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  1. Science & Research (Biologics)

Understanding the Interplay Between Host Immunity and Viral Factors for Rational Design of Vaccines Against Vector-Borne Viral Pathogens

Tony Wang, PhD

Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Vector-borne Viral Diseases



Dr. Tony Wang received his bachelor’s degree in medicine from the Beijing Medical University in 1996 and his PhD degree in microbiology in 2001 from the Department of Microbiology at Ohio State University. He completed two postdoctoral fellowships at the Howard Hughes Medical Institute/UCLA between 2002 and 2003, and then at the Los Alamos National Laboratory, New Mexico. He served as a faculty member at the University of Pittsburgh and a program director in virology at SRI International, a non-profit research institute, before joining CBER in 2018. Dr. Wang’s laboratory studies how human pathogenic Flaviviruses and Alphaviruses infect host cells.  The laboratory discovered the HCV entry factor occludin (JVI, 2009), identified the cellular RNase MCPIP1 as an HIV restriction factor in resting CD4+ cells (PNAS, 2013), and found that human endothelial cells are key cell types for the spread of Zika virus (Cir Res, 2016). Very recently, the laboratory began to study the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused a global pandemic. Leveraging our virology expertise, Dr. Wang’s laboratory established an in vitro pseudovirion-based neutralization assay, the live infectious SARS-CoV-2 culture system, and a hamster model that can be used to evaluate vaccine efficacy.

General Overview

CBER has identified increasing the nation's preparedness to address threats of emerging infectious diseases as one of its public health missions. LVVD plays a vital role in this mission through its studies of several vector-borne viral pathogens that pose an emerging or re-emerging threat to public health. Outbreaks of flaviviruses, such as DENV, WNV, and YFV, and, Zika virus (ZIKV), pose ongoing threats to public health. Also, diseases caused by the alphavirus, CHIKV, spread to nearby islands in the Caribbean (2014-2015). These viruses are typically spread to humans via Aedes mosquitoes. YFV and DENV outbreaks in the Western Hemisphere have occurred more frequently in the past several decades, and the viruses are endemic in certain regions of South America. WNV first appeared in the Western hemisphere in 1999 and now causes small focal and local outbreaks in the US. First isolated from a febrile rhesus macaque in 1947 in Africa, ZIKV spread to an island in Micronesia and from there to Brazil, much of the rest of South America, and eventually, Puerto Rico and Florida.

As a regulatory agency, FDA is responsible for ensuring the safety and efficacy of the nation’s vaccines. In the past several years, CBER has experienced an increasing volume of applications for viral vaccines against vector-borne viral diseases. Despite significant improvements in vaccine manufacturing technology over the past decades, it is not uncommon to witness serious adverse events associated with viral vaccines. For example, yellow fever vaccine based on the live attenuated YFV 17D strain was considered one of the safest vaccines; but in recent years it was reported that the vaccine could cause invasive and disseminated disease with high lethality in some otherwise healthy individuals.  Much evidence has shown that many live attenuated flaviviruses remain neurovirulent in animals if inoculated intracerebrally. The residual neurovirulence remains a potential risk if administered to pregnant women or immunocompromised individuals, or to individuals with unknown risk factors.

LVVDs believes pursuing parallel research goals relevant to vaccine safety enables us to provide insight into scientific issues inherent in the review process. Toward this goal, the division works to maintain high-quality research activities that are consonant with the mission of the laboratory and the nature of its regulatory responsibilities. Historically, the LVVD heavily relies on the use of the tools of molecular biology to elucidate mechanisms of flavivirus replication as they may relate to strategies to attenuate flavivirus virulence, thereby enhancing vaccine safety. Dr. Tony Wang is leading the effort to add animal models for testing vaccine safety.

Scientific Overview

The current LVVD research program concentrates on studying the virulence and attenuation of flaviviruses. We seek to understand the viral and host factors that contribute to the neuroinvasion and neurovirulence of flaviviruses in order to  develop critical parameters for assessing the safety of future vaccine candidates. Among the flaviviruses, WNV, TBEV, and JEV are more known for their neurovirulence. ZIKV is now recognized as a cause for pregnancy-associated microcephaly and other birth defects. Normally, the central nervous system (CNS) is protected from pathogens by the blood-brain barrier (BBB), which is composed of brain microvascular endothelial cells (BMECs) that line cerebral microvessels along with astrocytes, pericytes, and basal membrane. Yet recent studies have clearly established the ability of ZIKV to cross both the human fetal-placental barrier and the blood-brain barrier to reach the developing fetal brain/central nervous system.

We have previously reported that ZIKV uses the tyrosine-protein kinase receptor UFO (AXL) for entry into human umbilical vein endothelium and human brain microvascular endothelium. This work suggests that endothelial cells (ECs) might be a key target for ZIKV and that a hematogenous route of ZIKV spreading potentially contributes to breaching BBBs. To further understand the mechanism of ZIKV neuroinvasion, our laboratory is developing tools that allow the identification of genetic markers of ZIKV neurovirulence, the development of neutralization tests for the virus, the generation and characterization of infectious molecular clones, and the use of small animal models for pathogenesis studies and vaccine testing.

We are also trying to generate live attenuated viral vaccines. LVVD scientists have a long tradition of conducting research on DENV and WNV to understand how the genetic material of these viruses replicates inside infected cells and how the virus reproduces. This knowledge might inform the development of safe and effective live attenuated vaccines (LAVs). Such vaccines hold the greatest potential for stimulating long-lasting protective immunity, as compared to other types of vaccines, because the mechanism for inducing a response is similar to that induced by a natural infection. LAVs are usually the most cost-effective vaccines, because very often a single dose of a live vaccine will provide long-lasting or lifelong protection. Former LVVD scientists hold patents on attenuated DENV and WNV; for example, three of them (Drs. Falgout and Yu and Mr. Flores) constructed multiple infectious chimeric clones of ZIKV-Dengue and WNV carrying deletions in the 3SL genomic region. We are doing molecular analyses of these clones to understand many aspects of the viral life cycle. Most importantly, the materials provide a basis for us to rationally design LAVs. Our strategy is to alter the ability of viruses to grow in cells by genetic mutations. The mutations are intended to eliminate or weaken virulence. This work helps us to understand the complexities of novel candidate vaccines that may be submitted to FDA for review.


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