Presently, convalescent plasma (CP) transfusion is being developed as a therapy for COVID-19 patients and as a prophylactic for high risk individuals. In addition, treatment with plasma or neutralizing antibody preparations from convalescent patients could be the only treatment for emerging infectious diseases, for which no other treatments may be available. At the same time, CP transfusion exposes the recipient to the risk of transfusion transmitted diseases (TTD), a risk which is additionally exacerbated by the compromised immune conditions of the critically ill patients. The limited number of current TTD blood tests does not provide for full protection, restrict the critically limited donors pool and may not be available in some areas. Pathogen Inactivation can provide the solution. Unfortunately, the currently utilized treatments for pathogen reduction in plasma (solvent-detergent, pasteurization of dry heat, UV or gamma irradiations) are non-selective and can compromise the quality of plasmas neutralizing antibodies or other protective protein factors. We at ZATA Pharmaceuticals have developed a new class of pathogen inactivators (ZPI) based on the natural polyamines scaffold, which are truly selective in inactivating pathogens genomic molecules while sparing plasma proteins. Our preliminary results show that ZPI have high reactivity toward nucleic acids and do not modify model proteins (Cyt-C, RSV fusion protein) and animal sera growth factors. Using them, we inactivated different types of pathogens (G+ and G- bacteria, mycoplasma, fungi, protozoa) and high titer preparations of enveloped or non-enveloped viruses. Currently we are developing ZPI for pathogens reduction in transfusion red blood cells, research funded by NIH SBIR grant (R44 HL145783). In this application we propose to adapt the new pathogen inactivation process for treatment of convalescent plasma (CP) by: (1) using 6 virus species in human plasma to select the optimal ZPI and conditions for pathogen inactivation in human plasma; (2) using already developed analytical methods to establish conditions for complete neutralization and/or removal of the residual inactivator from the treated plasma; (3) using specific antibodies against 4 virus species to demonstrate by ELISA that the virus inactivation treatment has no effect on the binding of the antibodies to their targets; (4) using neutralizing antibodies against SARS-CoV-2 S protein to demonstrate preservation of the virus neutralizing properties of the antibodies after plasma treatment; (5) using repeated autologous infusion of treated plasma to establish its in vivo the safety in the rabbit models.After accomplishment of those initial goals we will apply for funding, including SBIR funding to complete, in collaboration with New York Blood Center, its pre-clinical evaluation and to initiate phase I human trials, or alternatively, will license the treatment procedure for completion of its development and marketing. Ultimately, this proposal will lead to a safe and high quality convalescent human plasma for treatment or prophylactics of COVID19 or other deadly diseases for which no other effective treatment is currently available. Public Health Relevance Statement NarrativePresently, convalescent plasma transfusion is being developed as a therapy for COVID-19 patients and as a prophylactic for high risk persons. Convalescent plasma transfusion exposes the recipient to the risk of transfusion transmitted diseases, a risk which is additionally exacerbated by the compromised immune conditions of the critically ill patients. Proposed pathogen reduction technology enables inactivation of all types of pathogens in convalescent plasma without compromising its therapeutic properties.
Project Terms: Adenoviruses ; Adenoviridae ; Animals ; Antibodies ; Antigens ; immunogen ; Bacteria ; Blood ; Blood Reticuloendothelial System ; Blood donor ; Blood Transfusion ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Critical Illness ; Critically Ill ; Detergents ; Disease ; Disorder ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Filtration ; Filtration Fractionation ; fungus ; Future ; Goals ; Grant ; Hematological Disease ; Blood Diseases ; Hematologic Diseases ; Hematological Disorder ; blood disorder ; Blood Tests ; Hematologic Tests ; Hematological Tests ; Hematology Testing ; Hospitals ; Human ; Modern Man ; Infection ; Marketing ; Mycoplasma ; Eperythrozoon ; Haemobartonella ; Persons ; United States National Institutes of Health ; NIH ; National Institutes of Health ; New York ; Nucleic Acids ; Patients ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Plasma Proteins ; Polyamines ; Polyamine Compound ; Proteins ; Protozoa ; Protozoal ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Research ; Risk ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; Safety ; Sales ; Savings ; Solvents ; Technology ; Testing ; Time ; Vesicular stomatitis Indiana virus ; VSV ; Vesicular Stomatitis Virus ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Virus ; Erythrocyte Transfusion ; Red Blood Cell Transfusion ; Chimeric Proteins ; Chimera Protein ; Fusion Protein ; analytical method ; base ; Procedures ; Transfusion ; Packed Red Blood Cell Transfusion ; PRBC Transfusion ; Area ; Residual state ; Residual ; Phase ; Blood-Borne Pathogens ; Bloodborne Pathogens ; Evaluation ; Individual ; Recovery ; Licensing ; Funding ; Collaborations ; Therapeutic ; scaffolding ; scaffold ; Life ; Immunes ; Immune ; Autologous ; prophylactic ; blood product ; neutralizing antibody ; Infusion ; Infusion procedures ; experience ; success ; pasteurization ; Viral Inactivation ; Virus Inactivation ; Toxicities ; Toxic effect ; Reporting ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Modeling ; Property ; Emerging Infectious Diseases ; Emerging Communicable Diseases ; Molecular Interaction ; Binding ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; in vivo ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Preparation ; Process ; Development ; developmental ; nano ; ultraviolet irradiation ; UV irradiated ; UV irradiation ; UV irridated ; ultra violet irradiation ; pathogen ; high risk ; effective therapy ; effective treatment ; preclinical evaluation ; pre-clinical evaluation ; Growth Factor ; Growth Agents ; Growth Substances ; Proteins Growth Factors ; preservation ; gamma irradiation ; γ-irradiation ; pathogen genomics ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; 2019-nCoV ; 2019 novel corona virus ; 2019 novel coronavirus ; COVID-19 virus ; COVID19 virus ; CoV-2 ; CoV2 ; SARS corona virus 2 ; SARS-CoV-2 ; SARS-CoV2 ; SARS-associated corona virus 2 ; SARS-associated coronavirus 2 ; SARS-coronavirus-2 ; SARS-related corona virus 2 ; SARS-related coronavirus 2 ; SARSCoV2 ; Severe Acute Respiratory Distress Syndrome CoV 2 ; Severe Acute Respiratory Distress Syndrome Corona Virus 2 ; Severe Acute Respiratory Distress Syndrome Coronavirus 2 ; Severe Acute Respiratory Syndrome CoV 2 ; Severe Acute Respiratory Syndrome-associated coronavirus 2 ; Severe Acute Respiratory Syndrome-related coronavirus 2 ; Severe acute respiratory syndrome associated corona virus 2 ; Severe acute respiratory syndrome corona virus 2 ; Severe acute respiratory syndrome coronavirus 2 ; Severe acute respiratory syndrome related corona virus 2 ; Wuhan coronavirus ; coronavirus disease 2019 virus ; hCoV19 ; nCoV2 ; human coronavirus ; HCoV ; human CoV ; human corona virus ; COVID-19 treatment ; COVID-19 therapy ; COVID19 therapy ; COVID19 treatment ; SARS-CoV-2 therapy ; SARS-CoV-2 treatment ; coronavirus disease 2019 therapy ; coronavirus disease 2019 treatment ; severe acute respiratory syndrome coronavirus 2 therapy ; severe acute respiratory syndrome coronavirus 2 treatment ; treat COVID-19 ; treat COVID19 ; treat SARS-CoV-2 ; treat coronavirus disease 2019 ; treat severe acute respiratory syndrome coronavirus 2 ; convalescent plasma ; SARS-CoV-2 spike protein ; 2019-nCoV S protein ; 2019-nCoV spike glycoprotein ; 2019-nCoV spike protein ; COVID-19 S protein ; COVID-19 spike glycoprotein ; COVID-19 spike protein ; COVID19 S protein ; COVID19 spike glycoprotein ; COVID19 spike protein ; SARS-CoV-2 S protein ; SARS-CoV-2 spike glycoprotein ; SARS-CoV2 S protein ; SARS-CoV2 spike glycoprotein ; SARS-CoV2 spike protein ; Severe acute respiratory syndrome coronavirus 2 S protein ; 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patient with COVID ; patient with COVID-19 ; patient with COVID19 ; patient with SARS-CoV-2 ; patient with coronavirus disease ; patient with coronavirus disease 2019 ; patient with severe acute respiratory distress syndrome coronavirus 2 ; severe acute respiratory syndrome coronavirus 2 infected patient ; severe acute respiratory syndrome coronavirus 2 patient ; severe acute respiratory syndrome coronavirus 2 positive patient ; SARS-CoV-2 antibody ; COVID-19 antibody ; SARS-CoV2 antibody ; antibody against COVID-19 ; antibody against SARS-CoV-2 ; antibody against SARS-CoV2 ; antibody against coronavirus disease 2019 ; antibody against severe acute respiratory syndrome coronavirus 2 ; antibody to COVID-19 ; antibody to SARS-CoV-2 ; antibody to SARS-CoV2 ; antibody to coronavirus disease 2019 ; antibody to severe acute respiratory syndrome coronavirus 2 ; coronavirus disease 2019 antibody ; severe acute respiratory syndrome coronavirus 2 antibody ; detection limit ; SARS-CoV-2 transmission ; 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