CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1056LB NEUROLOGIC CONSEQUENCES OF POSTNATAL ZIKA VIRUS INFECTION IN INFANTS Maud Mavigner 1 , Justin O’Neal 2 , Siddhartha Bhaumik 1 , Jakob Habib 1 , Cameron Robinson 1 , Maria Alvarado 3 , Xiaodong Zhang 3 , Jens Wrammert 1 , Mehul Suthar 2 , Ann Chahroudi 1 1 Emory Univ, Atlanta, GA, USA, 2 Emory Vaccine Center, Atlanta, GA, USA, 3 Yerkes Natl Primate Rsr Cntr, Atlanta, GA, USA Background: Zika virus (ZIKV) infection can have devastating neurologic consequences for infants infected in utero, particularly during the first trimester. Little is known, however, about the impact of ZIKV infection close to the time of delivery or in the period of infancy. Methods: To address this gap, we developed a model of postnatal ZIKV infection in infant rhesus macaques (RMs). Infant RMs were infected with 10(5) PFU of ZIKV strain PRVABC59 s.c. at five weeks of age. A subset of RMs was sacrificed soon after infection to determine tissue tropism of ZIKV in infants and another subset was followed longitudinally. Viral loads in plasma and tissues were measured by qPCR. Binding and neutralization antibody responses were quantified by ELISA and focus reduction neutralization test (FRNT), respectively. At three months of age, infant RMs underwent structural T1-weighted magnetic resonance imaging (MRI), resting-state functional MRI, and Diffusion Tensor Imaging (DTI). A Human Intruder task was used to quantify the response to acute stress. Results: Six infant RMs were challenged with ZIKV with peak viral loads in plasma at day 2-3 that cleared by day 7 after infection. ZIKV was not detected in urine, saliva, or CSF. Infant RMs developed anti-ZIKV binding IgG and IgM antibodies as well as neutralization activity in plasma. In two infant RMs sacrificed at the peak of viremia, ZIKV RNA was detected in multiple lymph nodes and the spleen. In two infant RMs sacrificed two weeks after infection, ZIKV RNA was additionally detected in the frontal cortex, parietal cortex, occipital cortex, cauda equina, and trigeminal ganglion. MRI and DTI performed at three months of age revealed increased size of the lateral ventricles, microstructural alteration in the corpus callosum, and reduction in the functional connectivity of the primary motor (M1) and somatosensory (S1) cortices in ZIKV-infected infant RMs as compared to age- matched controls. ZIKV-infected infants also showed emotional dysregulation, failing to demonstrate the species-typical freezing behavior in response to an acute social stressor as compared to similarly reared controls. Conclusion: In summary, we demonstrate for the first time that postnatal ZIKV infection of infants disseminates into the central nervous system and has structural and functional neurologic consequences. This model can be used to test therapeutic approaches to prevent or reverse the damage caused by ZIKV infection in infants. 1057LB ZIKA VIRUS PROTECTION BY A SINGLE LOW-DOSE NUCLEOSIDE-MODIFIED mRNA VACCINATION Michael J. Hogan 1 , Norbert Pardi 1 , Rebecca S. Pelc 2 , Hanne Anderson 3 , Charles McGee 4 , Michael J. Hope 5 , Mark G. Lewis 3 , Theodore C. Pierson 2 , Barton F. Haynes 4 , DrewWeissman 1 1 Univ of Pennsylvania, Philadelphia, PA, USA, 2 NIAID, Bethesda, MD, USA, 3 Bioqual, Inc, Rockville, MD, USA, 4 Duke Univ, Durham, NC, USA, 5 Acuitas Therapeutics, Vancouver, BC, Canada Background: Zika virus (ZIKV) has recently emerged as an explosive pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives; thus, development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) containing modified nucleosides is emerging as a versatile and highly effective vaccine platform, which generates potent T follicular helper (Tfh) cell and neutralizing antibody responses to diverse viral pathogens. In this study, we developed a nucleoside-modified mRNA-based vaccine against ZIKV and determined its immunogenicity and protective efficacy in mice and non-human primates. Methods: Nucleoside-modified mRNA encoding the pre-membrane (prM) and envelope (E) glycoproteins from a 2013 ZIKV outbreak strain (H/PF/2013) was transcribed with T7 phage RNA polymerase using 1-methylpseudouridine triphosphate in place of UTP. mRNA was purified by HPLC and incorporated into lipid nanoparticles (LNPs). Mice and rhesus macaques were immunized once intradermally with prM-E mRNA-LNPs. Serology was followed by IgG ELISA and three types of neutralization assay: plaque and focus reduction neutralization tests and reporter viral particle assay. Animals were challenged with ZIKV PRVABC59 (Puerto Rico, 2015) and viral loads were followed by quantitative RT-PCR. Results: High and stable levels of Zika E-specific IgG and neutralizing antibody were generated after a single immunization of ZIKV mRNA-LNPs in both mice and rhesus macaques. Neutralizing titers in multiple assays exceeded levels that previously protected animals in passive transfer experiments. A single immunization with 30 μg of ZIKV mRNA-LNPs protected mice from detectable viremia (<200 copies/ml) following a ZIKV challenge at 2 weeks (short-term) or 5 months (long-term) post-vaccination. A single low-dose immunization with 50 μg (0.02 mg/kg) protected rhesus macaques from detectable viremia (<50 copies/ml) following a challenge at 5 weeks post-vaccination. Conclusion: The ZIKV prM-E nucleoside-modified mRNA-LNP vaccine is potently immunogenic in mice and rhesus macaques. This vaccine platform requires only a single administration of a low dose of mRNA to generate a rapid, long-lived, and protective immune response, which is mediated by potent Tfh cell induction. Nucleoside-modified mRNA-LNP represents a new and advantageous vaccine candidate for a global public health campaign against ZIKV, with ongoing expansion to other pathogens.

Poster and Themed Discussion Abstracts

CROI 2017 456