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Principal Investigator: Rongsheng Jin
Organization: TUFTS UNIVERSITY BOSTON
Fiscal Year: 2024
Award: $802,815
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
In previous NIH sponsored research we successfully tested the hypothesis that integrating structural and
mechanistic information into heteromultimeric VHH-based neutralizing agent (VNA) design facilitated
development of antitoxins with even greater efficacy and versatility. In this renewal proposal, we will apply these
findings to test the hypothesis that our designer VNA platform, which is rapidly responsive to new threats, will
permit development of highly practical, next-generation antitoxin and antiviral products that possess excellent
potencies in treating intoxications or viral infections and are effective against a broad range of natural pathogen
variants. Our research will focus on two pathogens that are major current threats which could benefit from next-
generation therapeutics: botulinum neurotoxin (BoNT) and SARS-CoV-2. We propose two Specific Aims which
will be underway simultaneously throughout the five years of research. In Aim 1, we will develop a small pool of
antitoxin VNAs that protect against all subtypes of the three prevalent BoNT serotypes (A, B and E). BoNTs are
CDC Tier 1 select agents. However, the few available antitoxin treatments against BoNTs primarily derive from
large animal polyclonal antisera, such as the equine botulism antitoxin HBAT, which suffer from multiple
manufacturing and storage challenges. Our goal is to test the platform’s ability to produce highly practical VNAs
as a next-generation BoNT antitoxin product, likely delivered as RNA nanoparticles, which improves on the
potencies and natural variant specificities of the current HBAT antitoxin product and is rapidly responsive to
potential new BoNT threats. In Aim 2 we will develop a single VNA antiviral agent that protects against known
variants of SARS-CoV-1 and SARS-CoV-2. SARS-CoV-2 is the viral cause of the ongoing COVID-19 pandemic.
A promising strategy for rapid development of a therapy is development of SARS-CoV-2 neutralizing antibodies,
especially antibodies targeting the spike protein, for prophylactic or passive immunotherapies. However, novel
variants of SARS-CoV-2, which cause enhanced infection and transmission, have emerged, and more
dangerous variants are expected to evolve. Of immediate concern are variants that partially escape
neutralization by current Ab-based therapies and in vaccinated or previously-infected COVID-19 patients, leading
to reduced vaccine efficacy in certain areas with a high prevalence of these variants. We propose an mRNA-
based antiviral product that, once administered, elicits expression of a VNA with extremely high virus neutralizing
potency. The VNA will contain multiple covalently linked VHHs binding to conserved epitopes of the spike protein.
This approach will test the platform’s ability to develop a product that minimizes the risks of immune escape
through evolution and selection of clinical strains of SARS-CoV-2 and SARS-CoV-1. If successful, this
technology platform could have broad applications in creating practical therapeutics for a wide variety of
emerging and potential pandemic viral infections, bioterror threat agents, and other infectious diseases.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-D><3-Dimensional><3D><Affinity><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Antibodies><Antibody Therapy><Antigenic Determinants><Antisera><Area><Assay><Autoimmune><Binding><Binding Determinants><Bioassay><Biological Assay><Biological Terrorism><Bioterror><Bioterrorism><Bontoxilysin><Botulin><Botulinum Toxins><Botulism><C diff><C difficile><C. diff><C. difficile><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 years><COVID19 patient><COVID19 positive patient><COVID19 virus><Cancers><Cell Culture Techniques><Characteristics><Clinical><Clinical Treatment Moab><Clostridioides difficile><Clostridium botulinum Toxins><Clostridium difficile><CoV-2><CoV2><Communicable Diseases><Complex><Dangerousness><Data><Development><Disease><Disorder><Domestic Horse><Epitopes><Equine><Equine Species><Equus caballus><Equus przewalskii><Evolution><Family><Funding><Future><Goals><High Prevalence><Horses><Human><Immune><Immune Sera><Immunes><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intoxication><Intramuscular><Lead><Length><Life><Link><MAb Therapeutics><Malignant Neoplasms><Malignant Tumor><Mediating><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><NIH><National Institutes of Health><Non-Polyadenylated RNA><Passive Immunotherapy><Pathology><Pb element><Poisoning><Production><Property><Prophylactic treatment><Prophylaxis><Proteins><RNA><RNA Gene Products><Research><Ribonucleic Acid><Route><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serotyping><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure><Testing><Therapeutic><Therapeutic Agents><Therapeutic Effect><Therapeutic Monoclonal Antibodies><Therapeutic antibodies><Toxico-Infectious Botulism><Toxin><Transmission><United States National Institutes of Health><Vaccinated><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><anti-toxin><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><botulinum neurotoxin><cell culture><cell cultures><clinical relevance><clinically relevant><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus patient><cost><design><designing><developmental><disease prevention><disorder prevention><emergent virus><emerging virus><hCoV19><heavy metal Pb><heavy metal lead><human disease><immune serum><improved><in vivo><mAbs><mRNA><malignancy><manufacture><microbial><model of animal><monoclonal Abs><monoclonal antibody drugs><nCoV2><nano particle><nano-sized particle><nanobodies><nanobody><nanoparticle><nanosized particle><neoplasm/cancer><neutralizing antibody><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pandemic concern><pandemic potential><pandemic risk><pandemic threat><passive immune therapy><passive immunotherapeutics><pathogen><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><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><pig model><piglet model><poisoned><porcine model><prevent><preventing><product development><prophylactic><public health relevance><receptor binding><receptor bound><risk minimization><sdAb><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 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