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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

Tony.Wang@fda.hhs.gov

Biosketch

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.

Publications

  1. J Virol 2024 May;98(5):e0034724
    The TRAF3-DYRK1A-RAD54L2 complex maintains ACE2 expression to promote SARS-CoV-2 infection.
    Mao D, Liu S, Phan AT, Renner S, Sun Y, Wang TT, Zhu Y
  2. Vaccine 2024 Jan 25;42(3):608-19
    Vaccine-associated respiratory pathology correlates with viral clearance and protective immunity after immunization with self-amplifying RNA expressing the spike (S) protein of SARS-CoV-2 in mouse models.
    Kachko A, Selvaraj P, Liu S, Kim J, Rotstein D, Stauft CB, Chabot S, Rajasagi N, Zhao Y, Wang T, Major M
  3. PLoS Pathog 2023 Nov 9;19(11):e1011788
    Effects of N-glycan modifications on spike expression, virus infectivity, and neutralization sensitivity in ancestral compared to Omicron SARS-CoV-2 variants.
    Lusvarghi S, Stauft CB, Vassell R, Williams B, Baha H, Wang W, Neerukonda SN, Wang T, Weiss CD
  4. Nat Commun 2023 Jun 9;14(1):3393
    Intranasal or airborne transmission-mediated delivery of an attenuated SARS-CoV-2 protects Syrian hamsters against new variants.
    Stauft CB, Selvaraj P, D'Agnillo F, Meseda CA, Liu S, Pedro CL, Sangare K, Lien CZ, Weir JP, Starost MF, Wang TT
  5. J Infect Dis 2023 Jan 15;227(2):202-5
    Differences in new variant of concern replication at physiological temperatures in vitro.
    Stauft CB, Sangare K, Wang TT
  6. Antib Ther 2023 Jan;6(1):49-58
    Comparative assessment of the binding and neutralisation activity of bispecific antibodies against SARS-CoV-2 variants.
    Dean AQ, Stauft CB, Twomey JD, Tan J, Varani L, Wang TT, Zhang B
  7. Int J Mol Sci 2022 Dec 29;24(1):558
    HIF-1alpha-dependent metabolic reprogramming, oxidative stress, and bioenergetic dysfunction in SARS-CoV-2-infected hamsters.
    Jana S, Heaven MR, Stauft CB, Wang TT, Williams MC, D'Agnillo F, Alayash AI
  8. Nat Commun 2022 Nov 10;13(1):6792
    Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters.
    Liu S, Stauft CB, Selvaraj P, Chandrasekaran P, D'Agnillo F, Chou CK, Wu WW, Lien CZ, Meseda CA, Pedro CL, Starost MF, Weir JP, Wang TT
  9. Cell Rep 2022 Sep 13;40(11):111359
    Spike protein-independent attenuation of SARS-CoV-2 Omicron variant in laboratory mice.
    Liu S, Selvaraj P, Sangare K, Luan B, Wang TT
  10. J Virol 2022 Sep;96(17):e0114022
    Characterization of entry pathways, species-specific angiotensin-converting enzyme 2 residues determining entry, and antibody neutralization evasion of Omicron BA.1, BA.1.1, BA.2, and BA.3 variants.
    Neerukonda SN, Wang R, Vassell R, Baha H, Lusvarghi S, Liu S, Wang T, Weiss CD, Wang W
  11. Clin Infect Dis 2022 Jul 1;75(1):e459-65
    Pharmacokinetics and efficacy of human hyperimmune intravenous immunoglobulin treatment of SARS-CoV-2 infection in adult Syrian hamsters.
    Stauft CB, Tegenge M, Khurana S, Lee Y, Selvaraj P, Golding H, Wang T, Golding B
  12. J Med Virol 2022 Jun;94(6):2833-6
    Long-term immunity in convalescent Syrian hamsters provides protection against new-variant SARS-CoV-2 infection of the lower but not upper respiratory tract.
    Stauft CB, Selvaraj P, Lien CZ, Starost MF, Wang TT
  13. PLoS One 2022 Mar 17;17(3):e0262967
    Identification of salivary gland escape barriers to western equine encephalitis virus in the natural vector, Culex tarsalis.
    Stauft CB, Phillips AT, Wang TT, Olson KE
  14. J Virol 2022 Mar;96(6):e0221621
    Stable cell clones harboring self-replicating SARS-CoV-2 RNAs for drug screen.
    Liu S, Chou CK, Wu WW, Luan B, Wang TT
  15. NPJ Vaccines 2021 Dec 3;6(1):145
    MVA vector expression of SARS-CoV-2 spike protein and protection of adult Syrian hamsters against SARS-CoV-2 challenge.
    Meseda CA, Stauft CB, Selvaraj P, Lien CZ, Pedro C, Nuñez IA, Woerner AM, Wang TT, Weir JP
  16. Sci Rep 2021 Nov 12;11(1):22195
    Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration and infectivity in human lung cells.
    Caohuy H, Eidelman O, Chen T, Liu S, Yang Q, Bera A, Walton NI, Wang TT, Pollard HB
  17. J Chem Inf Model 2021 Oct 25;61(10):5133-40
    Structure-function analysis of resistance to Bamlanivimab by SARS-CoV-2 variants Kappa, Delta, and Lambda.
    Liu S, Huynh T, Stauft CB, Wang TT, Luan B
  18. iScience 2021 Sep 24;24(9):103006
    Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern.
    Tang J, Lee Y, Ravichandran S, Grubbs G, Huang C, Stauft CB, Wang T, Golding B, Golding H, Khurana S
  19. J Neuroinflammation 2021 Jul 31;18(1):169
    Aicardi-Goutieres syndrome-associated mutation at ADAR1 gene locus activates innate immune response in mouse brain.
    Guo X, Wiley CA, Steinman RA, Sheng Y, Ji B, Wang J, Zhang L, Wang T, Zenatai M, Billiar TR, Wang Q
  20. Lancet Microbe 2021 Jun;2(6):e259-66
    A method for detection of SARS-CoV-2 RNA in healthy human stool: a validation study.
    Coryell MP, Iakiviak M, Pereira N, Murugkar PP, Rippe J, Williams DB, Heald-Sargent T, Sanchez-Pinto LN, Chavez J, Hastie JL, Sava RL, Lien CZ, Wang TT, Muller WJ, Fischbach MA, Carlson PE Jr
  21. mSphere 2021 Jun;6(3):e0050721
    SARS-CoV-2 B.1.1.7 infection of Syrian hamster does not cause more severe disease, and naturally acquired immunity confers protection.
    Nuñez IA, Lien CZ, Selvaraj P, Stauft CB, Liu S, Starost MF, Wang TT
  22. Life Sci Alliance 2021 Feb 11;4(4):e202000886
    SARS-CoV-2 infection induces protective immunity and limits transmission in Syrian hamsters.
    Selvaraj P, Lien CZ, Liu S, Stauft CB, Nunez IA, Hernandez M, Nimako E, Ortega MA, Starost MF, Dennis JU, Wang TT
  23. Virology 2021 Apr;556:96-100
    The G614 pandemic SARS-CoV-2 variant is not more pathogenic than the original D614 form in adult Syrian hamsters.
    Stauft CB, Lien CZ, Selvaraj P, Liu S, Wang TT
  24. J Virol 2021 Mar;95(11):e01751-20
    The PRRA insert at the S1/S2 site modulates cellular tropism of SARS-CoV-2 and ACE2 usage by the closely related Bat RaTG13.
    Liu S, Selvaraj P, Lien CZ, Nunez IA, Wu WW, Chou CK, Wang TT
  25. PLoS One 2021 Mar 10;16(3):e0248348
    Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2.
    Neerukonda SN, Vassell R, Herrup R, Liu S, Wang T, Takeda K, Yang Y, Lin TL, Wang W, Weiss CD
  26. Sci Rep 2020 Sep 24;10(1):15643
    Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design.
    Kames J, Holcomb DD, Kimchi O, DiCuccio M, Hamasaki-Katagiri N, Wang T, Komar AA, Alexaki A, Kimchi-Sarfaty C
  27. Sci Transl Med 2020 Jul 1;12(550):eabc3539
    Antibody signature induced by SARS-CoV-2 spike protein immunogens in rabbits.
    Ravichandran S, Coyle EM, Klenow L, Tang J, Grubbs G, Liu S, Wang T, Golding H, Khurana S
  28. Biochem J 2019 Oct 15;476(19):2927-38
    Selective degradation of plasmid-derived mRNAs by MCPIP1 RNase.
    Qian Y, Li X, Miao R, Liu S, Xin HB, Huang X, Wang TT, Fu M
  29. EBioMedicine 2019 Sep;47:269-83
    Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus.
    Martinez-Lopez A, Persaud M, Chavez MP, Zhang H, Rong L, Liu S, Wang TT, Sarafianos SG, Diaz-Griffero F
  30. J Am Chem Soc 2019 Aug 14;141(32):12891-900
    Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors.
    Zhang W, Chu J, Cyr AM, Yueh H, Brown LE, Wang TT, Pelletier J, Porco JA Jr
  31. Int J Antimicrob Agents 2019 Jul;54(1):80-4
    Phloretin inhibits Zika virus infection by interfering with the cellular glucose utilization.
    Lin SC, Chen MC, Liu S, Callahan VM, Bracci NR, Woodson CM, Dahal B, de la Fuente CL, Lin CC, Wang TT, Kehn-Hall K
  32. J Am Chem Soc 2019 Jan 23;141(3):1312-23
    Chemical synthesis enables structural reengineering of aglaroxin c leading to inhibition bias for hepatitis C viral infection.
    Zhang WH, Liu SF, Maiga RI, Pelletier J, Brown LE, Wang TT, Porco JA

 

 

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