First identified in California in 2012, acute flaccid myelitis in children, associated with enterovirus D68 (EV-D68) infection, has been increasing in incidence with outbreaks detected every 2 years. Enteroviruses are well-known causes of central nervous system pathologies, ranging from aseptic meningitis to sometimes fatal brainstem encephalitis and myelitis, which can lead to permanent debilitating paralysis. Additionally, EV-D68 infects the respiratory tract, causing severe respiratory disease and facilitating person-to-person transmission via respiratory droplets. Despite EV-D68s emergence as a major cause of severe respiratory and neurological disease, there are no vaccines or therapeutics available to combat and control the spread of this pathogen. HDT Bio has developed a self-amplifying replicon RNA (repRNA) vaccine platform delivered by a Lipid InOrganic Nanoparticle (LION) scheduled to enter phase I clinical trials in the first quarter of 2021 as a vaccine against COVID-19. These activities will enable rapid translation of other vaccine candidates, utilizing the same platform, into the clinic. Additionally, HDT has an ongoing program to develop broad-spectrum anti-EV-D68 antibody therapeutics, in which we have identified promising RNA-based vaccines that encode the necessary genes for production of divergent EV-D68 virus like particles (VLPs) in vivo upon intramuscular administration. Our preliminary data establishes that 1) we can launch VLPs of non-enveloped viruses from our repRNA platform, 2) we can rapidly adapt this approach for genotypic and/or antigenic variants of EV-D68, and 3) these antigens are very immunogenic in small and large animals, generating robust neutralizing antibody responses after a single dose. In this application, we propose to screen six vaccine candidates, which are currently being evaluated as a mixture in alpacas for antibody discovery efforts, to identify a single candidate that induces the best cross- neutralizing antibody responses. We will then characterize safety, immunogenicity and efficacy in neurological- and respiratory-disease mouse models of EV-D68 infection. Finally, we will evaluate safety and immunogenicity in pregnant mouse models and efficacy in birthed pups while characterizing maternal antibody transfer. Public Health Relevance Statement
Project narrative: Biennial outbreaks of enterovirus D68 infections, the resulting cases of acute flaccid myelitis, and the alarming rate of increasing case numbers, has prompted the development of vaccines and therapeutics against this pathogen of concern. The objective of this project is to select a broad-spectrum RNA vaccine candidate, capable of inducing cross-neutralizing antibody responses against the six sub- clades of the species/serotype, and evaluate its safety, immunogenicity, and efficacy in respiratory- and neurological-disease mouse models of enterovirus D68 infection. Also, due to the prevalence of enterovirus D68 infection in children, this project will also evaluate maternal vaccination, maternal-fetal antibody transfer, and efficacy in pups born to vaccinated mothers.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Alpaca ; Animals ; Antibodies ; Viral Antibodies ; anti-viral antibody ; antiviral antibody ; Antigens ; immunogen ; Birth ; Parturition ; Brain Stem ; Brainstem ; California ; Cerebrospinal Fluid ; cerebral spinal fluid ; spinal fluid ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Coxsackie Viruses ; Coxsackievirus ; Disease Outbreaks ; Outbreaks ; Embryo ; Embryonic ; Encephalitis ; Brain Inflammation ; Endocarditis ; Enterovirus ; Evolution ; Family ; Fetal Development ; Developing fetus ; Fever ; Pyrexia ; febrile ; febris ; Genes ; Genome ; Genotype ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Hepatitis ; Human ; Modern Man ; Immunity ; Incidence ; Infection ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Licensure ; Lipids ; Lung diseases ; Pulmonary Diseases ; Pulmonary Disorder ; Respiratory Disease ; Respiratory System Disease ; Respiratory System Disorder ; disease of the lung ; disorder of the lung ; lung disorder ; Meningitis ; Aseptic Meningitis ; Mothers ; Mus ; Mice ; Mice Mammals ; Murine ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Myelitis ; Inflammatory Myelopathy ; Spinal Cord Inflammation ; Persons ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Netherlands ; Pathology ; Family Picornaviridae ; Picornaviridae ; Picornaviruses ; Pregnancy ; Gestation ; Pregnant Women ; expectant mother ; expecting mother ; pregnant mothers ; Production ; Replicon ; Replication Unit ; Respiratory System ; Pulmonary Body System ; Pulmonary Organ System ; Respiratory Tracts ; Respiratory tract structure ; Rhinovirus ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; RNA-Directed RNA Polymerase ; EC 2.7.7.48 ; RNA Replicase ; RNA-Dependent RNA Polymerase ; RNA Viruses ; viral RNA ; virus RNA ; Safety ; Serotyping ; Syndrome ; Target Populations ; Technology ; Toxicology ; Translations ; United States ; Vaccination ; Vaccines ; Inactivated Vaccines ; Inactivated Virus Vaccine ; Killed Vaccines ; Virus ; Yeasts ; Schedule ; TimeLine ; base ; Phase ; Variant ; Variation ; Human poliovirus ; Polio Virus ; Poliovirus ; poliomyelitis virus ; Evaluation ; Therapeutic ; programs ; Intramuscular ; Clinic ; neutralizing antibody ; respiratory ; fetal ; Palsy ; Plegia ; paralysis ; paralytic ; Paralysed ; Prevent infection ; Infection prevention ; recombinant virus ; respiratory virus ; develop a vaccine ; development of a vaccine ; vaccine formulation ; vaccine development ; Maternal antibody ; reproductive ; immunogenic ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; CNS Nervous System ; Central Nervous System ; Neuraxis ; Antigenic Diversity ; virus-like nanoparticles ; viruslike particle ; Virus-like particle ; Dose ; Symptoms ; Data ; in vivo ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Update ; Vaccinated ; transmission process ; Transmission ; Preparation ; Development ; developmental ; neonate ; immunogenicity ; design ; designing ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Biodistribution ; pathogen ; Enterovirus 71 ; Prevalence ; Therapeutic antibodies ; mouse model ; murine model ; pup ; pregnant ; combat ; vaccine candidate ; Enterovirus 68 ; Enterovirus D68 ; Antibody Response ; Formulation ; maternal vaccination ; maternal immunization ; efficacy study ; clinical development ; RNA vaccine ; RNA-based vaccine ; mRNA vaccine ; mRNA-based vaccine ; lead candidate ; acute flaccid myelitis ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; COVID-19 vaccine ; 2019-nCoV vaccine ; COVID19 vaccine ; SARS-CoV-2 vaccine ; SARS-CoV2 vaccine ; SARS-coronavirus-2 vaccine ; Severe Acute Respiratory Syndrome CoV 2 vaccine ; Severe acute respiratory syndrome coronavirus 2 vaccine ; corona virus disease 2019 vaccine ; coronavirus disease 2019 vaccine ; vaccine against 2019-nCov ; vaccine against SARS-CoV-2 ; vaccine against SARS-CoV2 ; vaccine against SARS-coronavirus-2 ; vaccine against Severe Acute Respiratory Syndrome CoV 2 ; vaccine against Severe acute respiratory syndrome coronavirus 2 ; vaccine for novel coronavirus ; COVID-19 pandemic ; COVID crisis ; COVID epidemic ; COVID pandemic ; COVID-19 crisis ; COVID-19 epidemic ; COVID-19 global health crisis ; COVID-19 global pandemic ; COVID-19 health crisis ; COVID-19 public health crisis ; COVID19 crisis ; COVID19 epidemic ; COVID19 global health crisis ; COVID19 global pandemic ; COVID19 health crisis ; COVID19 pandemic ; COVID19 public health crisis ; SARS-CoV-2 epidemic ; SARS-CoV-2 global health crisis ; SARS-CoV-2 global pandemic ; SARS-CoV-2 pandemic ; SARS-CoV2 epidemic ; SARS-CoV2 pandemic ; SARS-coronavirus-2 epidemic ; SARS-coronavirus-2 pandemic ; Severe Acute Respiratory Syndrome CoV 2 epidemic ; Severe Acute Respiratory Syndrome CoV 2 pandemic ; Severe acute respiratory syndrome coronavirus 2 epidemic ; Severe acute respiratory syndrome coronavirus 2 pandemic ; corona virus disease 2019 epidemic ; corona virus disease 2019 pandemic ; 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 pandemic ; coronavirus disease 2019 public health crisis ; coronavirus disease crisis ; coronavirus disease epidemic ; coronavirus disease pandemic ; severe acute respiratory syndrome coronavirus 2 global health crisis ; severe acute respiratory syndrome coronavirus 2 global pandemic ; neonatal mice ; antibody transfer ;
