Intranasal administration of anti-pathogen polyclonal blood derivatives for prevention and / or treatment of airborne diseases

Abstract

The present invention relates to a blood derivative comprising a polyclonal antibody against a pathogen for use in the prevention and / or treatment of airborne diseases caused by said pathogen, characterized in that said blood derivative is administered intranasally.

Description

Technical Field

[0001] The present invention relates to the field of serum therapy or serum prevention, more specifically to the use of serum or plasma containing polyclonal antibodies for the prevention and / or treatment of airborne diseases such as Covid-19. The serum is administered intranasally. Background Art

[0002] Diseases can be spread by direct contact, inhalation, swallowing, biting or through venereal routes. Most infectious diseases are usually spread by the respiratory route, such as airborne diseases which are usually highly contagious.

[0003] A given pathogen may be characterized by its virulence, transmissibility, and / or ability to evade immunity acquired through prior infection or vaccination. The virulence of a pathogen is often associated with the severity of disease and, therefore, morbidity and mortality.

[0004] The severity of infectious diseases can be prevented either prophylactically or therapeutically, as demonstrated by the Covid-19 pandemic, which has sparked unprecedented research, particularly into the development of vaccines and treatments.

[0005] For example, vaccines developed by Pfizer / BioNTech, Moderna, J&J, and Astra-Zeneca provide good protection against the severity of disease associated with subsequent SARS-CoV-2 infection. In addition, therapeutically administered monoclonal antibodies, / Monoprevir (Merck) and / Ritonavir (Pfizer) shows promise in reducing the severity of Covid-19.

[0006] The contagiousness of an infection can significantly affect the functioning of communities, as too many simultaneous infections put unsustainable pressure on health systems. Impeding contagion requires keeping distance, wearing masks, limiting the density of closed spaces or even lockdowns… However, these measures have unsustainable economic effects in the long term. Moreover, there are always places where density is difficult to reduce without locking down communities, such as public transport, schools… Moreover, even if vaccines against several airborne diseases already exist, they are difficult to obtain (for example in developing countries).

[0007] In certain specific cases, transmission is hampered by a spontaneous or post-vaccination immune response known as "sterilizing" immunity. However, this is very rare. For example, in the case of Covid-19, people who have been previously infected with SARS-CoV-2 and have recovered, as well as people who have been vaccinated, can be reinfected. Admittedly, they can remain asymptomatic or lack typical symptoms, but they replicate the virus, spread it into the environment and can transmit it to one or more third parties.

[0008] Every day, more than 650,000 new cases of Covid-19 are recorded around the world. Although Covid-19 vaccines have been proven to be safe and effective, 90% of experts believe that Covid-19 will become endemic. 1 . As a result, the SARS-CoV-2 virus will infect millions of people each year, which could lead to new epidemics as it proves capable of mutating into more infectious or contagious variants.

[0009] On the one hand, vaccines against Covid-19 are only partially effective 2 (60-90%), whose effectiveness decreases over time 3 , and a large portion of the population will not be vaccinated for medical or personal reasons. On the other hand, the drugs being developed or licensed to treat Covid-19 are very expensive. 4 , and therefore is not suitable for treating moderate disease.

[0010] Finally, in general, since primary infection and vaccines do not provide curative immunity against airborne diseases (or provide very little), there is no solution other than physical distancing, hand hygiene and wearing masks to prevent contagion. This is also the case if no vaccine is available or the number of people vaccinated is too low (e.g. in developing countries).

[0011] To date, there are no safe and cost-effective drugs for the prevention / treatment of airborne diseases such as Covid-19, but also influenza, common cold, measles, ... Safe and cost-effective solutions to effectively prevent / treat individuals before the onset of illness or in the event of moderate illness (e.g., moderate Covid-19) are also critical to preventing new endemic infections or possible pandemics. Safe and cost-effective solutions are also needed to effectively reduce or stop the spread of viruses, such as the SARS-CoV-2 virus.

[0012] Therefore, new solutions are needed to prevent and / or treat airborne diseases, such as Covid-19, even more effectively. There is also an urgent need for a safe solution that can be used as self-medication, non-invasive, to alleviate symptoms, especially to prevent infection and / or reduce or stop viral transmission. Ideally, such a new solution should be easy to implement industrially and cheap, so that it can be available to as many people as possible. Such a solution should also be able to maintain its anti-infective activity against possible variants of pathogens that cause airborne diseases, such as different SARS-CoV-2, influenza A virus... Summary of the invention

[0013] The present invention is based on the inventors' results demonstrating that these needs are met by intranasal administration of polyclonal antibodies, such as anti-SARS-CoV-2 polyclonal antibodies.

[0014] Kangro et al. 5 Administration of anti-SARS-CoV-2 polyclonal antibodies by the intranasal route has been described. However, Kangro et al. have administered anti-SARS-CoV-2 polyclonal antibodies derived from bovine colostrum, whereas in the present invention, a blood derivative such as serum is administered. The administration of a blood derivative such as serum in the present invention provides substantial benefits. Indeed, intranasal administration of anti-SARS-CoV-2 polyclonal blood derivatives such as serum can prevent and / or treat Covid-19, whereas in Kangro et al., preparations derived from colostrum are used only for preventive purposes. Furthermore, blood derivatives such as serum are easy to obtain (even easier than colostrum), easy to administer, and provide a simple and cost-effective solution for everyone. Furthermore, the results show that the blood derivative (serum) of the present invention is also more effective than anti-SARS-CoV-2 polyclonal antibodies derived from bovine colostrum. Indeed, in Kangro et al., colostrum had a neutralizing titer of about 25 (see Kangro et al. Figure 2 C), while in the present invention, when the blood derivative (serum) was collected from rabbits, the neutralization titer was at least about 160, and when the blood derivative (serum) was collected from hamsters, the neutralization titer was at least about 640 (see Examples 1-3). In addition, in Kangro et al., the bovine IgG concentration decreased from 5.65 μg / mL to 2.36 μg / mL 1-4 hours after administration, which means that the nasal spray containing the polyclonal antibody derived from bovine colostrum must be administered every 3-4 hours, while Example 1 of the present invention proves that once-daily administration is sufficient.

[0015] Agurto-arteaga etc. 6 The preclinical evaluation of IgY antibodies against recombinant SARS-CoV-2 RBD protein for the prevention and post-infection treatment of COVID-19 is also discussed. Agurto-arteaga et al. have administered egg yolk antibodies against SARS-CoV-2 recombinant proteins, while in the present invention, blood derivatives such as serum are administered. In addition, in contrast to Agurto-arteaga et al., the present invention demonstrates that intranasal administration of polyclonal blood derivatives such as serum against SARS-CoV-2 can also reduce or prevent the spread of the virus (see Examples 5-6).

[0016] Therefore, the present invention relates to a blood derivative comprising polyclonal antibodies against pathogens for use in the prevention and / or treatment of airborne diseases caused by said pathogens, characterised in that said blood derivative is administered intranasally.

[0017] The present invention relates to a blood derivative comprising polyclonal antibodies against pathogens for use in preventing airborne diseases caused by said pathogens, characterised in that said blood derivative is administered intranasally. The present invention is particularly useful for preventing infection by pathogens, preferably viruses and / or reducing or stopping the spread of pathogens, preferably viruses. More specifically, the present invention relates to a blood derivative comprising polyclonal antibodies against viruses for use in preventing infection by said viruses and / or reducing or stopping the spread of said viruses.

[0018] The term "blood derivative" refers to any fraction produced from whole blood that may contain polyclonal antibodies against pathogens.

[0019] According to an embodiment of the present invention, the term "blood derivative" as used herein refers to serum or plasma (preferably serum).

[0020] Therefore, in a preferred embodiment, the present invention relates to a serum comprising polyclonal antibodies against a pathogen for use in the prevention and / or treatment of airborne diseases caused by said pathogen, characterized in that said serum is administered intranasally.

[0021] The term "serum" as used herein refers to the liquid portion of whole blood after coagulation, which is usually collected after centrifugation. Therefore, serum usually corresponds to the supernatant obtained after centrifugation. The term "plasma" as used herein refers to the liquid portion of whole blood collected in the presence of an anticoagulant. In other words, serum refers to blood serum and plasma refers to blood plasma. According to an embodiment of the present invention, serum does not contain coagulation factors, fibrinogen, leukocytes, erythrocytes or platelets. According to an embodiment of the present invention, plasma does not contain leukocytes, erythrocytes or platelets. Preferably, the blood derivative, serum or plasma contains polyclonal antibodies, electrolytes, hormones ... According to the present invention, blood derivatives such as serum do not contain serum complement or contain inactivated serum complement. For example, complement can be inactivated by heating, and complement-depleted serum can be prepared by immunoadsorption, membrane filtration ... According to an embodiment of the present invention, blood derivatives such as serum may also contain at least one antigen. In this case, a separation step may be performed to remove the antigen from the blood derivative. Preferably, the blood derivative is hyperimmune. Preferably, serum refers to hyperimmune serum. As used herein, the term "hyperimmune" refers to a high concentration of antibodies produced in response to repeated exposure to, contact with, or injection of an antigen (a pathogen or part thereof). Thus, "hyperimmune serum" refers to serum containing a high concentration of antibodies produced in response to repeated exposure to, contact with, or injection of an antigen (a pathogen or part thereof). As used herein, "high concentration of antibodies" refers to a neutralization titer 50 of at least 80, at least 160, preferably at least 320; for example, "serum containing a high concentration of antibodies" refers to a serum having a neutralization titer 50 or NT50 of at least 80, at least 160, preferably at least 320.

[0022] As used herein, the term "pathogen" refers to any infectious agent that is capable of causing an airborne disease in its host. In other words, the pathogen is the cause of an airborne disease. The term "pathogen" encompasses any variant of the pathogen variant. For example, it can be a virus, a bacterium, a fungus or a yeast. Without limitation, such pathogens include coronaviruses (e.g., SARS-CoV virus, SARS-CoV-2 virus, MERS-CoV virus), influenza virus (e.g., influenza virus subtype H1N1 or H3N2), measles virus, adenovirus, mumps virus, rotavirus, poxvirus, enterovirus, rhinovirus, hantavirus, varicella zoster virus, Mycobacterium tuberculosis, Bacillus anthracis, Bordetella pertussis, Neisseria meningitidis, Streptococcus pneumoniae, Aspergillus fungi (e.g., Aspergillus fumigatus, Aspergillus flavus, Aspergillus nidulans, Aspergillus versicolor, Aspergillus niger, niger) and Aspergillus terreus), bacteria belonging to the Legionella family (such as Legionella pneumophila), dermatitis blastomycetes yeasts of the genus Cryptococcus (such as Cryptococcus neoformans)...

[0023] In a preferred embodiment, the pathogen is a virus, more preferably a virus that replicates in the nasal mucosa. Preferably, the virus is a rhinovirus, influenza A virus, influenza B virus, influenza C virus, coronavirus, respiratory syncytial virus (RSV) or parapneumovirus.

[0024] The term "airborne disease" as used herein relates to a disease caused by a pathogen that is transmitted through the air, in particular through fine respiratory droplets. Such pathogens may be of any type and may be transmitted by inhalation, sneezing, coughing, talking or any other action that may produce aerosolized particles and / or contaminate surfaces. Typically, the aerosolized particles originate from body secretions of the infected subject, but they may also originate from animals. Preferably, the airborne disease is selected from Bacillus anthracis infection, aspergillosis, blastomycosis, chickenpox, adenovirus infection, enterovirus infection, rhinovirus infection, rotavirus infection, influenza, meningitis, Legionnaires' disease, measles, mumps, smallpox, cryptococcosis, tuberculosis, pertussis, Streptococcus pneumoniae infection, severe acute respiratory syndrome, Middle East respiratory syndrome or Covid-19. Preferably, the disease is Covid-19.

[0025] Therefore, in one embodiment, the present invention relates to a blood derivative comprising polyclonal antibodies against SARS-CoV-2 for use in the prevention and / or treatment of Covid-19, characterized in that the blood derivative is administered intranasally.

[0026] In a preferred embodiment, the present invention relates to a serum comprising polyclonal antibodies against SARS-CoV-2 for use in the prevention and / or treatment of Covid-19, characterized in that the serum is administered intranasally.

[0027] As used herein, the term "anti-pathogen polyclonal antibody" means that the antibody can bind to the pathogen or a portion thereof.

[0028] As used herein, "polyclonal antibodies" refer to a mixture of different antibodies and / or fragments thereof that bind to different immunogenic determinants within an antigen (e.g., an antigen of a pathogen, such as a SARS-CoV-2 antigen). As used herein, the term "fragment" refers to any molecule or portion of an antibody that can bind to an antigen or a portion thereof. For example, these fragments are Fab, scFv, (scFv)2, F(ab')2, VHH or nanobodies. The antibodies in the blood derivatives of the present invention, such as serum, bind to different epitopes of the antigen. This is advantageous because it confers cross-protection, so the blood derivatives of the present invention, such as serum, are insensitive to the genetic evolution of pathogens such as viruses, preferably SARS-CoV-2. In other words, even when and if pathogens such as viruses, preferably SARS-CoV-2 viruses continue to mutate, the blood derivatives of the present invention, such as serum, also maintain their efficacy. This is an important advantage compared to monoclonal antibodies. Preferably, polyclonal antibodies specifically bind to the antigens of pathogens. Preferably, polyclonal antibodies specifically bind to SARS-CoV-2 antigens.

[0029] The term "prevention" as used herein refers to the prevention of airborne diseases, preferably Covid-19. The blood derivatives such as serum according to the present invention prevent or limit the risk of developing airborne diseases, preferably Covid-19. The blood derivatives (preferably serum) according to the present invention also prevent or limit or prevent the infection or spread of pathogens such as SARS-CoV-2. In a preferred embodiment, the blood derivatives such as serum according to the present invention prevent or limit or prevent the infection or spread of SARS-CoV-2. Therefore, the present invention is perfectly suitable before risk exposure.

[0030] The term "treatment" as used herein refers to the treatment of airborne diseases, preferably Covid-19. For example, when a person is contaminated / infected by a pathogen, such as a virus such as SARS-CoV-2, the blood derivatives of the present invention, such as serum, can be used to alleviate symptoms and / or prevent moderate disease from developing into severe disease.

[0031] Preferably, the blood derivatives (preferably serum) of the present invention prevent pathogens from docking to their cell surface receptors. In one embodiment of the present invention, the blood derivatives of the present invention, such as serum, prevent the SARS-CoV-2 virus from docking to its cell surface receptors, such as ACE2, NRP1, AXL, TIM1 and / or TIM4, preferably ACE2. Thus, polyclonal antibodies act on the surface of the upper respiratory tract, such as the lining epithelium of the nasal mucosa: in any case, they do not penetrate the cells.

[0032] The term "SARS-CoV-2" as used herein refers to a virus belonging to the Coronaviridae family, to the genus Betacoronavirus and to the subgenus Sabeivirus. It is an enveloped virus with a spiral capsid, whose genome consists of a single-stranded RNA of about 30,000 nucleotides. The structure of the SARS-CoV-2 virion is particularly as follows: it contains a spiral capsid formed by protein N, a matrix formed by protein M and a lipid envelope, in which at least two types of proteins are embedded: (glyco) protein S (spike protein) and small envelope protein (E). More specifically, the term "SARS-CoV-2" according to the present invention refers to a virus whose sequence was originally described in GenBank with accession number MN90894, as well as all variants of the virus. Therefore, the term "SARS-CoV-2" should be understood as "SARS-CoV-2 virus and its variants". For example, variants refer to the so-called α (B.1.1.7), β (B.1.351), γ (P.1), δ (B.1.617.2) and Omicron (B.1.1.529) variants, as well as variants B.1.640, B.1.427, B.1.429, B.1.616, B.1.525, P.3, B.1.617.2, B.1.620, B.1.617.3, B .1.214.2, A.23.1, A.27, A.28, C.16, B.1.351, B.1.526, B.1.526.1, B.1.526.2, P.2, B. 1.1.519, AV.1, AT.1, C.36, B.1.621, C.37, AY.4.2, B.1.1.318, B.1.617.2, C.1.2, BA.2. More information about SARS-CoV-2 sequences, mutations, and variants can be found at https: / / www.ncbi.nlm.nih.gov / sars-cov-2 / ; https: / / www.cdc.gov / coronavirus / 2019-ncov / cases-updates / variant-surve illance / variant-info.html; https: / / www.gisaid.org / or https: / / www.ecdc.europa.eu / en / covid-19 / variants-concern.

[0033] The term "Covid-19" as used herein refers to the disease caused by the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2) and its variants.

[0034] As used herein, the term "intranasal" refers to the delivery of a blood derivative (preferably serum) to any part of the upper respiratory tract, such as the nose, pharynx, larynx and bronchi. Preferably, it refers to any part of the nasal mucosa, more preferably the nasal epithelium.

[0035] All antibodies have a common core structure of two light chains and two heavy chains. A light chain is connected to each heavy chain, and the two heavy chains are connected to each other to form a "Y" shaped molecule. However, despite this structural similarity, antibodies (also referred to as immunoglobulins) can be divided into several isotypes and subtypes according to physiology and physiochemical properties. In mammals, the isotype of antibody is named IgA, IgG, IgD, IgE and IgM. The IgG isotype can also be divided into IgG1, IgG2, IgG3 and IgG4 and the IgA isotype can be divided into IgA1 and IgA2. The present invention also encompasses antibodies (HCAb) with only camel heavy chains.

[0036] In one embodiment of the invention, the blood derivative (preferably serum) comprises at least IgA and IgG type polyclonal antibodies, and in a preferred embodiment, the blood derivative (preferably serum) comprises IgA, IgM and IgG type polyclonal antibodies. In one embodiment of the invention, the blood derivative (preferably serum) may also comprise polyclonal antibodies of IgA, IgG, IgM, IgD and IgE types. Preferably, the blood derivative (preferably serum) comprises polyclonal antibodies of isotype IgG1, IgG2, IgG3 and IgG4 and / or isotype IgG1, IgG2, IgG, IgG4, IgA1 and IgA2.

[0037] In one embodiment of the invention, the antibodies in the blood derivative (preferably serum) are neutralizing antibodies. Such neutralizing antibodies act on the surface of the upper respiratory tract, such as the nasal mucosa, and neutralize pathogens such as SARS-CoV-2 that can no longer bind to their receptors (such as ACE2) and penetrate cells. Such antibodies are retained in the upper respiratory tract, for example, on the epithelium of the nasal mucosa.

[0038] Antibodies can be divided into two fragments: the region that binds to the antigen (Fab region) and the tail region that activates the immune system (Fc region). The Fc region of an antibody has amino acids that can be connected to N-glycans (oligosaccharides). According to the present invention, the Fc region of a polyclonal antibody can be connected to at least one oligosaccharide. In a preferred embodiment, this oligosaccharide is not only N-glycolylneuraminic acid (NGNA). It can be N-acetylneuraminic acid (NANA) or a mixture of N-glycolylneuraminic acid and N-acetylneuraminic acid. Therefore, in one embodiment, the present invention relates to a blood derivative (preferably serum) containing polyclonal antibodies against pathogens, which is used to prevent and / or treat airborne diseases, characterized in that the blood derivative (preferably serum) is administered intranasally, and that the antibody has an Fc region connected to (i) NANA or to (ii) NANA and NGNA. In a preferred embodiment, the present invention relates to a blood derivative (preferably serum) comprising polyclonal antibodies against SARS-CoV-2 for use in the prevention and / or treatment of Covid-19, characterized in that the blood derivative (preferably serum) is administered intranasally and in that the antibodies have an Fc region linked to (i) NANA or to (ii) NANA and NGNA.

[0039] Blood derivatives (preferably serum) of the present invention can be obtained from any mammal, preferably mammals except cattle, sheep, goats. In a preferred embodiment of the present invention, the blood derivatives (preferably serum) are from humans, rabbits, chickens, pigs, camels and / or hamsters, preferably rabbits and / or chickens.

[0040] Blood derivatives (preferably serum) can be obtained after a subject is infected with a pathogen such as SARS-CoV-2. For example, blood derivatives (preferably serum) can be collected 10-100 days, preferably 14-40 days after infection. The term "subject infection" means that the subject has been naturally contaminated / infected with a pathogen such as SARS-CoV-2 or at least one of its antigens, and has produced polyclonal antibodies against pathogens such as SARS-CoV-2, but also refers to the subject being intentionally contaminated / infected with a pathogen such as SARS-CoV-2 or at least one of its antigens to produce polyclonal antibodies against pathogens such as SARS-CoV-2. The contamination / infection step can be considered an immunization step. Contamination / infection can be carried out in any manner, such as inhalation, intravenous injection... Blood derivatives (preferably serum) can also be obtained by immunizing (or hyperimmunizing) or vaccinating the subject against the pathogen, for example by injecting an attenuated virus, or a viral protein, or an RNA encoding a viral protein,..., so that the subject produces polyclonal antibodies against the pathogen (or a portion thereof).

[0041] In one embodiment of the invention, the blood derivative (preferably serum) is obtained after the subject is infected with a pathogen, which is the same or different from a variant of the same pathogen that causes or is susceptible to causing an airborne disease in the subject to be treated or prevented. Preferably, in one embodiment of the invention, the blood derivative (preferably serum) is obtained after the subject is infected with SARS-CoV-2, which is the same or different from the SARS-CoV-2 that causes or is susceptible to causing Covid-19 in the subject to be treated or prevented. In fact, blood derivatives (preferably serum) collected after contamination / infection with a variant of SARS-CoV-2 do not limit its prevention and / or treatment against the same variant. Due to the polyclonal nature of antibodies in blood derivatives (preferably serum), blood derivatives (preferably serum) collected after contamination / infection with a variant of SARS-CoV-2 (e.g., B.1.1.7) can be used to prevent and / or treat other types of variants (e.g., B.1.1.529).

[0042] In addition, the mammal from which the blood derivative (preferably serum) is prepared does not limit its use to the same mammal. In fact, blood derivatives such as serum collected after contamination / infection in one mammal (e.g., hamster) can be used to prevent and / or treat another mammal (e.g., human): this is heterologous polyclonal serum therapy. Blood derivatives such as serum collected after contamination / infection in one mammal (e.g., hamster) can also be used to prevent and / or treat the same mammal (here, human): this is homologous polyclonal serum therapy.

[0043] In one embodiment of the invention, the blood derivative is a purified blood derivative, preferably purified serum.

[0044] In one embodiment of the present invention, the blood derivative such as serum further comprises a pharmaceutically acceptable carrier. The blood derivative such as serum may also comprise additional substances, such as one or more excipients or another substance, to, for example, adjust the pH, increase the half-life of the antibody in nasal mucus, change the solubility of the antibody, etc.

[0045] In a preferred embodiment of the present invention, the blood derivative such as serum is administered at least once a day. The blood derivative such as serum can also be administered twice a day. This blood derivative such as serum can be administered once every 24 hours or twice every 12 hours. In one embodiment of the present invention, the blood derivative such as serum of the present invention is administered in both nostrils.

[0046] In one embodiment of the invention, the blood derivative, such as serum, is administered to the nasal mucosa.

[0047] In one embodiment of the present invention, the blood derivative such as serum is in liquid, lyophilized or any powder form.

[0048] In one embodiment of the invention, the blood derivative, such as serum, is administered by spray, powder, drops, aerosol or nebulization.

[0049] In a preferred embodiment of the invention, the blood derivative, such as serum, is contained in a nasal spray or powder.

[0050] The blood derivatives such as serum of the present invention contain a therapeutically effective amount of polyclonal antibodies. In one embodiment of the present invention, the blood derivatives such as serum have a neutralization titer 50 of at least 80, preferably 320. As used herein, "neutralization titer 50" or NT50 refers to the highest dilution of serum that prevents 50% infection in vitro.

[0051] In one embodiment of the invention, the blood derivative, such as serum, is administered to a subject, preferably a human or an animal. The subject may be vaccinated against an airborne disease, such as Covid-19, or may not be vaccinated against an airborne disease, such as Covid-19. For example, a subject "vaccinated against an airborne disease, such as Covid-19" means that the subject has received at least one injection of a vaccine against an airborne disease, such as Covid-19, at least two injections of a vaccine against an airborne disease, such as Covid-19, or at least three injections of a vaccine against an airborne disease, such as Covid-19.

[0052] In one embodiment of the invention, a blood derivative such as serum as defined herein is contained in the composition. Therefore, the present invention also relates to a composition comprising a blood derivative as defined herein for use in the prevention and / or treatment of airborne diseases caused by said pathogens, characterized in that said composition is administered intranasally.

[0053] In one embodiment, the present invention also relates to a method for preventing and / or treating an airborne disease caused by a pathogen, comprising intranasally administering a therapeutically effective amount of a blood derivative, such as serum, comprising polyclonal antibodies against said pathogen.

[0054] In one embodiment, the invention also relates to a method for preventing and / or treating Covid-19, comprising intranasal administration of a therapeutically effective amount of a blood derivative such as serum comprising polyclonal antibodies against SARS-CoV-2. The invention also relates to a method for preventing or reducing or stopping viral transmission, comprising intranasal administration of a therapeutically effective amount of a blood derivative such as serum comprising polyclonal antibodies against SARS-CoV-2.

[0055] In one embodiment, the present invention also relates to the use of blood derivatives such as serum containing polyclonal antibodies against pathogens in the preparation of intranasal medicaments for the prevention / treatment of airborne diseases caused by said pathogens, preferably Covid-19. In one embodiment, the present invention also relates to the use of blood derivatives such as serum containing polyclonal antibodies against SARS-CoV-2 in the preparation of intranasal medicaments for preventing or reducing or stopping the spread of SARS-CoV-2.

[0056] References:

[0057] 1 Torjesen,I.Covid-19 Will Become Endemic but with Decreased Potencyover Time,Scientists Believe.BMJ 2021,372,n494.https: / / doi.org / 10.1136 / bmj.n494

[0058] 2 Efficacy and protection,RIVM https: / / www.rivm.nl / en / covid-19-vaccination / vaccines / efficacy-and-protection(accessed 2021-11-02)

[0059] 3 Tartof, SY; Slezak, JM; Fischer, H.; Hong, V.; Ackerson, BK; Ranasinghe, ON; Frankland, TB; Ogun, OA; Zamparo, JM; Gray, S.; Valluri, SR; Pan, K.; Angulo, FJ; Jodar, L.; 6Months in a Large Integrated Health System in the USA:ARetrospective Cohort Study.The Lancet 2021,398(10309),1407–1416.https: / / doi.org / 10.1016 / S0140-6736(21)02183-8.

[0060] 4 Lupkin,S.Remdesivir Priced At More Than$3,100For A Course OfTreatment.NPR.June 29,2020.

[0061] 5 Bovine Colostrum Derived Antibodies Against SARS-CoV-2Show GreatPotential to Serve as a Prophylactic Agent. Kadri Kangro, Mihhail Kiira Gildemann, Eve Sankovski, Eva Laura Sandra Lello, Raini Pert, Ants Kavak, Poikalainen, Lembit Lepasalu, Marilin Kuusk, Robin Pau, SanderPiiskopp, Siimu Rom, Ruth Oltjer, Kairi Tiirik, Karin Kogermann, Mario Plaas, ToomasTiirats, Birgit Mihkel Plaas, Dagni Krinka, Ene Talpsep, Meelis Kadaja, Joachim M. Gerhold, Anu Planken, Andres Tover, Andres Merits, Andres MartUstav Jr., Mart Ustav.doi:https: / / doi.org / 10.1101 / 2021.06.08.21258069

[0063] 6Preclinical assessment of IgY antibodies against recombinant SARS-CoV-2RBD protein for prophylaxis and post-Infection treatment of COVID-19. Andres Agurto-Arteaga, Astrid Poma-Acevedo, Dora Rios-Matos, Ricardo Choque-Guevara, Ricardo Montesinos-Millan, Angela Montalvan, Gisela Isasi-Rivas, Yudith Cauna-Orocollo, Maria de Grecia Cauti-Mendoza, Norma Perez-Martinez, Kristel Gutierrez-Manchay, Ingrid Ramirez-Ortiz, Dennis MarioI.Salguedo-Bohorquez,Stefany Manolo Fernandez Diaz,LuisA.Guevara Sarmiento,Mirko Zimic1,2and COVID-19Working Group in Peru.FrontImmunol.10May 2022May;Vol 13,Article 881604.doi:10.3389 / fimmu.2022.881604.

[0064] The invention will now be illustrated by the following non-limiting examples together with the tables and figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 Represents the effect of intranasal treatment on the evolution of body weight in hamsters with Covid-19 that have received once-daily administration of hyperimmune serum obtained from hamsters.

[0066] Figure 2 Represents the effect of intranasal treatment on the evolution of body weight in hamsters with Covid-19 that have received twice daily administration of hyperimmune serum obtained from hamsters.

[0067] Figure 3 Represents the effect of intranasal treatment on the evolution of body weight in Covid-19 hamsters that have received twice-daily administration of hyperimmune serum obtained from rabbits.

[0068] Figure 4Represents the effect of intranasal treatment on the evolution of body weight in Covid-19 hamsters that have received twice-daily administration of hyperimmune serum obtained from humans.

[0069] In the figures, "bi" means before inoculation, and "pi" means after inoculation. DETAILED DESCRIPTION

[0070] Example 1 : Once-daily intranasal homologous polyclonal serum therapy

[0071] Three groups of hamsters (n=10) were recruited into the experiment.

[0072] Three groups were intranasally administered 100 microliters (100 μL) of 10 5 TCID 50 / mL of SARS-CoV-2 (α variant) virus solution. In addition, Group 1 received 100 μL of PBS intranasally at 24-hour intervals starting 24 hours after virus inoculation for 5 consecutive times (black box). Group 2 received monoprevir (an antiviral agent) orally once a day for 5 days starting 24 hours after virus inoculation (gray box). Group 3 received 100 μL of hamster hyperimmune serum to complement intranasally, and then received it for 5 consecutive times at 24-hour intervals starting 24 hours after virus inoculation (white box). A hyperimmune serum pool (NT50=1 / 640) was formed with serum collected from hamsters infected with SARS-CoV-2 (α variant) 14 days before bleeding.

[0073] Animal body weight was used here as an indicator of morbidity associated with experimental COVID-19. Once-daily intranasal serotherapy attenuated the magnitude and shortened the duration of induced disease-associated weight loss, and in doing so outperformed monoprevir.

[0074] The results are as follows Figure 1 The results showed that once-daily intranasal homologous polyclonal serotherapy initiated 24 hours after SARS-CoV-2 infection outperformed the reference treatment monopivir in mitigating COVID-19-associated morbidity.

[0075] Example 2 : Twice-daily intranasal homologous polyclonal serum therapy

[0076] Three groups of hamsters (n=6) were recruited in the experiment.

[0077] Three groups were intranasally administered 100 microliters (100 μL) of 10 5 TCID 50 / mL of SARS-CoV-2 (α variant) virus solution. In addition, Group 1 received 100 μL of PBS intranasally at 12-hour intervals starting 24 hours after virus inoculation for 10 consecutive times (black frame). Groups 2 and 3 received 100 μL of decomplemented hamster non-immune (gray frame) or hyperimmune (white frame) serum intranasally using the same time schedule. A hyperimmune serum pool (NT50=1 / 640) was formed using serum collected from 10 hamsters infected with SARS-CoV-2 (α variant) 14 days before bleeding.

[0078] Animal body weight was used here as an indicator of morbidity associated with experimental COVID-19. Twice-daily intranasal serum therapy inhibited weight loss associated with induced disease.

[0079] The results are as follows Figure 2 As shown, twice-daily intranasal homologous polyclonal serum therapy starting 24 hours after SARS-CoV-2 infection inhibits COVID-19-associated morbidity.

[0080] Example 3 : Twice-daily intranasal allogeneic polyclonal serum therapy

[0081] Three groups of hamsters (n=6) were recruited in the experiment.

[0082] Three groups were intranasally administered 100 microliters (100 μL) of 10 5 TCID 50 / mL of SARS-CoV-2 (α variant) virus solution. In addition, Group 1 received 100 μL of PBS intranasally at intervals of 12 hours starting 24 hours after virus inoculation for 10 consecutive times (black box). Using the same time schedule, Groups 2 and 3 received 100 μL of rabbit non-immune (gray box) or hyperimmune (black box) serum to complement, respectively, intranasally. A rabbit hyperimmune serum pool (NT50=1 / 160) was formed by aggregating serum collected from 2 rabbits inoculated with inactivated SARS-CoV-2 (α variant).

[0083] Animal weight was used here as an indicator of morbidity associated with experimental COVID-19. Twice-daily intranasal allogeneic serum therapy suppressed disease-associated weight loss to a degree comparable to that conferred by homologous hyperimmune serum.

[0084] The results are as follows Figure 3 As shown, twice-daily intranasal heterologous polyclonal serum therapy starting 24 hours after SARS-CoV-2 infection inhibits COVID-19-associated morbidity.

[0085] Another hyperimmune serum pool from rabbits vaccinated with inactivated SARS-CoV-2 (α variant) was also obtained, with a neutralization titer (NT50 on Vero E6 cells) against SARS-CoV-2 of 1 / 5120 and as high as at least 1 / 40960.

[0086] Example 4 : Twice-daily intranasal allogeneic polyclonal serum therapy

[0087] Three groups of hamsters (n=6) were recruited in the experiment.

[0088] Three groups were intranasally administered 100 microliters (100 μL) of 10 5 TCID 50 / mL of SARS-CoV-2 (α variant) virus solution. In addition, Group 1 received 100 μL of PBS intranasally at intervals of 12 hours starting 24 hours after virus inoculation for 10 consecutive times (black box). Using the same time schedule, Groups 2 and 3 received 100 μL of complement-free human non-immune (gray box) or hyperimmune (black box) serum intranasally, respectively. A human hyperimmune serum pool (NT50=1 / 160) was formed by aggregating serum collected from 2 people "inoculated" with inactivated SARS-CoV-2 (α variant).

[0089] Animal weight was used here as an indicator of morbidity associated with experimental COVID-19. Twice-daily intranasal allogeneic serum therapy suppressed disease-associated weight loss to a degree comparable to that conferred by homologous hyperimmune serum.

[0090] The results are as follows Figure 4 As shown, twice-daily intranasal heterologous polyclonal serum therapy starting 24 hours after SARS-CoV-2 infection inhibits COVID-19-associated morbidity.

[0091] Example 5 : Administration of a single homologous polyclonal serum therapy reduces the transmission rate of SARS-CoV-2.

[0092] Three groups of hamsters (n=10) were recruited into the experiment.

[0093] The first group (intentionally infected hamsters, hereinafter referred to as "donors") were intranasally administered 100 microliters (100 μL) of a solution containing 10 5 TCID 50 / mL of SARS-CoV-2 virus (α variant) solution. 100 microliters of non-immune or hyperimmune hamster serum was administered intranasally to the other two groups ("recipient" hamsters) once, and they were placed in close contact with the donors 5 minutes later. After the donors were inoculated with the virus for 24 or 28 hours, each recipient was introduced into the donor cage for 4 hours. Then, the recipients were raised alone for another 14 days. The seroconversion of animals to SARS-CoV-2 nucleoprotein was used as an indicator of previous infection. The seroconversion rate of each group reflects the success rate of transmission between hamsters. H1 refers to hamster #1, H2 refers to hamster #2, and so on. The white box contains hamsters that did not seroconvert on the 14th day after infection (pi). The gray box refers to those that seroconverted (H11, H12, H8, H9, H10). Each donor was co-housed with 1 hamster from each treatment group (hyperimmune vs non-immune nasal spray). 24-28 hours or 28-32 hours after inoculation of the donor, 1:1 was raised for 4 hours. Prophylactic intranasal serotherapy significantly reduced the seroconversion rate and, therefore, the rate of transmission among hamsters.

[0094]

[0095] Table 1 .result

[0096] Example 6 : Intranasal administration of a single homologous polyclonal serum therapy reduces the morbidity associated with infection, if disseminated.

[0097] Three groups of hamsters (n=10) were recruited into the experiment.

[0098] The first group (intentionally infected hamsters, hereinafter referred to as "donors") were intranasally administered 100 microliters (100 μL) of 10 5 TCID 50 / mL of SARS-CoV-2 virus (α variant) solution. Two other groups ("recipient" hamsters) were intranasally administered 100 microliters of non-immune or hyperimmune hamster serum once and placed in close contact with the donor 5 minutes later. 24 or 28 hours after the first group was inoculated with the virus, each recipient was introduced into the donor cage for 4 hours. The recipients were then housed alone for another 14 days. The evolution of the animal's weight within 4 days after co-housing with the donor (expressed as a percentage of the weight before contact) was used as an indicator of the severity of COVID-19 that may be transmitted between hamsters. It can be clearly seen that (1) COVID-19 infection through hamster-to-hamster transmission is much less severe than infection through intentional intranasal inoculation (donors lost an average of 16.2% weight in a similar time window), and (2) a single intranasal serum therapy just before the risk event (co-housing with infected partners) reduced the incidence rate, even if the virus was transmitted. The light gray box contains hamsters that did not seroconvert at day 14 post-infection (pi). The dark gray box refers to those that seroconverted. Each donor was co-housed with 1 hamster from each treatment group (hyperimmune vs non-immune nasal spray). Co-housed 1:1 for 4 hours 24-28 hours or 28-32 hours after donor inoculation.

[0099] The results, shown below in Table 2, demonstrate that a single homologous polyclonal serum therapy administered intranasally 5 minutes prior to co-housing with infectious animals significantly reduced the morbidity associated with the infection, if transmitted.

[0100]

[0101] Table 2 .result

Claims

1. A blood derivative comprising polyclonal antibodies against pathogens for use in the prevention and / or treatment of airborne diseases caused by said pathogens, characterized in that The blood derivative is administered intranasally.

2. The blood derivative according to claim 1, wherein the blood derivative is serum or plasma, preferably serum.

3. The blood derivative according to any one of claims 1-2, wherein the blood derivative comprises polyclonal antibodies of at least IgA and IgG type, preferably IgA, IgM and IgG.

4. The blood derivative according to any one of claims 1 to 3, wherein the blood derivative comprises polyclonal antibodies of the IgA, IgG, IgM, IgD and IgE types.

5. The blood derivative according to any one of claims 1 to 4, wherein the IgG is IgG1, IgG2, IgG3 and IgG4.

6. A blood derivative according to any one of claims 1 to 5, wherein the pathogen is SARS-CoV-2 and the airborne disease is Covid-19.

7. The blood derivative according to any one of claims 1 to 6, wherein the blood derivative is from human, rabbit, chicken, pig, camel and / or hamster, preferably rabbit and / or chicken.

8. A blood derivative according to any one of claims 1 to 7, wherein the blood derivative is obtained after infection, immunization and / or vaccination of a subject with a variant of the pathogen, such as SARS-CoV-2, which is the same or different from the variant of the pathogen, such as SARS-CoV-2, that causes or is susceptible to causing the airborne disease, such as Covid-19, in the subject to be prevented or treated.

9. The blood derivative according to any one of claims 1 to 8, wherein the blood derivative is administered by spray, powder, drops, aerosol or nebulization.

10. The blood derivative according to any one of claims 1 to 9, wherein the blood derivative is administered at least once a day, preferably twice a day.

11. The blood derivative according to any one of claims 1 to 10, wherein the blood derivative is contained in a nasal spray or powder.

12. The blood derivative according to any one of claims 1-11, wherein the blood derivative has a neutralization titer 50 of at least 80, preferably 320.

13. The blood derivative according to any one of claims 1 to 12, wherein the blood derivative is administered to a subject, preferably a human or an animal.

14. A blood derivative according to any one of claims 1 to 13, wherein the subject is vaccinated against an airborne disease such as Covid-19, or is not vaccinated against an airborne disease such as Covid-19.

15. A composition comprising a blood derivative as defined in any one of claims 1 to 14 for use in preventing and / or treating airborne diseases caused by said pathogens, characterized in that The composition is administered intranasally.

Images