XK, XL, XM, XM. N、XP、XQXRXRXSXSXTXT XU XV XVXW XYXY XZXXXAXXAXXAE H、SHOES、SHOES、SHOES、SHOES、ALSO、SHOES、SHOES、SHOES、SHOES、SHOES、SHOES、XAV、SHOES、SHOES、SHOES.1 -XAY.3、XAZ、XBA、XBB、XBB.1-XBB.9、XBC、XBC.1、XBC.2、XBD、XBE、XBF、XBF .1-XBF.10、XBG、XBH、XBJ、XBJ.1-XBJ.4、XBK、XBK.1、XBL、XBL.1-XBL.3、XBM XBN、XBP、XBQ、XBR、XBW、XBY、XBZ、XCA、XCB、XCC、XCD、XCE、XCF、XCF.1、XCF .2、XCG、XCH、XCH.1、XCJ、XCK、XCL、XCM、XCN、XCP、U.1-U.3、V.1、V.2、W.1-W.4. Y.1, Z.1, their respective sublineages, and any future lineages not yet defined. SARS-CoV-2 variants also include GISAID clades S, L, O, V, G, GH, GR, GV, and any future clades not yet defined, the identification and characterization of which are within the skill of those skilled in the art. SARS-CoV-2 variants also include Nextstrain clades 19A, 19B, 20A, 20B, 20C, 20D, 20E, 20F, 20G, 20H, 20I, 20J, and any future clades not yet defined, the identification and characterization of which are within the skill of those skilled in the art.

[0056] As used herein, “post-acute COVID-19 sequelae” and “PASC” are used interchangeably with the terms “long COVID” and “long COVID-19” to refer to the persistence, occurrence, or manifestation of COVID-19 symptoms after the standard incubation period, transmission period, or symptomatic period of COVID infection, which periods are known to those skilled in the art. To distinguish COVID-19 syndrome or symptoms from such sequelae or PASC, if not otherwise defined or suggested herein, such sequelae should be present for more than 28 days after the patient's first positive PCR test and confirmed infection with SARS-CoV-2, or from the selected infection date (as understood by those skilled in the art), or should last for more than 28 days after the infection date (see also Thaweethai T et al. JAMA. 2023; 329(22): 1934-1946). In an embodiment, the sequelae should last for 30 or more days after infection. In an embodiment, the sequelae should last for four weeks or more after infection. In embodiments, after infection, sequelae should continue for about four weeks or longer. In embodiments, after infection, sequelae should continue for more than 1 month, including continuing for more than 2 months, more than 3 months, more than four months, more than 5 months, more than 6 months, even longer, including more than 1 year. In embodiments, after infection, sequelae should continue for more than 3 months, and continue for at least 2 months. In embodiments, after infection, sequelae should exist for 30 days or more days. In embodiments, after infection, sequelae should exist for four weeks or longer. In embodiments, after infection, sequelae should exist for about four weeks or longer. In embodiments, after infection, sequelae should exist for more than 1 month, including after infection, there is more than 2 months, more than 3 months, more than four months, more than 5 months, more than 6 months, even longer, including more than 1 year. In embodiments, after infection, sequelae should exist for more than 3 months, and continue for at least 2 months. Other definitions that may be used to describe the onset and / or persistence of sequelae will be known to those skilled in the art and include (citing Sherif ZA et al. Elife. 2023;12:e86002): “persistence of COVID-19 symptoms or onset of new symptoms for 4 weeks or longer after SARS-CoV-2 infection (http: / / www.CDC.gov), or persistence of symptoms >30 days after infection (http: / / www.NIH.gov)” or symptoms “typically appear 3 months after COVID-19 onset… persist for at least 2 months and cannot be explained by an alternative diagnosis (http: / / www.WHO.int)” or “persistent, recurrent, or new symptoms or other health effects after the acute phase of SARS-CoV-2 infection (i.e., present four weeks or longer after acute infection)”.

[0057] If the context does not define or suggest otherwise, the term "sequelae" or the broad term "PASC" and its synonyms herein, refers to any condition, disease, syndrome, symptom or defect that a patient exhibits after SARS-CoV-2 infection, or that persists for a period of time (such as more than a period of time) after the initial SARS-CoV-2 infection, and that is likely to be causally related to the SARS-CoV-2 infection, regardless of whether the patient experiences any syndromes or symptoms of COVID-19 or does not experience these syndromes or symptoms. In embodiments, such sequelae are different from the known spectrum of syndromes and symptoms of COVID-19. In embodiments, sequelae are different from the syndromes and symptoms of the initial SARS-CoV-2 infection reported by the subject. That is, in some embodiments herein, the disclosed compositions and methods are used to treat sequelae that are different from the syndromes and symptoms of the initial SARS-CoV-2 infection reported by the subject (i.e., "new" symptoms). In embodiments, the sequelae are the same syndromes and symptoms reported by the subject as a result of the initial SARS-CoV-2 infection, but the sequelae are reported to persist for a period of time (such as longer than a period of time) after the initial SARS-CoV-2 infection.

[0058] For example, “aftereffects” after the acute phase include fatigue (including chronic fatigue syndrome or CFS), shortness of breath (dyspnea), (long-term) cough, joint pain, chest pain and muscle weakness, difficulty thinking and concentrating (“brain fog”), depression, muscle pain, headache, intermittent fever, rapid heartbeat (or racing heartbeat) (“palpitations”), myocardial inflammation, abnormal lung function, acute kidney injury, rash, hair loss, tooth loss, sleep disturbances, insomnia, memory problems, anxiety, mood swings, mild fever, pins and needles in the arms and legs, diarrhea, vomiting, sore throat, difficulty swallowing, and new-onset diabetes and high blood pressure. In an embodiment, sequelae following the acute phase will specifically include neurological or psychiatric sequelae, and also include any of (ischemic) stroke, bilateral frontotemporal hypoperfusion, intracranial hemorrhage, paralysis, hemiplegia, ataxia, cranial nerve deficits, encephalopathy, acute necrotizing encephalitis, delirium, cerebrospinal meningitis, seizures, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, accelerated aging, aphasia, cognitive decline, decreased level of consciousness, and Guillain-Barre syndrome.

[0059] In the embodiment, the sequelae after the acute phase include any one of anorexia, anxiety, arrhythmia, confusion ("brain fog"), dementia, depression, dyspnea, fatigue, hair loss, headache, heart failure, cardiomyopathy, angina, liver dysfunction, hyperglycemia, type 2 diabetes, increased heart rate, inflammation, loss of appetite, memory loss, loss of smell, mood disorders, muscle weakness, myocardial ischemia, post-exertional fatigue, neurocognitive decline, decreased sensory function, pulmonary infiltrates or fibrosis, postural orthostatic hypotension, renal dysfunction, and respiratory distress. In the embodiment, the sequelae include any one of myalgia, fibromyalgia, idiopathic pulmonary fibrosis, fatigue (including persistent fatigue, exertional fatigue, and muscle fatigue), mitochondrial dysfunction, post-exertional dyspnea, postural orthostatic tachycardia syndrome, tachycardia, mood disorders, and depression.

[0060] By referring to the disclosure herein, including any of the definitions herein, and the general knowledge in the art, those skilled in the art will be aware of other post-acute sequelae, which may also be referred to herein as "symptoms of PASC" or "symptoms of post-acute sequelae of COVID-19."

[0061] As used herein, "antiviral agent" refers to an agent intended for use against viral infections in humans, mammals, or any other animal. For example, antiviral agents may include: uncoating inhibitors, entry inhibitors, protease inhibitors, immunostimulants, latency reversal agents, reverse transcriptases, reverse transcriptase inhibitors, integration inhibitors, nucleoside analogs, replication inhibitors, polymerase inhibitors (e.g., RNA polymerase inhibitors), agents that act on viral uncapping, neuraminidase inhibitors, fusion inhibitors, interferons, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors.

[0062] As used herein, "interferon" refers to a single or multiple signaling proteins. For example, interferon can be produced by leukocytes, fibroblasts, lymphocytes, or other host cells in response to the presence of a virus. Interferon can be naturally derived or artificial. "Interferon" further refers to interferons classified as α, β, γ, and related subtypes. In addition, "interferon" refers to type I interferon, type II interferon, type III interferon, and related subtypes.

[0063] As used herein, "monoclonal antibody" refers to an antibody derived from a single cell line or a single clone. For example, monoclonal antibodies include: whole monoclonal antibodies, antigen-binding fragments, single-chain variable fragments, single-domain antibodies, trifunctional antibodies, chemically linked antibodies, and bispecific T cell engaging antibodies. "Monoclonal antibody" also refers to IgA antibodies, IgD antibodies, IgE antibodies, IgG antibodies, or IgM antibodies, anti-B lymphocyte stimulating (anti-BlyS) antibodies (e.g., belimumab, ), humanized antibodies, synthetic antibodies, long-acting monoclonal antibodies, broadly neutralizing monoclonal antibodies, and any derivatives thereof. "Long-acting monoclonal antibodies" refer to antibodies with a longer half-life than standard monoclonal antibodies. "Broadly neutralizing monoclonal antibodies" refer to antibodies that activate immune cells other than those targeted by standard monoclonal antibodies. Monoclonal antibodies can target any existing SARS-CoV-2 variant or future variants or lineages that have yet to be defined.

[0064] As used herein, "polyclonal antibodies" refer to a heterogeneous mixture of antibodies. For example, polyclonal antibodies can be derived from multiple cell lines or multiple clones. Polyclonal antibodies can be a combination of any one of IgA antibodies, IgD antibodies, IgE antibodies, IgG antibodies, or IgM antibodies (but not limited to this), anti-BlyS antibodies, humanized antibodies, synthetic antibodies, long-acting antibodies, broad-spectrum neutralizing antibodies, and any derivatives thereof. "Long-acting polyclonal antibodies" refer to antibodies with a longer half-life relative to standard polyclonal antibodies. "Broad-spectrum neutralizing polyclonal antibodies" refer to antibodies that activate immune cells other than standard monoclonal antibody targets. Polyclonal antibodies can target any existing SARS-CoV-2 variant or future variants or lineages that have not yet been defined.

[0065] B.Pharmacy

[0066] In some aspects, disclosed are pharmaceutical combinations of two or more agents, which may be antiviral agents, antibodies, or additional active agents, such as described herein and below.

[0067] a. Antiviral agents

[0068] In some aspects, disclosed are pharmaceutical combinations of two or more agents, wherein at least one agent is an antiviral agent.

[0069] In embodiments, the antiviral agent is a protease inhibitor.

[0070] In embodiments, the antiviral agent is an inhibitor of the SARS-CoV-2 major protease ("Mpro inhibitor") (see Huang C et al. Signal Transduct Target Ther. 2023 Mar 16;8(1):128). In embodiments, the Mpro inhibitor is namatevir, Enstevir (e.g., ), Enstevir, Senotevir, Senotevir, and Ritonavir (e.g., ) or SY110 (see Huang, supra).

[0071] In embodiments, the antiviral agent is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase ("RdRp inhibitor"). In embodiments, the RdRp inhibitor is remdesivir, monoclavir, renmindevir, or azithromycin.

[0072] In an embodiment, the antiviral agent is an ACE2 decoy receptor drug. Without being bound by theory, such drugs are soluble molecules that are structurally similar to the normal membrane-bound ACE2 receptor and are able to recognize and bind to the spike protein of the SARS-CoV-2 variant, thereby neutralizing the virus before it infects the host cell (Torchia JA et al. Sci Adv. 2022 Dec 9;8(49):eabq6527).

[0073] In an embodiment, the antiviral agent is any one of ritonavir, nematevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, semideprevir, and telaprevir.

[0074] In an embodiment, the antiviral agent is any one of monolavuvir, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, favipiravir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), senotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), and acyclovir.

[0075] In some embodiments where the antiviral agent is sofosbuvir, sofosbuvir is administered with daclatasvir. In some embodiments, sofosbuvir is administered with daclatisvir and ribavirin. In embodiments, sofosbuvir is administered with ledipasvir (e.g., HARVONI TM In embodiments, the antiviral agent is any one of sofosbuvir, daclatasvir, ribavirin, or ledipasvir, including all combinations thereof.

[0076] In an embodiment, the antiviral agent can be provided as a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or non-toxic base, which can be synthesized by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or free base form of these agents with a stoichiometric amount of a suitable base or a suitable acid in water or an organic solvent, or in a mixture of water or an organic solvent; in general, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, a salt of a compound is one in which the counterion is a pharmaceutically acceptable salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acetylphylline, acetate, acetylglycinate, adipate, alginate, aminosalicylate, ammonium salts, aminostilbenesulfonate, ascorbate, aspartate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, ethylenediamine, Calcium tetraacetate, calcium salt, camphor carbonate, camphorate, camphorsulfonate, camsylate, carbonate, bile salt, citrate, clavulanate, cyclopentanepropionate, cyclopentanepropionate, D-aspartate, D-camphorsulfonate, D-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edentate, edetate, edisylate, esylate, esylate thanesulfonate), ethyl sulfate, fumarate, furoate, fusidate, galactonate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, para-glycolylaminophenylarsonic acid salt, hemisulfate, heptanoate (heptanoate, enanthate), hepta noate), hexafluorophosphate, hexanoate, hexyl metabisphenolate, hippurate, hydroxybenzoate, halamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, L-aspartate, L-camphorsulfonate, L-lactate, lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate,Methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, naphthalene disulfonate, naphthoate, naphthate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, diphosphate, picrate, pivalate, polygalacturonate, potassium salt, propionate, pyrophosphate salt, saccharate, salicylate, salicylate sulfate, sodium salt, stearate, subacetate, succinate, sulfate, sulfosalicylate, sulfosalicylate, sullanate, tannate, tartrate, theoclate, terephthalate, thiocyanate, thiosalicylate, toluenesulfonate, tribromophenate, triethyl iodide, undecanoate, undecenoate, valerate, valproate, xinafoate, zinc salt, etc. (Berge et al. (1977) J. Pharm. Sci. 66: 1-19),

[0077] b. Antibodies

[0078] In some aspects, methods are disclosed using a pharmaceutical combination of two or more agents, wherein at least one agent is an antibody.

[0079] In embodiments, the antibody is tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, trastuzumab, Any of bacuzumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dexuzumab, elotuzumab, reslizumab, bezoclozumab, obituximab, avelumab, sotoviromab, betelovirimab, casirivirimab, idevumab, etezvirimab, barenvirumab, ambavirimab, redavimab, romisvir, edinvirumab, 002-S21F2, and durvalumab.

[0080] In embodiments, the antibody is any one of AZD3152, renzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonaprivir, veloxazolizumab, casirizumab, salilumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, evolocumab, blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronumab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, and AER002.

[0081] In an embodiment, the antibody is a monoclonal antibody.

[0082] In an embodiment, the antibody is a polyclonal antibody.

[0083] In an embodiment, the antibody is an immunoglobulin A (IgA) antibody, an immunoglobulin D (IgD) antibody, an immunoglobulin E (IgE) antibody, an immunoglobulin G (IgG) antibody, or an immunoglobulin M (IgM) antibody. In some preferred embodiments, the antibody is an IgG antibody.

[0084] In an embodiment, the antibody is an IgG1 antibody or an IgG3 antibody (ie, an IgG antibody in the subclass IgG1 or subclass IgG3). In an embodiment, the antibody is an IgG2 antibody or an IgG4 antibody.

[0085] In embodiments, the antibody is an anti-BlyS antibody.

[0086] In embodiments, the antibody is a broadly neutralizing antibody.

[0087] In embodiments, the antibody is a broadly neutralizing monoclonal antibody.

[0088] In embodiments, the antibody is a long-acting antibody.

[0089] In an embodiment, the antibody is a long-acting monoclonal antibody.

[0090] In an embodiment, the antibody is an anti-spike protein antibody, as understood by the skilled artisan (see, e.g., Mikulska M et al. Clin Infect Dis. 2023 Jul 26;77(2):280-286).

[0091] In embodiments, the antibody is selected so that the antibody remains bioavailable in the subject for an extended period of time. In embodiments, the antibody is an IgG antibody selected so that the antibody remains bioavailable in the subject for an extended period of time.

[0092] In embodiments, "longer" can refer to a half-life of more than one month to more than one year. In embodiments, "longer" refers to a period of time or a relative ratio relative to a comparator, and a skilled artisan will be aware of the selection of comparators and the calculation of comparators. For example, longer can refer to a period of time greater than one month longer than a comparator, or can refer to a bioavailability that is, for example, 10%, 20%, 50%, or 100% greater than a comparator. In some preferred embodiments, when an antibody remains bioavailable in a subject for a longer period of time, the antibody will remain clinically active during this period.

[0093] In embodiments, the antibody remains in the subject's body for a longer period of time due to a synergistic effect with another agent in the drug combination (including an antiviral agent, another antibody, or an additional active agent). In embodiments, the additional active agent is selected so that it acts synergistically with the antibody, and this synergistic effect increases the period of time that the antibody is biologically active in the subject's body.

[0094] In the embodiments, the antibody is specifically engineered to maintain bioavailability in the subject for a long time. In the embodiments, the antibody is an IgG antibody specifically engineered to maintain bioavailability in the subject for a long time. Various methods for antibody engineering are known to those skilled in the art, and the method can be used for mAb to be added to the IgG scaffold by their SARS-CoV-2 binding specificity, so that they maintain bioavailability in the subject for a long time. In addition to factors related to antigen specificity, such as binding affinity and avidity, the mechanism of action (MoA) of therapeutic monoclonal antibodies (mAbs) also encompasses Fc-mediated effector functions. These functions include antibody-dependent cellular cytotoxicity (ADCC) and its closely related antibody-dependent cellular phagocytosis (ADCP). In order to evaluate these effector functions, various cell-based assays can be used, as well as a variety of readout methods (such as Fcγ receptor (FcγR)-mediated lysis, fluorescence or luminescence) to study different combinations of effector cells and target cells. In order to optimize the clinical safety and efficacy of FcγR-mediated effector functions, several modification strategies can be adopted. Such strategies will be understood to involve techniques such as introducing point mutations, altering glycosylation patterns, combining different Fc subclasses (cross-isotypes), and truncating the Fc portion of mAbs. Such techniques may allow for the development of additional therapeutic mAbs, which will be understood to be useful in the present invention. In embodiments, FcγR-mediated effector functions will be considered when evaluating the effectiveness of therapeutic monoclonal antibodies based on their effects in an MoA. In embodiments, ADCC, ADCP, or other aspects of an MoA will be considered.

[0095] In embodiments, antibodies are selected based on their neutralizing activity against circulating strains at the time of selection. In embodiments, antibodies are selected based on their neutralizing activity against strains that circulated prior to selection, such as those that actually or likely caused PASC or PASC symptoms in the subject to whom the antibody was administered. In embodiments, antibodies are selected based on both neutralizing activity against circulating strains and against prior strains.

[0096] In embodiments, the antibodies have reduced Fc receptor binding. In embodiments, antibodies are selected based on their Fc receptor binding levels, such as having reduced Fc receptor binding relative to a comparator. In some embodiments, where the antibodies have reduced Fc receptor binding, the antibodies will have a reduced risk of antibody-dependent enhancement of viral infection or enhancement of disease.

[0097] In embodiments, the antibody has reduced complement CIq binding.In embodiments, the antibody is selected based on its complement CIq binding, such as having reduced complement CIq binding relative to a comparator.

[0098] c. Additional active agents

[0099] In some aspects, methods are disclosed using pharmaceutical combinations of two or more agents, and the pharmaceutical combinations further comprise an additional active agent.

[0100] In embodiments, the additional active agent is selected to provide an additional therapeutic effect, such as the effect of an antioxidant, anti-inflammatory, analgesic, anti-neurotropic, anti-nociceptive, anti-migraine, antianxiety, antidepressant, antipsychotic, anti-PTSD, immunostimulant, anticancer, antiemetic, appetite enhancer, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotectant, empathy-inducing agent, tranquilizer, hallucinogen, dissociative, nootropic, euphoric, sedative, or stimulant. In an embodiment, the additional active agent can be any of an amino acid, an antioxidant, an anti-inflammatory, an analgesic, an anti-neurotropic and anti-nociceptive, an anti-migraine, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD, an immunostimulant, an anticancer, an antiemetic, an appetite enhancer, an antiulcer, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotective agent, a monoamine oxidase inhibitor, an empathy-inducing agent, a tranquilizer, a hallucinogen, a dissociative, a nootropic, a euphoric, a sedative, a stimulant, and a vitamin. These active agents can be in ionic, free base, or salt form, including polymorphs, and can be isomers.

[0101] In an embodiment, the additional active agent is any of an uncoating inhibitor, an entry inhibitor, a protease inhibitor, an immunostimulant, a latency reversal agent, a reverse transcriptase, a reverse transcriptase inhibitor, an integration inhibitor, a nucleoside analog, an RNA polymerase inhibitor, a viral uncapping agent, a neuraminidase inhibitor, a fusion inhibitor, an interferon, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor.

[0102] In embodiments, additional active agent is immunostimulant, antiviral agent or antibody. In embodiments, additional active agent is immunostimulant. Not bound by theory, immunostimulant is the medicament that stimulates immune system. When using in disclosed method or combination, immunostimulant can provide treatment or synergistic beneficial effect, thereby increase the therapeutic efficacy of disclosed method or combination. Exemplary immunostimulant includes latency reversal agent, cationic peptide, cationic polypeptide, protamine, protamine, nucleolar protein, spermine, spermidine, cationic polysaccharide, chitosan, TDM, MDP, muramyl dipeptide, pluronic (pluronic), alum solution, aluminum hydroxide and polyphosphazene. In embodiments, additional active agent is antibody, such as monoclonal antibody, polyclonal antibody, broad spectrum and monoclonal antibody, long-acting monoclonal antibody, broad spectrum and polyclonal antibody or long-acting polyclonal antibody.

[0103] In an embodiment, the additional active agent is a COVID-19 vaccine. Exemplary COVID-19 vaccines include (Pfizer-BioNTech), (Moderna), (Bharat Biotech), NVX-CoV2373 (Novavax), and others readily apparent to those skilled in the art.

[0104] In embodiments, the additional active agent is an additional agent with antiviral activity. When used in the disclosed method or combination, the additional agent with antiviral activity can provide treatment or synergistic beneficial effects, thereby increasing the therapeutic efficacy of the disclosed method or combination. Exemplary additional agents with antiviral activity include uncoating inhibitors, entry inhibitors, protease inhibitors, immunostimulants, latency reversal agents, reverse transcriptase, reverse transcriptase inhibitors, integration inhibitors, nucleoside analogs, RNA polymerase inhibitors, agents acting on viral uncapping, neuraminidase inhibitors, fusion inhibitors, interferons, nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors.

[0105] In one embodiment, the additional agent having antiviral activity is a MIR (siR-7-EM / KK-46), baicalin, peginterferon λ, metformin, ursodeoxycholic acid (UCDA), TVGN-489, LAU-7b, sabirutamide, azithromycin, ivermectin, opanib, baricitinib, mycophenolate mofetil, APN01, epigallocatechin gallate (EGCG), diphenhydramine, quercetin, Chinese herbal preparations, nicotine, lactoferrin, nattokinase, or ubiquinone.

[0106] In an embodiment, the Chinese herbal medicine preparation may be any one of Qingfei Paidu Decoction (QFPDT), Lianhua Qingwen (LQ), Qingguan No. 1 (NRICM101), and Jingsi Bencao Yin (JSHD).

[0107] In embodiments, the additional agent with antiviral activity is a viral uncoating inhibitor. In embodiments, the additional agent with antiviral activity is a viral entry inhibitor. In embodiments, the additional agent with antiviral activity is a viral replication inhibitor. In embodiments, the additional agent with antiviral activity is a viral polymerase inhibitor. In embodiments, the additional agent with antiviral activity is a polyclonal antibody. In embodiments, the additional agent with antiviral activity is a broadly neutralizing monoclonal antibody. In embodiments, the additional agent with antiviral activity is a long-acting monoclonal antibody.

[0108] In the embodiment, the additional agent with antiviral activity is an interferon. In the embodiment, the interferon is alpha interferon, beta interferon, gamma interferon or any combination thereof. In the embodiment, the interferon is alpha interferon. In the embodiment, the interferon is beta interferon. In the embodiment, the interferon is gamma interferon. In the embodiment, the interferon is type I interferon, type II interferon, type III interferon or any combination thereof. In the embodiment, the interferon is type I interferon. In the embodiment, the interferon is type II interferon. In the embodiment, the interferon is type III interferon. In the embodiment, the interferon is selected from the group consisting of: interferon alpha-n3, interferon alpha-2b, interferon alfacon-1, pegylated interferon alpha-2a, interferon beta-1a, interferon beta-1b and interferon gamma 1-b.

[0109] In an embodiment, the additional agent having antiviral activity is another compound having such activity known to one skilled in the art, for example as described in Banerjee S et al. Vaccines (Basel). 2023 Feb 1; 11(2):332, the entire disclosure of which is incorporated by reference as if fully set forth herein.

[0110] In embodiments, the additional drug with antiviral activity is any of the antiviral agents described and listed above in the Antiviral Agents section. For example, in embodiments, a drug combination may comprise a first antiviral agent, a second antiviral agent, and an additional active agent selected from the same list (which is a third antiviral agent).

[0111] In embodiments, the additional active agent may be provided as a pharmaceutically acceptable salt.

[0112] In embodiments, the additional active agent acts to increase therapeutic effect, provide an additional therapeutic effect, reduce undesirable effects, increase stability and / or shelf life, enhance bioavailability, induce or provide synergy, or alter pharmacokinetics or pharmacodynamics.

[0113] In an embodiment, an additional active agent provides synergy, or is selected to provide synergy. In an embodiment, "synergy" is understood to include an increase in effectiveness, biological activity, bioaccessibility, bioavailability or therapeutic effect, and the synergy is greater than the added contribution of each component acting alone, and / or greater than the contribution of the individual compounds themselves. It is known to those skilled in the art that there are many methods to determine whether there is synergy for a particular effect, that is, when two or more components are mixed together, whether the effect is greater than the sum of the effects when the individual components are applied alone, thereby producing "1+1>2". Suitable methods include isobologram analysis (or contour method) (Huang, Front Pharmacol., 2019; 10: 1222) and Loewe (Loewe) additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326). Synergy can also be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453) and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). The corresponding graphs associated with the above equations are the concentration-effect curve and the combination index curve, respectively. Each equation can be applied to experimental data to generate a corresponding graph to help evaluate the effect of the drug combination.

[0114] C. Drug Combinations

[0115] In some aspects, pharmaceutical combinations comprising two or more of the disclosed agents are disclosed and can be used in the disclosed methods. In embodiments, a "pharmaceutical combination" refers to a combination of the disclosed agents that can be used in the disclosed methods and comprises two or more of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; iii) a first antibody; iv) a second antibody; and v) an additional active agent.

[0116] a. First Antiviral Agent and First Antibody

[0117] In an embodiment, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) a first antibody.

[0118] In embodiments, the first antiviral agent is a protease inhibitor. In embodiments, the first antiviral agent is an Mpro inhibitor. In embodiments, the first antiviral agent is an RdRp inhibitor. In embodiments, the first antiviral agent is an ACE2 decoy receptor drug. In embodiments, the first antiviral agent is selected from the group consisting of ritonavir, namatevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, semideprevir, and telaprevir.

[0119] In an embodiment, the first antiviral agent is selected from the group consisting of: monolavuvir, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, favipiravir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), sennotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245) and acyclovir.

[0120] In embodiments, the first antiviral agent is ritonavir. In embodiments, the first antiviral agent is nematevir. In embodiments, the first antiviral agent is remdesivir. In embodiments, the first antiviral agent is amprenavir. In embodiments, the first antiviral agent is remdesivir. In embodiments, the first antiviral agent is atazanavir. In embodiments, the first antiviral agent is darunavir. In embodiments, the first antiviral agent is fosamprenavir. In embodiments, the first antiviral agent is indinavir. In embodiments, the first antiviral agent is lopinavir. In embodiments, the first antiviral agent is nelfinavir. In embodiments, the first antiviral agent is saquinavir. In embodiments, the first antiviral agent is tipranavir. In embodiments, the first antiviral agent is asunaprevir. In embodiments, the first antiviral agent is boceprevir. In embodiments, the first antiviral agent is grazoprevir. In embodiments, the first antiviral agent is glecaprevir. In embodiments, the first antiviral agent is paritaprevir. In embodiments, the first antiviral agent is semaprevir. In embodiments, the first antiviral agent is telaprevir. In embodiments, the first antiviral agent is monoprevir. In embodiments, the first antiviral agent is GC376. In embodiments, the first antiviral agent is arbidol (umifenovir). In embodiments, the first antiviral agent is SSAA09E2. In embodiments, the first antiviral agent is ribavirin. In embodiments, the first antiviral agent is favipiravir. In embodiments, the first antiviral agent is oseltamivir. In embodiments, the first antiviral agent is zanamivir. In embodiments, the first antiviral agent is abacavir. In embodiments, the first antiviral agent is stavudine. In embodiments, the first antiviral agent is valganciclovir. In embodiments, the first antiviral agent is ganciclovir. In embodiments, the first antiviral agent is cidofovir. In embodiments, the first antiviral agent is entecavir. In embodiments, the first antiviral agent is lamivudine. In embodiments, the first antiviral agent is maraviroc. In embodiments, the first antiviral agent is azidothymidine. In embodiments, the first antiviral agent is nelfinavir. In embodiments, the first antiviral agent is dolutegravir. In embodiments, the first antiviral agent is olsetamivir. In embodiments, the first antiviral agent is enstevir (Xocova). In embodiments, the first antiviral agent is senotevir. In embodiments, the first antiviral agent is benifosbuvir (AT-527). In embodiments, the first antiviral agent is deuterated remdesivir (VV116). In embodiments, the first antiviral agent is azithromycin. In embodiments, the first antiviral agent is sofosbuvir. In embodiments, the first antiviral agent is obidesivir (GS-5245). In embodiments, the first antiviral agent is acyclovir.

[0121] In an embodiment, the first antiviral agent is not a protease inhibitor. In an embodiment, the first antiviral agent is not an Mpro inhibitor. In an embodiment, the first antiviral agent is not an RdRp inhibitor. In an embodiment, the first antiviral agent is not an ACE2 decoy receptor drug.

[0122] In embodiments, the first antiviral agent is not ritonavir. In embodiments, the first antiviral agent is not nematevir. In embodiments, the first antiviral agent is not remdesivir. In embodiments, the first antiviral agent is not amprenavir. In embodiments, the first antiviral agent is not remdesivir. In embodiments, the first antiviral agent is not atazanavir. In embodiments, the first antiviral agent is not darunavir. In embodiments, the first antiviral agent is not fosamprenavir. In embodiments, the first antiviral agent is not indinavir. In embodiments, the first antiviral agent is not lopinavir. In embodiments, the first antiviral agent is not nelfinavir. In embodiments, the first antiviral agent is not saquinavir. In embodiments, the first antiviral agent is not tipranavir. In embodiments, the first antiviral agent is not asunavir. In embodiments, the first antiviral agent is not boceprevir. In embodiments, the first antiviral agent is not grazoprevir. In embodiments, the first antiviral agent is not glecaprevir. In embodiments, the first antiviral agent is not paritaprevir. In embodiments, the first antiviral agent is not semidaprevir. In embodiments, the first antiviral agent is not telaprevir. In embodiments, the first antiviral agent is not monolavir. In embodiments, the first antiviral agent is not GC376. In embodiments, the first antiviral agent is not arbidol (umifenovir). In embodiments, the first antiviral agent is not SSAA09E2. In embodiments, the first antiviral agent is not ribavirin. In embodiments, the first antiviral agent is not favipiravir. In embodiments, the first antiviral agent is not oseltamivir. In embodiments, the first antiviral agent is not zanamivir. In embodiments, the first antiviral agent is not abacavir. In embodiments, the first antiviral agent is not stavudine. In embodiments, the first antiviral agent is not valganciclovir. In embodiments, the first antiviral agent is not ganciclovir. In embodiments, the first antiviral agent is not cidofovir. In embodiments, the first antiviral agent is not entecavir. In embodiments, the first antiviral agent is not lamivudine. In embodiments, the first antiviral agent is not maraviroc. In embodiments, the first antiviral agent is not azidothymidine. In embodiments, the first antiviral agent is not nelfinavir. In embodiments, the first antiviral agent is not dolutegravir. In embodiments, the first antiviral agent is not olsetamivir. In embodiments, the first antiviral agent is not enstevir (Xocova). In embodiments, the first antiviral agent is not senotevir. In embodiments, the first antiviral agent is not benifosbuvir (AT-527). In embodiments, the first antiviral agent is not deuteramidvir (VV116). In embodiments, the first antiviral agent is not azithromycin. In embodiments, the first antiviral agent is not sofosbuvir. In embodiments, the first antiviral agent is not obidesivir (GS-5245).In embodiments, the first antiviral agent is not acyclovir.

[0123] In embodiments, the first antiviral agent is an antiviral agent from any one of the list of "Additional Agents with Antiviral Activity" in the Additional Active Agents section.

[0124] In embodiments, the first antiviral agent is ritonavir or nematevir. In some embodiments, the first antiviral agent is ritonavir. In other embodiments, the first antiviral agent is nematevir.

[0125] In embodiments, the first antibody (herein referred to as "first Ab"; and "Ab" is generally used as an abbreviation for "antibody" herein) is a monoclonal antibody. In embodiments, the first Ab is a polyclonal antibody. In embodiments, the first Ab is an IgA antibody. In embodiments, the first Ab is an IgD antibody. In embodiments, the first Ab is an IgE antibody. In embodiments, the first Ab is an IgG antibody. In embodiments, the first Ab is an IgM antibody. In embodiments, the first Ab is an anti-BlyS antibody. In some preferred embodiments, the first Ab is an IgG antibody. In embodiments, the first Ab is a broadly neutralizing antibody. In embodiments, the first Ab is a broadly neutralizing monoclonal antibody. In embodiments, the first Ab is a long-acting antibody. In embodiments, the first Ab is a long-acting monoclonal antibody. In embodiments, the first Ab is an anti-spike protein antibody. In embodiments, the first Ab is an IgG1 antibody or an IgG3 antibody. In embodiments, the first Ab is an IgG2 antibody or an IgG4 antibody.

[0126] In embodiments, the first antibody is not an IgA antibody. In embodiments, the first Ab is not an IgD antibody. In embodiments, the first Ab is not an IgE antibody. In embodiments, the first Ab is not an IgG antibody. In embodiments, the first Ab is not an IgM antibody. In embodiments, the first Ab is not an anti-BlyS antibody. In embodiments, the first Ab is not a broadly neutralizing antibody. In embodiments, the first Ab is not a broadly neutralizing monoclonal antibody. In embodiments, the first Ab is not a long-acting antibody. In embodiments, the first Ab is not a long-acting monoclonal antibody. In embodiments, the first Ab is not an anti-spike protein antibody. In embodiments, the first Ab is not an IgG1 antibody or an IgG3 antibody. In embodiments, the first Ab is not an IgG2 antibody or an IgG4 antibody.

[0127] In an embodiment, the first antibody is selected from the group consisting of (equivalent to "any of") tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, Monoclonal antibody, ipilimumab, pertuzumab, resibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dexuzumab, elotuzumab, reslizumab, bezolozumab, obituximab, avelumab, sotovir, bectelovir, casirivirimab, idevumab, entezvir, barenvirumab, ambavirimab, rendavirumab, romisvir, edinviromab, 002-S21F2, and durvalumab.

[0128] In embodiments, the first antibody is AZD3152, renzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonaprivir, velolimab, casirizumab, salilumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, evolocumab, blinatumomab, adotrastuzumab, brentuximab, or Any one of: monoclonal antibody, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, and anti-endothelin receptor B antibody (AER002).

[0129] In embodiments, the first antibody is tesagvir. In embodiments, the first Ab is cegavir. In embodiments, the first Ab is pembrolizumab. In embodiments, the first Ab is nivolumab. In embodiments, the first Ab is bevacizumab. In embodiments, the first Ab is ocrelizumab. In embodiments, the first Ab is rituximab. In embodiments, the first Ab is daratumumab. In embodiments, the first Ab is pertuzumab. In embodiments, the first Ab is trastuzumab. In embodiments, the first Ab is infliximab. In embodiments, the first Ab is tocilizumab. In embodiments, the first Ab is atezolizumab. In embodiments, the first Ab is tositumomab. In embodiments, the first Ab is olaratumumab. In embodiments, the first Ab is rituximab. In embodiments, the first Ab is basiliximab. In embodiments, the first Ab is ibritumomab tiuxetan. In embodiments, the first Ab is cetuximab. In embodiments, the first Ab is natalizumab. In embodiments, the first Ab is panitumumab. In embodiments, the first Ab is ranibizumab. In embodiments, the first Ab is eculizumab. In embodiments, the first Ab is ofatumumab. In embodiments, the first Ab is belimumab. In embodiments, the first Ab is ipilimumab. In embodiments, the first Ab is pertuzumab. In embodiments, the first Ab is resibacumab. In embodiments, the first Ab is atezolizumab. In embodiments, the first Ab is certolizumab. In embodiments, the first Ab is ramucirumab. In embodiments, the first Ab is vedolizumab. In embodiments, the first Ab is alemtuzumab. In embodiments, the first Ab is necituzumab. In embodiments, the first Ab is detuximab. In embodiments, the first Ab is elotuzumab. In embodiments, the first Ab is reslizumab. In embodiments, the first Ab is bezolozumab. In embodiments, the first Ab is obituximab. In embodiments, the first Ab is avelumab. In embodiments, the first Ab is sotoviromab. In embodiments, the first Ab is bectrovizumab. In embodiments, the first Ab is casirivirimab. In embodiments, the first Ab is idevizumab. In embodiments, the first Ab is etesviromab. In embodiments, the first Ab is barniviromab. In embodiments, the first Ab is ambaviromab. In embodiments, the first Ab is redavimab. In embodiments, the first Ab is romisviromab. In embodiments, the first Ab is edinviromab. In embodiments, the first Ab is 002-S21F2. In embodiments, the first Ab is AZD3152. In embodiments, the first Ab is renzlumab. In embodiments, the first Ab is ravlizumab.In embodiments, the first Ab is canakinumab. In embodiments, the first Ab is adalimumab. In embodiments, the first Ab is salilumab. In embodiments, the first Ab is lonaprivir. In embodiments, the first Ab is velolimumab. In embodiments, the first Ab is casiruzumab. In embodiments, the first Ab is salilumab. In embodiments, the first Ab is lelizumab. In embodiments, the first Ab is golimumab. In embodiments, the first Ab is tabarumab. In embodiments, the first Ab is veltuzumab. In embodiments, the first Ab is mepolizumab. In embodiments, the first Ab is secukinumab. In embodiments, the first Ab is evolocumab. In embodiments, the first Ab is blinatumomab. In embodiments, the first Ab is ado-trastuzumab. In embodiments, the first Ab is brentuximab. In embodiments, the first Ab is ipilumumab. In embodiments, the first Ab is denosumab. In embodiments, the first Ab is ustekinumab. In embodiments, the first Ab is catumaxomab. In embodiments, the first Ab is efalizumab. In embodiments, the first Ab is tositumomab-1131. In embodiments, the first Ab is palivizumab. In embodiments, the first Ab is basiliximab. In embodiments, the first Ab is daclizumab. In embodiments, the first Ab is abciximab. In embodiments, the first Ab is muronomab. In embodiments, the first Ab is certolizumab pegol. In embodiments, the first Ab is benralizumab. In embodiments, the first Ab is dupilumab. In embodiments, the first Ab is omalizumab. In embodiments, the first Ab is muromonab-CD3. In embodiments, the first Ab is AER002. In embodiments, the first Ab is durvalumab.

[0130] In embodiments, the first antibody is not tesagvir. In embodiments, the first Ab is not celagavir. In embodiments, the first Ab is not pembrolizumab. In embodiments, the first Ab is not nivolumab. In embodiments, the first Ab is not bevacizumab. In embodiments, the first Ab is not ocrelizumab. In embodiments, the first Ab is not rituximab. In embodiments, the first Ab is not daratumumab. In embodiments, the first Ab is not pertuzumab. In embodiments, the first Ab is not trastuzumab. In embodiments, the first Ab is not infliximab. In embodiments, the first Ab is not tocilizumab. In embodiments, the first Ab is not atezolizumab. In embodiments, the first Ab is not tositumomab. In embodiments, the first Ab is not olaratumumab. In embodiments, the first Ab is not rituximab. In embodiments, the first Ab is not basiliximab. In embodiments, the first Ab is not ibritumomab tiuxetan. In embodiments, the first Ab is not cetuximab. In embodiments, the first Ab is not natalizumab. In embodiments, the first Ab is not panitumumab. In embodiments, the first Ab is not ranibizumab. In embodiments, the first Ab is not eculizumab. In embodiments, the first Ab is not ofatumumab. In embodiments, the first Ab is not belimumab. In embodiments, the first Ab is not ipilimumab. In embodiments, the first Ab is not pertuzumab. In embodiments, the first Ab is not resibacumab. In embodiments, the first Ab is not atezolizumab. In embodiments, the first Ab is not certolizumab. In embodiments, the first Ab is not ramucirumab. In embodiments, the first Ab is not vedolizumab. In embodiments, the first Ab is not alemtuzumab. In embodiments, the first Ab is not necituzumab. In embodiments, the first Ab is not detuximab. In embodiments, the first Ab is not elotuzumab. In embodiments, the first Ab is not reslizumab. In embodiments, the first Ab is not bezolozumab. In embodiments, the first Ab is not obituximab. In embodiments, the first Ab is not avelumab. In embodiments, the first Ab is not sotoviromab. In embodiments, the first Ab is not betroviromab. In embodiments, the first Ab is not casirivirimab. In embodiments, the first Ab is not idevimab. In embodiments, the first Ab is not etesviromab. In embodiments, the first Ab is not barniviromab. In embodiments, the first Ab is not ambaviromab. In embodiments, the first Ab is not redamviromab. In embodiments, the first Ab is not romisviromab. In embodiments, the first Ab is not edinviromab. In embodiments, the first Ab is not 002-S21F2.In embodiments, the first Ab is not AZD3152. In embodiments, the first Ab is not renzlumab. In embodiments, the first Ab is not ravlizumab. In embodiments, the first Ab is not canakinumab. In embodiments, the first Ab is not adalimumab. In embodiments, the first Ab is not salilutumab. In embodiments, the first Ab is not lonaprivir. In embodiments, the first Ab is not velolimumab. In embodiments, the first Ab is not casiruzumab. In embodiments, the first Ab is not salilutumab. In embodiments, the first Ab is not lelizumab. In embodiments, the first Ab is not golimumab. In embodiments, the first Ab is not tabarumab. In embodiments, the first Ab is not veltuzumab. In embodiments, the first Ab is not mepolizumab. In embodiments, the first Ab is not secukinumab. In embodiments, the first Ab is not evolocumab. In embodiments, the first Ab is not blinatumomab. In embodiments, the first Ab is not ado-trastuzumab. In embodiments, the first Ab is not brentuximab. In embodiments, the first Ab is not ipilumumab. In embodiments, the first Ab is not denosumab. In embodiments, the first Ab is not ustekinumab. In embodiments, the first Ab is not catumaxomab. In embodiments, the first Ab is not efalizumab. In embodiments, the first Ab is not tositumomab-1131. In embodiments, the first Ab is not palivizumab. In embodiments, the first Ab is not basiliximab. In embodiments, the first Ab is not daclizumab. In embodiments, the first Ab is not abciximab. In embodiments, the first Ab is not muronomab. In embodiments, the first Ab is not certolizumab pegol. In embodiments, the first Ab is not benralizumab. In embodiments, the first Ab is not dupilumab. In embodiments, the first Ab is not omalizumab. In embodiments, the first Ab is not muromonab-CD3. In embodiments, the first Ab is not AER002. In embodiments, the first Ab is not durvalumab.

[0131] In embodiments, the first antibody is tesagvir or segavir. In some embodiments, the first antibody is tesagvir. In other embodiments, the first antibody is segavir.

[0132] In embodiments, the first antiviral agent and the first antibody together provide a synergistic effect, or are selected to provide a synergistic effect.

[0133] b. First antiviral agent, first antibody, and second antiviral agent

[0134] In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof. In these embodiments, the combination may comprise any of the above combinations further comprising a second antiviral agent.

[0135] In embodiments, the second antiviral agent is a protease inhibitor. In embodiments, the second antiviral agent is an Mpro inhibitor. In embodiments, the second antiviral agent is an RdRp inhibitor. In embodiments, the second antiviral agent is an ACE2 decoy receptor drug.

[0136] In an embodiment, the second antiviral agent is selected from the group consisting of ritonavir, nematevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, semideprevir, telaprevir.

[0137] In an embodiment, the second antiviral agent is selected from the group consisting of: monolavuvir, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, favipiravir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), sennotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), and acyclovir.

[0138] In embodiments, the second antiviral agent is ritonavir. In embodiments, the second antiviral agent is nematevir. In embodiments, the second antiviral agent is remdesivir. In embodiments, the second antiviral agent is amprenavir. In embodiments, the second antiviral agent is atazanavir. In embodiments, the second antiviral agent is darunavir. In embodiments, the second antiviral agent is fosamprenavir. In embodiments, the second antiviral agent is indinavir. In embodiments, the second antiviral agent is lopinavir. In embodiments, the second antiviral agent is nelfinavir. In embodiments, the second antiviral agent is saquinavir. In embodiments, the second antiviral agent is tipranavir. In embodiments, the second antiviral agent is asunaprevir. In embodiments, the second antiviral agent is boceprevir. In embodiments, the second antiviral agent is grazoprevir. In embodiments, the second antiviral agent is glecaprevir. In embodiments, the second antiviral agent is paritaprevir. In embodiments, the second antiviral agent is semideprevir. In embodiments, the second antiviral agent is telaprevir. In embodiments, the second antiviral agent is monoclavir. In embodiments, the second antiviral agent is GC376. In embodiments, the second antiviral agent is arbidol (umifenovir). In embodiments, the second antiviral agent is SSAA09E2. In embodiments, the second antiviral agent is ribavirin. In embodiments, the second antiviral agent is favipiravir. In embodiments, the second antiviral agent is oseltamivir. In embodiments, the second antiviral agent is zanamivir. In embodiments, the second antiviral agent is abacavir. In embodiments, the second antiviral agent is stavudine. In embodiments, the second antiviral agent is valganciclovir. In embodiments, the second antiviral agent is ganciclovir. In embodiments, the second antiviral agent is cidofovir. In embodiments, the second antiviral agent is entecavir. In embodiments, the second antiviral agent is lamivudine. In embodiments, the second antiviral agent is maraviroc. In embodiments, the second antiviral agent is azidothymidine. In embodiments, the second antiviral agent is nelfinavir. In embodiments, the second antiviral agent is dolutegravir. In embodiments, the second antiviral agent is olsetamivir. In embodiments, the second antiviral agent is enstevir (Xocova). In embodiments, the second antiviral agent is senotevir. In embodiments, the second antiviral agent is benifosbuvir (AT-527). In embodiments, the second antiviral agent is deuterated remdesivir (VV116). In embodiments, the second antiviral agent is azithromycin. In embodiments, the second antiviral agent is sofosbuvir. In embodiments, the second antiviral agent is obidesivir (GS-5245). In embodiments, the second antiviral agent is acyclovir.

[0139] In embodiments, the second antiviral agent is not a protease inhibitor. In embodiments, the second antiviral agent is not an Mpro inhibitor. In embodiments, the second antiviral agent is not an RdRp inhibitor. In embodiments, the second antiviral agent is not an ACE2 decoy receptor drug.

[0140] In embodiments, the second antiviral agent is not ritonavir. In embodiments, the second antiviral agent is not nematevir. In embodiments, the second antiviral agent is not remdesivir. In embodiments, the second antiviral agent is not amprenavir. In embodiments, the second antiviral agent is not atazanavir. In embodiments, the second antiviral agent is not darunavir. In embodiments, the second antiviral agent is not fosamprenavir. In embodiments, the second antiviral agent is not indinavir. In embodiments, the second antiviral agent is not lopinavir. In embodiments, the second antiviral agent is not nelfinavir. In embodiments, the second antiviral agent is not saquinavir. In embodiments, the second antiviral agent is not tipranavir. In embodiments, the second antiviral agent is not asunavir. In embodiments, the second antiviral agent is not boceprevir. In embodiments, the second antiviral agent is not grazoprevir. In embodiments, the second antiviral agent is not glecaprevir. In embodiments, the second antiviral agent is not paritaprevir. In embodiments, the second antiviral agent is not semideprevir. In embodiments, the second antiviral agent is not telaprevir. In embodiments, the second antiviral agent is not monoclavir. In embodiments, the second antiviral agent is not GC376. In embodiments, the second antiviral agent is not arbidol (umifenovir). In embodiments, the second antiviral agent is not SSAA09E2. In embodiments, the second antiviral agent is not ribavirin. In embodiments, the second antiviral agent is not favipiravir. In embodiments, the second antiviral agent is not oseltamivir. In embodiments, the second antiviral agent is not zanamivir. In embodiments, the second antiviral agent is not abacavir. In embodiments, the second antiviral agent is not stavudine. In embodiments, the second antiviral agent is not valganciclovir. In embodiments, the second antiviral agent is not ganciclovir. In embodiments, the second antiviral agent is not cidofovir. In embodiments, the second antiviral agent is not entecavir. In embodiments, the second antiviral agent is not lamivudine. In embodiments, the second antiviral agent is not maraviroc. In embodiments, the second antiviral agent is not azidothymidine. In embodiments, the second antiviral agent is not nelfinavir. In embodiments, the second antiviral agent is not dolutegravir. In embodiments, the second antiviral agent is not olsetamivir. In embodiments, the second antiviral agent is not enstevir (Xocova). In embodiments, the second antiviral agent is not senotevir. In embodiments, the second antiviral agent is not benifosbuvir (AT-527). In embodiments, the second antiviral agent is not deuteramidvir (VV116). In embodiments, the second antiviral agent is not azithromycin. In embodiments, the second antiviral agent is not sofosbuvir. In embodiments, the second antiviral agent is not obidesivir (GS-5245). In embodiments, the second antiviral agent is not acyclovir.

[0141] In embodiments, the second antiviral agent is an antiviral agent from any one of the list of "Additional Agents with Antiviral Activity" in the Additional Active Agents section.

[0142] In embodiments, the second antiviral agent is ritonavir or nematevir. In some embodiments, the second antiviral agent is ritonavir. In other embodiments, the second antiviral agent is nematevir.

[0143] In an embodiment, the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; and the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof.

[0144] In embodiments, the first antiviral agent, the first antibody, and the second antiviral agent together provide a synergistic effect, or are selected to provide a synergistic effect.

[0145] c. First antiviral agent, first antibody, second antiviral agent, and second antibody

[0146] In an embodiment, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) a second antibody. In these embodiments, the combination may comprise any of the above combinations, further comprising a second antibody.

[0147] In embodiments, the second antibody (referred to as "second Ab") is a monoclonal antibody. In embodiments, the second Ab is a polyclonal antibody. In embodiments, the second Ab is an IgA antibody. In embodiments, the second Ab is an IgD antibody. In embodiments, the second Ab is an IgE antibody. In embodiments, the second Ab is an IgG antibody. In embodiments, the second Ab is an IgM antibody. In embodiments, the second Ab is an anti-BlyS antibody. In some preferred embodiments, the first antibody is an IgG antibody. In embodiments, the second Ab is a broadly neutralizing antibody. In embodiments, the second Ab is a broadly neutralizing monoclonal antibody. In embodiments, the second Ab is a long-acting antibody. In embodiments, the second Ab is a long-acting monoclonal antibody. In embodiments, the second Ab is an anti-spike protein antibody. In embodiments, the second Ab is an IgG1 antibody or an IgG3 antibody. In embodiments, the second Ab is an IgG2 antibody or an IgG4 antibody.

[0148] In embodiments, the second antibody is not an IgA antibody. In embodiments, the second Ab is not an IgD antibody. In embodiments, the second Ab is not an IgE antibody. In embodiments, the second Ab is not an IgG antibody. In embodiments, the second Ab is not an IgM antibody. In embodiments, the second Ab is not an anti-BlyS antibody. In embodiments, the second Ab is not a broadly neutralizing antibody. In embodiments, the second Ab is not a broadly neutralizing monoclonal antibody. In embodiments, the second Ab is not a long-acting antibody. In embodiments, the second Ab is not a long-acting monoclonal antibody. In embodiments, the second Ab is not an anti-spike protein antibody. In embodiments, the second Ab is not an IgG1 antibody or an IgG3 antibody. In embodiments, the second Ab is not an IgG2 antibody or an IgG4 antibody.

[0149] In embodiments, the second antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab , pertuzumab, rexibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dexuzumab, elotuzumab, reslizumab, bezolozumab, obituximab, avelumab, sotovir, bectelovir, casirivirimab, idevumab, entezvir, barenvirumab, ambavirimab, rendavirumab, romisvir, edinviromab, 002-S21F2, and durvalumab.

[0150] In embodiments, the second antibody is selected from the group consisting of AZD3152, renzlumab, ravlizumab, canakinumab, adalimumab, salilumab, lonaprivir, velolimab, casirizumab, salilumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, evolocumab, blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronumab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, and AER002.

[0151] In embodiments, the second antibody is tesagvir. In embodiments, the second Ab is celagavir. In embodiments, the second Ab is pembrolizumab. In embodiments, the second Ab is nivolumab. In embodiments, the second Ab is bevacizumab. In embodiments, the second Ab is ocrelizumab. In embodiments, the second Ab is rituximab. In embodiments, the second Ab is daratumumab. In embodiments, the second Ab is pertuzumab. In embodiments, the second Ab is trastuzumab. In embodiments, the second Ab is infliximab. In embodiments, the second Ab is tocilizumab. In embodiments, the second Ab is atezolizumab. In embodiments, the second Ab is tositumomab. In embodiments, the second Ab is olaratumumab. In embodiments, the second Ab is rituximab. In embodiments, the second Ab is basiliximab. In embodiments, the second Ab is ibritumomab tiuxetan. In embodiments, the second Ab is cetuximab. In embodiments, the second Ab is natalizumab. In embodiments, the second Ab is panitumumab. In embodiments, the second Ab is ranibizumab. In embodiments, the second Ab is eculizumab. In embodiments, the second Ab is ofatumumab. In embodiments, the second Ab is belimumab. In embodiments, the second Ab is ipilimumab. In embodiments, the second Ab is pertuzumab. In embodiments, the second Ab is resibacumab. In embodiments, the second Ab is atezolizumab. In embodiments, the second Ab is certolizumab. In embodiments, the second Ab is ramucirumab. In embodiments, the second Ab is vedolizumab. In embodiments, the second Ab is alemtuzumab. In embodiments, the second Ab is necituzumab. In embodiments, the second Ab is detuximab. In embodiments, the second Ab is elotuzumab. In embodiments, the second Ab is reslizumab. In embodiments, the second Ab is bezolozumab. In embodiments, the second Ab is obituximab. In embodiments, the second Ab is avelumab. In embodiments, the second Ab is sotoviromab. In embodiments, the second Ab is beteloviromab. In embodiments, the second Ab is casirizumab. In embodiments, the second Ab is idevizumab. In embodiments, the second Ab is etezviromab. In embodiments, the second Ab is barniviromab. In embodiments, the second Ab is ambaviromab. In embodiments, the second Ab is redanviromab. In embodiments, the second Ab is romisviromab. In embodiments, the second Ab is edinviromab. In embodiments, the second Ab is 002-S21F2. In embodiments, the second Ab is AZD3152. In embodiments, the second Ab is lenzlumab. In embodiments, the second Ab is ravlizumab. In embodiments, the second Ab is canakinumab.In embodiments, the second Ab is adalimumab. In embodiments, the second Ab is salipolumab. In embodiments, the second Ab is lonaprivir. In embodiments, the second Ab is velolimumab. In embodiments, the second Ab is casiruzumab. In embodiments, the second Ab is salipolumab. In embodiments, the second Ab is lelizumab. In embodiments, the second Ab is golimumab. In embodiments, the second Ab is tabarumab. In embodiments, the second Ab is veltuzumab. In embodiments, the second Ab is mepolizumab. In embodiments, the second Ab is secukinumab. In embodiments, the second Ab is evolocumab. In embodiments, the second Ab is blinatumomab. In embodiments, the second Ab is ado-trastuzumab. In embodiments, the second Ab is brentuximab. In embodiments, the second Ab is ipilumumab. In embodiments, the second Ab is denosumab. In embodiments, the second Ab is ustekinumab. In embodiments, the second Ab is catumaxomab. In embodiments, the second Ab is efalizumab. In embodiments, the second Ab is tositumomab-1131. In embodiments, the second Ab is palivizumab. In embodiments, the second Ab is basiliximab. In embodiments, the second Ab is daclizumab. In embodiments, the second Ab is abciximab. In embodiments, the second Ab is muronomab. In embodiments, the second Ab is certolizumab pegol. In embodiments, the second Ab is benralizumab. In embodiments, the second Ab is dupilumab. In embodiments, the second Ab is omalizumab. In embodiments, the second Ab is muromonab-CD3. In embodiments, the second Ab is AER002. In embodiments, the second Ab is durvalumab.

[0152] In embodiments, the second antibody is not tesagvir. In embodiments, the second Ab is not celagavir. In embodiments, the second Ab is not pembrolizumab. In embodiments, the second Ab is not nivolumab. In embodiments, the second Ab is not bevacizumab. In embodiments, the second Ab is not ocrelizumab. In embodiments, the second Ab is not rituximab. In embodiments, the second Ab is not daratumumab. In embodiments, the second Ab is not pertuzumab. In embodiments, the second Ab is not trastuzumab. In embodiments, the second Ab is not infliximab. In embodiments, the second Ab is not tocilizumab. In embodiments, the second Ab is not atezolizumab. In embodiments, the second Ab is not tositumomab. In embodiments, the second Ab is not olaratumumab. In embodiments, the second Ab is not rituximab. In embodiments, the second Ab is not basiliximab. In embodiments, the second Ab is not ibritumomab tiuxetan. In embodiments, the second Ab is not cetuximab. In embodiments, the second Ab is not natalizumab. In embodiments, the second Ab is not panitumumab. In embodiments, the second Ab is not ranibizumab. In embodiments, the second Ab is not eculizumab. In embodiments, the second Ab is not ofatumumab. In embodiments, the second Ab is not belimumab. In embodiments, the second Ab is not ipilimumab. In embodiments, the second Ab is not pertuzumab. In embodiments, the second Ab is not resibacumab. In embodiments, the second Ab is not atezolizumab. In embodiments, the second Ab is not certolizumab. In embodiments, the second Ab is not ramucirumab. In embodiments, the second Ab is not vedolizumab. In embodiments, the second Ab is not alemtuzumab. In embodiments, the second Ab is not necituzumab. In embodiments, the second Ab is not detuximab. In embodiments, the second Ab is not elotuzumab. In embodiments, the second Ab is not reslizumab. In embodiments, the second Ab is not bezolozumab. In embodiments, the second Ab is not obituximab. In embodiments, the second Ab is not avelumab. In embodiments, the second Ab is not sotovir. In embodiments, the second Ab is not betrovir. In embodiments, the second Ab is not casirizumab. In embodiments, the second Ab is not idevizumab. In embodiments, the second Ab is not etesvir. In embodiments, the second Ab is not barnivir. In embodiments, the second Ab is not ambavir. In embodiments, the second Ab is not redamvir. In embodiments, the second Ab is not romisvir. In embodiments, the second Ab is not edinvir. In embodiments, the second Ab is not 002-S21F2. In embodiments, the second Ab is not AZD3152.In embodiments, the second Ab is not renzlumab. In embodiments, the second Ab is not ravlizumab. In embodiments, the second Ab is not canakinumab. In embodiments, the second Ab is not adalimumab. In embodiments, the second Ab is not salilutumab. In embodiments, the second Ab is not lonaprivir. In embodiments, the second Ab is not velolimumab. In embodiments, the second Ab is not casiruzumab. In embodiments, the second Ab is not salilutumab. In embodiments, the second Ab is not lelizumab. In embodiments, the second Ab is not golimumab. In embodiments, the second Ab is not tabarumab. In embodiments, the second Ab is not veltuzumab. In embodiments, the second Ab is not mepolizumab. In embodiments, the second Ab is not secukinumab. In embodiments, the second Ab is not evolocumab. In embodiments, the second Ab is not blinatumomab. In embodiments, the second Ab is not ado-trastuzumab. In embodiments, the second Ab is not brentuximab. In embodiments, the second Ab is not ipilumumab. In embodiments, the second Ab is not denosumab. In embodiments, the second Ab is not ustekinumab. In embodiments, the second Ab is not catumaxomab. In embodiments, the second Ab is not efalizumab. In embodiments, the second Ab is not tositumomab-1131. In embodiments, the second Ab is not palivizumab. In embodiments, the second Ab is not basiliximab. In embodiments, the second Ab is not daclizumab. In embodiments, the second Ab is not abciximab. In embodiments, the second Ab is not muronomab. In embodiments, the second Ab is not certolizumab pegol. In embodiments, the second Ab is not benralizumab. In embodiments, the second Ab is not dupilumab. In embodiments, the second Ab is not omalizumab. In embodiments, the second Ab is not muromonab-CD3. In embodiments, the second Ab is not AER002. In embodiments, the second Ab is not durvalumab.

[0153] In embodiments, the second antibody is tesagvir or segavir. In some embodiments, the second antibody is tesagvir. In other embodiments, the second antibody is segavir.

[0154] In the embodiment, the first antibody ("first Ab") and the second antibody ("second Ab") are both monoclonal antibodies. In the embodiment, the first Ab is a monoclonal antibody, and the second Ab is a polyclonal antibody. In other embodiments, the first Ab is a polyclonal antibody, and the second Ab is a monoclonal antibody. In the embodiment, the first Ab and the second Ab are both polyclonal antibodies. In the embodiment, the first Ab and the second Ab are both broad-spectrum neutralizing antibodies. In the embodiment, the first Ab and the second Ab are both broad-spectrum neutralizing monoclonal antibodies. In the embodiment, the first Ab and the second Ab are both broad-spectrum neutralizing polyclonal antibodies. In the embodiment, the first Ab and the second Ab are both long-acting antibodies. In the embodiment, the first Ab and the second Ab are both long-acting monoclonal antibodies. In the embodiment, the first Ab and the second Ab are both long-acting polyclonal antibodies. In the embodiment, the first Ab and the second Ab are both not monoclonal antibodies. In the embodiment, the first Ab and the second Ab are both not polyclonal antibodies. In the embodiment, the first Ab and the second Ab are both not broad-spectrum neutralizing antibodies. In the embodiment, the first Ab and the second Ab are both not broad-spectrum neutralizing monoclonal antibodies. In the embodiment, the first Ab and the second Ab are both not broad-spectrum neutralizing polyclonal antibodies. In an embodiment, both the first Ab and the second Ab are not long-acting antibodies. In an embodiment, both the first Ab and the second Ab are not long-acting monoclonal antibodies. In an embodiment, both the first Ab and the second Ab are not long-acting polyclonal antibodies.

[0155] In an embodiment, the first antibody is tesagvir and the second antibody is segavir. In an embodiment, the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir; and the second antibody is segavir.

[0156] In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are provided as separate pharmaceutical compositions. In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are provided in the same pharmaceutical composition. In some preferred embodiments, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; and the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof; nematevir and ritonavir are provided together in the same antiviral composition. In some such embodiments, the antiviral composition is PAXLOVID TM .

[0157] In embodiments, the first antibody and the second antibody are provided as separate pharmaceutical compositions. In embodiments, the first antibody and the second antibody are provided in the same pharmaceutical composition. In embodiments, wherein the first antibody is tesagvir and the second antibody is segavir, tesagvir and segavir are provided together in the same antibody composition. In some such embodiments, the antibody composition is EVUSHELD TM .

[0158] In some embodiments, the pharmaceutical combination comprises an effective amount of PAXLOVID TM and an effective amount of EVUSHELD TM .

[0159] In embodiments, the first antiviral agent, the first antibody, the second antiviral agent, and the second antibody together provide a synergistic effect, or are selected to provide a synergistic effect.

[0160] In some embodiments, where the drug combination comprises two or more antibodies, the drug combination provides broader neutralizing capacity and reduces the likelihood of antigenic escape of viral variants in future strains, the measurement of which will be understood by those skilled in the art.

[0161] d. Combinations containing additional active agents

[0162] In embodiments, the pharmaceutical combination will comprise an additional active agent.In embodiments, the pharmaceutical combination may comprise any of the above combinations, further comprising an additional active agent.

[0163] In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antibody; and ii) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) an additional active agent. In embodiments, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antibody; and iv) an additional active agent. In an embodiment, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; iv) a second antibody; and v) an additional active agent.

[0164] For example, in an embodiment, the additional active agent is interferon. Exemplary embodiments include interferon as the following additional active agent, and similar embodiments will be readily understood for other additional active agents. In an embodiment, the drug combination includes: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) interferon. In an embodiment, the drug combination includes: i) a first antibody; and ii) interferon. In an embodiment, the drug combination includes: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) interferon. In an embodiment, the drug combination includes: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) interferon. In an embodiment, the drug combination includes: i) a first antibody; ii) a second antibody; and iii) interferon. In an embodiment, the drug combination includes: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) interferon. In an embodiment, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antibody; and iv) an interferon. In an embodiment, the pharmaceutical combination comprises: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; iv) a second antibody; and v) an interferon.

[0165] In embodiments, the additional active agent provides a synergistic effect with any one or more of the first antiviral agent, the first antibody, the second antiviral agent, or the second antibody (when each of them is present), or is selected to provide a synergistic effect. In embodiments, the additional active agent provides a synergistic effect with any one or more of the first antiviral agent, the first antibody, the second antiviral agent, or the second antibody (when each of them is present), or is selected to provide a synergistic effect.

[0166] e. Other Features of Certain Exemplary Embodiments

[0167] In an embodiment, a drug combination may be further described or known by the absence of one or more agents, such as in certain embodiments described above, and in other embodiments below or elsewhere herein. In an embodiment, the drug combination does not comprise redcievir. In an embodiment, the drug combination does not comprise nematevir. In an embodiment, the drug combination does not comprise ritonavir. In an embodiment, the drug combination does not comprise monolavin. In an embodiment, the drug combination does not comprise redcievir, nematevir, ritonavir, or monolavin. In an embodiment, the drug combination does not comprise redcievir, nematevir, or ritonavir. In an embodiment, the drug combination does not comprise redcievir, nematevir, or ritonavir. In an embodiment, the drug combination does not comprise redcievir, nematevir, or ritonavir. In an embodiment, the drug combination does not comprise redcievir, nematevir, or monolavin. In an embodiment, the drug combination does not comprise redcievir, nematevir, or monolavin. In an embodiment, the drug combination does not comprise nematevir, ritonavir, or monolavin. In an embodiment, the drug combination does not comprise redcievir or nematevir. In an embodiment, the drug combination does not comprise redcievir or ritonavir. In embodiments, the drug combination does not include remdesivir or monolavir. In embodiments, the drug combination does not include nematevir or ritonavir. In embodiments, the drug combination does not include nematevir or monolavir. In embodiments, the drug combination does not include ritonavir or remdesivir. In embodiments, the drug combination does not include ritonavir or monolavir.

[0168] D. Pharmaceutical Compositions

[0169] In an embodiment, any one of the first antiviral agent, or a pharmaceutically acceptable salt thereof, the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, the second antibody, or any combination thereof, can be administered to a subject as a pharmaceutical composition or multiple pharmaceutical compositions. In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are contained in the same pharmaceutical composition. In an embodiment, the first antibody and the second antibody are contained in the same pharmaceutical composition.

[0170] For example, in an embodiment, the disclosed method comprises administering to a patient a first pharmaceutical composition comprising a first antiviral agent, or a pharmaceutically acceptable salt thereof, and a second antiviral agent, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a first antibody and, optionally, a second antibody. For another example, the disclosed method comprises administering to a patient a first pharmaceutical composition comprising a first antiviral agent, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a second antiviral agent, or a pharmaceutically acceptable salt thereof; and a third pharmaceutical composition comprising a first antibody and a second antibody.

[0171] Such pharmaceutical compositions can be formulated or formulated into any suitable dosage form, such as aqueous oral dispersions, aqueous oral suspensions, solid dosage forms (including oral solid dosage forms), aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, pulsatile release formulations, multiparticulate formulations, immediate release formulations, controlled release formulations, sustained release formulations, extended release formulations and modified release formulations, as well as mixed immediate and controlled release formulations.

[0172] In an embodiment, the pharmaceutical composition can be incorporated into a variety of preparations (e.g., pharmaceutically acceptable vehicles) for therapeutic administration. For example, in an embodiment, the antiviral agent or monoclonal antibody of the present disclosure can be formulated into a pharmaceutical composition by preparing it together with one or more pharmaceutically acceptable carriers, diluents and / or excipients, and can be formulated into solid, semisolid, liquid or gaseous form preparations, such as tablets, capsules, powders, granules, ointments (e.g., skin creams), solutions, suppositories, injections, inhalants and aerosols. Therefore, the administration of the antiviral agent or monoclonal antibody can be achieved in a variety of ways, for example, oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, intravenous or intramuscular administration.

[0173] For oral preparations, any one of the first antiviral agent, or a pharmaceutically acceptable salt thereof, the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, the second antibody, or any combination thereof, can be used alone or in combination with appropriate additives to prepare tablets, powders, granules or capsules, for example, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate; and, if necessary, with diluents, buffers, wetting agents, preservatives and flavorings.

[0174] For intravenous or intramuscular administration, the first antiviral agent, or a pharmaceutically acceptable salt thereof, the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, any of the second antibody, or any combination thereof, can be formulated into an injectable preparation dissolved, suspended, or emulsified in an aqueous solvent or non-aqueous solvent (such as vegetable oil or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol); and, if necessary, formulated with conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives. In some preferred embodiments, the antibody is formulated for delivery by intramuscular injection. In embodiments, the antibody is administered by intramuscular injection. In embodiments, the antibody is formulated not for delivery by intravenous infusion. In embodiments, the antibody is not administered by intravenous infusion.

[0175] Unit dosage forms for oral administration, such as syrups, elixirs, and suspensions, can be provided, wherein each dosage unit (e.g., teaspoon, tablespoon, tablet, or suppository) contains a predetermined amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof, a second antiviral agent, or a pharmaceutically acceptable salt thereof, a first antibody, a second antibody, or any combination thereof. Similarly, unit dosage forms for injection or intravenous administration can contain a first antiviral agent, or a pharmaceutically acceptable salt thereof, a second antiviral agent, or a pharmaceutically acceptable salt thereof, a first antibody, a second antibody, or any combination thereof, the unit dosage form being a composition in the form of a solution in sterile water, normal saline, or another pharmaceutically acceptable carrier.

[0176] As used herein, the phrase "unit dosage form" refers to a physically discrete unit suitable as a bulk dose for a patient to be treated, each unit containing a predetermined quantity of active agent, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are generally used to facilitate administration and uniformity of dosage. A unit dosage form may contain a single or individual dose or unit, subdose, or an appropriate fraction thereof (e.g., half of a "full" dose) of the administered pharmaceutical composition. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules, and vials, which may contain the composition in a freeze-dried or lyophilized state; for example, a sterile liquid carrier may be added prior to in vivo administration or delivery. Unit dosage forms also include ampoules and vials filled with a liquid composition. Unit dosage forms also include compounds for transdermal administration, such as "patches" that are in contact with the patient's epidermis for prolonged or short periods of time.

[0177] In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, any of the second antibody, or any combination thereof, can be formulated into a pharmaceutically acceptable oral dosage form, including an oral solid dosage form and an oral liquid dosage form. In an embodiment, the composition is formulated into a pharmaceutically acceptable oral solid dosage form, including lozenges, lozenges, tablets, capsules, caplets, powders, pellets, multi-granules, beads, spheres, capsules, pills and / or any combination thereof. Oral solid dosage forms can be formulated as immediate release formulations, controlled release formulations, sustained release formulations, extended release formulations or modified release formulations. In an embodiment, the disclosed antibodies are formulated for oral administration by means of a gastric automatic injector, for example, as known by reference to Abramson A et al. Nat Biotechnol. 2022 Jan; 40(1): 103-109, which is incorporated herein by reference.

[0178] In an embodiment, the solid dosage form can include a pharmaceutically acceptable excipient, such as a filler, a diluent, a lubricant, a surfactant, a glidant, a binding agent, a dispersant, a suspending agent, a disintegrant, a tackifier, a film former, a granulation aid, a flavoring agent, a sweetener, a coating agent, a solubilizing agent, and a combination thereof. In an embodiment, the solid dosage form can include a pharmaceutically acceptable additive, alone or in combination, such as a compatible carrier, a complexing agent, an ion dispersion regulator, a disintegrant, a surfactant, a lubricant, a coloring agent, a wetting agent, a plasticizer, a stabilizer, a wetting agent, a defoamer, and a supplementary active agent, including preservatives, antioxidants, antimicrobials (including biocides and biostats, such as antibacterials, antivirals, and antifungals). Preservatives can be used to inhibit microbial growth or increase the stability of active ingredients, thereby extending the shelf life of the pharmaceutical preparation, and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoate (such as sodium benzoate). Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid (ALA).

[0179] Because a variety of formulations and dosage forms of each disclosed agent are known to the skilled artisan, the skilled artisan will understand how to select such formulations and dosage forms for use in the disclosed pharmaceutical combinations or methods, as well as how to prepare other formulations or dosage forms of the agents, based on the general knowledge in the art and the information in this disclosure.

[0180] In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, or the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, the second antibody, or any combination thereof, is present in an amount such that a single dose (in milligrams per kilogram of body weight of the patient) is, for example, 0.25 mg / kg or less (including doses of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, At least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 3.0 mg / kg, at least 3.1 mg / kg, at least 3.2 mg / kg, at least 3.3 mg / kg, at least 3.4 mg / kg, at least 3.5 mg / kg, at least 3.6 mg / kg, at least 3.7 mg / kg, at least 3.8 mg / kg, at least 3.9 mg / kg, or at least 4.0 mg / kg, or at least 5.0 mg / kg, and amounts within these ranges.

[0181] In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, or the second antiviral agent, or a pharmaceutically acceptable salt thereof, the first antibody, the second antibody, or any combination thereof, can be present in an amount such that a single dose (whether or not the dose is in a unit dosage form) is, for example, 25 mg or less (including doses of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg, at least 100 mg At least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 400 mg or at least 500 mg, and amounts within these ranges.

[0182] In embodiments, wherein the disclosed methods or combinations comprise an additional active compound or a pharmaceutically acceptable salt thereof, the additional active compound, or a pharmaceutically acceptable salt thereof, can be present in an amount such that a single dose (in milligrams per kilogram of body weight of the patient) is, for example, 0.25 mg / kg or less (including doses of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 2.

[00145] In some embodiments, the present invention provides an amount of at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, at least 3.0 mg / kg, at least 3.1 mg / kg, at least 3.2 mg / kg, at least 3.3 mg / kg, at least 3.4 mg / kg, at least 3.5 mg / kg, at least 3.6 mg / kg, at least 3.7 mg / kg, at least 3.8 mg / kg, at least 3.9 mg / kg, at least 4.0 mg / kg, or at least 5.0 mg / kg, and amounts within these ranges.

[0183] In embodiments, wherein the disclosed methods or combinations comprise an additional active compound, or a pharmaceutically acceptable salt thereof, the additional active compound, or a pharmaceutically acceptable salt thereof, can be present in an amount such that a single dose (whether or not such dose is presented in a unit dosage form) is, for example, 25 mg or less (including doses of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg , at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, or at least 350 mg, at least 400 mg or at least 500 mg, and amounts within these ranges.

[0184] Because a variety of dosage forms and dosages of each disclosed agent are known to the skilled artisan, the skilled artisan will understand how to prepare or select other dosage forms or dosages for the disclosed pharmaceutical combinations or methods, as well as how to prepare or select other dosage forms or dosages of the agents based on the knowledge and disclosure in the art.

[0185] For example, in an embodiment in which the first antiviral agent is namatevir, or a pharmaceutically acceptable salt thereof, and in which the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof, the subject's dose may be 300 mg namatevir and 100 mg ritonavir. In an embodiment, one dose may be administered to the subject at the same time each morning, and one dose may be administered at the same time each evening. In an embodiment, one dose comprises two tablets of namatevir and one tablet of ritonavir. In other embodiments, the subject's dose may be 150 mg namatevir and 100 mg ritonavir. In an embodiment, one dose may be administered to the subject at the same time each morning, and one dose may be administered at the same time each evening. In an embodiment, one dose comprises one tablet of namatevir and one tablet of ritonavir. Other such available dosage forms and standard doses will be known to the skilled person, for example, by reference to package inserts, storage, dosage and administration guides or similar informational materials, such as informational materials from manufacturers, and such available dosage forms and standard doses may be used in some embodiments in which other dosage forms or standard doses are not known by reference to the disclosure herein. For another example, in an embodiment where the first antibody is tesagvir and the second antibody is segavir, the subject's dose can be 300 mg segavir and 300 mg tesagvir, administered by intramuscular injection. In other embodiments, the subject's dose can be 150 mg segavir and 150 mg tesagvir, administered by intramuscular injection.

[0186] E. Drug kit

[0187] In some aspects, pharmaceutical kits are disclosed that contain the disclosed pharmaceutical combinations, eg, prepared as one or more pharmaceutical compositions, and the one or more pharmaceutical compositions can be used in the disclosed methods.

[0188] In an embodiment, a pharmaceutical kit comprises one or more antiviral agents or monoclonal antibodies described herein, or a composition comprising one or more antiviral agents or monoclonal antibodies described herein. In an embodiment, the kit comprises an antiviral agent as described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a first antiviral agent as described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a second antiviral agent as described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a first antiviral agent as described herein, or a pharmaceutically acceptable salt thereof, and a second antiviral agent as described herein, or a pharmaceutically acceptable salt thereof. In an embodiment, the kit comprises a monoclonal antibody as described herein. In one embodiment, the kit comprises a first antibody as described herein. In one embodiment, the kit comprises a second antibody as described herein. In one embodiment, the kit comprises both a first antibody as described herein and a second antibody as described herein. In an embodiment, the kit comprises a first antiviral agent as described herein, or a pharmaceutically acceptable salt thereof, and a second antiviral agent as described herein, or a pharmaceutically acceptable salt thereof; and both the first antibody and the second antibody.

[0189] The kit generally includes suitable packaging. The kit may include one or more containers comprising any agent or composition described herein. Each component (if more than one component) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. The kit may include components in unit dosage form, bulk (e.g., multi-dose packaging) or subunit dosage form. For example, a kit may be provided containing sufficient doses of an antiviral agent or monoclonal antibody as disclosed herein and / or other pharmaceutically active compounds to provide effective treatment for an extended period of time (such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months or longer). The kit may also include multiple unit doses of antiviral agents and monoclonal antibodies and instructions for use, and may be packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and dispensing pharmacies).

[0190] The kit may optionally include a set of instructions, which may be printed instructions packaged with the kit, or reference to electronic instructions (such as on a website, or in a mobile phone or smartphone application, e.g., providing a website link, QR code, or application name). The instructions included with the kit typically include information about their components and the administration of the components to a patient. The kit may include, for example, package inserts, storage, dosing, and administration instructions, etc.

[0191] Since pharmaceutical kits of various disclosed agents are known to the skilled artisan, and the pharmaceutical kits can include one, two, or more agents packaged together, the skilled artisan will understand how to prepare other such pharmaceutical kits containing the disclosed drug combinations, and their use in the disclosed methods, based on the general knowledge in the art and the information in this disclosure.

[0192] For example, in an embodiment where the first antibody is tesagvir and the second antibody is cegavir, the first and second antibodies can be co-packaged as a pharmaceutical kit, wherein the kit comprises a carton comprising two vials, one vial for each antibody: one vial contains a tesagvir injection solution and one vial contains a cegavir injection solution, both of which are administered by intramuscular injection, and both have a concentration of 150 mg antibody / 1.5 mL. The subject will receive separate, sequential intramuscular injections of 150 mg tesagvir and 150 mg cegavir, which can be administered at different injection sites. The vials are identified by being white with dark gray caps.

[0193] For example, in an embodiment in which the first antiviral agent is namatevir, or a pharmaceutically acceptable salt thereof, and in which the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof, the first antiviral agent and the second antiviral agent can be formulated into a solid dosage form. In these embodiments, the unit dosage form can include standard dose packaging or reduced dose packaging. In these embodiments, the standard dose packaging comprises three tablets. In these embodiments, the reduced dose packaging comprises two tablets. In these embodiments, the unit dosage form contains the first antiviral agent and the second antiviral agent in the form of a solid dosage form (such as a tablet dosage form). In these embodiments, multiple unit dosage forms can be packaged together. For example, in these embodiments, each drug kit includes five blister cards, and these blister cards have the first antiviral agent and the second antiviral agent for morning and evening doses, respectively.

[0194] F. Treatment Methods

[0195] In some aspects, methods of using the disclosed pharmaceutical compositions and disclosed pharmaceutical kits for treating a subject suffering from PASC or one or more symptoms of PASC are disclosed.

[0196] In an embodiment, the method comprises administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) a first antibody.

[0197] In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof.

[0198] In embodiments, the method comprises administering to the subject effective amounts of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) a second antibody.

[0199] In some preferred embodiments, the method comprises administering to the subject an effective amount of a combination of: nematevir, or a pharmaceutically acceptable salt thereof; ritonavir, or a pharmaceutically acceptable salt thereof; tesagvirumab; and segavirumab.

[0200] In some preferred embodiments, the method comprises administering to the subject an effective amount of PAXLOVID TM and an effective amount of EVUSHELD TM .

[0201] In embodiments, the disclosed methods further comprise administering to the subject an additional active agent, such as an effective amount of an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antibody; and ii) an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) an additional active agent. In embodiments, the methods comprise administering to the subject an effective amount of a combination of: i) a first antibody; ii) a second antibody; and iii) an additional active agent. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) an additional active agent. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antibody; and iv) an additional active agent. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; iv) a second antibody; and v) an additional active agent.

[0202] In embodiments, the additional active agent is interferon. Exemplary embodiments include interferon as the following additional active agent, and similar embodiments will be readily understood as other additional active agents. In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; and ii) interferon. In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antibody; and ii) interferon. In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; and iii) interferon. In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iii) interferon. In embodiments, the method comprises administering to the subject an effective amount of a combination of: i) a first antibody; ii) a second antibody; and iii) interferon. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; and iv) an interferon. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antibody; and iv) an interferon. In embodiments, the method comprises administering to a subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) a first antibody; iii) a second antiviral agent, or a pharmaceutically acceptable salt thereof; iv) a second antibody; and v) an interferon.

[0203] a. Administration

[0204] In an embodiment, wherein the method of treating a subject with PASC comprises administering to the subject an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof; optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; a first antibody; and optionally, a second antibody; and further comprises administering, optionally, an additional active agent; each such antiviral agent, antibody, and additional active agent (if present), or a composition comprising the same, may be administered to the subject separately, sequentially, or simultaneously. As used herein, any antiviral agent, antibody, or additional active agent (if present in combination) may be referred to as a "pharmaceutical agent" for short. When one or more pharmaceutical agents are formulated together, such a formulation may be referred to herein as a "pharmaceutical composition."

[0205] In embodiments, administration "sequentially" refers to administration of one agent or pharmaceutical composition immediately after administration of another agent or pharmaceutical composition (e.g., within about 5 minutes of administration of the first agent or pharmaceutical composition). In embodiments, administration "simultaneously" refers to administration of one agent or pharmaceutical composition substantially simultaneously with another agent or pharmaceutical composition. In embodiments, administration "separately" refers to administration of one agent or pharmaceutical composition and at least one other agent or pharmaceutical composition, with a period of time between the two administrations.

[0206] In embodiments where two or more pharmaceutical agents or compositions are administered separately, such administrations can include a period of about 5 minutes to about 30 minutes, about 10 minutes to about 60 minutes, about 30 minutes to about 180 minutes, about 180 minutes to about 360 minutes, or more than 360 minutes, such as 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 21 days, 30 days, and any such durations therebetween, between each administration.

[0207] In an embodiment, administration can include separate, sequential or simultaneous oral administration, sublingual administration, buccal administration, intravenous injection, intraarterial injection, intraperitoneal injection, intraosseous injection, intramuscular injection, intrathecal injection, intracerebroventricular injection, rectal administration, vaginal administration, ocular administration, nasal administration, skin administration, topical administration, ear administration, transdermal administration or a combination thereof, as will be apparent to the skilled artisan depending on the desired therapeutic effect. In addition, as described above, in an embodiment, the disclosed combination agents and / or pharmaceutical compositions are administered to a patient by more than one administration, wherein the mode of administration for each administration is different.

[0208] In an embodiment, one agent or pharmaceutical composition is administered separately from at least one other agent or pharmaceutical composition. In an embodiment, two or more agents or pharmaceutical compositions are administered sequentially. In an embodiment, two or more agents or pharmaceutical compositions are administered simultaneously.

[0209] In embodiments, where the method of treating a subject having PASC comprises administering to the subject an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof, and an effective amount of a first antibody, the first antiviral agent, or a pharmaceutically acceptable salt thereof, can be administered to the subject prior to treatment with the first antibody, concurrently with treatment with the first antibody, or after treatment with the first antibody.

[0210] In an embodiment, administering an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof, to a subject "before" treatment with the first antibody means administering an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, to the subject prior to treatment with an effective amount of the first antibody. In an embodiment, an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, may be administered to the subject immediately prior to treatment with an effective amount of the first antibody. For example, in an embodiment, an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered to the subject immediately prior to treatment (within about 5 minutes of treatment with an effective amount of the first antibody). In other embodiments, "prior" to treatment refers to separate administrations, wherein the time interval between each administration is greater than about 5 minutes, e.g., from about 5 minutes to about one hour, from about one hour to one day, from about one day to one week, or from about one week to one month.

[0211] In an embodiment, administering an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof, to a subject "concurrently" with the treatment with the first antibody means administering an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, to the subject substantially simultaneously with the treatment with the first antibody.

[0212] In an embodiment, administering an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof, to a subject "after" treatment with a first antibody means administering an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, to a subject after treatment with an effective amount of the first antibody is administered to the subject. In an embodiment, an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, may be administered to a subject immediately after treatment with an effective amount of the first antibody. In an embodiment, an effective amount of the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered to a subject immediately after treatment (within about 5 minutes of treatment with an effective amount of the first antibody). In other embodiments, "after" treatment refers to separate administrations, wherein the time interval between each administration is greater than about 5 minutes, e.g., from about 5 minutes to about one hour, from about one hour to one day, from about one day to one week, or from about one week to one month.

[0213] In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the first antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the first antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the first antibody. In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the first antibody. In other embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the first antibody. In yet other embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the first antibody.

[0214] In embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the first antibody; or the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the first antibody; or the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the first antibody. In embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the first antibody. In other embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the first antibody. In yet other embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the first antibody.

[0215] In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the second antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the second antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the second antibody. In embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the second antibody. In other embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the second antibody. In yet other embodiments, the first antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the second antibody.

[0216] In embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the second antibody; or the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the second antibody; or the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the second antibody. In embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered prior to treatment with the second antibody. In other embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered after treatment with the second antibody. In yet other embodiments, the second antiviral agent, or a pharmaceutically acceptable salt thereof, is administered concurrently with treatment with the second antibody.

[0217] In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered before treatment with the first antibody and / or the second antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered after treatment with the first antibody and / or the second antibody; or the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered concurrently with treatment with the first antibody and / or the second antibody.

[0218] In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered prior to treatment with the first antibody and / or the second antibody. In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered after treatment with the first antibody and / or the second antibody. In an embodiment, the first antiviral agent, or a pharmaceutically acceptable salt thereof, and the second antiviral agent, or a pharmaceutically acceptable salt thereof, are both administered concurrently with treatment with the first antibody and / or the second antibody.

[0219] In embodiments, the disclosed pharmaceutical combinations and compositions can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal. Such compositions can be prepared according to methods known in the pharmaceutical art (see, e.g., Adejare A, ed., Remington. 2020), and will generally be known by reference to the active agents present in the combination or composition and their desired delivery.

[0220] For example, in an embodiment in which the first antiviral agent is namatevir, or a pharmaceutically acceptable salt thereof, and in which the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof, a solid dosage form (such as a tablet) comprising namatevir and a separate solid dosage form (such as a tablet) comprising ritonavir can be orally administered to the subject. In an embodiment, the first antiviral agent and the second antiviral agent are co-formulated into a single dosage form, such as a unit dosage form, such as a fixed dose combination (FDC). In one such exemplary embodiment, namatevir, or a pharmaceutically acceptable salt thereof, and ritonavir, or a pharmaceutically acceptable salt thereof, are co-formulated into a single solid dosage form (such as a tablet) comprising two antiviral agents.

[0221] In one example, in an embodiment where the first antibody is tesagvir and the second antibody is segavir, an injection of tesagvir and an injection of segavir can be administered consecutively in any order by intramuscular injection at two separate injection sites (e.g., into the gluteal or buttocks muscles). In an embodiment, the first and second antibodies are co-formulated into a single dosage form. In one such exemplary embodiment, tesagvir and segavir are co-formulated together into a single injection dosage form, such as a formulation for intramuscular administration comprising both antibodies.

[0222] b. Dosage

[0223] In embodiments, the disclosed pharmaceutical combinations and compositions are administered and dosed according to good medical practice, taking into account the method and schedule of administration, prior and concomitant medications and medical supplements, the individual patient's clinical condition and the severity of the underlying disease, the patient's age, sex, weight, and other such factors relevant to the practitioner and knowledge of the specific compound being used. Therefore, dosage levels may vary from patient to patient, from individual patient to individual patient over time, and from pharmaceutical composition to pharmaceutical formulation, but should be determined by one of ordinary skill.

[0224] The determination of appropriate dosage should not only include the determination of single dosage, but also include dosage number and time schedule, and the determination of the application time or preferred application time in one day.Administration and dosage can be based on the onset, progression, severity, frequency, duration, probability or susceptibility of the symptoms for which treatment is directed, desired clinical endpoint, previous treatment, simultaneous treatment or subsequent treatment, the patient's general health, age, sex and race, bioavailability, potential adverse systemic side effects, regional side effects or local side effects, the presence of other conditions or diseases in the patient's body and other factors understood by those skilled in the art (e.g., medical or family history) and change. Depending on the desired clinical outcome, condition or symptom state, any adverse side effects or concomitant medication for treatment or therapy, dosage, frequency or duration can be increased or decreased. Those skilled in the art will understand that the factors that can affect dosage, frequency and time schedule are to provide an amount sufficient to or effectively provide a therapeutic effect or beneficial effect, and to do so according to the desired therapeutic effect type, and to avoid adverse reactions or to minimize adverse reactions necessary. In an embodiment, the actual dosage administered will be determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual composition administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms, and therefore any dosage range disclosed herein is not intended to limit the scope of the present invention. In some cases, a dosage level below the lower limit of the disclosed range is sufficient, while in other cases, a dosage above a certain range may be used without causing any harmful side effects, for example, provided that such a larger dose can also be divided into several smaller doses for administration together or separately.

[0225] In general, although individual differences are expected, the disclosed methods will be understood to be applicable to any subject and will be understood based on the disclosure and common techniques. When there are differences between individuals, modifications to the disclosed combinations, compositions, and methods will be understood based on the teachings herein and the general knowledge in the art. In some cases, certain individualized or precision medicine approaches can be adopted based on individual characteristics, including changes in drug metabolism (e.g., involving the metabolism of any one or more agents in the combination), genetics, or immune system changes (e.g., differences in immunocompromised subjects).

[0226] In embodiments, genetic variation is a phenotype that can be associated with susceptibility to PASC or symptoms of PASC. In embodiments, genetic variation is a variation associated with lung-related diseases, autoimmune diseases or inflammatory diseases. In embodiments, genetic variation can be attributed to a specific chromosomal locus. In embodiments, the locus is 3p21.31, ABO, PPP1R15A, SLC6A20, DPP9, FOXP4, TYK2, CXCR6, LZTFL1, IFNAR2, OAS1, OAS2, OAS3 or any combination thereof. The term "genetic variation" refers to a change in a gene sequence relative to a reference sequence (e.g., common and / or wild-type sequence) in this article. Genetic variation can be a recombination event or a mutation, such as a substitution / deletion / insertion event, such as a point mutation and a splice site mutation.

[0227] In embodiments, the disclosed methods reduce the severity of PASC or one or more symptoms thereof in a subject. In embodiments, the severity of PASC or its symptoms in a subject is quantified by one or more PASC biomarkers. PASC biomarkers can be detected from a biological sample (e.g., blood (such as plasma or serum) or saliva) of a subject. In embodiments, PASC biomarkers are assessed by measuring serum concentrations. In embodiments, the biomarker signature expressed by a subject with PASC is different from that of a healthy individual, an individual recovered from PASC, and / or an individual with acute COVID-19 infection. In embodiments, the level of PASC biomarkers in a subject with PASC is higher than that of a healthy individual, an individual recovered from PASC, and / or an individual with acute COVID-19 infection. In embodiments, the level of PASC biomarkers in a subject with PASC is lower than that of a healthy individual, an individual recovered from PASC, and / or an individual with acute COVID-19 infection.

[0228] In embodiments, the disclosed methods reduce the concentration of a PASC biomarker by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In embodiments, the disclosed methods increase the concentration of a PASC biomarker by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In an embodiment, the disclosed methods cause the change in the concentration of a PASC biomarker to be closer to a baseline level. "Baseline level" refers to the level of a biomarker observed in a healthy population that has not undergone PASC. Baseline levels vary between biomarkers and are known to those skilled in the art or can be measured by standard techniques (Lai YJ et al. Front Med (Lausanne). 2023; 10: 1085988; Yong SJ et al. Rev Med Virol. 2023; 33(2): e2424).

[0229] In embodiments, the PASC biomarker is an acute phase protein. Without being bound by theory, acute phase proteins are a class of proteins whose plasma concentrations change in response to inflammation or tissue damage. In embodiments, the acute phase protein PASC biomarker is albumin, complement 5b-9 (C5b-9), C-reactive protein (CRP), ferritin, or fibrinogen.

[0230] In embodiments, PASC biomarkers are biochemical markers. In embodiments, biochemical markers are ratios between two molecules. In embodiments, biochemical PASC biomarkers are 1-methylnicotinamide, 2-phenylphenol, 3,5-dihydroxybenzoic acid, ADA (adenosine deaminase), alanine aminotransferase (ALT), aspartate aminotransferase (AST), β-glucan, CPA3, glutamine / glutamate ratio, indole-3-lactic acid, L-cysteine, lactate dehydrogenase (LDH), L-glutamine, L-methionine, ornithine, pipecolic acid, quinolinic acid, quinolinic acid / tryptophan, sarcosine, S-sulfocysteine, sulfotransferase 1A1 (ST1A1), taurine, tryptase, urokinase-type plasminogen activator (uPA).

[0231] In one embodiment, the PASC biomarker is a cytokine. Cytokines are small signaling proteins that coordinate the interactions of different cell types involved in the amplification and regulation of inflammatory responses. In one embodiment, the cytokine is a chemokine. Chemokines are a class of cytokines that induce other cell types to migrate, such as toward sites of tissue damage. In embodiments, the cytokine PASC biomarker is CCL2, CCL3, CCL4, CCL5, CCL7, CCL19, CCL20, CCL23, CXCL1, CXCL9, CXCL10, CXCL11, Flt3L, G-CSF, GM-CSF, IFN-α, IFN-β, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10, IL-10Rβ, IL-12β, IL-13, IL-17, IL-18, IL-33, IP-10, M-CSF, SCF, TGF-α, TGF-β, TNF-α, TNF-β.

[0232] In embodiments, PASC biomarkers are neurological biomarkers. Without being bound by theory, neurological biomarkers are proteins that provide information about nervous system function or condition. In embodiments, neurological PASC biomarkers are granulocyte colony stimulating factor (GDNF), glial cell-derived neurotrophic factor (GFAP), nerve growth factor beta (NGF-β), neurofilament light chain (NFL), neurotrophin 3 (NT-3), plasma neurofilament light chain / plasma glial fibrillary acidic protein (pGFAP / pNFL).

[0233] In an embodiment, the PASC biomarker is a cardiovascular biomarker. Without being bound by theory, cardiovascular biomarkers are proteins that provide information about the function or status of the cardiovascular system. In an embodiment, the cardiovascular protein PASC biomarker is angiopoietin 2 (Ang-2), type I collagen alpha 2 (Col1A2), type III collagen alpha 1 (Col3A1), D-dimer, erythrocyte sedimentation rate (ESR), endothelin 1 (ET-1), antihemophilic factor (factor VIII), hemoglobin, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 9 (MMP-9), myeloperoxidase (MPO), nitric oxide (NO), platelet-derived growth factor BB (PDGF-BB), soluble intercellular adhesion molecule 1 (sICAM-1), soluble thrombomodulin (sTM), soluble vascular endothelial growth factor receptor (sVEGFR), soluble vascular cell adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF), von Willebrand factor antigen (VWF:Ag), von Willebrand factor propeptide (VWF:pp).

[0234] In embodiments, a PASC biomarker is any protein whose concentration increases or decreases relative to baseline in a sample collected from a subject. In an embodiment, the protein PASC biomarker is anti-severe acute respiratory syndrome coronavirus 2 antibody (Ab), artemin (ARTN), alpha smooth muscle actin (α-SMA), AXIN1, caspase-8 (CASP-8), cystatin D (CST-5), cystatin C, high-sensitivity troponin T (Hs TnT), insulin-like growth factor binding protein 4 (IGFBP-4), lipopolysaccharide binding protein (LBP), miRNA21, myeloid-associated protein 8 / 14 (MRP8 / 14), neutrophil gelatinase-associated lipocalin (NGAL), N-terminal pro-B-type natriuretic peptide / N-terminal B-type natriuretic peptide (NT-proBNP / NT-BNP), osteoprotegerin (OPG), oncostatin M (OSM), sirtuin 2 (SIRT2), STAM binding protein (STAMBP), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and disintegrin.

[0235] In embodiments, the PASC biomarker is albumin. In embodiments, the PASC biomarker is CRP. In embodiments, the PASC biomarker is ferritin. In embodiments, the PASC biomarker is granulocyte colony stimulating factor (G-CSF). In embodiments, the PASC biomarker is interferon alpha (IFN-α). In embodiments, the PASC biomarker is interleukin-1 beta (IL-1 beta). In embodiments, the PASC biomarker is interleukin-6 (IL-6). In embodiments, the PASC biomarker is interleukin-13 (IL-13). In embodiments, the PASC biomarker is interleukin-17 (IL-17). In embodiments, the PASC biomarker is tumor necrosis factor alpha (TNF-α). In embodiments, the PASC biomarker is D-dimer. In embodiments, the PASC biomarker is erythrocyte sedimentation rate (ESR). In embodiments, the PASC biomarker is hemoglobin.

[0236] c. Treatment of PASC symptoms

[0237] In some aspects, methods of treating a subject suffering from post-acute sequelae of COVID-19 (PASC) or one or more symptoms thereof ("symptoms of PASC" or "PASC-associated symptoms") are disclosed. As used herein, the term "treating" can refer to reducing or alleviating one or more symptoms of PASC in a subject. Reducing also includes "eliminating" a symptom when "reducing" a symptom includes reducing it by an amount up to and including 100%.

[0238] In embodiments, the disclosed methods or combinations reduce or alleviate symptoms of PASC by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. One skilled in the art will recognize appropriate symptoms associated with symptoms of PASC and corresponding clinically measurable indicators. Reduction or alleviation of symptoms includes reducing the incidence or severity of specific symptoms. PASC symptoms typically include neurological symptoms, cardiac symptoms, and / or pulmonary symptoms (Lai YJ et al. Front Med (Lausanne). 2023; 10: 1085988; Proal AD, Van Elzakker MB. Front Microbiol. 2021; 12: 698169).

[0239] Without being bound by theory, the symptoms of PASC are caused by several biological mechanisms. Without being bound by theory, one potential cause may be the persistence of SARS-CoV-2 virus or viral RNA as a viral reservoir in tissues. Without being bound by theory, the persistence of replicating virus or viral RNA can continue to activate the host immune system, leading to the persistence of certain immune responses (such as inflammation). Without being bound by theory, the immune response to low but sustained immune activation of latent PASC is different from the immune response to acute COVID-19 infection. Without being bound by theory, the difference in immune response leads to differences in pathology, symptoms, and biomarker profiles between the two indications (Proal AD et al. Nat Immunol. 2023; 24(10): 1616-1627). In embodiments, the disclosed methods or combinations support immune responses associated with PASC to treat subjects with PASC or one or more symptoms thereof.

[0240] Neurological symptoms

[0241] In embodiments, the symptoms of PASC are neurological symptoms. In embodiments, the disclosed methods can be used to treat the neurological symptoms of PASC. Neurological symptoms of PASC include sleep disorders, chronic headaches, olfactory disturbances, taste disturbances, brain fog, memory loss, decreased concentration, depression, anxiety, post-traumatic stress disorder (PTSD), dizziness, vertigo, tinnitus, hearing loss, balance disorders, delirium, hallucinations, small fiber neuropathy, postural tremor, chronic pain, neurodegeneration, and myalgia (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83).

[0242] In embodiments, the neurological symptom is a sleep disorder. In embodiments, the neurological symptom is a chronic headache. In embodiments, the neurological symptom is an olfactory disorder. In embodiments, the neurological symptom is a taste disorder. In embodiments, the neurological symptom is brain fog. In embodiments, the neurological symptom is memory loss. In embodiments, the neurological symptom is decreased concentration. In embodiments, the neurological symptom is depression. In embodiments, the neurological symptom is anxiety. In embodiments, the neurological symptom is post-traumatic stress disorder (PTSD). In embodiments, the neurological symptom is dizziness. In embodiments, the neurological symptom is vertigo. In embodiments, the neurological symptom is tinnitus. In embodiments, the neurological symptom is hearing loss. In embodiments, the neurological symptom is a balance disorder. In embodiments, the neurological symptom is delirium. In embodiments, the neurological symptom is hallucinations. In embodiments, the neurological symptom is small fiber neuropathy. In embodiments, the neurological symptom is postural tremor. In embodiments, the neurological symptom is chronic pain. In embodiments, the neurological symptom is neurodegeneration. In embodiments, the neurological symptom is myalgia.

[0243] In the embodiments, treating a neurological symptom restores the level of a biomarker to within about 50%, 40%, 30%, 20%, 10%, 5% or 1% of the baseline level. Neurological biomarkers include, but are not limited to, GDNF, GFAP, NGF-β, NFL, NT-3 and / or pGFAP / pNFL. In the embodiments, treating a neurological symptom increases serum GDNF concentration. In the embodiments, treating a neurological symptom decreases serum GFAP concentration. In the embodiments, treating a neurological symptom increases serum NGF-β concentration. In the embodiments, treating a neurological symptom decreases serum NT-3 concentration. In the embodiments, treating a neurological symptom decreases serum pGFAP / pNFL concentration (Lai YJ et al. Front Med (Lausanne). 2023; 10: 1085988).

[0244] cardiovascular symptoms

[0245] In embodiments, the symptoms of PASC are cardiovascular symptoms. In embodiments, the disclosed methods can be used to treat cardiovascular symptoms of PASC. Cardiovascular symptoms of PASC include nonspecific chest pain, chest tightness, palpitations, tachycardia, conduction disturbances, arrhythmias, orthostatic hypotension, vasovagal syncope, postural orthostatic tachycardia syndrome (POTS), phlebitis, and thrombophlebitis (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83).

[0246] In embodiments, a cardiovascular symptom (herein referred to as "CV symptom") is nonspecific chest pain. In embodiments, a CV symptom is chest tightness. In embodiments, a CV symptom is palpitations. In embodiments, a CV symptom is tachycardia. In embodiments, a CV symptom is a conduction disorder. In embodiments, a CV symptom is an arrhythmia. In embodiments, a CV symptom is orthostatic hypotension. In embodiments, a CV symptom is vasovagal syncope. In embodiments, a CV symptom is postural orthostatic tachycardia syndrome. In embodiments, a CV symptom is phlebitis. In embodiments, a CV symptom is thrombophlebitis.

[0247] In embodiments, treating cardiovascular symptoms restores the level of a biomarker to within about 50%, 40%, 30%, 20%, 10%, 5%, or 1% of baseline levels. Cardiovascular biomarkers include Ang-2, Col1A2, Col3A1, D-dimer, ESR, ET-1, Factor VIII, hemoglobin, MMP-1, MMP-9, MPO, NO, PDGF-BB, sICAM-1, sTM, sVEGFR, sVCAM-1, VEGF, VWF:Ag, and / or VWF:pp. In embodiments, treating cardiovascular (CV) symptoms increases serum Ang-2 concentration. In embodiments, treating CV symptoms decreases serum Col1A2 concentration. In embodiments, treating CV symptoms decreases serum Col3A1 concentration. In embodiments, treating CV symptoms decreases serum D-dimer concentration. In embodiments, treating CV symptoms decreases ESR. In embodiments, treating CV symptoms decreases serum ET-1 concentration. In embodiments, treating CV symptoms reduces serum Factor VIII concentration. In embodiments, treating CV symptoms increases serum hemoglobin concentration. In embodiments, treating CV symptoms increases serum MMP-1 concentration. In embodiments, treating CV symptoms reduces serum MMP-9 concentration. In embodiments, treating CV symptoms reduces serum MPO concentration. In embodiments, treating CV symptoms increases serum NO concentration. In embodiments, treating CV symptoms reduces serum PDGF-BB concentration. In embodiments, treating CV symptoms reduces serum sICAM-1 concentration. In embodiments, treating CV symptoms reduces serum sTM concentration. In embodiments, treating CV symptoms increases serum sVEGFR concentration. In embodiments, treating CV symptoms reduces serum sVCAM-1 concentration. In embodiments, treating CV symptoms reduces serum VEGF concentration. In embodiments, treating CV symptoms reduces serum VWF:Ag concentration. In embodiments, treating CV symptoms reduces serum VWF:pp concentration (Lai YJ et al. Front Med (Lausanne). 2023;10:1085988).

[0248] Pulmonary symptoms

[0249] In embodiments, the symptoms of PASC are pulmonary symptoms. In embodiments, the disclosed methods can be used to treat the pulmonary symptoms of PASC. Pulmonary symptoms of PASC include dyspnea, persistent cough, wheezing, worsening asthma, decreased lung diffusion capacity, persistent abnormal imaging findings, pleurisy, cough, sleep apnea, and sore throat (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83; Wang L et al. J Biomed Inform. 2022; 125:103951).

[0250] In embodiments, the pulmonary symptom is dyspnea. In embodiments, the pulmonary symptom is cough, including in some such embodiments, persistent cough. In embodiments, the pulmonary symptom is wheezing. In embodiments, the pulmonary symptom is worsening asthma. In embodiments, the pulmonary symptom is decreased lung diffusion capacity. In embodiments, the pulmonary symptom is persistent abnormal imaging findings. In embodiments, the pulmonary symptom is pleurisy. In embodiments, the pulmonary symptom is sleep apnea. In embodiments, the pulmonary symptom is sore throat.

[0251] Musculoskeletal symptoms

[0252] In embodiments, the symptoms of PASC are musculoskeletal symptoms. In embodiments, the disclosed methods can be used to treat the musculoskeletal symptoms of PASC. Musculoskeletal symptoms of PASC include arthritis, back pain, gait abnormalities, and joint pain (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83; Wang L et al. J Biomed Inform. 2022; 125:103951).

[0253] In embodiments, the musculoskeletal symptom is arthritis. In embodiments, the musculoskeletal symptom is back pain. In embodiments, the musculoskeletal symptom is gait abnormality. In embodiments, the musculoskeletal symptom is joint pain.

[0254] Endocrine symptoms

[0255] In embodiments, the symptoms of PASC are endocrine symptoms. In embodiments, the disclosed methods can be used to treat endocrine symptoms of PASC. Endocrine symptoms of PASC include impaired glucose metabolism, subacute thyrotoxicosis, Hashimoto's disease, Graves' disease, and dyslipidemia (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83).

[0256] In embodiments, the endocrine symptom is impaired glucose metabolism. In embodiments, the endocrine symptom is subacute thyrotoxicosis. In embodiments, the endocrine symptom is Hashimoto's disease. In embodiments, the endocrine symptom is Graves' disease. In embodiments, the endocrine symptom is dyslipidemia.

[0257] Skin symptoms

[0258] In embodiments, the symptoms of PASC are skin symptoms. In embodiments, the disclosed methods can be used to treat the skin symptoms of PASC. Skin symptoms of PAC include rash, urticaria, skin lesions, telogen effluvium, nail changes, erythema, and scalp pain (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83; Wang L et al. J Biomed Inform. 2022; 125:103951).

[0259] In embodiments, the skin symptom is a rash. In embodiments, the skin symptom is hives. In embodiments, the skin symptom is a skin lesion. In embodiments, the skin symptom is telogen effluvium. In embodiments, the skin symptom is nail changes. In embodiments, the skin symptom is erythema. In embodiments, the skin symptom is scalp pain.

[0260] Kidney symptoms

[0261] In embodiments, the symptoms of PASC are renal symptoms. In embodiments, the disclosed methods can be used to treat renal symptoms of PASC. Renal symptoms of PASC include decreased glomerular filtration rate, urinary incontinence, and microscopic hematuria (Takao M, Ohira M. Psychiatry Clin Neurosci. 2023; 77(2):72-83; Wang L et al. J Biomed Inform. 2022; 125:103951).

[0262] In embodiments, the renal symptom is decreased glomerular filtration rate (GFR). In embodiments, the renal symptom is urinary incontinence. In embodiments, the renal symptom is decreased microscopic hematuria.

[0263] Other symptoms

[0264] In embodiments, symptoms of PASC include fever, chills, muscle aches, body aches, chest pain, stomach pain, nausea, vomiting, diarrhea. In embodiments, symptoms of PASC are gastroesophageal reflux, stress, swelling, bleeding, weight loss, weight gain, abdominal pain, constipation, pain in the extremities, paresthesia, peripheral edema, pruritus, lymphadenopathy, and edema (Wang L et al. J Biomed Inform. 2022; 125: 103951).

[0265] In embodiments, symptoms of PASC include fatigue, muscle aches, body aches, headaches, loss of taste, loss of smell, sore throat, nasal congestion, runny nose, nausea, vomiting, diarrhea, difficulty thinking or concentrating (i.e., brain fog), sleep problems (e.g., insomnia), dizziness, neuropathic pain, nerve sensitivity, altered taste, altered smell, depression, anxiety, palpitations, joint pain, chest pain, and stomach pain. PASC or "long COVID" symptoms typically include fatigue, headaches, sleep problems (e.g., insomnia), dizziness, difficulty thinking or concentrating (i.e., brain fog), altered or lost sense of smell or taste, depression, and anxiety.

[0266] In embodiments, the disclosed methods or combinations reduce the incidence or severity of fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, body aches, headache, loss of taste, loss of smell, sore throat, nasal congestion, runny nose, nausea, vomiting, diarrhea, difficulty thinking or concentrating (i.e., brain fog), sleep problems (e.g., insomnia), dizziness, neuropathic pain, nerve sensitivity, change in taste, change in smell, depression, anxiety, palpitations, joint pain, chest pain, or stomach pain associated with COVID-19 post-acute sequelae (PASC) by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, body aches, headache, loss of taste, loss of smell, sore throat, nasal congestion, runny nose, nausea, vomiting, diarrhea, difficulty thinking or concentrating (i.e., brain fog), sleep problems (e.g., insomnia), dizziness, neuropathic pain, nerve sensitivity, altered taste, altered smell, depression, anxiety, heart palpitations, joint pain, chest pain, or stomach pain.

[0267] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated fatigue, headache, sleep problems (e.g., insomnia), dizziness, difficulty thinking or concentrating (i.e., brain fog), altered sense of smell, altered sense of taste, loss of smell, loss of taste, depression, or anxiety by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated fatigue, headache, sleep problems (e.g., insomnia), dizziness, difficulty thinking or concentrating (i.e., brain fog), altered sense of smell or loss, altered sense of taste or loss, depression, or anxiety.

[0268] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC (such as, any symptom or "sequelae" of PASC herein) by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, up to and including 100%. In embodiments, the disclosed methods or combinations eliminate the symptoms of PASC.

[0269] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related fatigue by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related fatigue.

[0270] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related headaches by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related headaches.

[0271] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related sleep problems by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related sleep problems.

[0272] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated dizziness by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated dizziness.

[0273] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated changes or loss of smell by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated changes or loss of smell.

[0274] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated taste changes or loss by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated taste changes or loss.

[0275] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related depression by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related depression.

[0276] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related anxiety by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related anxiety.

[0277] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-related difficulty thinking or concentration (i.e., brain fog) by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-related difficulty thinking or concentration (i.e., brain fog).

[0278] In embodiments, the symptoms of PASC are symptoms related to functional status or quality of life, respiratory diseases, neurological diseases, psychiatric diseases, symptoms affecting motor ability, or symptoms affecting balance and risk of falls. In embodiments, the disclosed methods or combinations reduce the incidence or severity of symptoms related to PASC related to functional status or quality of life, respiratory diseases, neurological diseases, psychiatric diseases, or symptoms affecting balance and risk of falls by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate symptoms of PASC related to functional status or quality of life, respiratory diseases, neurological diseases, psychiatric diseases, or symptoms affecting balance and risk of falls.

[0279] In embodiments, the disclosed methods or combinations reduce the incidence or severity of symptoms of PASC associated with functional status or quality of life by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate symptoms of PASC associated with functional status or quality of life.

[0280] In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated respiratory disease by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated respiratory disease.

[0281] In embodiments, the disclosed methods or combinations reduce the incidence or severity of a PASC-associated neurological disease by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate a PASC-associated neurological disease.

[0282] In embodiments, the disclosed methods or combinations reduce the incidence or severity of a PASC-associated psychiatric disorder by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate a PASC-associated psychiatric disorder.

[0283] In embodiments, the disclosed methods or combinations reduce the incidence or severity of symptoms of PASC that affect motor performance by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate symptoms of PASC that affect motor performance.

[0284] In embodiments, the disclosed methods or combinations reduce the incidence or severity of symptoms of PASC that affect balance and fall risk by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate symptoms of PASC that affect balance and fall risk.

[0285] PASC is associated with a variety of cytopathic effects, such as mitochondrial damage or dysfunction, oxidative stress, immune dysregulation, tissue damage, and cell death (Gonzalez-Garcia et al., Int. J. Mol. Sci. 2023, 24(9), 8290). In embodiments, the disclosed methods or combinations reduce the incidence or severity of PASC-associated cytopathic effects by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In embodiments, the disclosed methods or combinations eliminate PASC-associated cytopathic effects.

[0286] In embodiments where the disclosed methods or combinations are used to treat PASC or symptoms of PASC, the disclosed methods or combinations will treat one or more "sequelae" such as defined above.

[0287] In embodiments where the disclosed methods or combinations are used to treat PASC or a symptom of PASC, the disclosed methods or combinations can achieve one or more of the following: a) reducing or preventing myalgia; b) reducing or preventing fibromyalgia; c) reducing or preventing idiopathic pulmonary fibrosis; d) reducing or preventing fatigue; e) reducing or preventing muscle fatigue; f) reducing or preventing muscle dysfunction; g) reducing or preventing mitochondrial dysfunction; h) reducing or preventing dyspnea after exertion; i) improving exercise tolerance or the ability to perform activities of daily living; j) reducing or preventing postural orthostatic tachycardia syndrome; or k) reducing or preventing tachycardia; l) improving mitochondrial function; m) improving mitochondrial capacity or energetics (e.g., improvement in oxidative ATP synthesis after exercise or exertion); n) reducing oxidative stress and / or reducing reactive oxygen species (ROS); o) improving mood disorders and / or depression; p) improving cognitive function; q) increasing vascular perfusion to skeletal muscle or other organs; r) improving endothelial function; s) reducing or preventing diabetes (e.g., new-onset diabetes); or t) improving inflammation.

[0288] In embodiments, the disclosed methods and combinations are used to treat PASC or at least one symptom of PASC, while in other embodiments, the disclosed methods and combinations are used to treat conditions, diseases, syndromes, symptoms, or defects that a patient exhibits after SARS-CoV-2 infection, after the standard incubation period, transmission period, or symptomatic period of COVID infection, and these conditions, diseases, syndromes, symptoms, or defects may be grouped using different conceptual categories and / or terms, some of which may be distinguished from PASC or symptoms of PASC, or understood by a skilled artisan to be different from PASC or symptoms of PASC. For example, in embodiments, the disclosed methods and combinations are used to treat post-COVID-19 conditions (PCC). In embodiments, the disclosed methods and combinations are used to treat long-term COVID. In embodiments, the disclosed methods and combinations are used to treat extended COVID. In embodiments, the disclosed methods and combinations are used to treat chronic COVID. In embodiments, the disclosed methods and combinations are used to treat recurrent COVID. In embodiments, the disclosed methods and combinations are used to treat persistent COVID. In embodiments, the disclosed methods and combinations are used to treat post-COVID-19 syndrome. In yet other embodiments, the disclosed methods and combinations are used to treat PASC or at least one symptom of PASC, but are not used to treat one or more of such other conditions, diseases, syndromes, symptoms, or defects described above. For example, in embodiments, the disclosed methods and combinations are not used to treat post-COVID-19 condition (PCC). In embodiments, the disclosed methods and combinations are not used to treat long-term COVID. In embodiments, the disclosed methods and combinations are not used to treat extended-phase COVID. In embodiments, the disclosed methods and combinations are not used to treat chronic COVID. In embodiments, the disclosed methods and combinations are not used to treat recurrent COVID. In embodiments, the disclosed methods and combinations are not used to treat protracted COVID. In embodiments, the disclosed methods and combinations are not used to treat post-COVID-19 syndrome.

[0289] Those skilled in the art will know the appropriate symptoms and corresponding clinically measurable indicators for diagnosing and / or evaluating symptoms of PASC. As used herein, "assessment" refers to a means or method used by a patient to qualitatively or quantitatively measure, estimate, or evaluate a patient's condition, symptom, or characteristic, performed by a therapist or other clinician (e.g., an interview), performed by the patient themselves (e.g., a self-report questionnaire), performed by a third party or computer (including a medical device (e.g., a medical device defined by the FDA or other regulatory agencies) or other device (e.g., a medical sensor or biosensor, watch, or fitness tracker), and scored by a human decision maker or artificial intelligence, machine learning, or computer algorithm. Assessments can include self-report indicators, patient-stated surveys, questionnaires, interviews, and the like.

[0290] Tables 1 and 2 below show exemplary assessment tools for evaluating PASC symptoms. These and other indicators can also be found in the Centers for Disease Control and Prevention's Health Indicator Toolbox (see, for example, Post-COVID Conditions: Information for Healthcare Providers, URL: https: / / www.cdc.gov / coronavirus / 2019-ncov / hcp / clinical-care / post-covid-conditions.html, updated on September 22, 2022, last accessed on the date of this patent application), the American Academy of Physical Medicine and Rehabilitation's functional assessment, and other assessment tools for rehabilitation needs (e.g., bowel and bladder function, pain, activities of daily living, cognition, mobility, sleep). The assessment should be adjusted based on the subject's symptoms and presentation.

[0291] Table 1: Exemplary Assessment Tools for Evaluating Subjects with PASC Symptoms

[0292]

[0293] Table 2: Exemplary functional and other testing tools for evaluating subjects with PASC symptoms

[0294]

[0295]

[0296] The assessment may be conducted in a computer-assisted manner, and in addition to the assessments described above, other computer-assisted assessments may be conducted. The term "computer-assisted" in "computer-assisted assessment" is intended to include assessments conducted using electronic tools (such as online tools, smart phones, wireless devices, or health applications) (also referred to as "digital phenotyping" in some such instances). Computer-assisted assessments will include the use of electronic psychiatric recording systems, in which relevant clinical information is recorded by face-to-face interaction between the therapist and the patient during treatment, and will also include the use of computer systems in which the therapist interacts with the patient virtually (synchronously or asynchronously), as well as in which the patient interacts only with the computer ("computer" is broadly defined as any electronic tool suitable for such purposes, including desktop computers, laptop computers, and notebook computers; tablet computers, smart phones and other mobile devices; watches, fitness trackers, and personal electronic devices; etc.). One or more other aspects of psychosocial therapy, behavioral therapy, or medication-assisted therapy may also be conducted in a "computer-assisted" manner, in which one or more steps of such therapy involve the use of a computer to supplement or replace some of the work originally performed by the therapist.

[0297] G. Examples

[0298] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention, which should be understood by reference to the full disclosure and appended claims.

[0299] Example 1: Treatment of Patients with PASC

[0300] PASC is diagnosed in the patient according to diagnostic techniques known to the skilled person, for example, by detecting the SARS-CoV-2 virus (e.g., by real-time reverse transcriptase-polymerase chain reaction (RT-PCR)) after a first positive PCR test or within a period of at least 28 days from the date selected as the date of infection; or PASC is diagnosed based on the patient's medical history (e.g., due to the persistence or appearance after SARS-CoV-2 infection of a condition, disease, syndrome, symptom or defect that is most likely causally related to SARS-CoV-2 infection).

[0301] After PASC is diagnosed, the patient will be treated according to the disclosed methods. Specifically, an effective amount of a first antiviral agent, or a pharmaceutically acceptable salt thereof; optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; a first antibody; and optionally, a second antibody is administered to the patient. Exemplary treatments are as follows:

[0302] Patient 1:Patient 1 was administered a single dose of sotovir (500 mg) as a single intravenous dose. On the same day, Patient 1 was started on a daily dose of 100 mg of remdesivir (administered orally) for a total of five consecutive days. Patient 1 showed improvement in at least one symptom of PASC or at least one biomarker of PASC.

[0303] Patient 2: Patient 2 was administered a single dose of tesagvir and selgavir as a single 300 mg intramuscular dose (150 mg tesagvir and 150 mg selgavir, as a single injection). On the same day, Patient 2 was started on twice-daily doses of nematevir and ritonavir tablets, which were co-packaged as Paxlovid according to the package insert. TM Specifically, Patient 2 was administered a morning dose consisting of one 150 mg tablet of nematevir and one 150 mg tablet of ritonavir (both administered orally); and an evening dose consisting of one 150 mg tablet of nematevir and one 150 mg tablet of ritonavir (both administered orally). Patient 2 continued to receive nematevir and ritonavir according to this schedule for a total of five consecutive days. Patient 2 showed improvement in at least one symptom or biomarker of PASC.

[0304] Patient 3: Patient 3 was given an initial single dose of efalizumab (administered subcutaneously at a dose of 0.7 mg). On the same day, patient 3 was started on a 400 mg dose of sofosbuvir orally. Patient 3 was given this dose of sofosbuvir once daily for a period of 12 weeks. Patient 3 continued to receive additional doses of efalizumab (administered subcutaneously at a dose of 1 mg weekly). Patient 3 showed improvement in at least one symptom or biomarker of PASC.

[0305] Patient 4 Patient 4 was administered a loading dose of abciximab (0.25 mg by intravenous infusion). Patient 4 then received a maintenance dose of abciximab (10 mcg / min by intravenous infusion). On the same day, patient 4 was started on sofosbuvir at a dose of 400 mg orally. Patient 4 was administered sofosbuvir at this dose once daily for a period of 12 weeks. Patient 4 showed improvement in at least one symptom or biomarker of PASC.

[0306] Patient 5 Patient 5 was given a standard dose of Nematevir / ritonavir (Paxlovid TM), i.e., 300 mg of nematevir and 100 mg of ritonavir. According to the package insert, patient 5 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 5 was administered a standard dose at the same time each morning and at the same time each evening for a period of five days. On the same day, patient 5 received an intravenous administration of a 600 mg dose of lenzilumab. Eight hours later, patient 5 received an intravenous administration of a second dose (containing 600 mg) of lenzilumab. Eight hours later, patient 5 received a final dose of lenzilumab (containing 600 mg) (administered intravenously). Patient 5 showed improvement in at least one symptom or biomarker of PASC.

[0307] Patient 6 Patient 6 was administered a reduced dose of nematevir / ritonavir (Paxlovid TM ), i.e., 150 mg of namatevir and 100 mg of ritonavir. According to the package insert, patient 6 was started on a reduced dose of one namatevir tablet (150 mg) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 6 was administered a reduced dose at the same time each morning and at the same time each evening for a period of five days. On the same day, patient 6 received subcutaneous administration of a 150 mg dose of canakinumab. Patient 6 received an additional dose of 150 mg of canakinumab (once every 8 weeks, by subcutaneous administration). Patient 6 showed improvement in at least one symptom or biomarker of PASC.

[0308] Patient 7 Patient 7 was given a standard dose of Nematevir / ritonavir (Paxlovid TM ), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 7 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, a standard dose was administered to Patient 7 at the same time each morning and at the same time each evening for a period of ten days. Two days later, Patient 7 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM)(150 mg of tesagvir and 150 mg of celecoxib). Eight days after the first dose of tesagvir / celecoxib, patient 7 continued to receive standard doses of namatevir / ritonavir by oral administration. Patient 7 continued to receive a single dose of tesagvir / celecoxib (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for two months. Patient 7 was administered a standard oral dose of namatevir / ritonavir, starting two days before each dose of tesagvir / celecoxib and continuing for eight days after each dose of tesagvir / celecoxib. Patient 7 showed improvement in at least one symptom or biomarker of PASC.

[0309] Patient 8 Patient 8 was given a standard dose of Nematevir / Ritonavir (Paxlovid TM ), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 8 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 8 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Two days later, patient 8 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM )(150 mg tesagvir and 150 mg celecoxib). Eight days after the first dose of tesagvir / celecoxib, patient 8 continued to receive standard oral doses of nematevir / ritonavir. Patient 8 showed improvement in at least one symptom or biomarker of PASC.

[0310] Patient 9 Patient 9 was given a standard dose of Nematevir / ritonavir (Paxlovid TM ), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 9 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (containing 100 mg) twice daily. Specifically, patient 9 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Two days later, patient 9 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM)(150 mg of tesagvir and 150 mg of cegavir). Eight days after the first dose of tesagvir / cegavir was administered, patient 9 continued to receive a standard oral dose of nematevir / ritonavir. Patient 9 continued to receive a single dose of tesagvir / cegavir (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for five consecutive months. Patient 9 was administered a standard oral dose of nematevir / ritonavir, starting two days before each dose of tesagvir / cegavir and continuing for eight days after each dose of tesagvir / cegavir. Patient 9 showed improvement in at least one symptom or biomarker of PASC.

[0311] Patient 10 Patient 10 was given a standard dose of Nematevir / ritonavir (Paxlovid TM ), that is, 300mg namatevir and 100mg ritonavir. Patient 10 was started with a standard dose of two namatevir tablets (150mg each) and a ritonavir tablet (containing 100mg) twice daily. Specifically, a standard dose was administered to patient 10 at the same time in the morning and at the same time in the evening for a period of ten days. After two days, a single dose of tesagvir / west tadalafil (Evusheld™) (150mg tesagvir and 150mg west tadalafil) was administered to patient 10 by intramuscular injection. Eight days after administering the first dose of tesagvir / west tadalafil, standard oral doses of namatevir / ritonavir were continued to be administered to patient 10. Patient 10 continued to receive a single dose of tesagvir / west tadalafil (administered by intramuscular injection, once a month) for two weeks after receiving the first dose and then continued for two months. Patient 10 was given standard oral doses of nematevir / ritonavir starting two days before and continuing for eight days after each dose of tesagvir / celegavir. Patient 10 showed improvement in at least one symptom or biomarker of PASC.

[0312] Patient 11 Patient 11 was given a standard dose of Nematevir / ritonavir (Paxlovid) orally. TM), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 11 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (containing 100 mg) twice daily. Specifically, patient 11 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. After five days, patient 11 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM )(150 mg of tesagvir and 150 mg of cegavir). Five days after the first dose of tesagvir / cegavir was administered, patient 11 continued to receive a standard oral dose of nematevir / ritonavir. Patient 11 continued to receive a single dose of tesagvir / cegavir (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for two months. Patient 11 was administered a standard oral dose of nematevir / ritonavir, starting five days before each dose of tesagvir / cegavir and continuing for five days after each dose of tesagvir / cegavir. Patient 11 showed improvement in at least one symptom or biomarker of PASC.

[0313] Patient 12 Patient 12 was given a single dose of Evusheld™ (150 mg of tesagvir and 150 mg of cegavir) by intramuscular injection. Five days later, patient 12 was given a standard dose of nematevir / ritonavir (Paxil) by oral administration. TM ), that is, 300 mg of namatevir and 100 mg of ritonavir. Patient 12 was initially administered a standard dose of two namatevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 12 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Patient 12 continued to receive a single dose of tesagvir / sigavir monoclonal antibody (administered by intramuscular injection once a month), which began one month after receiving the first dose and was continued for two months. Patient 12 was administered a standard oral dose of namatevir / ritonavir, which began five days after each dose of tesagvir / sigavir monoclonal antibody was administered. Patient 12 showed improvement in at least one symptom or biomarker of PASC.

[0314] Patient 13 Patient 13 was given a standard dose of Nematevir / Ritonavir (Paxlovid TM), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 13 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 13 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Three days later, patient 13 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM )(150 mg of tesagvir and 150 mg of celecoxib). Seven days after the first dose of tesagvir / celecoxib, patient 13 was continued to receive a standard oral dose of nematevir / ritonavir. Patient 13 continued to receive a single dose of tesagvir / celecoxib (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for two months. Patient 13 was administered a standard oral dose of nematevir / ritonavir, starting 3 days before each dose of tesagvir / celecoxib and continuing for 7 days after each dose of tesagvir / celecoxib. Patient 13 showed improvement in at least one symptom or biomarker of PASC.

[0315] Patient 14 Patient 14 was given a standard dose of Nematevir / ritonavir (Paxlovid TM ), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 14 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (100 mg) twice daily. Specifically, patient 14 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Three days later, patient 14 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM)(150 mg of tesagvir and 150 mg of celecoxib). Seven days after the first dose of tesagvir / celecoxib, patient 14 was continued to receive a standard oral dose of nematevir / ritonavir. Patient 14 continued to receive a single dose of tesagvir / celecoxib (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for two months. Patient 14 was administered a standard oral dose of nematevir / ritonavir, starting 3 days before each dose of tesagvir / celecoxib and continuing for 7 days after each dose of tesagvir / celecoxib. Patient 11 showed improvement in at least one symptom or biomarker of PASC.

[0316] Patient 15 Patient 15 was given a standard dose of Nematevir / ritonavir (Paxlovid TM ), i.e., 300 mg of nematevir and 100 mg of ritonavir. Patient 15 was initially administered a standard dose of two nematevir tablets (150 mg each) and one ritonavir tablet (containing 100 mg) twice daily. Specifically, patient 15 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. After seven days, patient 15 was administered a single dose of tesagvir / segavir monoclonal antibody (Evusheld) by intramuscular injection. TM )(150 mg of tesagvir and 150 mg of celecoxib). Three days after the first dose of tesagvir / celecoxib, patient 15 was continued to receive a standard oral dose of nematevir / ritonavir. Patient 15 continued to receive a single dose of tesagvir / celecoxib (administered by intramuscular injection once a month), which began one month after receiving the first dose and continued for two months. Patient 15 was administered a standard oral dose of nematevir / ritonavir, starting seven days before each dose of tesagvir / celecoxib and continuing for three days after each dose of tesagvir / celecoxib. Patient 15 showed improvement in at least one symptom or biomarker of PASC.

[0317] Patient 16 Patient 16 was given a single dose of Evusheld™ (150 mg of tesagvir and 150 mg of celecoxib) by intramuscular injection. Three days later, patient 16 was given a standard dose of Paxil / ritonavir by oral administration. TM), that is, 300 mg of namatevir and 100 mg of ritonavir. Patient 16 was initially administered a standard dose of two namatevir tablets (150 mg each) and one ritonavir tablet (containing 100 mg) twice daily. Specifically, patient 16 was administered a standard dose at the same time each morning and at the same time each evening for a period of ten days. Patient 16 continued to receive a single dose of tesagvir / sigavir monoclonal antibody (administered by intramuscular injection once a month), which began one month after receiving the first dose and was continued for two months. Patient 16 was administered a standard oral dose of namatevir / ritonavir, which began three days after each dose of tesagvir / sigavir monoclonal antibody was administered. Patient 16 showed improvement in at least one symptom or biomarker of PASC.

[0318] Patient 17 Patient 17 was given a single dose of tesagvir / celegavir by intramuscular injection (Evusheld TM Seven days later, patient 17 was given a standard dose of nematevir / ritonavir (Paxlovid) by oral administration. TM ), that is, 300 mg of namatevir and 100 mg of ritonavir. Patient 17 was started with a standard dose of two namatevir tablets (150 mg each) and one ritonavir tablet (containing 100 mg) twice a day. Specifically, patient 17 was administered a standard dose at the same time every morning and the same time every evening for a period of 10 days. Patient 17 continued to receive a single dose of tesagvir / sigavir monoclonal antibody (administered by intramuscular injection once a month), which began one month after receiving the first dose and was continued for two months. Patient 17 was administered a standard oral dose of namatevir / ritonavir, which began seven days after each dose of tesagvir / sigavir monoclonal antibody was administered. Patient 17 showed improvement in at least one symptom or biomarker of PASC.

[0319] Patient 18 Patient 18 was given a single dose of tesagvir / celegavir by intramuscular injection (Evusheld TM ) (150 mg each of tesagvir and segavir). On the same day, patient 18 began oral administration of 400 mg of sofosbuvir. Patient 18 was administered this dose of sofosbuvir once daily for a period of 12 weeks. Patient 18 showed improvement in at least one symptom or biomarker of PASC.

[0320] Patient 0: In this example, patients were given 3 doses of Evusheld TM Treatment was administered once a month for 3 consecutive months, with the dose doubled after the first dose (following the FDA-recommended dose increase, as per FDA guidelines). Patients also received 3 x 10 days of Paxlovid TM Treatment, the treatment is 3 times Evusheld TM Each treatment was administered 2 days prior and continued for 8 days thereafter. The patient showed significant improvement in multiple PASC symptoms.

[0321] Other exemplary treatment methods include any of the foregoing embodiments, as described above for Patients 0 to 18, but wherein sofosbuvir is administered instead of nematevir / ritonavir (Paxlovid TM Other exemplary treatment methods include any of the foregoing embodiments, but wherein any antiviral agent disclosed herein, or a pharmaceutically acceptable salt thereof, is administered in place of sofosbuvir, namatevir / ritonavir (or Paxlovid TM ), remdesivir, or any other antiviral agent used by patients 0 to 18. Other exemplary treatment methods include any of the foregoing embodiments, but wherein any antibody disclosed herein is administered instead of tesagvir / segavir (Evusheld TM ) or any other antibody used in patients 0 to 18. Other exemplary treatment methods include any of the foregoing embodiments, but wherein any of the combinations used in patients 0 to 18 further comprises one or more additional active agents, as disclosed herein. It will be readily appreciated that other such substitutions can be made using any one or more of the other agents disclosed herein to provide additional drug combinations that can be used in accordance with the methods disclosed herein.

[0322] Example 2: Evaluation study of the disclosed methods or combinations for treating patients with PASC

[0323] Purpose: The efficacy of the disclosed methods and combinations for treating patients with PASC is measured.

[0324] qualified:All subjects are required to collect medical histories and undergo physical examinations. A treatment group is established that includes individuals diagnosed with PASC. PASC is diagnosed in subjects according to diagnostic techniques known to technicians, for example, by detecting the SARS-CoV-2 virus (e.g., by real-time reverse transcriptase-polymerase chain reaction (RT-PCR)) after the first PCR test is positive, or within a period of at least 28 days from the date selected as the date of infection; or PASC is diagnosed based on the subject's medical history (e.g., due to the persistence or appearance of a condition, disease, syndrome, symptom, or defect that is most likely to be causally related to SARS-CoV-2 infection after SARS-CoV-2 infection). A control group is established that includes healthy subjects with no history of SARS-CoV-2 viral infection. Subjects must be over 18 years of age. Subjects may withdraw from the study at any time for any reason. Subjects who are unwilling to participate in the study or who suffer from medical conditions that are not suitable for treatment with the disclosed methods or combinations will also be excluded from the study.

[0325] Overview of Study Design: Subjects will be given a data logbook or a clinical application by phone, or other means for recording the incidence and severity of symptoms, in which they will record the number and severity of PASC symptoms they experience daily, such as fatigue, headache, dizziness, difficulty thinking or concentrating (i.e., brain fog), changes or loss of smell or taste, depression, anxiety, chest pain, joint pain, tachycardia, cough, skin lesions, kidney problems. Subjects will be contacted every two days by mail, email, phone, and / or reminders sent through the clinical phone application to review symptoms and protocol compliance.

[0326] Subjects will also undergo laboratory testing for PASC diagnostic markers, including measurement of serum concentrations of the PASC biomarkers albumin, CRP, ferritin, G-CSF, IFN-α, IL-1β, IL-6, IL-13, IL-17, IP-10, TNF-α, D-dimer, and hemoglobin. The serum concentrations of each PASC biomarker measured for control subjects will be averaged. The average value for each PASC biomarker will be used to create a "healthy PASC biomarker profile" for subsequent comparison.

[0327] Symptoms will be recorded for an appropriate period of time before treatment. The subjects in the treatment group will then be divided into the following groups:

[0328] Group treat 1 Standard of care (control treatment) 2 (1) Antiviral Agents 3 (First) antiviral agent + (first) antibody 4 (First) antiviral agent + (Second) antiviral agent + (First) antibody 5 (First) antiviral agent + (First) antibody + (Second) antibody 6 (First) antiviral agent + (Second) antiviral agent + (First) antibody + (Second) antibody

[0329] In general, the administration and dosage of the antiviral agents and antibodies will be as disclosed herein, or according to the package insert or generally accepted medical guidelines, both of which are known to those skilled in the art.Control subjects will not receive any treatment.

[0330] Observations and measurements of the study: Efficacy observations will include evaluation of PASC symptoms (e.g., fatigue, headache, dizziness, difficulty thinking or concentrating (i.e., brain fog), changes or loss of smell or taste, depression, anxiety, chest pain, joint pain, tachycardia, cough, skin lesions, kidney problems). Any other adverse reactions will also be monitored. Patients will have laboratory tests to measure post-treatment serum concentrations of PASC biomarkers (albumin, CRP, ferritin, G-CSF, IFN-α, IL-1β, IL-6, IL-13, IL-17, IP-10, TNF-α, D-dimer, and hemoglobin).

[0331] result: The results showed that before treatment, the PASC biomarker profiles of the treated subjects were significantly different from the PASC biomarker profiles of healthy subjects. Furthermore, the PASC biomarker profiles of each treated subject correlated with the symptoms they reported and the severity of their symptoms. Following treatment with the disclosed methods or combinations, the PASC biomarker profiles of the treated subjects did not differ significantly from the PASC biomarker profiles of healthy subjects. The results show that the disclosed methods or combinations reduce the incidence of PASC symptoms, eliminate the incidence of PASC symptoms, or reduce the severity of PASC symptoms.

[0332] Example 3: In vitro efficacy of the disclosed combination for treating PASC-associated cytopathic conditions

[0333] The ability of the disclosed combination to prevent PASC-related cell death or cytopathic effect can be assessed in vitro by cell viability, using a luciferase assay to measure intracellular ATP as an endpoint. In short, VeroE6 cells rich in hACE2 expression were inoculated with SARS-CoV-2 in batches. The virus-inoculated cells were then added to an assay plate containing an antiviral agent or monoclonal antibody or a combination thereof, as described herein. After multiple days of incubation, or when the virus-induced cytopathic effect reached 95% under untreated infection control conditions, Cell Titer Glo (Promega) was used to evaluate cell viability according to the manufacturer's protocol (quantitative ATP levels). The cytotoxicity of antivirals, monoclonal antibodies, and combinations thereof was assessed in parallel uninfected cells. The test combination of antivirals and antibodies was tested individually or in the presence of a P-glycoprotein (P-gp) inhibitor CP-100356 at a concentration of 2 pM. CP-100356 was included to evaluate whether the test antiviral agents were excreted from VeroE6 cells, which have high levels of P-glycoprotein expression. The percent effect of the test antiviral agent, monoclonal antibody, or combination thereof at each concentration was calculated based on the values ​​of the virus-free control wells and the virus-containing control wells on each assay plate. The concentration required for a 50% response (EC 50 ) values ​​were determined from these data using a 4-parameter logistic model. EC was assigned when the Hill slope was >3 and the highest dose achieved a 50% effect. 50 The curve was fitted to a Hill slope of 3. If a cytotoxic effect greater than 30% was detected, the corresponding concentration data were removed from the EC 50 Eliminate in confirmation.

[0334] For cytotoxicity panels, the percent effect of the antiviral agent, antibody, or combination thereof at each concentration was calculated based on the values ​​of the cell-only control wells and the hyamine control wells on each assay plate. 50 The values ​​were calculated using a 4-parameter logistic model. Then CC 50 Value divided by EC 50 value to calculate TI.

[0335] The results show that the disclosed combinations can effectively prevent PASC-associated cell death or cytopathic effects, which indicates that the disclosed methods can reduce the incidence or severity of PASC-associated cytopathic effects.

[0336] Example 4: Adaptive Trial Design for Selecting Additional Pharmaceutical Compositions

[0337] In conducting clinical trials, an "adaptive" trial design mechanism can be employed to measure the efficacy of the disclosed methods or combinations for treating subjects suffering from PASC or symptoms of PASC. Without being bound by theory, an adaptive design is a design that allows the trial and / or the statistical procedures of the trial to be modified after the trial and / or the statistical procedures of the trial have begun without compromising their validity and integrity. Thus, an adaptive design can make clinical trials more flexible by utilizing the accumulated results from the trial to modify the trial process according to pre-specified rules. Therefore, adaptively designed trials are generally more efficient, more informative, and more ethical than traditional fixed-design trials because they generally make better use of resources (such as time and money) and may require fewer participants. Adaptive trial designs can be applied to all stages of clinical research, from early dose escalation to confirmatory trials.

[0338] In this document, in non-limiting examples, adaptive trial designs can be used to select combinations of agents for use in the disclosed methods, select patient populations for treatment (e.g., based on biomarkers), select dosage forms, doses, and / or dosing regimens, select when to start or stop treatment, select PASC symptoms that can be treated, and / or other such uses. According to such methods as described herein, adaptive trial designs are expected to allow for faster and more rigorous exploration of the combination space than a series of separate combination trials.

[0339] In the first step of an exemplary adaptive trial design for practicing the present invention, a specific drug combination is selected to be administered to a subject to treat PASC. In the second step, a clinical trial is initiated in which the selected drug combination is administered to the subject. While the subject is receiving treatment, clinical observations appropriate to the trial are made, e.g., safety or efficacy. Observations of efficacy can include reduction or elimination of PASC symptoms (e.g., fatigue, headache, sleep problems (e.g., insomnia), dizziness, difficulty thinking or concentrating (i.e., brain fog), changes or loss of smell or taste, depression, or anxiety). Adverse reactions can be monitored. Observations are reviewed during the trial but prior to completion (as in a fixed-sample design). As observations are reviewed, the trial design can be modified during the course of the trial based on accumulated results and pre-specified rules, such as those known to those skilled in the art.

[0340] For purposes of explanation, the foregoing description uses specific nomenclature to provide a full understanding of the present invention. However, it will be understood by those skilled in the art that specific details are not required to practice the present invention. The foregoing description of specific embodiments is provided for illustration and description purposes only. It is not intended to be exhaustive or to limit the invention to the precise methods, compositions, formulations, etc. disclosed; various modifications and variations can be made according to the teachings. The embodiments are chosen and described in order to best explain the principles of the invention and its practical application by illustrating specific examples, thereby allowing others in the art to best utilize the present invention and various embodiments, and when the specific uses envisioned exceed the specific examples disclosed, various modifications are made to accommodate such uses. Therefore, the scope of the present invention is limited only by the following claims and their equivalents.

Claims

1. A method of treating a subject suffering from post-acute sequelae of COVID-19 (PASC), the method comprising administering to the subject an effective amount of a combination of: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; iii) a primary antibody; and iv) Optionally, a secondary antibody.

2. The method of claim 1, wherein the first antiviral agent is a protease inhibitor.

3. The method of claim 1, wherein the first antiviral agent is selected from the group consisting of ritonavir, namatevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, monovaccin, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, famovir, valproate ... Pilavir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), senotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), acyclovir and pharmaceutically acceptable salts thereof. The method of claim 1 , wherein the first antibody is a monoclonal antibody.

5. The method of claim 1, wherein the first antibody is an immunoglobulin G (IgG) antibody.

6. The method of claim 1, wherein the first antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, natalizumab, Aspirin, Panitumumab, Ranibizumab, Eculizumab, Ofatumumab, Belimumab, Ipilimumab, Pertuzumab, Resibacumab, Atezolizumab, Certuximab, Ramucirumab, Vedolizumab, Alemtuzumab, Nexitumomab, Dietuximab, Elotuzumab, Reslizumab, Bezoloxetine, Obituximumab, Avelumab, Sotovir, Bectetuzumab, Casirimab, Idevelumab, Esterasevir, barenvir, ambavir, remdesivir, romisvir, edinvir, 002-S21F2, AZD3152, lenzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonaprivir, velolimab, casirizumab, salilumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, evolocumab , blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, anti-endothelin receptor B antibody (AER002), and durvalumab.

7. The method of claim 1, wherein the second antiviral agent is a protease inhibitor.

8. The method of claim 1, wherein the second antiviral agent is selected from the group consisting of ritonavir, namatevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, selumeprevir, telaprevir, monovaccin, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, famovir, valproate ... Pilavir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), senotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), acyclovir and pharmaceutically acceptable salts thereof.

9. The method of claim 1, wherein the second antibody is a monoclonal antibody.

10. The method of claim 1, wherein the second antibody is an IgG antibody.

11. The method of claim 1, wherein the second antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab , natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, resibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dextrostatin, elotuzumab, reslizumab, bezoloxetine, obituxumab, avelumab, sotovir, bectavirumab, casiruzumab, Idevelumab, etesvir, barenvir, ambavir, radanvetumab, romisvir, edinvir, 002-S21F2, AZD3152, lenzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonaprivir, veloprena, casirizumab, salilumab, lelizumab, golimumab, tabarumab, velutuzumab, mepolizumab, sekinin monoclonal antibody, evolocumab, blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, AER002, and durvalumab.

12. The method of claim 1, further comprising administering an effective amount of an additional active agent.

13. The method of claim 12, wherein the additional active agent is any of an amino acid, an antioxidant, an anti-inflammatory, an analgesic, an anti-neurotropic and anti-nociceptive, an anti-migraine, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD, an immunostimulant, an anticancer, an antiemetic, an anorectic, an antiulcer, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotectant, a monoamine oxidase inhibitor, an empathy-inducing agent, a tranquilizer, a hallucinogen, a dissociative, a nootropic, a euphoric, a sedative, a stimulant, and a vitamin.

14. The method of claim 12, wherein the additional active agent is any one of an uncoating inhibitor, an entry inhibitor, a protease inhibitor, an immunostimulant, a latency reversal agent, a reverse transcriptase, a reverse transcriptase inhibitor, an integration inhibitor, a nucleoside analog, an RNA polymerase inhibitor, a viral decapping agent, a neuraminidase inhibitor, a fusion inhibitor, an interferon, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor.

15. The method of claim 12, wherein the additional active agent is an immunostimulant, a COVID-19 vaccine, an additional agent with antiviral activity, or an additional antibody.

16. The method of claim 15, wherein the additional agent having antiviral activity is a MIR (siR-7-EM / KK-46), baicalin, pegylated interferon λ, metformin, ursodeoxycholic acid (UCDA), TVGN-489, LAU-7b, sabirutamide, azithromycin, ivermectin, opanib, baricitinib, mycophenolate mofetil, APN01, epigallocatechin gallate (EGCG), diphenhydramine, quercetin, Qingfei Paidu Decoction (QFPDT), Lianhua Qingwen (LQ), Qingguan No. 1 (NRICM101), Jingsi Bencao Yin (JSHD), nicotine, lactoferrin, nattokinase, or ubiquinone.

17. The method of claim 1, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; sofosbuvir, or a pharmaceutically acceptable salt thereof; or ritonavir, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1, wherein the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof.

19. The method of claim 1, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; and the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof.

20. The method of claim 1, wherein the first antibody is tesagvir or celegavir.

21. The method of claim 1, wherein the first antibody is tesagvir and the second antibody is celecoxib.

22. The method of claim 1, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir; and the second antibody is segavir.

23. The method of claim 1, wherein the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir; and the second antibody is segavir.

24. The method of claim 1, wherein the first antiviral agent and the second antiviral agent are administered in a single pharmaceutical composition, or wherein the first antibody and the second antibody are administered in a single pharmaceutical composition.

25. The method of claim 1, which reduces the incidence or severity of at least one symptom of PASC.

26. The method of claim 25, wherein the symptom of PASC is a neurological symptom, a cardiovascular symptom, a pulmonary symptom, a musculoskeletal symptom, an endocrine symptom, a skin symptom, or a renal symptom.

27. The method of claim 26, wherein the neurological symptoms are selected from the group consisting of sleep disorders, chronic headaches, smell disorders, taste disorders, brain fog, memory loss, decreased concentration, depression, anxiety, post-traumatic stress disorder (PTSD), dizziness, vertigo, tinnitus, hearing loss, balance disorders, delirium, hallucinations, small fiber neuropathy, postural tremor, chronic pain, neurodegeneration, and myalgia.

28. The method of claim 26, wherein the cardiovascular symptoms are selected from the group consisting of nonspecific chest pain, chest tightness, palpitations, tachycardia, conduction disturbances, arrhythmias, orthostatic hypotension, vasovagal syncope, postural orthostatic tachycardia syndrome (POTS), phlebitis, and thrombophlebitis.

29. The method of claim 26, wherein the pulmonary symptoms are selected from the group consisting of dyspnea, persistent cough, wheezing, worsening asthma, decreased lung diffusion capacity, persistent abnormal imaging findings, pleurisy, cough, sleep apnea, and sore throat.

30. The method of claim 26, wherein the musculoskeletal symptoms are selected from the group consisting of arthritis, back pain, gait abnormalities, and joint pain.

31. The method of claim 26, wherein the endocrine symptom is selected from the group consisting of impaired glucose metabolism, subacute thyrotoxicosis, Hashimoto's disease, Graves' disease, and dyslipidemia.

32. The method of claim 26, wherein the skin symptoms are selected from the group consisting of rash, hives, skin lesions, telogen effluvium, nail changes, erythema, and scalp pain.

33. The method of claim 26, wherein the renal symptom is selected from the group consisting of decreased glomerular filtration rate, urinary incontinence, and microscopic hematuria.

34. The method of claim 25, wherein the symptoms of PASC are selected from the group consisting of fever, chills, muscle aches, body aches, chest pain, stomach pain, nausea, vomiting, diarrhea, gastroesophageal reflux, stress, swelling, bleeding, weight loss, weight gain, abdominal pain, constipation, pain in an extremity, paresthesia, peripheral edema, pruritus, lymphadenopathy, and edema.

35. The method of claim 25, wherein the incidence of PASC symptoms is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% compared to the incidence of PASC symptoms prior to treatment with the method.

36. The method of claim 25, wherein the severity of the PASC symptoms is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% compared to the severity of the PASC symptoms prior to treatment with the method.

37. The method of claim 1, which restores the serum concentration of a PASC biomarker to within about 50%, 40%, 30%, 20%, 10%, 5%, or 1% of the baseline concentration.

38. The method of claim 37, wherein the PASC biomarker is a neurological biomarker.

39. The method of claim 38, wherein the nervous system biomarker is GDNF, GFAP, NGF-β, NFL, NT-3, or pGFAP / pNFL.

40. The method of claim 37, wherein the PASC biomarker is a cardiovascular biomarker.

41. The method of claim 40, wherein the cardiovascular biomarker is Ang-2, Col1A2, Col3A1, D-dimer, ESR, ET-1, Factor VIII:C, hemoglobin, MMP-1, MMP-9, MPO, NO, PDGF-BB, sICAM-1, sTM, sVEGFR, sVCAM-1, VEGF, VWF:Ag, or VWF:pp.

42. A pharmaceutical kit for treating a subject suffering from post-acute sequelae (PASC) of COVID-19, comprising: i) a first antiviral agent, or a pharmaceutically acceptable salt thereof; ii) optionally, a second antiviral agent, or a pharmaceutically acceptable salt thereof; iii) a primary antibody; and iv) Optionally, a secondary antibody.

43. The kit of claim 42, wherein the first antiviral agent is a protease inhibitor.

44. The kit of claim 42, wherein the first antiviral agent is selected from the group consisting of ritonavir, nematevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, semideprevir, telaprevir, monovaccin, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, Favipiravir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), senotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), acyclovir and pharmaceutically acceptable salts thereof.

45. The kit of claim 42, wherein the first antibody is a monoclonal antibody.

46. ​​The kit of claim 42, wherein the first antibody is an immunoglobulin G (IgG) antibody.

47. The kit of claim 42, wherein the first antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, Natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, resibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dextrostatin, elotuzumab, reslizumab, bezoloxetine, obituxumab, avelumab, sotovir, bectetuzumab, casiruzumab, idevelumab Antibodies, etesvir, barenvir, ambavir, radanvir, romisvir, edinvir, 002-S21F2, AZD3152, lenzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonapriv, velolimab, casiruzumab, salilumab, lelizumab, golimumab, tabarumab, veltuzumab, mepolizumab, secukinumab, elouzumab Anti-VEGF, blinatumomab, ado-trastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, anti-endothelin receptor B antibody (AER002), and durvalumab.

48. The kit of claim 42, wherein the second antiviral agent is a protease inhibitor.

49. The kit of claim 42, wherein the second antiviral agent is selected from the group consisting of ritonavir, nematevir, remdesivir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunavir, boceprevir, grazoprevir, glecaprevir, paritaprevir, semideprevir, telaprevir, monovaccin, GC376, arbidol (umifenovir), SSAA09E2, ribavirin, Favipiravir, oseltamivir, zanamivir, abacavir, stavudine, valganciclovir, ganciclovir, cidofovir, entecavir, lamivudine, maraviroc, azidothymidine, nelfinavir, dolutegravir, olsetamivir, enstevir (Xocova), senotevir, benifobuvir (AT-527), deuteramidvir (VV116), azithromycin, sofosbuvir, obidesivir (GS-5245), acyclovir and pharmaceutically acceptable salts thereof.

50. The kit of claim 42, wherein the second antibody is a monoclonal antibody.

51. The kit of claim 42, wherein the second antibody is an IgG antibody.

52. The kit of claim 42, wherein the second antibody is selected from the group consisting of tesagvir, cegavir, pembrolizumab, nivolumab, bevacizumab, ocrelizumab, rituximab, daratumumab, pertuzumab, trastuzumab, infliximab, tocilizumab, atezolizumab, tositumomab, olaratumumab, rituximab, basiliximab, ibritumomab tiuxetan, cetuximab, Monoclonal antibody, natalizumab, panitumumab, ranibizumab, eculizumab, ofatumumab, belimumab, ipilimumab, pertuzumab, resibacumab, atezolizumab, certolizumab, ramucirumab, vedolizumab, alemtuzumab, necituzumab, dextrostatin, elotuzumab, reslizumab, bezoloxetine, obituxumab, avelumab, sotovir, betrocycline, casiruzumab , idevumab, etesvir, barenvir, ambavir, radanvir, romisvir, edinvir, 002-S21F2, AZD3152, lenzlumab, ravulizumab, canakinumab, adalimumab, salilumab, lonapriv, veloprevir, casiruzumab, salilumab, lelizumab, golimumab, tabarumab, velutuzumab, mepolizumab, su Jinumab, evolocumab, blinatumomab, adotrastuzumab, brentuximab, ipilimumab, denosumab, ustekinumab, catumaxomab, efalizumab, tositumomab-1131, palivizumab, basiliximab, daclizumab, abciximab, muronomab, certolizumab pegol, benralizumab, dupilumab, omalizumab, muromonab-CD3, AER002, and durvalumab.

53. The kit of claim 42, further comprising an additional active agent.

54. The kit of claim 53, wherein the additional active agent is any of an amino acid, an antioxidant, an anti-inflammatory, an analgesic, an anti-neurotropic and anti-nociceptive, an anti-migraine, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD, an immunostimulant, an anti-cancer, an antiemetic, an anorectic, an anti-ulcer, an antihistamine, an antihypertensive, an anticonvulsant, an anti-epileptic, a bronchodilator, a neuroprotectant, a monoamine oxidase inhibitor, an empathy-inducing agent, a tranquilizer, a hallucinogen, a dissociative, a nootropic, a euphoric, a sedative, a stimulant, and a vitamin.

55. The kit of claim 53, wherein the additional active agent is any of an uncoating inhibitor, an entry inhibitor, a protease inhibitor, an immunostimulant, a latency reversal agent, a reverse transcriptase, a reverse transcriptase inhibitor, an integration inhibitor, a nucleoside analog, an RNA polymerase inhibitor, a viral decapping agent, a neuraminidase inhibitor, a fusion inhibitor, an interferon, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor.

56. The kit of claim 53, wherein the additional active agent is an immunostimulant, a COVID-19 vaccine, an additional agent with antiviral activity, or an additional antibody.

57. The kit of claim 56, wherein the additional agent having antiviral activity is a MIR (siR-7-EM / KK-46), baicalin, pegylated interferon λ, metformin, ursodeoxycholic acid (UCDA), TVGN-489, LAU-7b, sabirutamide, azithromycin, ivermectin, opanib, baricitinib, mycophenolate mofetil, APN01, epigallocatechin gallate (EGCG), diphenhydramine, quercetin, Qingfei Paidu Decoction (QFPDT), Lianhua Qingwen (LQ), Qingguan No. 1 (NRICM101), Jingsi Bencao Yin (JSHD), nicotine, lactoferrin, nattokinase, or ubiquinone.

58. The kit of claim 42, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; sofosbuvir, or a pharmaceutically acceptable salt thereof, or ritonavir, or a pharmaceutically acceptable salt thereof.

59. The kit of claim 42, wherein the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof.

60. The kit of claim 42, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; and the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof.

61. The kit of claim 42, wherein the first antibody is tesagvir or celegavir.

62. The kit of claim 42, wherein the first antibody is tesagvir and the second antibody is celecoxib.

63. The kit of claim 42, wherein the first antiviral agent is nematevir, or a pharmaceutically acceptable salt thereof; the second antiviral agent is ritonavir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir; and the second antibody is segavir.

64. The kit of claim 42, wherein the first antiviral agent is sofosbuvir, or a pharmaceutically acceptable salt thereof; the first antibody is tesagvir; and the second antibody is segavir.

65. The kit of claim 42, wherein the first antiviral agent and the second antiviral agent are co-formulated as a single pharmaceutical composition, or wherein the first antibody and the second antibody are co-formulated as a single pharmaceutical composition.

66. Use of the pharmaceutical kit according to claim 42 for treating PASC.

67. Use of the pharmaceutical kit according to claim 42 for the manufacture of a medicament for treating PASC.

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