Composition comprising plasma and immunoglobulin for treating or preventing infectious diseases

Abstract

The present invention relates to a composition for treating or preventing a respiratory infectious disease in a subject wherein the composition comprises plasma and an immunoglobulin against a pathogenic factor of the respiratory infectious disease, wherein the immunoglobulin is obtained from a donor subject that has generated a humoral immune response to the pathogenic factor of the respiratory infectious disease; and wherein the composition is administered intranasally, and optionally orally. The present invention also relates to a transnasal, nasal-oropharyngeal or oral-nasal spray device comprising such a composition, as well as to a transnasal, nasal-oropharyngeal or oral-nasal spray comprising plasma and an immunoglobulin against a pathogenic factor of said respiratory infectious disease, wherein the immunoglobulin is obtained from a donor subject that has produced a humoral immune response to the pathogenic factor of the respiratory infectious disease.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating or preventing infectious diseases, more preferably respiratory infectious diseases (such as those caused by respiratory viruses). Some specific examples of such viruses are the Coronaviridae family, more specifically SARS-CoV, MERS-CoV or SARS-CoV-2 that cause COVID-19. Background Art

[0002] Epidemic outbreaks of infectious diseases pose a significant threat to public health. Passive immunotherapy, achieved by transferring specific antibodies from convalescent donors to patients, has been used to treat infectious diseases (including respiratory infectious diseases) for more than a century, and the first Nobel Prize in Medicine was awarded to Emil von Behring in 1901. However, despite this, the successful application and safety of convalescent plasma have only been demonstrated in a limited number of case studies.

[0003] Recently, several multicenter, open-label, randomized clinical trials have been designed to show that clinical outcomes can be improved after intravenous treatment with convalescent COVID-19 plasma (CCP) (containing high titers of anti-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies). However, despite more than 10 published studies and more than 100 ongoing studies, the clinical efficacy of intravenous CCP for COVID-19 has been shown to be limited to a subset (immunocompromised) of patients. Results from completed clinical studies (such as the Belgian DAWn-PLASMA, German CAPSID, and UK RECOVERY studies) have shown that intravenous administration of convalescent plasma has little or no effect in hospitalized COVID-19 patients. Additionally, intravenous infusion of CCP in healthy individuals to prevent infection (such as SARS-CoV-2 infection) is also problematic. First, this is a logistical nightmare as blood transfusions can only be performed in a hospital by authorized personnel under medical supervision. Second, the risk of transfusion complications always exists (although minimal). Third, there is no evidence that infusion of CCP confers a benefit. And finally, ethical considerations apply as not everyone can receive a transfusion given that the plasma supply is not infinite.

[0004] In the past 20 years, several β-coronaviruses (lineages B and C) have emerged that cause severe and even fatal respiratory diseases. The emergence of these viruses in humans is mainly due to zoonotic transmission. To date, the three β-coronaviruses that have caused the most clinically severe viral outbreaks are the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2013, and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in 2019. The latter is the cause of the pandemic that has so far been associated with an estimated 253 million infections and 5 million deaths globally. Like all respiratory viruses, the SARS-CoV-2 virus infects starting from the upper respiratory tract. In addition, symptoms such as shortness of breath, fever, and dry cough can occur in COVID-19 patients, and life-threatening inflammatory reactions (i.e., acute respiratory distress syndrome (ARDS)) can also suddenly appear in the lungs, where fluid rapidly accumulates, making it difficult to absorb oxygen.

[0005] Several vaccines for respiratory infectious diseases (such as COVID-19) are available on the commercial market. While such vaccines generally provide protection against hospitalization, the emerging new variants have escaped the current humoral protection, promoting the propagation of the disease. In addition, the elderly and patients with comorbidities are only limitedly protected by the vaccine or not protected at all. Moreover, access to vaccines in low- and middle-income countries is limited or delayed. "Vaccine hesitancy" has also led to gaps in widespread population protection.

[0006] Since the development of de novo antiviral drugs and vaccines is a time-consuming process, new, easily accessible, and clinically relevant methods are needed to treat or prevent infections caused by agents that generally cause respiratory infectious diseases, and more particularly, infections by pathogens transmitted through the naso-oro-pharyngeal route, whether or not they cause local infections and / or more systemic effects. SUMMARY OF THE INVENTION

[0007] As demonstrated in the experimental section exemplifying certain representative embodiments of the present invention, the inventors have found that the infection and transmission of causative agents (i.e., pathogens, such as viruses, bacteria, bacterial spores, or fungi) entering and spreading through the naso-oro-pharyngeal route can be prevented or blocked by naso-oro-pharyngeal administration (i.e., uptake through the nasal or oropharyngeal mucosa) to a subject in need of treatment of a composition comprising plasma and immunoglobulins against the causative agent, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the causative agent.

[0008] More particularly, the inventors have found that respiratory infectious diseases (such as respiratory infectious diseases caused by causative agents (i.e., pathogens, such as viruses, bacteria, bacterial spores, or fungi) (preferably viruses)) can be treated and / or prevented by naso-oro-pharyngeal administration (i.e., uptake through the nasal or oropharyngeal mucosa) to the subject of a composition comprising plasma and immunoglobulins against the causative agent of the respiratory infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the causative agent of the respiratory infectious disease. This can generate a rapid response product that can help protect the population from widespread infection by respiratory pathogens (such as respiratory viruses) before conventional vaccines and / or antibiotics and antiviral drugs against the pathogen are developed.

[0009] As a proof of concept (see the Examples section); the inventors have shown in a SARS-CoV-2 hamster transmission model that intranasal administration to hamsters, one day before exposure to SARS-CoV-2-infected hamsters and for four days during exposure to SARS-CoV-2-infected hamsters (i.e., for a total of 5 consecutive days), of (i) convalescent plasma obtained from human donor subjects recovered from SARS-CoV-2 infection, or (ii) convalescent plasma obtained from human donor subjects recovered from SARS-CoV-2 infection and vaccinated against SARS-CoV-2, resulted in a significant reduction in both viral RNA and intact infectious virus in the lungs of the hamsters compared to control hamsters. Interestingly, administration of convalescent plasma to hamsters resulted in a greater reduction in intact infectious virus in the lungs of the hamsters compared to administration of purified human immunoglobulins in the absence of plasma. In addition, administration of non-immune hamster plasma comprising purified human immunoglobulins against the causative agent of the respiratory infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the causative agent of the respiratory infectious disease, resulted in a greater reduction in viral genetic material (RNA) in the lungs of the hamsters compared to administration of purified human immunoglobulins in the absence of non-immune hamster plasma.

[0010] Similar to the data associated with convalescent plasma from human subjects, the inventors have also shown in a SARS-CoV-2 hamster transmission model that intranasal administration of convalescent plasma obtained from a hamster donor subject that has recovered from SARS-CoV-2 infection to hamsters one day before exposure to SARS-CoV-2-infected hamsters and for four days during exposure to SARS-CoV-2-infected hamsters (i.e., for a total of five consecutive days) resulted in a significant reduction in both viral RNA and intact infectious virus in the lungs of the hamsters compared to control hamsters. Additionally, the inventors have shown that non-immune hamster plasma supplemented with purified human immunoglobulins can also significantly reduce viral RNA and intact infectious virus in the lungs of infected hamsters compared to control hamsters. Without wishing to be bound by theory, the inventors believe that the observed effects are due, at least in part, to: (i) the positive interaction between plasma components (such as clotting factors, complement cascade factors, cytokines, and chemokines) and antibodies against the causative agent of the respiratory infectious disease, and / or (ii) the positive effect of the matrix viscosity of the plasma on immunoglobulin availability.

[0011] Accordingly, the present invention generally provides a method for preventing infection and transmission of a causative agent (such as a virus, bacterium, bacterial spore, or fungus) that enters and is transmitted through the naso-oral pharyngeal route by naso-oral pharyngeal administration (i.e., uptake through the nasal or oral pharyngeal mucosa) to a subject in need of treatment of a composition comprising plasma components and immunoglobulins against the causative agent, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent. The disease caused by the causative agent can be local (i.e., in the naso-oral pharyngeal region), can be generally directed against the lower respiratory system (i.e., including the lungs), or can be systemic (i.e., the naso-oral pharyngeal region is merely an entry point for the causative agent to enter the subject's bloodstream, thereby causing a systemic disease), or can be directed against the gastrointestinal system.

[0012] More particularly, the present invention provides the following aspects:

[0013] Aspect 1. A method for preventing infection and transmission of a causative agent (such as a virus, bacterium, bacterial spore, or fungus) that enters and is transmitted through the naso-oral pharyngeal route by naso-oral pharyngeal administration (i.e., uptake through the nasal or oral pharyngeal mucosa) to a subject in need of treatment of a composition comprising plasma and immunoglobulins against the causative agent, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent. The present invention also provides such a composition for preventing infection and transmission of the causative agent as defined herein. In any of the embodiments herein, the plasma can be present in the form of (total, preferably convalescent) plasma or its isolated components.

[0014] Aspect 2. A method for preventing the infection and transmission of agents causing respiratory infectious diseases, which comprises administering via the nasal-oral pharynx (i.e., uptake through the nasal mucosa or the oral pharyngeal mucosa) a composition comprising plasma and immunoglobulins against the causative agents of the respiratory infectious diseases, wherein the immunoglobulins are obtained from a donor subject who has developed a humoral immune response against the causative agents.

[0015] Additionally, the aspect also provides a composition for preventing the infection and transmission of agents causing respiratory infectious diseases in a subject, and for treating or preventing respiratory infectious diseases, wherein the composition comprises plasma and immunoglobulins against the causative agents of the respiratory infectious diseases, the immunoglobulins being obtained from a donor subject who has developed a humoral immune response against the causative agents of the respiratory infectious diseases; and wherein the composition is administered via nasal-oral pharyngeal administration (i.e., uptake through the nasal mucosa or the oral pharyngeal mucosa).

[0016] Aspect 3. The method or composition according to the application of Aspect 1 or 2, which is used for reducing the progression of an infection (such as an upper respiratory tract infection) to the lower respiratory system, the systemic system, or the gastrointestinal system, and / or for preventing the spread of the infection in a population.

[0017] Aspect 4. The method or composition according to the application of any one of Aspects 1 to 3, wherein the composition comprises at least 70% (v / v) of the plasma and immunoglobulins against the causative agents, the immunoglobulins being obtained from a donor subject who has developed a humoral immune response against the causative agents.

[0018] Aspect 5. The method or composition according to the application of any one of Aspects 1 to 4, wherein the plasma is not platelet-enriched, preferably the plasma is not platelet-rich plasma (PRP).

[0019] Aspect 6. The method or composition according to the application of any one of Aspects 1 to 4, wherein the composition comprises convalescent plasma from a donor subject who has developed a humoral immune response against the causative agents.

[0020] Aspect 7. The method or composition according to the application of any one of Aspects 1 to 6, wherein the composition is administered to the subject at the following times: - Before the subject is exposed to the causative agent (i.e., to avoid transmission to unexposed subjects); - Before the subject is infected by the causative agent (i.e., to avoid transmission to exposed but uninfected subjects); - After the subject has been exposed to the causative agent (i.e., to avoid infection and the occurrence of disease); or - after the subject has been infected by the etiological agent (i.e., to avoid the development and / or progression of the disease).

[0021] Aspect 7. A composition for the use according to any one of Aspects 1 to 6, wherein the etiological agent of the respiratory infectious disease is a virus, bacterium, bacterial spore or fungus, preferably a virus.

[0022] Aspect 9. A method or composition for the use according to any one of Aspects 1 to 8, wherein the disease is a respiratory infectious disease, more preferably a viral respiratory infectious disease, more preferably wherein the etiological agent of the viral respiratory infectious disease is selected from: viruses of the family Coronaviridae, respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, adenovirus and bocavirus, preferably wherein the respiratory virus is a virus of the family Coronaviridae.

[0023] Aspect 10. A method or composition for the use according to Aspect 9, wherein the virus of the family Coronaviridae is a severe acute respiratory syndrome-related coronavirus, most preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing COVID-19).

[0024] Aspect 11. A method or composition for the use according to any one of Aspects 1 to 10, wherein the composition is a pulmonary aerosol preparation, nasal drops, oro-nasal drops, nasal spray, oro-nasal spray or nasal-oro-pharyngeal drops or spray.

[0025] Aspect 12. A method or composition for the use according to any one of Aspects 1 to 11, wherein the composition is used to support conventional (respiratory) infectious disease treatment, prevention or vaccination methods.

[0026] Aspect 13. A method or composition for the use according to any one of Aspects 1 to 11, wherein the composition is used in the absence of conventional (respiratory) infectious disease treatment, prevention or vaccination methods.

[0027] Aspect 14. A nasal, nasal-oro-pharyngeal or oro-nasal spray comprising plasma and immunoglobulins against the etiological agent of the (respiratory) infectious disease as defined herein, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response to the etiological agent. Preferably, the spray comprises a composition as defined in any one of Aspects 1 to 13.

[0028] Aspect 15. A transnasal, naso - oropharyngeal or oro - nasal spray device comprising a composition containing plasma and immunoglobulins against the causative agent of the (respiratory) infectious disease as defined herein, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent. Preferably, the spray comprises the composition as defined in any one of Aspects 1 to 13.

[0029] Aspect 16. A method of treating or preventing a respiratory infectious disease in a subject, comprising administering to the subject a composition containing plasma and immunoglobulins against the causative agent of the respiratory infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent of the respiratory infectious disease; and wherein the composition is administered intranasally or in the naso - oropharyngeal region, i.e., by uptake through the naso - oropharyngeal mucosa.

[0030] Aspect 17. The method according to Aspect 16, for reducing the progression of an upper respiratory tract infection to the lower respiratory tract, and / or for preventing the spread of an upper respiratory tract infection in a population.

[0031] Aspect 18. The method according to Aspect 16 or 17, wherein the composition comprises at least 70% (v / v) of the plasma and immunoglobulins against the causative agent of the respiratory infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent of the respiratory infectious disease.

[0032] Aspect 19. The method according to any one of claims 16 to 18, wherein the plasma is not platelet - enriched, preferably wherein the plasma is not platelet - rich plasma (PRP).

[0033] Aspect 20. The method according to any one of Aspects 16 to 19, wherein the composition comprises convalescent plasma from a donor subject that has developed a humoral immune response against the causative agent of the respiratory infectious disease.

[0034] Aspect 21. The method according to any one of Aspects 16 to 20, wherein the composition is administered to the subject at the following times: - before the subject is exposed to the causative agent of the respiratory infectious disease (i.e., to avoid transmission to unexposed subjects); - before the subject is infected with the causative agent of the respiratory infectious disease (i.e., to avoid transmission to exposed but uninfected subjects); - after the subject has been exposed to the causative agent of the respiratory infectious disease (i.e., to avoid infection and the occurrence of respiratory disease); or - after the subject has been infected with the causative agent of the respiratory infectious disease (i.e., to avoid the development and / or progression of a respiratory disease).

[0035] Aspect 22. The method according to any one of aspects 16 to 21, wherein the causative agent of the respiratory infectious disease is a virus, bacterium, bacterial spore or fungus, preferably a virus.

[0036] Aspect 23. The method according to any one of aspects 16 to 22, wherein the respiratory infectious disease is a viral respiratory infectious disease, and wherein the causative agent of the viral respiratory infectious disease is selected from: Coronaviridae viruses, respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, adenovirus and bocavirus, preferably wherein the respiratory virus is a Coronaviridae virus.

[0037] Aspect 24. The method according to aspect 23, wherein the Coronaviridae virus is a severe acute respiratory syndrome-related coronavirus, most preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing COVID-19).

[0038] Aspect 25. The method according to any one of aspects 16 to 24, wherein the composition is a pulmonary nebulization preparation, nasal drops, oral-nasal drops, nasal spray, oral-nasal spray or nasal-oro-pharyngeal drops or spray.

[0039] Aspect 26. The method according to any one of aspects 16 to 25, wherein the composition is for supporting the treatment, prevention or vaccination method of a conventional respiratory infectious disease.

[0040] Aspect 27. The method according to any one of aspects 16 to 26, wherein the composition is used in the absence of a treatment, prevention or vaccination method for a conventional respiratory infectious disease.

[0041] Aspect 28. Use of a composition comprising plasma and an immunoglobulin against a causative agent of an infectious disease as defined herein in the preparation of a medicament for treating and / or preventing said infectious disease in a subject, wherein the immunoglobulin is obtained from a donor subject that has developed a humoral immune response against the causative agent of the infectious disease; and wherein the composition is administered intranasally or in the nasal-oro-pharyngeal region, i.e., by uptake through the nasal-oro-pharyngeal mucosa.

[0042] Aspect 29. The use according to aspect 28, which is for reducing the progression of an infection, such as the progression of an upper respiratory tract infection to the lower respiratory system, a systemic infection or a gastrointestinal infection, and / or for preventing the spread of the infection in a population.

[0043] Aspect 30. The use according to aspect 28 or 29, wherein the composition comprises at least 70% (v / v) of the plasma and immunoglobulins against the pathogen of the infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the pathogen of the infectious disease.

[0044] Aspect 31. The use according to any one of aspects 28 to 30, wherein the plasma is not platelet-enriched, preferably wherein the plasma is not platelet-rich plasma (PRP).

[0045] Aspect 32. The use according to any one of aspects 28 to 31, wherein the composition comprises convalescent plasma obtained from donor subjects that have developed a humoral immune response against the pathogen of the infectious disease.

[0046] Aspect 33. The use according to any one of aspects 28 to 32, wherein the composition is administered to the subject at the following times: - Before the subject is exposed to the pathogen of the infectious disease (i.e., to prevent transmission to unexposed subjects); - Before the subject is infected with the pathogen of the infectious disease (i.e., to prevent transmission to exposed but uninfected subjects); - After the subject is exposed to the pathogen of the infectious disease (i.e., to prevent infection and the occurrence of respiratory diseases); or - After the subject is infected with the pathogen of the infectious disease (i.e., to prevent the development and / or progression of respiratory diseases).

[0047] Aspect 34. The use according to any one of aspects 28 to 33, wherein the pathogen of the infectious disease is a virus, bacterium, bacterial spore or fungus, preferably a virus.

[0048] Aspect 35. The use according to any one of aspects 28 to 34, wherein the infectious disease is a respiratory infectious disease, such as a viral respiratory infectious disease, and more preferably, wherein the pathogen of the viral respiratory infectious disease is selected from: Coronaviridae viruses, respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, adenovirus and bocavirus, preferably wherein the respiratory virus is a Coronaviridae virus.

[0049] Aspect 36. The use according to any one of aspects 35, wherein the Coronaviridae virus is a severe acute respiratory syndrome-related coronavirus, most preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing COVID-19).

[0050] Aspect 37. The use according to any one of aspects 28 to 36, wherein the composition is a pulmonary nebulization preparation, a nasal drop, an oral-nasal drop, a nasal spray, an oral-nasal spray or a nasal-oro-pharyngeal spray.

[0051] Aspect 38. The use according to any one of aspects 28 to 37, wherein the composition is used to support the treatment, prevention or vaccination method of conventional infectious diseases.

[0052] Aspect 39. The use according to any one of aspects 28 to 38, wherein the composition is used in the absence of a treatment, prevention or vaccination method for conventional infectious diseases.

[0053] Aspect 40. The method or composition according to any one of aspects 1 to 13, wherein the composition induces a humoral immune response against the pathogen in the subject to whom the composition is administered.

[0054] Aspect 41. A method for inducing a humoral immune response against a pathogen that enters or spreads through the nasal-oro-pharyngeal region in a subject in need thereof, which comprises administering to the subject a composition comprising plasma and an immunoglobulin against the pathogen, wherein the immunoglobulin is obtained from a donor subject that has developed a humoral immune response against the pathogen, and wherein the composition is administered intranasally or in the nasal-oro-pharyngeal region. Preferably, the composition is as defined in any one of aspects 1 to 13.

[0055] Aspect 42. A method for producing a vaccine, which comprises combining a composition comprising plasma and an immunoglobulin against a pathogen that enters or spreads through the nasal-oro-pharyngeal region with one or more pharmaceutically acceptable excipients, wherein the immunoglobulin is obtained from a donor subject that has developed a humoral immune response against the pathogen. Preferably, the composition is as defined in any one of aspects 1 to 13.

[0056] These and other aspects and preferred embodiments of the present invention are described in the following sections and the appended claims. The subject matter of the appended claims is hereby incorporated into this specification specifically. Brief Description of the Drawings

[0057] Figure 1. Intranasal administration of human (convalescent) plasma in the SARS-CoV-2 hamster transmission model. Multiple human plasma (derivatives), namely vaccinated COVID-19 convalescent plasma (VCCP), COVID-19 convalescent plasma (CCP), purified human antibodies from VCCP (purified hIg), or non-immune human plasma donated before the COVID-19 pandemic (NIP 人 ) were intranasally administered to sentinel hamsters. Phosphate-buffered saline was included as a negative buffer control. (a to c) The levels of IgG (a), IgA (b), and IgM (c) binding to the SARS-CoV-2 receptor binding domain (RBD) in human plasma samples were determined in an isotype ELISA and calibrated relative to the international WHO standard (BAU / mL) (n = 3, each tested in duplicate); the concentrations of IgG (e) and IgA (f) in human plasma were determined by ELISA (μg / mL) (n = 3, each tested in duplicate); (g) the neutralization capacity of plasma samples was tested in an inhibition ELISA and expressed as IU / mL (n = 3, each tested in duplicate); (h) inhibition of plaque formation by (convalescent) plasma. Plaque formation was tested in Vero E6 cultures with the SARS-CoV-2 ancestral W strain (n = 1, tested in duplicate); (i) setup of the Syrian hamster transmission study. Sentinel hamsters were treated daily with human plasma or buffer (25 μL / nostril). On day 0, indicator hamsters were intranasally inoculated with 2 × 10 6 TCID 50 of the ancestral W strain. Indicator hamsters were sacrificed on day 4 post-infection and sentinel hamsters were sacrificed on day 5 post-infection (for the VCCP, purified hIg, and NIP 人 groups, n = 6 for indicator and sentinel hamsters; for the CCP group from two independent experiments n = 18 and for the buffer control group from two independent experiments n = 14); (j) viral RNA levels in hamster lungs on day 4 (indicator) or day 5 (sentinel) quantified by RT-qPCR and expressed as RNA copies / mg lung tissue; (k) infectious virus loads in the lungs of hamsters and indicator hamsters prophylactically treated with different plasma samples, in log 10 TCID 50 / mg lung tissue representation; (l) cumulative lung scores of H&E-stained sections of lungs from infected (indicated) and exposed and prophylactically treated (sentinel) hamsters; (d) H&E images of sentinel hamster lungs on day 4 or 5 of buffer-treated hamsters versus CCP-treated hamsters. Lungs of hamsters treated with CCP showed lung cell hyperplasia (blue box). Scale bar, 200 μm. Individual data and median as well as 95% CI are shown. Intergroup statistical significance was calculated by Kruskal-Wallis and Dunn's post hoc tests. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns = not significant. IU / mL = international units per milliliter. BAU / mL = binding antibody units per milliliter.

[0058] Figure 2 . Intranasal administration of hamster plasma in a SARS-CoV-2 hamster transmission model. Intranasal administration of various hamster plasma (derivatives) to sentinel hamsters, namely COVID-19 convalescent hamster plasma (CCP 仓鼠 ), purified human antibodies from VCCP incorporated into non-immune hamster plasma (NIP 仓鼠 ) (purified hIg in NIP 仓鼠 ), or NIP 仓鼠 . (a) Setup of the Syrian hamster transmission study. Sentinel hamsters were treated daily with hamster plasma (25 μL / nostril). On day 0, indicated hamsters were intranasally inoculated with 2×10 6 TCID 50 of the parental W strain; (b) neutralizing capacity of plasma samples was tested in a neutralization ELISA and expressed in international WHO standard units (IU / mL) (n = 3, each tested in duplicate); (c) weight change of indicated hamsters (index) on day 4 post-infection (p.i.) (and on day 5 for sentinel hamsters) was expressed as a percentage and normalized to the weight at the time of infection / treatment on day 0 (all groups were n = 6 except for buffer controls from two independent experiments, n = 14); (d) viral RNA levels in hamster lungs on day 4 p.i. (indicated) or day 5 (sentinel) were expressed as RNA copies / mg lung tissue; (e) infectious virus load in lungs of hamsters and indicated hamsters prophylactically treated with different hamster plasma samples on day 4 or p.i. was expressed as 10 logTCID 50 / mg lung tissue representation; (f) cumulative lung scores of H&E-stained sections of lungs from infected (indicated) and exposed and prophylactically treated (sentinel) hamsters; (g) H&E images of lungs of plasma-treated hamsters on day 5. With CCP 仓鼠The lungs of treated hamsters did not show inflammation or lung cell hyperplasia. Scale bar, 200 μm. Individual data and median as well as 95% CI are shown. Statistical significance between groups was calculated by Kruskal-Wallis and Dunn post hoc tests. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns = not significant. IU / mL = international units per milliliter.

[0059] Figure 3 . Plaque reduction neutralization tests were performed with Delta (a) and Omicron (b) SARS-CoV-2 variants. VCCP, CCP, and NIP 人 serial dilutions were tested for their ability to inhibit plaque formation in Vero E6 cells infected with SARS-CoV-2 variants. For each plasma dilution of CCP expressed as 10 log(%) inhibition is shown (n = 1, tested in duplicate each).

[0060] Figure 4 . Intranasal administration of human plasma in a SARS-CoV-2 hamster infection model. Syrian hamsters were intranasally administered low-titer COVID-19 convalescent plasma (CCP 低 ), monoclonal murine anti-SARS-CoV-2 antibody (30 nM) (mAb) phosphate-buffered saline (buffer control). (a) Setup of the Syrian hamster infection study. Hamsters were treated with CCP, mAb, or buffer control (25 μL / nostril) on day 1 and infected with 10 3 TCID 50A second treatment was given one hour prior to intranasal inoculation with the original W strain; (b–d) IgG (b), IgA (c), and IgM (d) levels in human plasma samples were determined in an isotype ELISA and calibrated relative to the international WHO standard (BAU / mL) (n = 3, each tested in duplicate); IgG (f) and IgA (g) concentrations (μg / mL) in human plasma were determined by ELISA (n = 3, each tested in duplicate); (h) the neutralization capacity of plasma samples was tested in an inhibition ELISA and expressed in international WHO standard units (IU / mL) (n = 3, each tested in duplicate); (e) plaque reduction neutralization test (PRNT) of Vero E6 cells infected with the SARS-CoV-2 original W strain with serial dilutions of mAb, expressed as plaque formation (%) normalized to uninfected cells (n = 1, each tested in duplicate); (i) body weight change at 4 days post-infection (p.i.), expressed as a percentage and normalized to body weight at the time of infection / treatment on day 0 (n = 6); (j) viral RNA levels in the hamster lungs at 4 days p.i., expressed as RNA copies / mg lung tissue; (k) infectious virus load in the lungs of hamsters prophylactically treated with CCP or buffer on days 1 and 0 at 4 days p.i., expressed as log 10 TCID 50 / mg lung tissue; (l) cumulative lung scores of H&E-stained sections from the lungs of infected and prophylactically treated hamsters. Individual data and median and 95% CI are shown. Statistical significance between groups was calculated by Kruskal–Wallis and Dunn's post hoc test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns = not significant. IU / mL = international units per milliliter. BAU / mL = binding antibody units per milliliter.

[0061] Figure 5 . Human plasma and hamster plasma were administered intranasally in naïve Syrian hamsters. Naïve Syrian hamsters were challenged with COVID-19 convalescent plasma or serum (VCCP or VCCS) for intranasal vaccination, purified human antibodies from VCCP incorporated in buffer (purified hIg in buffer), purified human antibodies from VCCP incorporated in non-immune hamster plasma (NIP 仓鼠 ), non-immune human plasma donated prior to the COVID-19 pandemic (NIP 仓鼠 ), NIP 人 , and NIS 仓鼠 ​仓鼠 or buffer control. (a) Setup for Syrian hamster safety study. Primary hamsters were treated daily with VCCP, VCCS, NIP 仓鼠 , NIS 仓鼠 , NIP 人 , purified hIg in buffer, NIP 仓鼠 -purified hIg in or buffer control (25 μL / nostril); (b) Cumulative lung scores of H&E-stained sections of hamster lungs treated with plasma / serum or buffer (n = 6); (c) H&E images of hamster lungs treated with buffer vs. CCP on day 5. Hamster lungs treated with NIP 人 showed lung cell hyperplasia (blue box). Scale bar, 200 μm. Individual data and median and 95% CI are shown. Statistical significance between groups was calculated by Kruskal-Wallis and Dunn's post hoc tests. *p < 0.05, ns = not significant.

[0062] Figure 6 . Humoral immunity after intranasal administration of convalescent plasma: experimental setup. Abbreviations: CCP: convalescent plasma; TCID: tissue culture infectious dose. DETAILED DESCRIPTION

[0063] Unless the context clearly indicates otherwise, the singular forms include both singular and plural referents.

[0064] As used herein, the terms "comprising" and "including" or "containing" are synonymous and are inclusive or open-ended and do not exclude additional unrecited members, elements, or method steps. The term also encompasses "consisting of" and "consisting essentially of," which have recognized meanings in patent terminology.

[0065] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the corresponding ranges, as well as the recited endpoints.

[0066] When referring to measurable values such as parameters, amounts, temporal durations, etc., the term "about" or "approximately" as used herein is intended to cover variations of and relative to the specified value, such as variations of ±10% or less, preferably ±5% or less, more preferably ±1% or less, and still more preferably ±0.1% or less of the specified value, within which such variations are suitable for carrying out the disclosed invention. It is understood that the value itself modified by the modifier "about" is also specifically and preferably disclosed.

[0067] Although the term "one or more" or "at least one" (e.g., one or more members or at least one member of a group of members) is clear in itself, by way of further illustration, the term specifically encompasses a reference to any one of the members, or to any two or more of the members, such as any 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more of the members etc. and up to all of the members. In another instance, "one or more" or "at least one" can refer to 1, 2, 3, 4, 5, 6, 7 or more.

[0068] A discussion of the background of the invention is included herein to explain the context of the invention. This should not be regarded as an admission that any of the material referred to was publicly available, known, or part of the common general knowledge in any country as of the priority date of any claim.

[0069] Throughout this disclosure, various publications, patents, and published patent specifications are cited by identifying citation. All documents cited in this specification are hereby incorporated by reference in their entirety. In particular, the teachings or portions of such documents specifically mentioned herein are incorporated by reference.

[0070] Unless otherwise defined, all terms (including technical and scientific terms) used in disclosing the invention have the meanings commonly understood by a person of ordinary skill in the art to which the invention pertains. By way of further guidance, term definitions are included to better understand the teachings of the invention. Unless otherwise limited, when a particular term is defined in the context of a specific aspect or a specific embodiment of the invention, such meaning is intended to apply throughout this specification, i.e., also in the context of other aspects or embodiments of the invention.

[0071] In the following paragraphs, different aspects or embodiments of the invention are defined in more detail. Unless explicitly stated to the contrary, each aspect or embodiment so defined can be combined with any other aspect or embodiment. Specifically, any feature indicated as being preferred or advantageous can be combined with any other one or more features indicated as being preferred or advantageous.

[0072] Throughout this specification, references to "one embodiment" or "an embodiment" mean that the particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, in one or more embodiments, as will be apparent to those skilled in the art in light of the present disclosure, the particular features, structures, or characteristics may be combined in any suitable manner. Additionally, although some embodiments described herein include some features but not others included in other embodiments, as will be understood by those skilled in the art, combinations of features of different embodiments are intended to be within the scope of the invention and form different embodiments. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

[0073] As demonstrated in the experimental section that illustrates certain representative embodiments of the invention, the inventors unexpectedly found that infectious diseases originating in the naso-oro-pharyngeal region, more preferably respiratory infectious diseases (such as COVID-19), can be treated and / or prevented by intranasal or trans-naso-oro-pharyngeal administration of a composition comprising a plasma component (preferably whole plasma) and immunoglobulins against the causative agent of the infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the causative agent of the infectious disease.

[0074] As a proof of concept (see the Examples section), and as described above, the inventors conducted experiments in a SARS-CoV-2 hamster transmission and infection model. Hamsters are obligate nasal breathers and are often used to study human respiratory virus-induced diseases and to evaluate the efficacy of vaccines or drugs. In the case of SARS-CoV-2 infection, the hamster model used by the inventors is very suitable because these animals express the angiotensin-converting enzyme 2 (ACE) receptor (the SARS-CoV-2 entry receptor) in their airways. Additionally, intranasal inoculation of SARS-CoV-2 in hamsters can also effectively induce viral replication in the upper respiratory tract, making this model very suitable for preclinical studies.

[0075] Intranasal (e.g., nasal inhalation) or transnaso - oropharyngeal (e.g., by nasal inhalation or oral inhalation) administration of a composition comprising plasma and immunoglobulins against a pathogen of an infectious disease originating in the naso - oropharyngeal region (more preferably a respiratory infectious disease), for example by means of a spray, which requires only a small volume of plasma as compared to intravenous administration of convalescent plasma, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the pathogen of the infectious disease. Moreover, plasma (e.g., convalescent plasma) is readily available and inexpensive even in the very early stages of an epidemic, especially as compared to recombinant (monoclonal) antibodies or mixtures of nanobodies, and also as compared to small (antiviral) molecules. Intranasal or transnaso - oropharyngeal delivery of a composition comprising plasma and immunoglobulins as described herein (e.g., intranasal or transnaso - oropharyngeal delivery of convalescent plasma) can be used in the early stages of a pandemic, and can be used in patients who are only partially protected by vaccination or not protected by vaccination at all (e.g., many elderly people and patients with underlying primary diseases that affect humoral immunity), as well as in patients living in low - and middle - income countries that struggle with limited or delayed access to vaccines.

[0076] Accordingly, intranasal or transnaso - oropharyngeal delivery of a composition comprising plasma and immunoglobulins as described herein (e.g., delivery of convalescent plasma) allows for alleviating the burden on healthcare (including hospitals, nursing homes, and care facilities) as well as primary care physicians and (outpatient) care providers, and for reducing healthcare costs.

[0077] Accordingly, in a first aspect, there is provided a composition for treating and / or preventing an infectious disease originating in the naso - oropharyngeal region, more preferably a respiratory infectious disease, in a subject, wherein the composition comprises plasma and immunoglobulins against a pathogen of the infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the pathogen of the infectious disease; and wherein the composition is administered intranasally or in the naso - oropharyngeal region.

[0078] In another aspect, there is provided a method for treating and / or preventing an infectious disease originating in the naso - oropharyngeal region, more preferably a respiratory infectious disease, in a subject, wherein the method comprises administering to the subject an effective amount of a composition comprising plasma and immunoglobulins against a pathogen of the infectious disease, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the pathogen of the infectious disease; and wherein the composition is administered intranasally or in the naso - oropharyngeal region.

[0079] In some specific embodiments, a composition comprising plasma and immunoglobulins as described herein induces a humoral immune response against the pathogenic agent in the subject to whom the composition is administered.

[0080] In some specific embodiments, a composition comprising plasma and immunoglobulins as described herein is a composition that stimulates a humoral immune response. In some specific embodiments, a composition comprising plasma and immunoglobulins as described herein is a composition for vaccination, such as a first-line vaccine or a vaccine-like composition.

[0081] Accordingly, another aspect provides a method of inducing a humoral immune response against a pathogenic agent that enters or is transmitted through the naso-oral pharyngeal region in a subject in need thereof, comprising administering to the subject a composition comprising plasma and immunoglobulins against the pathogenic agent, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the pathogenic agent; and wherein the composition is administered intranasally or in the naso-oral pharyngeal region.

[0082] As used herein, the term "prevention" or variations thereof refers to reducing the risk of developing a disease or disorder (i.e., causing at least one clinical symptom of the disease not to occur in a subject (especially a human subject) that may be exposed to or is susceptible to the disease but has not yet experienced or manifested symptoms of the disease). In the present context, the term prevention also encompasses reducing or preventing the transmission of a pathogenic agent and / or reducing or preventing the infection by a pathogenic agent, thereby actively preventing the infection and / or the development and progression of the disease.

[0083] In one embodiment, the term "treatment" or variations thereof of any disease or disorder includes for improving the disease or disorder (i.e., preventing or reducing the progression of the disease or at least reducing one of the clinical symptoms of the disease). In another embodiment, "treatment" or variations thereof refers to improving at least one physical parameter, which may or may not be distinguishable by the subject (especially a human subject), but which is based on or related to the disease or disorder to be treated. In another embodiment, "treatment" or variations thereof refers to modulating or alleviating the disease or disorder, which may be physical (e.g., stabilizing distinguishable or indistinguishable symptoms) or physiological (e.g., stabilizing physiological parameters), or both. In another embodiment, "treatment" or variations thereof refers to delaying the onset or progression of the disease or disorder. Thus, "treatment" or variations thereof include any etiological treatment of the underlying disease or disorder (i.e., disease modification), as well as any treatment of the signs and symptoms of the disease or disorder (with or without disease modification), and any alleviation or improvement of the disease or disorder or its signs and symptoms. The terms "disease" and "disorder" are largely used interchangeably herein.

[0084] As used herein, the term "effective amount" may refer to a prophylactically effective amount, which is the amount of an active compound or agent (more particularly, a prophylactic agent) that a researcher, veterinarian, medical doctor, or other clinician seeks to inhibit or delay the onset of a disorder in a subject; or may refer to a therapeutically effective amount, which is the amount of an active compound or agent (more particularly, a therapeutic agent) that a researcher, veterinarian, medical doctor, or other clinician seeks to elicit a biological or medical response (which may particularly include alleviating the symptoms of the disease or disorder being treated) in a subject. Methods known in the art are used to determine the therapeutically effective dose and prophylactically effective dose of the agents taught herein. The effective amount may vary depending on the compound, the disease and its severity, the condition of the subject to be treated (particularly a human subject), age, weight, gender, etc. More specifically, a "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of a composition comprising plasma and immunoglobulins as described herein, which, when administered, produces a clinically positive response for the treatment of a subject afflicted with an infectious disease. Similarly, a "prophylactically effective amount" or "prophylactically effective dose" refers to the amount of a composition comprising plasma and immunoglobulins as described herein that a researcher, veterinarian, medical doctor, or other clinician seeks to inhibit or delay the onset of the clinical manifestation of an infectious disease. Those skilled in the art will appreciate that terms such as "quantity", "amount", and "level" are synonyms and have well-defined meanings in the art, and understand that these may particularly refer to the absolute quantification of a composition comprising plasma and immunoglobulins as described herein, which is considered the effective amount as applied herein; or may refer to the relative quantification of a composition comprising plasma and immunoglobulins as described herein, such as the concentration of a composition comprising plasma and immunoglobulins as described herein as a function of the subject's body weight. Appropriate values or ranges of values can be obtained from a single subject or from a group of subjects (i.e., at least two subjects).

[0085] It should be emphasized that although any values and ranges disclosed herein for a composition comprising plasma and immunoglobulins are suitable for different medical indications or purposes, those skilled in the art will appreciate that by considering a wide range of parameters to further optimize the optimal dose of the components, certain individuals may experience more improved benefits from treatment with a composition comprising plasma and immunoglobulins, the parameters including but not limited to the nature and extent of the infectious disease to be treated, subject gender, subject age, weight, other medical indications, nutritional status, mode of administration, metabolic status, interference or influence of other pharmaceutically active ingredients, or the potency of other pharmaceutically active ingredients, etc. In addition, each individual may have a certain degree of intrinsic responsiveness to the composition comprising plasma and immunoglobulins used.

[0086] As used herein, the term "infectious disease originating from the naso - oropharyngeal region" shall be construed in the broadest sense, i.e., any pathological infection that enters or is transmitted to a subject through the naso - oropharyngeal region (i.e., the nose, ear, mouth, throat, upper respiratory tract), where the causative agent is capable of being transmitted, for example, through respiratory secretions, exhalation, mucus, or saliva, from a first afflicted subject with the infectious disease to a second subject not having the said infectious disease. The disease caused by the causative agent can be local (i.e., in the naso - oropharyngeal region), can be directed at the entire lower respiratory system (i.e., including the lungs), or can be systemic (i.e., the naso - oropharyngeal region is just the entry point for the causative agent to enter the subject's bloodstream, causing a systemic disease), or can be directed at the gastrointestinal system. In the context of the present invention, both symptomatic and asymptomatic infections are contemplated, but symptomatic infections are more preferred.

[0087] In some specific embodiments, the compositions as described herein are used to reduce or completely inhibit the progression of an infection originating from the naso - oropharyngeal region to the lower respiratory system, reduce or completely inhibit the progression to a systemic infection, and reduce or completely inhibit the progression to a gastrointestinal system infection.

[0088] As used herein, the term "respiratory system infectious disease" shall be construed in the broadest sense, i.e., any pathological infection of the respiratory system (i.e., the respiratory tract, including the trachea, bronchi, bronchioles, alveoli, pleura, thoracic cavity), where the causative agent is capable of being transmitted, for example, through respiratory secretions (such as mucus or saliva), from a first afflicted subject with the respiratory system infectious disease to a second subject not having the said respiratory system infectious disease. Alternatives that can be used interchangeably with this term include, but are not limited to, "respiratory system infection", "airway infection", and "respiratory tract infection", each of which is a standard term in the medical field and is known to those skilled in the art. Such respiratory system infections can also be the result of an infection occurring outside the respiratory system. For example, SARS - CoV - 2 can enter through the gut and become a secondary respiratory system infection. In the context of the present invention, both symptomatic and asymptomatic respiratory system infections are contemplated, but symptomatic respiratory system infections are more preferred. It should be understood that the term "symptomatic" means the presence of one or more physical manifestations (i.e., symptoms) of a respiratory system infection. The typical symptoms of a (clinically mild) respiratory system infectious disease are diverse and include, but are not limited to, cough (with sputum), sneezing, sinus and / or lung congestion, runny nose, sore throat and / or irritation, muscle pain, shortness of breath, wheezing, tight chest, fever, malaise, itchy and / or watery eyes, and any combination thereof.

[0089] In certain embodiments, a respiratory infection is a respiratory infectious disease of the upper respiratory tract. In some alternative embodiments, a respiratory infection is a respiratory infectious disease of the lower respiratory tract. Generally, respiratory infectious diseases are typically classified according to the affected part of the respiratory system and can thus be upper respiratory tract infections and / or lower respiratory tract infections. Upper respiratory tract infections are mainly located in the nose, sinuses, pharynx, larynx, or any combination thereof, while lower respiratory tract infections are mainly located in the bronchi, bronchioles, alveoli, pleura, thoracic cavity, or any combination thereof. Many respiratory infections are characterized by the coexistence of pathogens in the upper and lower respiratory tracts.

[0090] In some specific embodiments, the compositions as described herein are used to reduce or completely inhibit the progression of upper respiratory tract infections to the lower respiratory tract.

[0091] In some specific embodiments, the compositions as described herein are used to reduce the initial replication of pathogens in the naso-oro-pharyngeal or upper respiratory tract region. In some other specific embodiments, the compositions as described herein are used to mitigate the primary infection in the naso-oro-pharyngeal region or upper respiratory tract region.

[0092] In some specific embodiments, the compositions as described herein are used to prevent, reduce, or completely inhibit the transmission of the causative agent (e.g., pathogen) of the infectious disease from one subject to another, e.g., by preventing infection of unexposed subjects, or by triggering their immune systems against the causative agent to inhibit infection in recently or newly exposed subjects.

[0093] In some specific embodiments, the compositions as described herein are used to reduce the amount of the causative agent (e.g., pathogen, e.g., virus) in the subject, preferably the amount of the infectious causative agent. The amount of the causative agent can be determined by any method in the art. For example, the median tissue culture infectious dose (TCID 50 ) assay can be used to determine the amount of infectious virus particles. For example, RT-qPCR can be used to quantify the amount of RNA of the causative agent.

[0094] In some specific embodiments, the causative agent of the infectious disease is a pathogen, such as a virus, bacterium, bacterial spore, protozoan, viroid, parasite, yeast, or fungus, preferably a virus. In other specific embodiments, the infectious disease as described herein is an infectious disease caused by a virus, bacterium, fungus, or parasite, i.e., an infectious disease having a virus, bacterium, fungus, or parasite (i.e., a pathogen) as the main causative agent. Obviously, the infectious disease as described herein can be caused by more than one causative agent co-existing in the subject. In certain embodiments, the infectious disease is caused by an opportunistic pathogen, where optionally the infected subject is an immunocompromised subject.

[0095] In some specific embodiments, the causative agent of the disease can be a pathogen that is transmitted through the naso - oropharyngeal route, regardless of whether the pathogen itself causes a respiratory infectious disease. For example, some pathogens can enter through the nasopharynx but thereby cause a systemic disease or a gastrointestinal disease.

[0096] In other embodiments, the infectious disease is a respiratory infectious disease, more specifically a viral respiratory infectious disease. In other embodiments, the viral respiratory infectious disease is caused by a virus of the realm Riboviria, preferably the family Coronaviridae (i.e., coronaviruses), more preferably a severe acute respiratory syndrome-related coronavirus, more preferably SARS-CoV, MERS-CoV, or SARS-CoV-2 (which causes COVID-19), most preferably SARS-CoV-2. In some alternative embodiments, the respiratory infectious disease is a viral respiratory disease caused by a virus selected from: influenza virus, respiratory syncytial virus (RSV), parainfluenza virus, metapneumovirus, rhinovirus, coronavirus, adenovirus, and bocavirus.

[0097] For the purposes of the present disclosure in particular, the viral respiratory pathogen is an RNA virus, preferably where the RNA virus is selected from the following: Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, Orthomyxoviridae, and Rhabdoviridae. In some further preferred embodiments, the pathogenic viral pathogen is a coronavirus, which is classified as a coronavirus species selected from the following: alpha coronavirus, beta coronavirus, gamma coronavirus, and delta coronavirus species. In some further preferred embodiments, the pathogenic viral pathogen is a coronavirus, which is classified as a coronavirus genus selected from the following: alpha coronavirus 1, human coronavirus 229E, human coronavirus NL63, little brown bat coronavirus 1, little brown bat coronavirus HKU8, porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512, beta coronavirus, Hedgehog coronavirus 1, human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, severe acute respiratory syndrome-related coronavirus, Tylonycteris bat coronavirus HKU4, avian coronavirus, beluga whale coronavirus SW1, Bulbul coronavirus HKU11, and porcine coronavirus HKU15. In some further preferred embodiments, the pathogenic viral pathogen is a beta coronavirus, preferably a beta coronavirus classified in the Sarbecovirus subgenus.

[0098] In some alternative embodiments, the viral pathogen is an RNA virus, preferably a positive-sense RNA virus, more preferably a positive-sense single-stranded RNA virus.

[0099] The "SARS-CoV-2 virus", commonly referred to as the "COVID-19 virus" and "hCoV-19", is a positive-sense single-stranded RNA virus that causes the respiratory SARS-CoV-2 or COVID-19 disease as described herein. It is apparent that when referring to SARS-CoV-2 herein, the term encompasses any documented and undocumented variants of the SARS-CoV-2 virus. In accordance with the general knowledge of a person skilled in the art, the term "(genetic) variant" as used herein refers to a pathogen subtype that is genetically different from the reference (i.e., "master") genetic strain of the pathogen. A suitable reference SARS-CoV-2 strain is the strain corresponding to the sequence WIV04 / 2019 (GISAIDS clade, PANGO lineage A, Nextstrain clade 19B), which sequence is commonly referred to as the sequence closest to the initial SARS-CoV-2 sequence capable of infecting human subjects (Zhukova et al., Origin, evolution and global spread of SARS-CoV-2, C R Biol, 2020). Such variants are also contemplated by the present disclosure. Some non-limiting examples of documented SARS-CoV-2 variants include, but are not limited to: Cluster 5 variant, lineage B.1.1.7 variant, lineage B.1.1.207 variant, lineage B.1.1.317 variant, lineage B.1.1.318 variant, lineage B.1.351 variant, lineage B.1.429 (CAL.20C) variant, lineage B.1.525 variant, lineage B.1.526 variant, lineage B.1.617 variant, lineage B.1.618 variant, lineage P.1 variant, lineage P.3 variant. In addition, the term SARS-CoV-2 also encompasses missense mutation variants, such as, but not limited to, variants characterized by missense mutations selected from: D614G, E484K, N501Y, S477G, S477N, P681H, E484Q, L452R, P614R, or any combination thereof.Other non-limiting examples include: the original W-Hu-1 of the SARS-CoV-2 isolate, Alpha variant (also known as the UK variant) (e.g., VOC 202012 / 01, B.1.1.7), Gamma variant (also known as the Brazil-Japan variant) (e.g., B.1.1.28 or P1), Beta variant (also known as the South Africa variant) (e.g., VOC 501Y.V2, B.1.351), Epsilon variant (also known as the California variant (e.g., B.1.427 or B.1.429), Iota variant (also known as the New York variant) (e.g., B.1.526 or B.1.526.1), Eta variant (also known as the UK / Nigeria variant) (e.g., B.1.525), Kappa variant (also known as the India variant) (e.g., B.1.617, B.1.617.1, B.1.617.2 or B.1617.3), Zeta variant (also known as the Brazil variant) (e.g., P.2), Theta variant (e.g., P3), Lambda variant (e.g., C.37), Mu variant (such as B.1.621), Delta variant (e.g., B.1.617.2) or Omicron variant (e.g., B.1.1.529). Those skilled in the art are aware of conventional sequencing methods that can be used to detect genetic mutations. In addition, both government agencies and research groups provide publicly available repositories that contain (new) genetic variant information (e.g., https: / / covid.cdc.gov / covid-data-tracker / #variant-proportions; and Rakha et al., COVID-19 Variants Database: A repository for Human SARS-CoV2 Polymorphism Data, BioRxiv, 2020).

[0100] In some preferred embodiments, the SARS-CoV-2 virus is the original W-Hu-1, beta, delta or omicron variant of SARS-CoV-2. In some preferred embodiments, the SARS-CoV-2 virus is the original W SARS-CoV-2 strain BetaCov / Belgium / GHB-03021 / 202 (EPI ISL 407976|2020-02-03) strain.

[0101] In a specific embodiment, the causative agent of the infectious disease (such as a respiratory infectious disease) to be treated or prevented in the subject can be a variant or mutant of the causative agent of a respiratory infectious disease against which the donor subject has generated a humoral immune response. For example, if the causative agent of the respiratory infectious disease to be treated or prevented in the subject is the beta variant of SARS-CoV-2, then the causative agent of the respiratory infectious disease against which the donor subject has generated a humoral immune response can be another variant, such as the original W variant, delta variant, or omicron variant of SARS-CoV-2, etc., and vice versa.

[0102] In some alternative embodiments, the infectious disease (such as a respiratory infectious disease) is a bacterial respiratory infectious disease. In some other embodiments, the bacterial infectious disease is caused by bacteria selected from: Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Corynebacterium diphtheria, Legionella pneumophila, Bordetella pertussis, Coxiella burnetii, Streptococcus pyogenes, Mycobacterium tuberculosis, Mycobacterium avium, Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Klebsiella pneumoniae, Mycoplasma pneumoniae, Pseudomonas aeruginosa, Candida spp., Acinetobacter spp., and E. coli.

[0103] In some alternative embodiments, the infectious disease (e.g., a respiratory infectious disease) is a fungal respiratory disease. In some other embodiments, the fungal infectious disease is caused by a fungus selected from the group consisting of Aspergillus fungi, Cryptococcus fungi, Pneumocystis fungi, and endemic mycoses. Some exemplary endemic mycoses include, but are not limited to, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenkii.

[0104] In some alternative embodiments, the infectious disease (e.g., a respiratory infectious disease) is a yeast respiratory infection, such as a yeast lung infection caused by Candida, such as candidiasis.

[0105] In some alternative embodiments, the infectious disease (e.g., a respiratory infectious disease) is a parasitic respiratory disease. In some other embodiments, the parasitic infectious disease is caused by a parasite selected from the group consisting of nematodes (e.g., Ascaris lumbricoides, Ancylostoma duodenale, Strongyloides stercoralis, Mammomonogamus laryngeus, Dirofilaria immitis, Brugia malayi, Wuchereria bancrofti, Toxocara canis, Toxocara catis, Trichinella spiralis), trematodes (e.g., Schistosomiasis, Paragonimiasis), cestodes (e.g., Echinococcus granulosus), and mesomycetozoea (e.g., Rhinosporidium seeberi).

[0106] Unless indicated otherwise, the terms "subject" or "patient" are used interchangeably and refer to an animal, preferably a warm-blooded animal, more preferably a vertebrate, even more preferably a mammal, such as a chimpanzee and other ape and monkey species, cattle, sheep, pigs, goats, horses, dogs, cats, mice, rats, guinea pigs, etc., still more preferably a primate, and particularly includes human patients and non-human mammals and primates. A preferred subject is a human subject including all genders and all age categories. The term "subject" is intended to cover adult subjects, elderly subjects, children, and neonatal subjects. The terms "subject" or "patient" include subjects in need of treatment, more particularly subjects who would benefit from treatment of a given condition (particularly an infectious disease). Such subjects may include, but are not limited to, those who have been diagnosed with the condition, those who are predisposed to developing the condition, and / or those in whom the condition is to be prevented. Unless the context clearly indicates otherwise, the terms "subject" or "patient" include one or more subjects or patients.

[0107] "Diagnosis" and its variations refer to the process of identifying, determining or concluding a disease, disorder or (adverse side effect) in a subject based on the results of symptoms and signs and / or a variety of diagnostic procedures (e.g., by understanding the presence, absence and / or quantity of one or more biomarkers of the diagnosed disease or disorder or the presence, absence and / or quantity of clinical symptoms specific to the diagnosed disease or disorder). "Diagnosing" a disease, disorder or (adverse) side effect taught herein in a subject may specifically mean that the subject suffers from such a disease or disorder. Although the subject exhibits one or more conventional symptoms or signs similar to such a disease or disorder, it can still be diagnosed as not suffering from such a disease or disorder. "Diagnosing" a disease or disorder taught herein in a subject may specifically mean that the subject suffers from an infectious disease. Alternatively, although the subject exhibits one or more conventional symptoms or signs similar to an infectious disease, it can still be diagnosed as not suffering from such an infectious disease. In the context of the present invention, "prognosis" refers to the prospect (e.g., probability, duration and / or extent) of the progression and recovery of a respiratory infection in a subject, and / or the severity of the infection or improvement of the infection. The term "good prognosis" generally encompasses an expectation of satisfactory partial or complete recovery from a diagnosed pain-inducing disease or painful condition, optionally within an acceptable time period. Alternatively, the term may also encompass an expectation that such a pain-inducing disease or painful condition will not further deteriorate or worsen, preferably within a given time period. The term "poor prognosis" for a disease or condition generally encompasses an expectation of substandard recovery and / or unsatisfactorily slow recovery, or no recovery at all, or further worsening of respiratory infection and / or any clinical manifestations associated with the disease or condition.

[0108] In connection with the foregoing, "prediction" or variations thereof generally refers to a statement, declaration, indication or prognosis of a disease or disorder in an object that has not (not yet) exhibited any or only limited clinical manifestations of the disease, disorder or (adverse) side effects. Prediction of certain clinical disease manifestations, disorders or adverse effects in an object can indicate the likelihood, chance or risk that the object will develop the clinical manifestations, disorder or (adverse) side effects, for example, within a certain time period after diagnosis of an infectious disease. The likelihood, chance or risk can be expressed in any suitable qualitative or quantitative expression, some non-limiting examples of quantitative expressions including absolute values, ranges or statistics. Alternatively, the likelihood, chance or risk can be expressed relative to a suitable control object or group of control objects (i.e., control population) (e.g., relative to a general, normal or healthy object or population). Thus, any likelihood, chance or risk can be advantageously expressed as an increase or decrease, upregulation or downregulation, multiplicative increase or multiplicative decrease relative to a suitable control object or group of control objects, or relative to a baseline value, which can be derived from a control object (population), a textbook reference value. Obviously, when a population of objects is used to define the baseline value, the baseline value will be a central measure of one or more values (parameters) in the population, such as the mean or median of the values. Those skilled in the art should also understand that monitoring of an infectious disease can permit prediction of the progression, exacerbation, alleviation or recurrence of the clinical picture or the severity of the infection. In addition, monitoring can be applied during the medical treatment of a patient. Such monitoring can include, for example, determining whether a patient can be discharged from a controlled clinical or medical practice setting, whether a change in treatment or therapy is needed, or whether hospitalization (extension) is required.

[0109] In certain preferred embodiments, the object is a hospitalized object. In some more preferred embodiments, the object is a hospitalized object who is considered to have a poor disease prognosis.

[0110] In certain preferred embodiments, the object is a non-hospitalized (community-treated) patient.

[0111] In certain preferred embodiments, the object has mild, moderate or severe symptoms or mild, moderate or severe clinical manifestations of an infectious disease, and the infectious disease is, for example, a respiratory infectious disease, such as but not limited to SARS-CoV-2 infection (COVID-19).

[0112] In some specific embodiments, the subject is at a relatively high risk of having a severe course of the respiratory infectious disease (such as but not limited to SARS-CoV-2 infection (COVID-19)), and / or in which conventional treatment may be insufficiently effective. Thus, in some specific embodiments, the subject for whom the disease is to be treated / prevented is 60 years of age or older, preferably 65 years of age or older, such as 70 years of age or older. In some specific embodiments, the subject for whom the disease is to be treated / prevented is a subject with severe immune impairment (immunocompromised). In some specific embodiments, the subject for whom the disease is to be treated / prevented has a disease or disorder selected from the following: hypertension, diabetes, kidney disease, human immunodeficiency virus infection, obesity, Down syndrome, cardiovascular disease, cancer, and chronic respiratory disease.

[0113] The applicability of the technical effects observed in the treatment with the composition comprising plasma and immunoglobulins described herein does not depend on whether the subject to whom the composition described herein is administered has completed the conventional vaccination program for the respiratory infectious disease (such as SARS-CoV-2 (COVID-19)).

[0114] In essence, the composition of the present invention can be used as a first response or rapid response means to avoid the spread of the pathogen to the population and cause a pandemic before or during the development of a conventional vaccine and / or treatment process.

[0115] Vaccination (such as a conventional vaccine) may not completely inhibit the spread of the pathogen of the infectious disease from one subject to another. In such a case, it may also be advantageous to administer the composition comprising plasma and immunoglobulins as described herein to the vaccinated subject. Thus, in some specific embodiments, the subject to whom the composition as described herein is administered has received a vaccine (such as a conventional vaccine) for the infectious disease before being administered the composition comprising convalescent plasma as described herein.

[0116] In some specific embodiments, the subject to whom the composition as described herein is administered has not received a vaccine (such as a conventional vaccine) for the infectious disease before being administered the composition comprising plasma and immunoglobulins as described herein. For example, in the early stages of an epidemic, a vaccine (such as a conventional vaccine) may still not be available. The composition comprising plasma and immunoglobulins as described herein allows for the treatment and / or prevention of infection in subjects during the early stages of the epidemic.

[0117] In some specific embodiments, administering to a subject a composition comprising plasma and immunoglobulins as described herein can be advantageous, not only as a first response or rapid response means to avoid the spread of a pathogen to the population and cause a pandemic, but also to induce a humoral immune response against the pathogen in the subject. Thus, a composition comprising plasma and immunoglobulins as described herein can be used as an early vaccine for the infectious disease.

[0118] In some specific embodiments, the infectious disease is a respiratory infectious disease, and more specifically, the respiratory infectious disease is SARS-CoV-2, and the subject to be treated and / or prevented from the disease does not have chronic olfactory dysfunction (COD).

[0119] In some specific embodiments, the donor subject from whom the convalescent plasma is obtained and the subject to whom the composition comprising plasma and immunoglobulins is administered are from the same animal species. For example, if the donor is human, the subject to whom the composition comprising plasma and immunoglobulins is administered is human.

[0120] In some specific embodiments, the composition to be administered to a subject comprises, consists essentially of, or consists of plasma and immunoglobulins against the pathogen of the infectious disease, preferably consists of them, wherein the immunoglobulins are obtained from a donor subject who has developed a humoral immune response against the pathogen of the infectious disease.

[0121] The combination of plasma and immunoglobulins against the pathogen of the infectious disease present in the composition to be administered to a subject can be convalescent plasma, which itself contains a combination of plasma and immunoglobulins, or can be plasma, such as healthy plasma, to which immunoglobulins against the pathogen of the infectious disease, such as purified immunoglobulins, are added. Preferably, the composition comprising plasma and immunoglobulins as described herein is convalescent plasma.

[0122] Thus, in some specific embodiments, when plasma is combined with purified immunoglobulins, the plasma is not convalescent plasma. Thus, in other words, in some specific embodiments, when plasma is combined with purified immunoglobulins, the plasma is not obtained from a donor subject who has developed a humoral immune response against the pathogen of the infectious disease. In some specific embodiments, when plasma is combined with purified immunoglobulins, the plasma is obtained from one or more healthy subjects. A healthy subject can be a subject not affected by pathological changes.

[0123] In some specific embodiments, the compositions as described herein comprise at least 20% (v / v), at least 25% (v / v), at least 30% (v / v), at least 35% (v / v), at least 40% (v / v), at least 45% (v / v), at least 50% (v / v), at least 55% (v / v), at least 60% (v / v), at least 65% (v / v), at least 70% (v / v), at least 75% (v / v), at least 80% (v / v), at least 85% (v / v), at least 90% (v / v) or at least 95% (v / v) plasma and immunoglobulins, such as at least 96% (v / v), at least 97% (v / v), at least 98% (v / v), at least 99% (v / v) or at least 100% (v / v) plasma and immunoglobulins.

[0124] In some specific embodiments, when plasma is combined with purified immunoglobulins, the compositions as described herein comprise at least 20% (v / v), at least 25% (v / v), at least 30% (v / v), at least 35% (v / v), at least 40% (v / v), at least 45% (v / v), at least 50% (v / v), at least 55% (v / v), at least 60% (v / v), at least 65% (v / v), at least 70% (v / v), at least 75% (v / v), at least 80% (v / v), at least 85% (v / v), at least 90% (v / v) or at least 95% (v / v) plasma, such as at least 96% (v / v), at least 97% (v / v), at least 98% (v / v) or at least 99% (v / v) plasma.

[0125] In some specific embodiments, when plasma is combined with purified immunoglobulins, the immunoglobulin (Ig) is purified from convalescent plasma from donor subjects that have developed a humoral immune response to the causative agent of the infectious disease. For example, immunoglobulins can be purified from convalescent plasma using affinity chromatography, such as affinity chromatography using Protein A (e.g., catalog number ab270308, Abcam) and Protein G resin (e.g., catalog number ab270309, Abcam).

[0126] The purified immunoglobulins can be a mixture of immunoglobulins specific for the causative agent of the respiratory infectious disease and other immunoglobulins present in the blood sample. In some specific embodiments, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25% or at least 30% of the total amount of purified immunoglobulins is immunoglobulins specific for the causative agent of the infectious disease.

[0127] The inventor has found that immunoglobulins present in the purified immunoglobulins but not directed against the pathogenic agent of the infectious disease do not interfere with the function of the targeted specific immunoglobulins against the pathogenic agent of the infectious disease.

[0128] In some specific embodiments, when plasma is combined with the purified immunoglobulins, the immunoglobulins (Ig) purified from the convalescent plasma of a donor subject who has developed a humoral immune response to the pathogenic agent of the infectious disease comprise IgG, IgA, and IgM, or consist essentially of or consist of the same.

[0129] In some specific embodiments, when plasma is combined with the purified immunoglobulins, the composition as described herein comprises at least 1 mg / ml, at least 2 mg / ml, at least 3 mg / ml, at least 4 mg / ml, at least 5 mg / ml, at least 6 mg / ml, at least 7 mg / ml, at least 8 mg / ml, at least 9 mg / ml, at least 10 mg / ml, such as at least 11 mg / ml, at least 12 mg / ml, or at least 13 mg / ml of Ig obtained from a donor subject who has developed a humoral immune response to the pathogenic agent of the infectious disease.

[0130] In some specific embodiments, when plasma is combined with purified immunoglobulins, the composition as described herein contains at least 100 binding antibody units (BAU) / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, or at least 3500 BAU / ml, preferably at least 450 BAU / ml, more preferably at least 750 BAU / ml, and even more preferably at least 900 BAU / ml of IgG against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the composition contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, or at least 3500 BAU / ml, preferably at least 450 BAU / ml, such as at least 600 BAU / ml, more preferably at least 750 BAU / ml, and even more preferably at least 900 BAU / ml of anti-receptor binding domain (RBD) IgG.

[0131] In some specific embodiments, when plasma is combined with purified immunoglobulins, the composition as described herein contains at least 5 μg / ml, at least 6 μg / ml, at least 7 μg / ml, at least 8 μg / ml, at least 9 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml, at least 15 μg / ml, at least 20 μg / ml, at least 30 μg / ml, at least 40 μg / ml, at least 50 μg / ml, at least 60 μg / ml, at least 70 μg / ml, at least 80 μg / ml, at least 90 μg / ml or at least 100 μg / ml, preferably at least 10 μg / ml, more preferably at least 15 μg / ml of IgG against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the composition contains at least 5 μg / ml, at least 6 μg / ml, at least 7 μg / ml, at least 8 μg / ml, at least 9 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml, at least 15 μg / ml, at least 20 μg / ml, at least 30 μg / ml, at least 40 μg / ml, at least 50 μg / ml, at least 60 μg / ml, at least 70 μg / ml, at least 80 μg / ml, at least 90 μg / ml or at least 100 μg / ml, preferably at least 10 μg / ml, more preferably at least 15 μg / ml of anti-receptor binding domain (RBD) IgG.

[0132] In some specific embodiments, when plasma is combined with purified immunoglobulins, the composition as described herein contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, at least 3500 BAU / ml, at least 4000 BAU / ml, at least 4500 BAU / ml, at least 5000 BAU / ml or at least 5500 BAU / ml, preferably at least 300 BAU / ml, more preferably at least 400 BAU / ml of IgA against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the composition contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, at least 3500 BAU / ml, at least 4000 BAU / ml, at least 4500 BAU / ml, at least 5000 BAU / ml or at least 5500 BAU / ml, preferably at least 300 BAU / ml, more preferably at least 400 BAU / ml of anti-RBD IgA.

[0133] In some specific embodiments, when plasma is combined with purified immunoglobulins, the composition as described herein contains at least 0.1 μg / ml, at least 0.15 μg / ml, at least 0.2 μg / ml, at least 0.25 μg / ml, at least 0.3 μg / ml, at least 0.35 μg / ml, at least 0.4 μg / ml, at least 0.45 μg / ml, at least 0.5 μg / ml, at least 1 μg / ml, at least 5 μg / ml, at least 7.5 μg / ml, at least 10 μg / ml, preferably at least 0.25 μg / ml, and more preferably at least 0.3 μg / ml of IgA against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the composition contains at least 0.1 μg / ml, at least 0.15 μg / ml, at least 0.2 μg / ml, at least 0.25 μg / ml, at least 0.3 μg / ml, at least 0.35 μg / ml, at least 0.4 μg / ml, at least 0.45 μg / ml, at least 0.5 μg / ml, at least 1 μg / ml, at least 5 μg / ml, at least 7.5 μg / ml, at least 10 μg / ml, preferably at least 0.25 μg / ml, and more preferably at least 0.3 μg / ml of anti-receptor binding domain (RBD) IgA.

[0134] In some specific embodiments, when plasma is combined with purified immunoglobulins, the composition as described herein contains - at least 5 μg / ml, at least 6 μg / ml, at least 7 μg / ml, at least 8 μg / ml, at least 9 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml or at least 15 μg / ml, preferably at least 10 μg / ml, and more preferably at least 15 μg / ml of IgG against the pathogen of the infectious disease; and - at least 0.1 μg / ml, at least 0.15 μg / ml, at least 0.2 μg / ml, at least 0.25 μg / ml, at least 0.3 μg / ml, preferably at least 0.25 μg / ml, and more preferably at least 0.3 μg / ml of IgA against the pathogen of the infectious disease.

[0135] In some specific embodiments, when plasma is combined with purified immunoglobulins, if the respiratory infectious disease is caused by SARS-CoV-2, the composition as described herein does not contain a detectable level of IgM against the pathogen of the respiratory infectious disease, such as anti-RBD IgM. In some specific embodiments, when plasma is combined with purified immunoglobulins, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the composition as described herein contains less than 50 BAU / ml, less than 40 BAU / ml, less than 30 BAU / ml, less than 20 BAU / ml, or less than 10 BAU / ml of IgM against the pathogen of the infectious disease, such as anti-RBD IgM.

[0136] In some specific embodiments, when plasma is combined with purified immunoglobulins, the donor subject of the plasma and the donor subject of the immunoglobulins are different subjects or groups of subjects.

[0137] As used herein, the term "convalescent plasma" refers to plasma obtained from a subject who has developed a humoral immune response against the pathogen of an infectious disease (such as an infectious disease). As a result, convalescent plasma contains antibodies against the current pathogen, such as immunoglobulins. A subject can acquire humoral immunity by resisting infection caused by the pathogen and / or recovering from infection caused by the pathogen, by variolation, by vaccination, or by any other means. Convalescent plasma typically contains one or more cytokines (e.g., IL-10, chemokine ligand 2 (CCL2), or tumor necrosis factor (TNF)), one or more downstream effectors of innate immunity, one or more complement activators (e.g., C3 complement), and / or one or more clotting factors, such as clotting factor I, clotting factor II, clotting factor III, clotting factor IV, clotting factor V, clotting factor VI, clotting factor VII, clotting factor VIII, clotting factor IX, clotting factor X, clotting factor XI, clotting factor XII, and / or clotting factor XIII. Preferably, one or more complement activators and / or clotting factors are present in convalescent plasma at normal physiological levels (i.e., the physiological concentration of the one or more clotting factors in a healthy subject).

[0138] Preferably, the convalescent plasma is obtained from donor subjects who have recovered from the infectious disease and / or have been vaccinated against the infectious disease. Prior infection can be determined by all methods known in the art, such as but not limited to PCR, chest computed tomography, or serological assays. If the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by the SARS-CoV2 virus, the donor subject may have been vaccinated with the anti-SARS-CoV2 Pfizer / BioNTech (Comirnaty) vaccine and the Moderna anti-SARS-CoV2 booster vaccine (Spikevax).

[0139] In some specific embodiments, the convalescent plasma is obtained from donor subjects who have recovered from the infectious disease and have not been vaccinated against the infectious disease.

[0140] In some specific embodiments, the convalescent plasma is obtained from donor subjects who have recovered from the infectious disease and have been vaccinated against the infectious disease prior to infection with the infectious disease.

[0141] In some specific embodiments, the convalescent plasma is obtained from a donor subject whose symptoms have resolved at least 10 days, at least 11 days, at least 12 days, at least 13 days, preferably at least 14 days prior to obtaining the convalescent plasma from the donor subject.

[0142] Preferably, the convalescent plasma is allogeneic convalescent plasma, meaning that the donor subject and the subject to whom the pharmaceutical composition containing the convalescent plasma is administered are from the same species but are genetically different.

[0143] The convalescent plasma as described herein is generally naturally enriched with antibodies against the causative agent (e.g., pathogen) of the infectious disease.

[0144] In some specific embodiments, the convalescent plasma contains at least 5 mg / ml, at least 6 mg / ml, at least 7 mg / ml, at least 8 mg / ml, at least 9 mg / ml, at least 10 mg / ml, such as at least 11 mg / ml, at least 12 mg / ml, at least 13 mg / ml, at least 15 mg / ml, at least 16 mg / ml, at least 17 mg / ml, or at least 18 mg / ml of Ig.

[0145] In some specific embodiments, the convalescent plasma contains at least 100 binding antibody units (BAU) / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, or at least 3500 BAU / ml, preferably at least 450 BAU / ml, more preferably at least 750 BAU / ml, and even more preferably at least 900 BAU / ml of IgG against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, or at least 3500 BAU / ml, preferably at least 450 BAU / ml, more preferably at least 750 BAU / ml, and even more preferably at least 900 BAU / ml (binding antibody units (BAU) / ml) of anti-receptor binding domain (RBD) IgG.

[0146] In some specific embodiments, the convalescent plasma contains at least 5 μg / ml, at least 6 μg / ml, at least 7 μg / ml, at least 8 μg / ml, at least 9 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml, at least 15 μg / ml, at least 20 μg / ml, at least 30 μg / ml, at least 40 μg / ml, at least 50 μg / ml, at least 60 μg / ml, at least 70 μg / ml, at least 80 μg / ml, at least 90 μg / ml or at least 100 μg / ml, preferably at least 10 μg / ml, more preferably at least 15 μg / ml of IgG against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma contains at least 5 μg / ml, at least 6 μg / ml, at least 7 μg / ml, at least 8 μg / ml, at least 9 μg / ml, at least 10 μg / ml, at least 11 μg / ml, at least 12 μg / ml, at least 13 μg / ml, at least 14 μg / ml, at least 15 μg / ml, at least 20 μg / ml, at least 30 μg / ml, at least 40 μg / ml, at least 50 μg / ml, at least 60 μg / ml, at least 70 μg / ml, at least 80 μg / ml, at least 90 μg / ml or at least 100 μg / ml, preferably at least 10 μg / ml, more preferably at least 15 μg / ml of anti-receptor binding domain (RBD) IgG.

[0147] In some specific embodiments, the convalescent plasma contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, at least 3500 BAU / ml, at least 4000 BAU / ml, at least 4500 BAU / ml, at least 5000 BAU / ml or at least 5500 BAU / ml, preferably at least 300 BAU / ml, more preferably at least 400 BAU / ml of IgA against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma contains at least 100 BAU / ml, at least 200 BAU / ml, at least 300 BAU / ml, at least 400 BAU / ml, at least 500 BAU / ml, at least 600 BAU / ml, at least 700 BAU / ml, at least 800 BAU / ml, at least 900 BAU / ml, at least 1000 BAU / ml, at least 1500 BAU / ml, at least 2000 BAU / ml, at least 2500 BAU / ml, at least 3000 BAU / ml, at least 3500 BAU / ml, at least 4000 BAU / ml, at least 4500 BAU / ml, at least 5000 BAU / ml or at least 5500 BAU / ml, preferably at least 300 BAU / ml, more preferably at least 400 BAU / ml of anti-RBD IgA.

[0148] In some specific embodiments, the convalescent plasma contains at least 0.05 mg / kg, at least 0.1 μg / ml, at least 0.15 μg / ml, at least 0.2 μg / ml, at least 0.25 μg / ml, at least 0.3 μg / ml, at least 0.35 μg / ml, at least 0.4 μg / ml, at least 0.45 μg / ml, at least 0.5 μg / ml, at least 1 μg / ml, at least 5 μg / ml, at least 7.5 μg / ml, at least 10 μg / ml, preferably at least 0.25 μg / ml, and more preferably at least 0.3 μg / ml of IgA against the pathogen of the infectious disease. In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma contains at least 0.1 μg / ml, at least 0.15 μg / ml, at least 0.2 μg / ml, at least 0.25 μg / ml, at least 0.3 μg / ml, at least 0.35 μg / ml, at least 0.4 μg / ml, at least 0.45 μg / ml, at least 0.5 μg / ml, at least 1 μg / ml, at least 5 μg / ml, at least 7.5 μg / ml, at least 10 μg / ml, preferably at least 0.25 μg / ml, and more preferably at least 0.3 μg / ml of anti-receptor binding domain (RBD) IgA. In some embodiments, the amount of IgA against the pathogen of the infectious disease contained in the convalescent plasma is at most 0.1 mg / kg, preferably at most 0.07 mg / kg of Ig against the pathogen.

[0149] In some specific embodiments, if the respiratory infectious disease is caused by SARS-CoV-2, the convalescent plasma does not contain a detectable level of IgM against the pathogen of the respiratory infectious disease, such as anti-RBD IgM. In some specific embodiments, if the respiratory infectious disease is caused by SARS-CoV-2, the convalescent plasma contains less than 50 BAU / ml, less than 40 BAU / ml, less than 30 BAU / ml, less than 20 BAU / ml, or less than 10 BAU / ml of IgM against the pathogen of the respiratory infectious disease, such as anti-RBD IgM.

[0150] In some specific embodiments, if the infectious disease is a respiratory infectious disease, such as a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma can inhibit the viral replication of SARS-CoV-2 virus strains (preferably the original SARS-CoV-2 W strain) in vitro (e.g., in Vero E6 cells).

[0151] In some specific embodiments, if the infectious disease is a respiratory infectious disease caused by SARS-CoV-2, the convalescent plasma has a half-maximal plasma SARS-CoV-2 neutralizing antibody titer at a plasma dilution of at least 1:500, at least 1:1000, at least 1:2000, at least 1:3000, at least 1:4000, or at least 1:5000. The neutralizing antibody titer can be determined by any method known in the art, such as using the plaque reduction neutralization test (PRNT). Then, the half-maximal neutralization titer represents the plasma dilution that results in a 50% reduction in SARS-CoV-2 plaques.

[0152] In some specific embodiments, the convalescent plasma is collected from a donor subject by plasmapheresis.

[0153] In some specific embodiments, the plasma or convalescent plasma is substantially cell-free (i.e., at most 50,000 cells / μl of convalescent plasma, preferably at most 40,000 cells / μl of convalescent plasma).

[0154] In some specific embodiments, the plasma or convalescent plasma is a pooled plasma sample, meaning that the plasma or convalescent plasma is obtained from a single sample pool, where the sample pool contains samples from two or more subjects and / or samples from a single subject collected at different time points. In some specific embodiments, the plasma or convalescent blood sample is a pooled sample, where the sample pool contains plasma or convalescent plasma from at most 100, at most 90, at most 80, at most 70, at most 60, at most 50, at most 40, at most 30, at most 20, at most 10, or at most 5 donor subjects. In some specific embodiments, the plasma or convalescent blood sample is obtained from a single donor subject.

[0155] In some specific embodiments, the plasma or convalescent blood sample is not platelet-rich plasma (PRP). In some specific embodiments, the compositions, plasma, or convalescent blood samples as described herein contain less than 100,000 platelets / μl, less than 90,000 platelets / μl, less than 80,000 platelets / μl, less than 70,000 platelets / μl, less than 60,000 platelets / μl, less than 50,000 platelets / μl, less than 40,000 platelets / μl, less than 30,000 platelets / μl, less than 20,000 platelets / μl, less than 10,000 platelets / μl, less than 5,000 platelets / μl, or less than 1,000 platelets / μl.

[0156] In some specific embodiments, the composition as described herein comprises at least 1% (v / v), at least 5% (v / v), at least 10% (v / v), at least 15% (v / v), at least 20% (v / v), at least 25% (v / v), at least 30% (v / v), at least 35% (v / v), at least 40% (v / v), at least 45% (v / v), at least 50% (v / v), at least 55% (v / v), at least 60% (v / v), at least 65% (v / v), at least 70% (v / v), at least 75% (v / v), at least 80% (v / v), at least 85% (v / v), at least 90% (v / v) or at least 95% (v / v), such as at least 96% (v / v), at least 97% (v / v), at least 98% (v / v), at least 99% (v / v) or 100% (v / v) of convalescent plasma obtained from the donor subject. In some specific embodiments, the composition as described herein consists of convalescent plasma obtained from the donor subject.

[0157] In some specific embodiments, in addition to antibodies (such as immunoglobulins) against the causative agents of infectious diseases present in the convalescent plasma, or in addition to purified immunoglobulins against the causative agents of infectious diseases present in the composition, the composition as described herein further comprises antibodies or antibody fragments against the causative agents of infectious diseases. In some specific embodiments, the composition may further comprise one or more recombinant antibodies or antibody fragments against the causative agents of infectious diseases, such as recombinant monoclonal antibodies. For example, if the infectious disease is a respiratory infectious disease and is COVID-19, the composition may further comprise immunoglobulin M (IgM) neutralizing antibody (IgM-14), as described in Zhiqiang Ku et al., Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variatns, Nature, 2021, 595:718-723.

[0158] The term "antibody" is used herein in its broadest sense and generally refers to any immunoconjugate, such as a complete antibody, including but not limited to chimeric, humanized, human, recombinant, transgenic, grafted, and single-chain antibodies, etc., or any fusion protein, conjugate, fragment, or derivative thereof containing one or more domains that selectively bind to an antigen of interest. Thus, the term antibody includes intact immunoglobulin molecules, monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, or immunologically effective fragments of any of these. Thus, the term specifically encompasses intact monoclonal antibodies, polyclonal antibodies, multivalent (e.g., bivalent, trivalent, or more valent) and / or multispecific antibodies (e.g., bispecific or more specific antibodies) formed from at least two intact antibodies, and antibody fragments (so long as they exhibit the desired biological activity (particularly the ability to specifically bind to an antigen of interest)), as well as multivalent and / or multispecific complexes of such fragments. The term "antibody" includes not only antibodies produced by methods including immunization, but also any polypeptide, such as a recombinantly expressed polypeptide, that is made to encompass at least one complementarity-determining region (CDR) capable of specifically binding to an epitope on an antigen of interest. Thus, the term applies to such molecules whether they are produced in vitro, in cell culture, or in vivo.

[0159] The term "antibody fragment" or "antigen-binding portion" encompasses a part or region of a full-length antibody, typically its antigen-binding domain or variable domain. Some examples of antibody fragments include Fab, Fab', F(ab)2, Fv, scFv fragments, single-domain (sd)Fv, such as V H domain, V L domain, and V HH domain, diabodies, linear antibodies, single-chain antibody molecules, particularly heavy-chain antibodies; and multivalent and / or multispecific antibodies formed from antibody fragments, such as diabodies, triabodies, and multibodies. The above names Fab, Fab', F(ab')2, Fv, scFv, etc. are intended to have their meanings as determined in the art. In certain embodiments, the antibody fragment can be

[0160] In some specific embodiments, the compositions described herein do not contain one or more recombinant antibodies or antibody fragments against a pathogen of an infectious disease, such as a recombinant monoclonal antibody.

[0161] In some specific embodiments, when the composition as described herein comprises convalescent plasma obtained from the donor subject who has developed a humoral immune response to the causative agent of the infectious disease, the convalescent plasma obtained from the donor subject who has developed a humoral immune response to the causative agent of the infectious disease is not subjected to a purification step to isolate and / or concentrate the antibodies or antibody fragments therein.

[0162] In some specific embodiments, the plasma and / or convalescent plasma is subjected to pathogen inactivation (also known as pathogen reduction). Pathogen inactivation of blood-derived products is known in the art and can be carried out using Intercept Blood System (CERUS, Concord CA), Mirasol Pathogen Reduction (Terumo BCT, Denver, CO) or Theraflex UVC (Macopharma, Tourcoing, FR).

[0163] In some specific embodiments, the plasma and / or convalescent plasma is substantially free of any infectious agents (e.g., microorganisms including bacteria, viruses and protozoa) that can cause disease in a subject to whom the plasma and / or convalescent plasma (or immunoglobulins purified from the convalescent plasma) is administered. In some more specific embodiments, the plasma and / or convalescent plasma is substantially free of human immunodeficiency virus (HIV), hepatitis (e.g., hepatitis B or hepatitis C) virus and Treponema pallidum (i.e., the bacterium that causes syphilis).

[0164] In some specific embodiments, the plasma and / or convalescent plasma can be fresh plasma and / or convalescent plasma, or can be stored prior to use. In some specific embodiments, the plasma and / or convalescent plasma is stored at a temperature of -210°C to 25°C. For example, the plasma and / or convalescent plasma can be stored at a temperature of -196°C to -210°C (e.g., in liquid nitrogen), at a temperature of -80°C (e.g., in a freezer), at a temperature of -20°C (e.g., in a freezer), at a temperature of 4°C (e.g., in a refrigerator) or at room temperature. The plasma and / or convalescent plasma can be stored for up to one year or longer (e.g., 2 years). For example, the plasma and / or convalescent plasma can be stored for more than one year at a temperature below -30°C. In another example, the plasma and / or convalescent plasma can be stored at a temperature of -25°C to -30°C for up to 6 months.

[0165] In some specific embodiments, the plasma and / or convalescent plasma can be stored for at least 0.5 hour, at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, at least 26 hours, at least 28 hours, or at least 30 hours before its use.

[0166] In some specific embodiments, if the plasma and / or convalescent plasma is frozen before its use, the convalescent plasma can be thawed at a temperature of at least 3°C, at least 4°C, at least 5°C, at least 10°C, at least 15°C, at least 20°C, at least 25°C, at least 30°C, at least 35°C, at least 36°C, or at least 37°C after freezing. For example, the plasma and / or convalescent plasma can be thawed at 4°C (e.g., in a refrigerator), at room temperature, or at 37°C (e.g., in a warm water bath).

[0167] The compositions as described herein are administered to the airway or respiratory tract to enhance the potency against the causative agent of the infectious disease.

[0168] Intranasal or naso - oropharyngeal administration of the compositions as described herein preferably saturates the nasopharyngeal and / or oropharyngeal mucosa, thereby preventing or delaying the infection by the causative agent of the infectious disease.

[0169] Administration to the airway or respiratory tract can be achieved by any recognized or known method and can include naso - oropharyngeal administration, inhaled administration, or intranasal administration. To enhance effectiveness, neutralizing antibodies are delivered to one or more of the upper and lower respiratory tracts, and can include the nasal cavity, nose, sinuses, throat, pharynx (including nasopharynx, oropharynx, and laryngopharynx), larynx, trachea, bronchi, and lungs.

[0170] Inhalation refers to the intake, particularly in the context of intake or administration / being administered, of delivering an agent or compound (including the compositions as described herein) to the respiratory tract. The respiratory tract can include the upper respiratory tract and / or the lower respiratory tract. The upper respiratory tract includes the nose, nasal cavity, sinuses, larynx, and trachea. The lower respiratory tract includes the lungs, airways (bronchi and bronchioles), and air sacs (alveoli). Inhalation can occur via the nose or via the mouth, or via direct administration to the lower respiratory tract (such as in endotracheal administration). Thus, inhalation can include only the nose or mainly include intranasal, inhalation via the mouth, oral inhalation, endotracheal inhalation, endotracheal instillation. Thus, inhalation provides and contemplates any means of administration by which the compositions as described herein are exclusively, specifically, or preferentially deposited at or in the respiratory tract, including the upper respiratory tract and / or the lower respiratory tract.

[0171] As used herein, the term intranasal includes, but is not limited to, administering, administration, or occurrence within or via the nose or nasal structures. The term intranasal as used herein and as exemplified as an embodiment in the Examples is not intended to be limited to or imply direct or specific or only via the nose or nasal cavity administration, particularly for the purpose of excluding other modes of administration, whereby the compositions described herein are delivered or otherwise provided to the respiratory tract, deposited in the respiratory tract, or otherwise distributed to the respiratory tract at or in the respiratory tract.

[0172] As used herein, the term naso - oropharyngeal includes, but is not limited to, administering, administration, or occurrence within or via the nose, oral cavity, or pharynx. The oropharynx is the part of the pharynx located posterior to the mouth, behind the oral cavity, and contains the soft palate, the lateral and posterior walls of the pharynx, the tonsils, and the posterior (about one - third) of the tongue.

[0173] Devices for administering or delivering to the respiratory tract or airway are known and recognized in the art and in clinical or medical practice and can be applied to the uses, pharmaceutical compositions, methods, and regimens of the present invention. Devices include metered spray pumps, hand - bulb atomizers, intranasal or naso - oropharyngeal spray devices, nebulizers, atomizers, metered dose inhalers (MDIs), pressurized dose inhalers, insufflators, intranasal inhalers, nasal spray bottles, unit - dose containers, pumps, droppers, squeeze bottles, or two - way devices. Convalescent plasma or pharmaceutical compositions can also be delivered by tubes, catheters, syringes, packtails, pledgets, nasal or naso - oropharyngeal tampons, or by submucosal infusion.

[0174] For example, a container closure system for a nasal spray includes a container and all components responsible for metering, atomizing, and delivering the formulation to a subject. The dose of the composition as described herein can be metered by the spray pump of a nasal or nasal-oral spray device, or can be pre-metered during manufacture. The nasal or nasal-oral spray unit can be designed for unit dose or can dispense a large metered spray containing the pharmaceutical composition as described herein. The nasal spray is applied to the nasal cavity to achieve local and / or systemic effects. Current container closure system designs for inhaled spray drug products include both pre-metered and device-metered presentations, both of which use mechanical or electrical assistance and / or energy from the patient's inspiration to generate a spray plume. The pre-metered presentation contains a pre-measured dose or dose portion in some type of unit (e.g., a single or multiple blisters or other cavities), which are then inserted into the device during preparation or by the patient prior to use. A typical device-metered unit has a reservoir containing a formulation sufficient for multiple doses, which are delivered as a metered spray by the device itself when activated by the patient.

[0175] In some specific embodiments, the composition as described herein is in a form suitable for administration to the airways or respiratory tract, e.g., in a form suitable for reaching the nasopharynx and optionally the oropharynx.

[0176] Preferably, the composition as described herein is in a form suitable for nasal or nasopharyngeal inhalation and / or oral inhalation, e.g., in the form of an inhalation solution or suspension.

[0177] In some specific embodiments, the composition as described herein is in a form suitable for administration to the nasal or naso-oro-pharyngeal mucosa.

[0178] In some specific embodiments, the composition as described herein is administered in the form of an aerosol, liquid, or liquid spray.

[0179] In some specific embodiments, the composition is a pulmonary aerosolized formulation, nasal or naso-oro-pharyngeal drops, oro-nasal drops, nasal or naso-oro-pharyngeal irrigants, nasal or naso-oro-pharyngeal sprays, or oro-nasal sprays. Consistent therewith, another aspect provided herein is a nasal, naso-oro-pharyngeal, or oro-nasal spray containing the composition, the composition comprising plasma and immunoglobulins against the causative agent of the infectious disease, wherein the immunoglobulins are obtained from a donor subject that has mounted a humoral immune response against the causative agent of the infectious disease. In some specific embodiments, the spray is an aerosol spray or a nebulized spray.

[0180] The compositions or sprays can be formulated into a form suitable for administration using methods known and acceptable in the art, the medical field, and clinical practice. In some specific embodiments, the compositions or sprays are pharmaceutical compositions. In addition to plasma and immunoglobulins as described herein, the compositions or sprays can contain one or more excipients (such as preservatives (such as biostatic agents), antioxidants, defoaming agents, viscosity regulators, emulsifiers, suspending agents, buffers). Commonly used defoaming agents are certain alcohols (cetostearyl alcohol), insoluble oils (castor oil), stearates, polydimethylsiloxane and other silicone derivatives, ethers, and ethylene glycols. Commonly used preservatives include benzoic acid, benzalkonium chloride, thimerosal, chlorobutanol, chlobutol, potassium sorbate, and methyl paraben. Commonly used buffers include glycerol, monopotassium phosphate, and / or dipotassium phosphate. Commonly used antioxidants include sodium metabisulfite, sodium bisulfate, butylated hydroxytoluene, and tocopherol.

[0181] In some specific embodiments, the compositions or sprays can contain up to 0.001% (w / w) of a preservative. In some specific embodiments, the compositions or sprays are preservative-free.

[0182] The pH of nasal or naso-oro-pharyngeal formulations or sprays is important for avoiding irritation of the nasal or naso-oro-pharyngeal mucosa. In some specific embodiments, the pH of the compositions or sprays is from 4.5 to 7.5, preferably from 5.5 to 6.5.

[0183] Extended residence time in the nasal or naso-oro-pharyngeal region can generally be achieved by using bioadhesive polymers, microspheres, chitosan, or by increasing the viscosity of the formulation or spray.

[0184] In some specific embodiments, the composition comprising plasma and immunoglobulins as described herein is administered to a subject at least once, such as once, twice, three times, or four times, preferably once or twice a day. In some specific embodiments, the composition comprising plasma and immunoglobulins as described herein is administered to a subject for at least 4 consecutive days, such as for at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, at least 10 consecutive days, at least 11 consecutive days, at least 12 consecutive days, at least 13 consecutive days, or at least 14 consecutive days.

[0185] Nasal, naso-oro-pharyngeal, or oro-nasal formulations are typically administered in small volumes of 25 to 200 μL or 50 to 150 μL (such as 100 μL).

[0186] The compositions as described herein can be administered to the subject before or after the subject has been exposed (i.e., has been subjected to) the causative agent (e.g., pathogen) of the infectious disease. Exposure does not always result in infection. For example, if a person is exposed to the causative agent for a very short time, if the amount of the causative agent entering the body is not in a sufficiently large amount, or if the immune system of the body can rapidly overcome it, the exposure will be less likely to result in infection. Exposure to the causative agent may occur as a result of the subject's close contact with an infected subject. Those skilled in the art will understand that the time between exposure to the causative agent and the appearance of symptoms depends on the type of infectious disease.

[0187] Thus, in some specific embodiments, the compositions as described herein are administered to the subject before the subject is exposed to the causative agent of the infectious disease. In some specific embodiments, the compositions as described herein are administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months or at least 6 months before the subject is exposed to the causative agent of the infectious disease.

[0188] In some specific embodiments, after the subject has been exposed to the causative agent of the infectious disease, e.g., after the subject has come into contact with a subject infected with the causative agent of the infectious disease, the compositions as described herein are administered to the subject (i.e., to avoid infection and the occurrence of respiratory diseases). Preferably, the compositions as described herein are administered to the subject immediately after the subject is informed that it has been exposed to the causative agent of the respiratory infectious disease. In some specific embodiments, the convalescent plasma is administered to the subject less than 1 hour, less than 2 hours, less than 6 hours, less than 12 hours, less than 18 hours, less than 1 day, less than 2 days, less than 3 days, less than 3 days, less than 5 days, less than 6 days, less than 7 days, less than 2 weeks, less than 3 weeks, less than 4 weeks after the subject has been exposed to the causative agent of the respiratory infectious disease. In some specific embodiments, the convalescent plasma is administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks after the subject has been exposed to the causative agent of the infectious disease.

[0189] In some specific embodiments, the composition as described herein is administered to the subject before the subject is infected with the causative agent of the infectious disease (i.e., to prevent transmission to an exposed but uninfected subject). In some specific embodiments, the composition as described herein is administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks before the subject is infected with the causative agent of the infectious disease.

[0190] In some specific embodiments, the composition as described herein is administered to the subject after the subject has been infected with the causative agent of the infectious disease (i.e., to prevent the occurrence and / or progression of a respiratory disease). In some specific embodiments, the composition as described herein is administered to the subject at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the subject is infected with the causative agent of the infectious disease.

[0191] A subject to whom the composition as described herein is administered may undergo conventional methods of treating, preventing, or vaccinating against infectious diseases.

[0192] In addition, the conventional treatment may be administered concomitantly with the composition as described herein or at different time points (e.g., before or after administering the composition as described herein). For example, a subject may have undergone conventional treatment before starting treatment with the composition as described herein.

[0193] The conventional treatment may be administered intranasally, naso - oropharyngeally, or by any other route of administration, such as orally only, intravenously, or intramuscularly.

[0194] In some specific embodiments, the composition as described herein is used to support conventional methods of treating, preventing, or vaccinating against infectious diseases.

[0195] In some specific embodiments, the composition as described herein is used in the absence of conventional methods of treating, preventing, or vaccinating against infectious diseases.

[0196] As used herein, "conventional treatment", which may be used interchangeably with "standard treatment", shall be construed as any treatment that a person skilled in the art would consider to have a reasonable chance of having any beneficial effect on an infected patient. These conventional treatments have been described in many instances in the art. For example, in embodiments where the infectious disease is a coronavirus, standard treatment procedures include, but are not limited to: administration of an active pharmaceutical ingredient that is not convalescent plasma, oxygen supplementation, mechanical respiratory assistance, or a combination thereof. In some more preferred embodiments, a composition comprising plasma and immunoglobulins as described herein is used to support at least one additional pharmaceutical active agent for treating an infectious disease in a subject. As referred to herein, "pharmaceutical active ingredient" or "API" shall be construed according to the definition of the term by the World Health Organization: "used in a finished pharmaceutical product (FPP) and intended to show pharmacological activity or otherwise have a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease or on the restoration, correction, or modification of a physiological function of a human being".

[0197] In some other more preferred embodiments, the at least one additional pharmaceutical active agent is an antiviral agent and / or an anti-inflammatory agent. As used herein, the terms "antiviral agent", "antiviral drug", or "antiviral therapeutic agent" denote any pharmaceutical active agent used for the treatment of viral infections. In some preferred embodiments, the antiviral agent is selected from the following: nucleoside / nucleotide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), integrase inhibitor, entry inhibitor, protease inhibitor (PI), post-attachment inhibitor, boosting agent (i.e., protease inhibitor stimulator), and any combination thereof. The terms "anti-inflammatory agent", "anti-inflammatory drug", or "anti-inflammatory therapeutic agent" denote any substance that reduces inflammation or swelling, preferably by inhibiting the activity of one or more cyclooxygenases (e.g., COX-1 and COX-2). For example, the anti-inflammatory drug may be a nonsteroidal anti-inflammatory drug (NSAID).

[0198] In some alternative preferred embodiments, at least one additional pharmaceutically active agent is selected from the following: corticosteroid, dexamethasone, tociluzamab, remdesivir, baricitinib, chloroquine, hydrochloroquine, lopinavir, ritonavir, favipiravir, camostat mesylate, azithromycin, interferon, immunomodulator, recombinant monoclonal antibody, ivermectin, colchicine, cyclooxygenase (COX)-1 and / or COX-2 inhibitor, angiotensin converting enzyme (ACE) inhibitor, or a combination thereof.

[0199] Accordingly, those skilled in the art will understand that the compositions comprising plasma and immunoglobulins as described herein can be administered in combination with any of the above pharmaceutically active agents, and preferred embodiments of such treatment strategies are described in further detail below.

[0200] Furthermore, the term "conventional treatment" should not be construed to refer only to treatment with pharmaceutically active ingredients or direct assistance with respiratory function, but also includes the post-acute rehabilitation process in a hospital setting, such as physical therapy exercises (Thomas et al., Physiotherapy management for COVID-19 in the acute hospital setting: clinical practice recommendations, J Physiother, 2020). In certain embodiments, the compositions comprising plasma and immunoglobulins as described herein are used in a post-acute hospital setting in a subject who additionally receives physical therapy to recover from or assist in the recovery from an infectious disease (such as SARS-CoV-2).

[0201] The invention also encompasses a delivery device suitable for nasal or nasal-oro-pharyngeal administration of the compositions comprising plasma and immunoglobulins (such as the compositions comprising convalescent plasma). If nasal or nasal-oro-pharyngeal (mucosal) administration is desired, the composition can be in a form and dispensed by a spraying device (such as a squeeze spray dispenser, droplet dispenser, pump dispenser, nebulizer or aerosol dispenser).

[0202] Accordingly, in another aspect, there is provided a nasal-oro-pharyngeal, nasal or oro-nasal spray device comprising a composition comprising plasma and immunoglobulins against a pathogen of an infectious disease, wherein the immunoglobulins are obtained from a donor subject that has mounted a humoral immune response against the pathogen of the infectious disease.

[0203] Those skilled in the art will understand that the spray device may comprise a container for containing a composition having a variable volume size. The choice of the filled volume of the container is typically determined by the intended frequency of use of the composition as described herein.

[0204] Those skilled in the art will understand that the spray device may comprise one or more doses of the composition as described herein. For example, the device may be a single-dose, double-dose or multi-dose delivery system. Preferably, the device is a single-dose delivery system, more preferably a disposable single-dose delivery system.

[0205] The spray device may have a certain spray volume. The choice of the spray volume is determined by the therapeutic dose.

[0206] The spray device may comprise a spray pump. The choice of the spray pump is determined by the volume of the composition as described herein required to support the dose.

[0207] In some specific embodiments, the nasal-oro-pharyngeal, nasal or oro-nasal spray device comprises a metered spray pump or a mechanical spray pump.

[0208] In some specific embodiments, the droplet size produced by the spray device is 0.1 to 300 μm, 10 to 200 μm, 50 to 200 μm or 100 to 200 μm.

[0209] In some specific embodiments, the spray device is an aerosol spray device or a nebulizer (e.g., a jet nebulizer, an ultrasonic nebulizer or a mesh nebulizer). Aerosols are typically maintained under pressure by hydrocarbons.

[0210] For example, the spray device may be an OptiNose liquid delivery nasal spray device or other similar devices that deliver drugs to both the olfactory and respiratory epithelia of the nasal cavity by spraying only when the connection between the nose and the lungs is closed, while preventing delivery to the lungs. In another example, the spray device may be a pressurized olfactory delivery device, such as an Impel NeuroPharma device, a metered dose nasal spray device or a unit dose nasal spray device. In another example, the spray device may be a single-dose (UDS) liquid nasal spray system from AptarPharma.

[0211] In some specific embodiments, a composition comprising plasma and immunoglobulins as described herein can stimulate a humoral immune response and, as a result, can be used as a first-line vaccine or vaccine-like composition. Accordingly, another aspect provides a method for producing a vaccine or vaccine-like composition, which comprises combining a composition comprising plasma and immunoglobulins against a pathogen that enters or spreads through the nasopharyngeal region with one or more pharmaceutically acceptable excipients, wherein the immunoglobulins are obtained from donor subjects that have developed a humoral immune response against the pathogen.

[0212] Those skilled in the art will understand that embodiments relating to compositions for the treatment or prevention of infectious diseases in a subject are also applicable to the naso-oro-pharyngeal, nasal or oro-nasal sprays and nasal or oro-nasal spray devices as described herein, and vice versa.

[0213] Although the invention has been described in connection with some specific embodiments of the invention, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0214] Aspects and embodiments of the invention disclosed herein are further supported by the following non-limiting examples. Example 1 Example 1. Intranasal administration of convalescent plasma provides protection against SARS-CoV-2 infection 1.1 Materials and methods Samples Human samples

[0215] Plasma samples were collected by plasmapheresis from donors (n = 2) recovered from SARS-CoV-2 infection or from vaccinated convalescent donors (n = 1), designated as COVID-19 convalescent plasma (CCP) and vaccinated COVID-19 convalescent plasma (VCCP), respectively. The CCP used during the study was designated as CCP1 and CCP2. Prior infections were determined by PCR, chest computed tomography, or serological assays. The neutralization titers of convalescent donations were determined by plaque reduction neutralization test (PRNT) at the Rega Institute for Medical Research (KU Leuven, Belgium) at least 14 days after symptom resolution. VCCP was collected after determination of high (neutralizing) antibody titers in an ELISA-based assay at least 14 days after symptom resolution. The VCCP donors received the Pfizer / BioNTech (Comirnaty) vaccine and the Moderna (Spikevax) booster vaccine. Plasma samples collected from a single donor prior to the COVID-19 pandemic were used as a naive non-immune control, designated as non-immune human plasma (NIP).人 )。 Hamster samples

[0216] Pooled non-immune hamster plasma (NIP 仓鼠 ) was provided by Janvier Labs (Le Genest-Saint-Isle, France) and by the Rega Institute for Medical Research (KU Leuven, Belgium). Convalescent hamster plasma (CCP 仓鼠 ) was obtained from Innovative Research Labs (Pearl Court Novi, USA). Human immunoglobulins in hamster plasma

[0217] Human immunoglobulins from vaccinated convalescent human plasma samples were purified by affinity chromatography using Protein A (catalog number ab270308, Abcam) and Protein G resin (catalog number ab270309, Abcam) according to the manufacturer's instructions. The purified human immunoglobulins were incorporated into phosphate buffered saline (PBS) at pH 7.4 (referred to as purified hIg) as the dialysis buffer (pH 7.4) or lyophilized with α1-4LSCbasic from Christ (Osterode am Harz, Germany) and reconstituted in NIP 仓鼠 and referred to as purified hIg in NIP 仓鼠 . In vitro characterization of human plasma samples SARS-CoV-2 in vitro enzyme-linked immunosorbent assay (ELISA)

[0218] A 96-well microtiter plate was coated overnight with recombinant SARS-CoV-2 receptor binding domain (RBD) (YP_009724390.1) (1 μg / mL). IgG / IgA / IgM isotype ELISA

[0219] The coated microtiter plate was blocked with assay buffer containing PBS at pH 7.4 with 1% [weight / volume] bovine serum albumin (BSA) for IgG isotype ELISA or PBS with 5% [volume / volume] rabbit serum for IgA and IgM isotype ELISAs. During the blocking step at room temperature (RT), plasma samples were diluted in the assay buffer: NIP 人Dilute 1 / 200 (IgG ELISA), 15 / 100 (IgA ELISA), or 1 / 10 (IgM ELISA). Dilute the CCP and purified hIg samples 1 / 2000 (IgG ELISA), 1.5 / 100 (IgA ELISA), or 1 / 10 (IgM ELISA) and dilute the VCCP 1 / 2000 (IgG and IgA ELISAs) or 1 / 10 (IgM ELISA). For all samples, perform in technical triplicate. Each plate includes a 16-step serial dilution of the CCP sample calibrated to the WHO international standard (NIBSC number: 20 / 136) as a standard (Bazett M, et al. Harnessing innate lung anti-cancer effector functions with a novel bacterial-derived immunotherapy. Oncoimmunology 7, e1398875 (2018). After a 1-hour incubation step at room temperature, incubate the specific rabbit anti-human secondary antibodies labeled with horseradish peroxide (HRP) targeting IgG (Fc γ fragment-specific), IgA (α-chain specific), or IgM (Fc 5μ fragment-specific) (IgG: catalog number 309-035-008, IgA: catalog number 309-035-011, IgM: catalog number 309-035-095, Jackson ImmunoResearch) for 1 hour at room temperature. For IgG isotype ELISA, incubate at a 1:15,000 dilution (5.33 ng / well) in assay buffer. Incubate the IgA and IgM isotype ELISAs at 1:10,000 dilution (8 ng / well) or 1:8,000 dilution (10 ng / well) in assay buffer, respectively. Develop color with 3,3’,5,5’-tetramethylbenzidine (TMB) substrate solution (catalog number T444, Sigma-Aldrich, St. Louis, MO, USA) for 6 minutes (IgG), 15 minutes (IgA), or 7 minutes (IgM). Measure the optical density at a wavelength of 450 nm in a spectrophotometer (Plate Reader Infinite F200 PRO, TECAN, Switzerland). For all isotype ELISAs, the coefficient of variation (CV) within and between assays is below 10% and 15%, respectively, and each is tested in quintuplicate. IgG / IgA Concentration ELISA

[0220] Blocking, sample dilution, and secondary antibody dilution were performed as previously described for IgG / IgA isotype ELISA. To determine antibody concentration, serial dilutions of anti-spike-RBD human IgG1 (catalog number srbd-mab1, Invivogen) incorporated in 1 / 200 human plasma pool (n = 15) or serial dilutions of anti-spike-RBD human IgA1 (catalog number srbd-mab6, Invivogen) in 15% NIP 人 were included as standards. Unless otherwise stated, all samples were run in technical triplicate. TMB was developed for 6 minutes (IgG) or 5 minutes (IgA). For both isotype concentration ELISAs (n = 4), the intra-assay and inter-assay CVs were below 15% and 20%, respectively. Inhibition ELISA

[0221] Inhibition ELISA from AcroBiosystems (catalog number EP-105, AcroBiosystems) was performed, with the exception of sample preparation (Almeida JR, et al. Harnessing snake venom phospholipases A2 to novel approaches for overcoming antibiotic resistance. Drug Dev Res 80, 68 - 85 (2019)), according to the manufacturer's instructions. Briefly, RBD was coated overnight at 4 °C. Plates were blocked with 2% [wt / vol] BSA in PBS. Plasma samples were serially diluted 2-fold in PBS containing 0.5% [wt / vol] BSA. The same CCP samples as used for IgG / IgA / IgM isotype ELISA were included in each plate as standards to allow conversion to units of the international WHO standard. A 1 / 2 mixture / well was prepared with biotinylated angiotensin-converting enzyme 2 (ACE2 receptor) and plasma diluent. After incubation, streptavidin-HRP was incubated. Development (10 minutes) and optical density readout were completed as previously described in the IgG / IgA / IgM isotype ELISA section. Data analysis

[0222] Data were processed in GraphPad Prism version 9 (GraphPad Software Inc., San Diego, CA, USA). For isotype ELISA, concentration ELISA and inhibition ELISA, the background signal (i.e., assay buffer or human plasma pool) was subtracted from the raw data. The (neutralizing) antibody levels determined by isotype and inhibition ELISA were calibrated against the international WHO standard (NIBSC number: 20 / 136) and expressed as binding antibody units / mL (BAU / mL) and international units / mL (IU / mL), respectively. IgG and IgA concentrations were expressed as μg / mL, which is the unit of standards with known concentrations (i.e., anti-spike-RBD human IgG1 or IgA1). Plaque reduction neutralization test (PRNT)

[0223] As described previously, PRNT was performed at the Rega Institute (KU Leuven) (Betrains A, etal. Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies. Br J Haematol 192, 1100-1105 (2021); Boudewijns R, et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nature communications 11, 1-10 (2020); Wouters E, et al. A novel competition ELISA for the rapid quantification of SARS-CoV-2 neutralizing antibodies in convalescent plasma. Transfusion 61, 2981-2990 (2021)).Variants of concern tested in PRNT were the original W SARS-CoV-2 strain (BetaCov / Belgium / GHB-03021 / 202, EPI_ISL_407976|2020-02-03, passage 5) (Spiteri G, et al. First cases of coronavirus disease 2019 (COVID-19) in the WHO European Region, 24 January to 21 February 2020. Eurosurveillance 25, 2000178 (2020)), Delta B.1.351 (hCoV-19 / Belgium / rega-1920 / 2021; EPI_ISL_896474, 2021-01-11, passage 2) (Park YJ, et al. Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science 375, 449-454 (2022)) and Omicron B.1.617.2 (passage 2). Briefly, for each SARS-CoV-2 variant (original W, Delta, and Omicron), tenfold serial dilutions were prepared in duplicate. Dose-dependent neutralization of the test samples was evaluated by mixing plasma dilutions with 100 plaque forming units (PFU) of the SARS-CoV-2 variant in DMEM supplemented with 2% FBS. The mixture was incubated at 37 °C for 1 h and subsequently added to a monolayer of VeroE6 cells (African green monkey kidney, ATCC CRL-1586) in a 12-well plate. After incubation at 37 °C for 1 h, the inoculum mixture was replaced with 0.8% (w / v) methylcellulose in DMEM containing 2% FBS. After incubation at 37 °C for three days, the overlay was removed and the cells were fixed with 3.7% PFA. The cells were stained with 0.5% crystal violet. The half-maximal neutralization titer (PRNT50) was determined, which represents the plasma dilution that results in a 50% reduction in plaques. 人 For animals Animal

[0224] Wild-type Syrian golden hamsters (Mesocricetus auratus) were purchased from Janvier Labs (Le Genest-Saint-Isle, France). Female hamsters, 6 to 8 weeks old, used throughout the study were specific-pathogen-free (SPF). Housing conditions and experimental procedures were approved by the Animal Experimentation Ethics Committee of KU Leuven (permit P065-2020). Food and water were provided ad libitum, together with cage enrichment (wood blocks). Animals were acclimatized for four days before the start of the study. SARS-CoV-2 Transmission Model in Hamsters

[0225] Hamster transmission models via direct contact have been described previously (Boudewijns R, et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2-infected hamsters. Nature communications 11, 1-10 (2020); Kaptein SJ, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proceedings of the National Academy of Sciences 117, 26955-26965 (2020); Sanchez-Felipe L, et al. A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature 590, 320-325 (2021)). Briefly, under anesthesia with ketamine / xylazine / atropine, 50 μL containing 2×10 6 50 50Intranasal infection of SARS-CoV-2 (25 μL / nostril) was indicated in hamsters (day 0). Virus titers against Vero E6 cells were determined by endpoint dilution by the Reed and Muench method (REED LJ, MUENCH H. A SIMPLE METHOD OF ESTIMATING FIFTY PERCENT ENDPOINTS12. American Journal of Epidemiology 27, 493-497 (1938)). Treated naïve hamsters (sentinels) were co-housed with infected hamsters (indicators) in ventilated isolator cages (IsoCage N Biocontainment System, Tecniplast). Treatment plan

[0226] According to a blinded study design, starting 1 day before exposure to indicator hamsters, sentinels were treated daily with human or hamster plasma samples under anesthesia with isoflurane for 5 consecutive days. The treatment was administered intranasally (25 μL / nostril). First, sentinels were treated with human plasma samples, namely CCP (n = 18 in two independent experiments), VCCP (n = 6), purified hIg (n = 6), or NIP 人 (n = 6). Sentinels were treated with hamster plasma samples with CCP 仓鼠 (n = 6), NIP 仓鼠 (n = 6), and purified hIg in NIP 仓鼠 (n = 6). As a negative control, sentinels were treated with PBS buffer at pH 7.4 (n = 14 in two independent experiments). SARS-CoV-2 infection model

[0227] Hamster infection models of SARS-CoV-2 have been previously described (Boudewijns R, et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nature communications 11, 1-10 (2020); Sanchez-Felipe L, et al. A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature 590, 320-325 (2021)). Briefly, wild-type Syrian golden hamsters were housed individually in ventilated isolation cages (IsoCage N Biocontainment System, Tecniplast). Experiments were conducted at the Rega Institute (KU Leuven). Treatment plan and virus infection

[0228] This study was conducted blindly at the Rega Institute (KU Leuven) for 5 days. Eighteen hamsters were evenly divided into three treatment groups: CCP, buffer control (PBS), and monoclonal anti-RBD neutralizing antibody (Catalog number 40592-MM57, SinoBiological).

[0229] All animals were inoculated with 10 3 TCID 50 of SARS-CoV-2 and treated as described in the "SARS-CoV-2 transmission model in hamsters" section. Treatments were administered 1 day and 1 hour before virus inoculation. Hamsters were housed for a 4-day period without further treatment. Hamsters were sacrificed on day 4. Sample collection

[0230] On day 4 post-exposure, sentinel hamsters were euthanized and on day 4 post-infection, indicator hamsters were euthanized. Hamsters were euthanized by intraperitoneal (i.p.) injection of 500 μL Dolethal (200 mg / mL sodium pentobarbital, Vétoquinol SA). Blood samples were collected intracardially in K2EDTA (BD Vacutainer) blood collection tubes. For plasma, blood samples were centrifuged at 4000 g for 5 minutes. The supernatant was collected. In the case of infected hamsters, plasma was UV inactivated for 1 hour under a UV lamp (250 nm) under laminar flow. Bronchoalveolar lavage (BAL) was collected by aspiration of 500 μL PBS by tracheal injection. Finally, BAL samples were centrifuged at 2000 g for 5 minutes. The supernatant was collected. The entire left lung lobe and nasal epithelium were collected for histopathology and immunofluorescence. Sections of the right lung lobe were collected for viral RNA and infectious virus quantification. RNA extraction and quantitative reverse transcription-PCR (RT-qPCR)

[0231] SARS-CoV-2 RT-qPCR has been previously described (Kaptein SJ, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proceedings of the National Academy of Sciences 117, 26955-26965 (2020)). Briefly, lung tissues were collected after euthanasia and placed in 350 μL TRK lysis buffer (E.Z.N.A. Total RNA was homogenized using bead beating (Precellys) in the Total RNA Kit, Omega Bio-tek). Cell debris was pelleted by centrifugation at 10,000 g for 5 min and RNA was extracted according to the manufacturer's instructions. Finally, 50 μL of eluate was recovered and 4 μL was used as template in the RT-qPCR reaction. The LightCycler 96 platform (Roche) was used for RT-qPCR. The nucleocapsid of SARS-CoV-2 was targeted using the iTaq Universal Probe One-Step RT-qPCR Kit (BioRad) with N2 primers and probe (Boudewijns R, et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nature communications 11, 1-10 (2020)). A standard containing SARS-CoV-2 cDNA of known concentration (from IDT) was used to express the amount of viral genome copies per mg of tissue. A standard curve of Ct versus genome copies / mL was generated using 10-fold dilutions of SARS-CoV-2 cDNA. Then, the total number of genome copies was calculated based on the elution volume of the RNA extract. The number of genome copies was normalized to the weight of the lung tissue from which the RNA was extracted. Quantification of SARS-CoV-2 infectious particles in lung tissue (TCID 50 )

[0232] Endpoint virus titration has been described previously (Kaptein SJ, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proceedings of the National Academy of Sciences 117, 26955-26965 (2020)). Briefly, lung tissues were homogenized using bead beating (Precellys) in 350 μL of minimal essential medium (MEM) and centrifuged at 10,000 g for 5 minutes to pellet cell debris. Infectious particles were quantified by endpoint titration of confluent Vero E6 cells in 96-well plates. Virus titers were calculated using the Lindenbach calculator by the Reed and Meunch method (REED LJ, MUENCH H. A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS 12. American Journal of Epidemiology 27, 493-497 (1938)). Virus titers were expressed as 50% tissue culture infectious dose (TCID 50 ) per mg of tissue. Histology

[0233] Histological examination of the lungs has been described previously (Kaptein SJ, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proceedings of the National Academy of Sciences 117, 26955-26965 (2020)). For histological examination, lungs were fixed overnight in 4% formaldehyde and embedded in paraffin. Longitudinal tissue sections (5 μm) were analyzed after H&E staining, and lung injury was blindly scored by a professional pathologist. Cumulative scores of 1 to 3 were assigned to the following scoring parameters: congestion, intra-alveolar hemorrhage, apoptotic bodies in bronchial epithelium, necrotizing bronchiolitis, perivascular edema, bronchopneumonia, perivascular inflammation, peribronchial inflammation, and vasculitis. Statistics

[0234] GraphPad Prism version 9 (GraphPad Software Inc., San Diego, CA, USA). Non-parametric Kruskall-Wallis and Dunn's post hoc tests were used to determine statistical significance between treatment groups. A P value < 0.05 was considered significant. 1.2 Results Intranasal administration of human (convalescent) plasma in a SARS-CoV-2 hamster transmission model In vitro characterization of human plasma samples

[0235] VCCP contained 3928 ± 405.9 BAU / mL anti-RBD IgG and 5949 ± 592.2 BAU / mL anti-RBD IgA ( Figure 1 a, b). As expected, CCP contained significantly less anti-RBD IgG (926.2 ± 101.6 BAU / mL) and anti-RBD IgA (450.2 ± 19.56 BAU / mL). Anti-RBD IgM levels were near or below the limit of detection of the assay ( Figure 1 c). The anti-RBD IgG concentration of VCCP was 104.6 ± 10.19 μg / mL and that of CCP was 20.06 ± 0.858 μg / mL ( Figure 1 e). The anti-RBD IgA concentration of VCCP was 12.15 ± 0.25 μg / mL and that of CCP was 0.447 ± 0.045 μg / mL ( Figure 1 f). All convalescent samples inhibited virus replication of the original W strain infecting Vero E6 cells in vitro ( Figure 1 h). Consistent with the serological data above, the PRNT in this assay 50 was maximal for VCCP (1:5,000), ten-fold higher than that of CCP (1:1,000) and fifty-fold higher than that of human non-immune plasma (NIP 人 , 1:100). These data were consistent with the inhibition of recombinant RBD and ACE2 binding in ELISA ( Figure 1 g).

[0236] To reduce non - humoral plasma components, the immunoglobulin fraction (hIg) of VCCP was purified using protein A and protein G affinity chromatography. Purity was qualitatively evaluated by Coomassie staining in SDS - PAGE (data not shown). Additionally, the purified protein content was quantified in a BCA assay, yielding a total protein concentration of 14.8 mg / mL. The anti - RBD IgG concentration was 94.89 ± 13.51 μg / mL( Figure 1 e), indicating that 0.6% of the total protein was anti - RBD IgG. Aliquots of samples before, in the flow - through, and after elution were tested by ELISA to examine the yield of neutralizing antibodies (data not shown). In ELISA, all fractions still inhibited the binding of RBD to ACE2, and there was no difference in the inhibition level between VCCP and hIg compared to the significant decrease in the flow - through sample. The anti - RBD IgG level was similar to that of VCCP, but the IgA level was significantly reduced to 459.1 ± 11.76 BAU / mL( Figure 1 a, b) or 0.236 μg / mL ± 0.019 μg / mL( Figure 1 f).

[0237] Convalescent plasma samples were also screened for in vitro neutralization of delta and omicron virus variants infecting Vero E6 cells( Figure 3 ). As expected, virus neutralization was reduced compared to the original W. The PRNT of the Delta variant of VCCP 50 was 1:2,000 and the PRNT of the Delta variant of CCP 50 was 1:250. The PRNT of the Omicron variant of VCCP 50 was 1:1,000 and the PRNT of the Omicron variant of CCP 50 was 1:100. The NIP 人 samples were not inhibitory. CCP donors were most likely infected with the original W strain, but the origin of VCCP is untraceable. Based on the donation time and the course of the pandemic, VCCP is almost certainly not against omicron. In vivo studies using a SARS - CoV - 2 transmission model

[0238] The prophylactic efficacy of intranasal (i.n.) administration of CCP was investigated in a hamster model of SARS-CoV-2 transmission. Sentinel hamsters were treated once daily with CCP, VCCP, purified human immunoglobulin (hIg), non-immune plasma (NIP), or buffer for five consecutive days. On day 0, the treatment protocol was initiated in the sentinel hamsters, and the index hamsters were independently infected with the SARS-CoV-2 ancestral W strain. One day later, the sentinel and index hamsters were co-housed in pairs ( Figure 1 Figure 1 i). The index and sentinel hamsters were euthanized on days 4 and 5, respectively. Lung tissues for analysis were prepared as described previously (Kaptein SJF, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proc Natl AcadSci U S A 117, 26955-26965 (2020)). No significant weight loss or signs of toxicity were observed during the entire treatment period of the in vivo study (data not shown).

[0239] Treatment with VCCP, CCP, and purified hIg significantly reduced the viral RNA titers in the lungs of sentinel hamsters by an average of 2.1, 2.7, and 2.5 10 log / mg tissue ([ Figure 1 Figure 1 j) compared to the buffer control. Treatment with NIP 人 resulted in a non-significant (P = 0.1963) 1.1 10 log / mg tissue reduction compared to the buffer control. Reductions of 3.1 and 2.5 10 log TCID 50 / mg tissue were found in VCCP and CCP, respectively, which were related to the dose of anti-RBD immunoglobulin found in the two convalescent plasma samples ( Figure 1 Figure 1 k). Infectious virus in the lungs of hamsters treated with purified hIg was reduced by 2.4 10 log / mg tissue compared to the buffer control, which was less than that of the VCCP from which it was derived. Lungs from hamsters treated with NIP 人 were not protected as well as those from buffer-treated controls ( Figure 1 Figure 1 d, l).

[0240] The data were distributed around the median, which means that the preventive efficacy of i.n. treatment with convalescent plasma was variable. However, when classified according to the infectious virus dose in the lung, no detectable virus was found in 2 / 6 (33%) hamsters in the VCCP group and 7 / 18 (39%) hamsters in the CCP group. A significant reduction in the infectious virus dose was found in 4 / 6 (67%) hamsters in the VCCP group and 7 / 18 (39%) hamsters in the CCP group. The remaining 0 / 6 in the VCCP treatment group and the remaining 4 / 18 (22%) in the CCP treatment group had infectious virus doses considered to be fully infected, i.e., similar to the index hamsters at euthanasia.

[0241] In hamsters treated with NIP 人 , the histopathological score of the lung tissue was 6.8 ± 2.6 (median ± IQR), and it was the highest in all groups. The lung score of the fully infected buffer control was 4.0 ± 1.6, which was significantly lower than that in NIP 人 ( Figure 1 l and data not shown). Unexpectedly, the lung scores of the CCP (4.0 ± 2.3) and VCCP groups (3.0 ± 2.9) were not significantly lower compared to the buffer control group. However, the type of lung tissue damage found in hamsters treated with human convalescent plasma (VCCP, CCP, or NIP 人 ) was different from the typical infectious inflammation caused by SARS-CoV-2 infection (data not shown). Instead, lung cell hyperplasia and eosinophils in the alveoli indicated allergic toxicity (data not shown). This characteristic histopathological image was not observed in any of the index hamsters infected or in any of the sentinel hamsters treated with buffer (data not shown) or purified hIg (data not shown). In vivo study using a SARS-CoV-2 infection model

[0242] It was hypothesized that continuous daily i.n. delivery of human plasma would result in specific clinical manifestations of pneumonia. Therefore, the preventive efficacy of i.n. administration of CCP was studied using a targeted SARS-CoV-2 infection model rather than a transmission model. In this model, hamsters were treated twice only with CCP, NIP 人 or control anti-RBD inhibitory mAb, and then manually inoculated with the virus ( Figure 4 a). CCP treatment was performed 24 hours and 1 hour before infection. Euthanasia was performed on day 4 after infection. The CCP (CCP2) in this study contained 630.4 BAU / mL ± 125.7 BAU / mL of anti-RBD IgG and 258.7 ± 10.04 BAU / mL of anti-RBD IgA, which were 1.5-fold and 1.7-fold lower, respectively, compared to CCP1 ( Figure 1 a, b, and Figure 4b, c). No detectable anti-RBD IgM antibodies were present ( Figure 1 c and Figure 4 d). The concentrations of anti-RBD IgG (15.72 ± 0.70 μg / mL) and IgA (0.306 ± 0.028 μg / mL) in CCP2 were similar to those in CCP1 ( Figure 4 f and g). In ELISA, similar neutralization levels were found for both CCP1 and CCP2, namely 471.9 IU / mL ± 6.14 IU / mL ( Figure 1 g and Figure 4 h). Using a control mAb at a concentration of 30 nM, its in vitro inhibition of the original W virus infection against Vero E6 cells was 92% ( Figure 4 e). This concentration was 3.5-fold lower than the IgG concentration of 104 nM found in CCP2 ( Figure 4 g).

[0243] During the experiment, no significant weight loss or obvious changes in vital signs were observed in any of the groups ( Figure 4 i). The viral RNA levels in the lung tissues did not differ significantly between the groups ( Figure 4 j). However, the infectious virus in the lungs of animals pre-treated with CCP2 was ten-fold lower than that of NIP ( 人 (P = 0.042) ( Figure 4 k). Notably, animals treated with inhibitory mAb were not protected and had similar levels of infectious virus as NIP ( 人 . There were no differences in lung scores between the groups. Additionally, there were no signs of lung cell hyperplasia and intra-alveolar eosinophils, indicating that allergic toxicity was avoided by reducing the number of consecutive interventions ( Figure 4 l and data not shown). In vivo studies were conducted using naïve hamsters treated i.n. with plasma

[0244] The above data suggest toxicity after consecutive administration of human plasma. To evaluate the interspecies effect, in a safety study without viral infection, (convalescent) plasma or serum from humans or hamsters was administered continuously over five days, followed by histopathological scoring of the lungs ( Figure 5 a). The controls were hIg in buffer, hIg in hamster plasma, and buffer. Compared to the buffer control, both convalescent and non-immune human plasma and serum increased the cumulative lung score (P = 0.020, n = 3 + 3 + 3) ( Figure 5 b and data not shown). In 2 / 3 of the hamsters treated with NIP ( 人 proliferative lung cells were present in only 10% of the lungs ( Figure 5c and data not shown). Compared to the buffer control, purified hIg in hamster plasma caused a slight non-significant (P = 0.108) median increase to 2.0 ± 1.8 (data not shown). However, most importantly, there was a complete absence of pneumonia involvement in animals treated with plasma or serum from hamsters, indicating the important role of the interspecies effect (data not shown). Qualitative analysis of lung sections showed perivascular edema in 2 / 3 of the NIP 人 , 1 / 6 of hIg in hamster plasma, and 1 / 3 of human serum, which was absent in the intraspecies-treated groups and buffer control ( Figure 5 and data not shown). Intraveolar hemorrhage was rare but present in 1 / 6 of hIg in hamster plasma and 2 / 6 of hIg in buffer, but absent in the intraspecies-treated groups or buffer control ( Figure 5 c and data not shown).

[0245] These experiments were conducted to study any interspecies effects on the histopathological scoring of the lungs in a safety study without viral infection. Figure 5 There is no indication that plasma and serum can be used interchangeably in subjects for the prevention or treatment of diseases caused by pathogens entering or spreading through the nasopharyngeal region. Intranasal administration of hamster (convalescent) plasma in the SARS-CoV-2 hamster transmission model

[0246] Since the most likely cause of lung cell hyperplasia and eosinophil infiltration is the continuous administration of human plasma (in particular), the next experiment again focused on transmission to hamsters treated i.n. with hIg in hamster CCP or hamster (non-immune) plasma. Non-immune hamster plasma and buffer were used as controls. Using the same protocol as in Figure 1 . In vitro characterization of hamster plasma samples

[0247] Hamster CCP and hIg in hamster plasma inhibited the binding of recombinant RBD to ACE2 to the same extent, at 4626 IU / mL ± 42.67 IU / mL and 6804 IU / mL ± 111.0 IU / mL, respectively. The inhibitory effect of non-immune hamster plasma was comparable to that of non-immune human plasma (no more inhibitory than non-immune human plasma), at 50.01 IU / mL ± 8.21 IU / mL ( Figure 2 a). In vivo studies using the SARS-CoV-2 transmission model

[0248] During the experiment, no significant weight loss or obvious changes in vital signs were observed in any of the groups ( Figure 2 b). Compared with the buffer control, the viral RNA titers in the lungs of sentinel hamsters treated with hamster CCP or hIg in hamster plasma were reduced by 3.1 and 4.5 10 log TCID 50 / mg tissue ( Figure 2 c). The effectiveness of non-immune hamster plasma was comparable to that of the buffer control (P = 0.2056). Compared with the buffer control, for hamster CCP, the infectious virus in the lungs was reduced by 2.7 10 log TCID 50 / mg lung, and for hIg hamster plasma, the infectious virus in the lungs was reduced by 2.3 10 log TCID 50 / mg lung ( Figure 2 d). The effectiveness of non-immune hamster plasma was comparable to that of the buffer control (P>0.999). Specifically, the lungs of 1 / 6 (17%) of the hamsters treated with hamster CCP and 2 / 6 (33.3%) of the hamsters treated with hIg in hamster plasma had no detectable virus. Compared with the corresponding indicator animals, a significant reduction was found in 3 / 6 (50%) of the hamsters treated with hamster CCP and 4 / 6 (66.6%) of the hamsters treated with hIg in hamster plasma. The remaining 2 / 6 (33%) in the hamster CCP group and none of the hamsters in the hIg group had infectious virus levels similar to those of the corresponding indicator hamsters.

[0249] In hamsters treated with hIg and NIP in hamster plasma 仓鼠 the histopathological scores of the lung tissue were 3.0 ± 3.0 and 3.8 ± 0.8 (median ± IQR), which were not significantly different from those of the buffer control (4.0 ± 1.6, P =>0.999) ( Figure 2 e and data not shown). Interestingly, the lung score of hamsters treated with CCP 仓鼠 was significantly reduced to 1.5 ± 0.3, reaching the lower limit of detection. In hamsters treated with CCP 仓鼠 and in hamsters treated with hIg or NIP in hamster plasma 仓鼠 no pulmonary cell hyperplasia and intra-alveolar eosinophils were observed ( Figure 2 f and data not shown). Discussion

[0250] CCP was studied as an intranasal prophylactic agent in a preclinical hamster model. The studies of the present inventors showed that there was a reduction in infectious virus in 78% of the treated hamsters, with half having no detectable virus. An even greater reduction in infectious virus was observed in all hamsters after intranasal delivery of vaccinated convalescent plasma, due to vaccination significantly enhancing the neutralization of SARS-CoV-2 infection. Importantly, intranasal treatment of exposed hamsters with CCP donated by humans led to lung tissue damage that was different from the typical infectious inflammation caused by SARS-CoV-2. Instead, lung cell hyperplasia and eosinophils within the alveoli indicated allergic toxicity. This characteristic histopathological image was not observed in any of the hamsters treated with hamster CCP, indicating cross-species side effects.

[0251] In preclinical animal studies, the intranasal application of monoclonal antibodies has shown clinical potential for COVID-19 prevention. However, the recombinant anti-SARS-CoV-2 IgG1 monoclonal antibody tested for prevention in the infection model of the present inventors could neither prevent nor reduce the viral load.

[0252] Furthermore, one dose of all CCP samples used in the studies of the present inventors had a very low anti-SARS-CoV-2 immunoglobulin content, ranging from 0.01 mg / kg of CCP, 0.05 mg / kg of purified hIg in buffer, to 0.06 mg / kg of VCCP. Thus, intranasal CCP prevents or attenuates SARS-CoV-2 infection at ultra-low doses.

[0253] In addition, treatment with VCCP produced less infectious virus compared to purified hIg in buffer. This additional benefit of VCCP may be caused by the plasma matrix and / or high levels of IgA.

[0254] The results of the studies of the present inventors suggest that intranasal administration of CCP to humans may protect a large part of the population during the critical early time window of an epidemic or pandemic. That is, if an (oropharyngeal) CCP spray is as successful in (susceptible) humans as in the in vivo animal studies of the present inventors, 40% of infections will be prevented and the progression of the disease will be slowed in the remaining 40%. Further development envisions an oropharyngeal spray to protect the elderly, patients with underlying (immunodeficiency) diseases, and healthcare workers. Additionally, an oropharyngeal spray filled with CCP can protect populations in low- and middle-income countries (LMICs) where access to vaccines is mainly limited or in countries with a large amount of vaccine scepticism. In the general population, such a CCP spray can help limit the spread of the disease, even in vaccinated individuals, who are now mostly spared from hospitalization but not from infection.

[0255] Since CCP availability is ultimately crucial for providing potential (oropharyngeal) sprays to (sub)populations, Belgian figures can be used to estimate the balance between supply and demand. In Belgium, the first wave started in March 2020. By the end of April, 5% of Belgian blood donors had positive anti-SARS-CoV-2 antibodies, representing 12,500 (known) donors. Four months later, the second wave hit the country, causing 7,500 hospitalizations in a short period, significantly straining the healthcare system. Assuming that these COVID-19 hospitalizations were a priori "susceptible" and that this population could be identified in May based on healthcare records, providing them with a CCP (oropharyngeal) spray used twice a day (200 μL / nare) for 200 consecutive days (i.e., winter) starting in September would require 1,200 liters of CCP. This only means 2,400 successful CCP donations starting from May. With 12,500 potential donors in the first wave and a logistic machine that anyway processes 200,000 plasma donations per year, this should be feasible.

[0256] Future epidemics or pandemics are best addressed with prophylactics such as vaccines to prevent people from becoming patients at home and in the hospital. The present inventors' research now shows that convalescent plasma can be developed in a similar way for SARS-CoV-2 and potentially other airborne pathogens. Example 2. Humoral immunity after intranasal administration of convalescent plasma

[0257] In this experiment, the present inventors wished to follow the humoral immunity against viral transmission in hamsters administered CCP (convalescent COVID-19 plasma) intranasally. The present inventors wished to determine the effect on the humoral response of hamsters that had a lower viral load due to intranasal CCP administration. The function of the immune response was to be evaluated by (a) the presence of IgG-type antiviral antibodies 21 days after primary infection and (b) reinfecting the hamsters with the same viral strain as in the primary infection (but at a lower dose). Method

[0258] Sentinel hamsters were intranasally treated for five consecutive days with hamster CCP (treatment group) or naïve hamster plasma (control group). The sentinels were co-housed with SARS-CoV-2-infected index hamsters (transmission model) for four days. Infection and treatment started one day before co-housing. The inventors will track viral load by swabbing the inner wall of the throat: RNA viral load will be tracked using RT-PCR, and infectious viral load will be tracked using TCID. For sentinel hamsters (day 4) and index hamsters (day 3), clinical disease progression in the lungs was determined by CT scan at the presumed peak of infection. Humoral immunity was evaluated by ELISA in a series of blood collections starting on day 6 after infection or treatment. The inventors will track the humoral response until day 28. On this day, the inventors will re-infect the hamsters with the virus to evaluate the function of the immune response generated in the sentinel hamsters. As a control, the inventors will track the index hamsters and also include non-immunized control hamsters to demonstrate that the second infection was successful. Viral load was determined daily for four days and blood was collected every other day. On day 32, a CT scan will be performed to determine the clinical status of the lungs after re-infection. Thereafter, the hamsters will be sacrificed and the lungs will be collected for histological evaluation, determination of infectious dose, and viral RNA determination.

Claims

1. A composition for preventing the infection and / or transmission associated with a pathogen or for preventing or treating a disease caused by a pathogen in a subject, wherein the pathogen enters or spreads through the oro-nasopharyngeal region, and wherein the composition comprises plasma and immunoglobulins against the pathogen; wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the pathogen; and wherein the composition is administered intranasally or in the oro-nasopharyngeal region.

2. The composition for use according to claim 1, wherein the pathogen causes a respiratory infectious disease, wherein the composition comprises plasma and immunoglobulins against the pathogen of the respiratory infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the pathogen of the respiratory infectious disease; and wherein the composition is administered intranasally or in the oro-nasopharyngeal region.

3. The composition for use according to claim 1 or 2 for preventing or reducing the progression of the infectious disease to the lower respiratory tract, progression to a systemic infection or progression to a gastrointestinal infection, and / or for preventing the spread of the infectious disease in a population.

4. The composition for use according to any one of claims 1 to 3, wherein the composition comprises at least 70% (v / v) of the plasma and immunoglobulins against the pathogen of the infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the pathogen of the infectious disease.

5. The composition for use according to any one of claims 1 to 4, wherein the plasma is not platelet-enriched, preferably wherein the plasma is not platelet-rich plasma (PRP).

6. The composition for use according to any one of claims 1 to 4, wherein the composition comprises convalescent plasma from a donor subject that has developed a humoral immune response against the pathogen of the infectious disease.

7. The composition for use according to any one of claims 1 to 6, wherein the composition is administered to the subject at: - before the subject is exposed to the pathogen of the infectious disease; - before the subject is infected with the pathogen of the infectious disease; - after the subject has been exposed to the pathogen of the infectious disease; or - after the subject has been infected with the pathogen of the infectious disease.

8. The composition for use according to any one of claims 1 to 7, wherein the pathogen of the infectious disease is a virus, bacterium, bacterial spore or fungus, preferably a virus.

9. The composition for use according to any one of claims 1 to 8, wherein the respiratory infectious disease is a respiratory infectious disease.

10. The composition for use according to claim 9, wherein the respiratory infectious disease is a viral respiratory infectious disease, and preferably wherein the causative agent of the viral respiratory infectious disease is selected from: respiratory syncytial virus (RSV), influenza virus, and coronaviridae viruses, preferably wherein the respiratory virus is a coronaviridae virus.

11. The composition for use according to claim 10, wherein the coronaviridae virus is a severe acute respiratory syndrome-related coronavirus, most preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing COVID-19).

12. The composition for use according to any one of claims 1 to 11, wherein the composition is a pulmonary aerosol preparation, nasal drops, oral-nasal drops, nasal spray, oral-nasal spray, or nasal-oro-pharyngeal spray.

13. The composition for use according to any one of claims 1 to 12, wherein the composition is for supporting the treatment, prevention, or vaccination method of a conventional infectious disease, or wherein the composition is used in the absence of a treatment, prevention, or vaccination method for a conventional infectious disease.

14. The composition for use according to any one of claims 1 to 12, wherein the composition is used in the absence of a treatment, prevention, or vaccination method for a conventional infectious disease.

15. A nasal, nasal-oro-pharyngeal, or oral-nasal spray comprising a composition containing plasma and immunoglobulins against the causative agent of the infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent of the respiratory infectious disease as defined in any one of claims 1 to 14.

16. A nasal, nasal-oro-pharyngeal, or oral-nasal spray device comprising a composition containing plasma and immunoglobulins against the causative agent of the respiratory infectious disease, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent of the respiratory infectious disease as defined in any one of claims 1 to 14.

17. The composition for use according to any one of claims 1 to 14, wherein the composition induces a humoral immune response against the causative agent in the subject to whom the composition is administered.

18. A method of inducing a humoral immune response against a causative agent that enters or spreads through the nasal-oro-pharyngeal region in a subject in need thereof, comprising administering to the subject a composition containing plasma and immunoglobulins against the causative agent, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent; and wherein the composition is administered intranasally or in the nasal-oro-pharyngeal region.

19. A method for producing a vaccine, comprising combining a composition containing plasma and immunoglobulins against a causative agent that enters or spreads through the nasal-oro-pharyngeal region with one or more pharmaceutically acceptable excipients, wherein the immunoglobulins are obtained from a donor subject that has developed a humoral immune response against the causative agent.

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