Zika Virus: Medical Countermeasure Development Challenges

REVIEW Zika Virus: Medical Countermeasure Development Challenges Robert W. Malone1,2*, Jane Homan3, Michael V. Callahan4, Jill Glasspool-Malone1,2, Lambodhar Damodaran5, Adriano De Bernardi Schneider5, Rebecca Zimler6, James Talton7, Ronald R. Cobb7, Ivan Ruzic8, Julie Smith-Gagen9, Daniel Janies5‡, James Wilson10‡, Zika Response Working Group 1 RW Malone MD LLC, Scottsville, Virginia, United States of America, 2 Class of 2016, Harvard Medical School Global Clinical Scholars Research Training Program, Boston, Massachusetts, United States of America, 3 ioGenetics, Madison, Wisconsin, United States of America, 4 Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 5 Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America, 6 University of Florida, Department of Entomology and Nematology, Florida Medical Entomology Laboratory, Vero Beach, Florida, United States of America, 7 Nanotherapeutics, NANO-ADM Advanced Development and Manufacturing Center, Alachua, Florida, United States of America, 8 Analytical Outcomes, Washington Crossing, Pennsylvania, United States of America, 9 School of Community Health Sciences, University of Nevada, Reno, Nevada, United States of America, 10 Nevada Center for Infectious Disease Forecasting, University of Nevada, Reno, Nevada, United States of America OPEN ACCESS Citation: Malone RW, Homan J, Callahan MV, Glasspool-Malone J, Damodaran L, Schneider ADB, et al. (2016) Zika Virus: Medical Countermeasure Development Challenges. PLoS Negl Trop Dis 10(3): e0004530. doi:10.1371/journal.pntd.0004530 Editor: Rebekah Crockett Kading, Colorado State University, UNITED STATES Published: March 2, 2016 Copyright: © 2016 Malone et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors received no specific funding support for this publication. The NANO-ADM has been funded in whole or in part with Federal funds from the US Army Contracting Command – APG, Natick Contracting Division, Department of Defense under Contract No. W911QY-13-C-0010. Research reported in this publication was supported by a UNC Research Opportunities Initiative grant to UNC Charlotte, NC State University, and UNC-Chapel Hill. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RWM and JGM are employees and equity holders in RW Malone MD LLC. JH is an ‡ The senior authors contributed equally to this work. * Abstract Introduction Reports of high rates of primary microcephaly and Guillain–Barré syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that the virus circulating in these regions is a rapidly developing neuropathic, teratogenic, emerging infectious public health threat. There are no licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. The Pan American Health Organization (PAHO) predicts that Zika virus will continue to spread and eventually reach all countries and territories in the Americas with endemic Aedes mosquitoes. This paper reviews the status of the Zika virus outbreak, including medical countermeasure options, with a focus on how the epidemiology, insect vectors, neuropathology, virology and immunology inform options and strategies available for medical countermeasure development and deployment. Methods Multiple information sources were employed to support the review. These included publically available literature, patents, official communications, English and Lusophone lay press. Online surveys were distributed to physicians in the US, Mexico and Argentina and responses analyzed. Computational epitope analysis as well as infectious disease outbreak modeling and forecasting were implemented. Field observations in Brazil were compiled and interviews conducted with public health officials. PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0004530 March 2, 2016 1 / 26 employee and equity holder in ioGenetics LLC. JT is an employee and equity holder in Nanotherapeutics, Inc. RRC is an employee of Nanotherapeutics, Inc. Background and Introduction Zika virus infection has spread rapidly in the tropical Americas since introduction to Brazil in 2014. Although a causal association is not yet confirmed, there is a growing consensus that Zika infection is linked to an upsurge in cases of Guillan Barré (GBS) syndrome and the birth of microcephalic infants following maternal infection [1, 2]. That association has become more likely with the publication of the report by Mlakar et al in which large numbers of viral particles were demonstrated in the central nervous tissue of an electively aborted microcephalic Zikainfected fetus [3]. The flavivirus Zika was first isolated from a Rhesus macaque obtained from the Zika forest of Uganda during 1947 [4, 5]. Zika virus is an enveloped, icosahedral positive strand RNA virus. The Zika virus reference genome (http://www.ncbi.nlm.nih.gov/nuccore/NC_012532.1) comprises a noncoding region and sequences coding for a 3419 amino acid polyprotein (http:// www.ncbi.nlm.nih.gov/protein/226377834). Zika virus is related to yellow fever (YF), dengue, West Nile, and Japanese encephalitis viruses, and most closely to Spondweni virus [6, 7]. Studies in Rhesus macaque suggest that adaptive immune responses to Zika infection interfere with, but do not fully protect against, YF infection and disease [8, 9]. Serologic cross-reactivity, including non-neutralizing antibodies, is observed with other closely related flaviviruses and flavivirus vaccines. Primates, including humans, are the best-documented Zika virus animal reservoir, with transmission to humans primarily by mosquito vectors (Aedes spp., including Ae. aegypti and Ae. albopictus [8, 10–13]. Soon after initial Zika virus discovery in Uganda, serologic evidence of human infection by Zika was observed in Egypt [14], India [15], Malaysia [15, 16], Thailand [16], Vietnam [16] and the Philippines [17]. Based on serology, but not verified by viral isolation, many other species may support Zika virus infection, including forest-dwelling birds [18], horses, goats, cattle, ducks and bats [19]. Recent reports indicate the potential for both human blood-borne and sexual transmission of Zika virus, including prolonged presence of virus in semen [20–23]. Zika virus is also present in the saliva of infected patients [24]. Perinatal transmission was documented in French Polynesia during the 2013–2014 outbreak where (...truncated)