Project summary:
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-D68’s 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.
