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Research:

The Shi lab integrates academic and industrial expertise for basic and translational research. Our research focuses on viruses that cause significant human diseases, such as dengue, Zika, West Nile, and SARS-CoV-2. We take a multidisciplinary approach (i) to study the molecular mechanism of viral replication and (ii) to translate the knowledge into antiviral, vaccine, and diagnostic products. Many of our projects are highly collaborative with both academic and pharmaceutical partners around the world. 

1. Flavivirus and coronavirus biology Understanding the virus life cycle at a molecular level is essential for development of novel intervention. Our basic research is designed to decipher how viral and cellular factors modulate each other during viral infection, leading to productive viral replication and effective immune response. Our experimental approach includes biochemistry, structural biology, chemical biology, molecular biology, and disease modeling in vivo. 
2. Drug discovery Four strategies are being pursued for antiviral discovery: (i) High-throughput screening (HTS) using viral infection assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing clinical drugs for treatment of viral infection. Through collaboration with medicinal chemists and pharmacologists, we advance these inhibitors to preclinical and clinical development.
3. Vaccine development We take several approaches for vaccine development: (i) Viruses defective in 2’O methylation as a live-attenuated vaccine; (ii) flavivirus with a 3’UTR deletion as a live-attenuated vaccine; (iii) DNA-launched live-attenuated flavivirus and alphavirus vaccines; (iv) DNA-launched self-amplifying RNA as a universal plug-and-play vaccine platform.
4. Diagnosis Plaque reduction assay remains the “gold standard” for viral serological diagnosis. This assay is labor intensive and low throughput. We are developing stable reporter flaviviruses, alphaviruses, and coronaviruses to replace the traditional plaque assay. These new assays will not only improve serological diagnosis but also facilitate drug discovery and vaccine evaluation.

Biography:
Pei-Yong Shi is an Adjunct Professor at University of Texas Medical Branch (UTMB). He works on RNA virus, drug discovery, and vaccine research. His unique expertise in public health laboratory (York State Department of Health), pharmaceutical companies (Novartis and Bristol-Myers Squibb), and academia (UTMB and Yale) allows him to work on both basic and translational research. He has published >350 peer-reviewed papers. His group developed the first reverse genetic systems for the epidemic West Nile virus and Zika virus and discovered flavivirus N7 and 2’O methyltransferase activities. His team also published the first peer-reviewed infectious clone and reporter virus for SARS-CoV-2. Besides academic excellence, he also has a stellar track record of senior leadership role at major pharmaceutical companies (e.g., Executive Director at Novartis Institute for Tropical Diseases) where he set up antiviral strategies and executed drug discovery and development. Many of his technologies have been licensed to leading pharmaceutical companies for countermeasure development. A recent example is his reporter neutralization assay that has enabled the rapid development of Pfizer’s COVID-19 vaccine, the first vaccine with efficacy in humans.

Representative recent publications

1. Zou et al. 2023. Neutralization of BA.4-5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine. N Engl J Med. doi: 10.1056/NEJMc2214916.

2. Muñoz et al., 2023. Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age. N Engl J Med. doi: 10.1056/NEJMoa2211031

3. Winokur et al. 2023. Bivalent Omicron BA.1-Adapted BNT162b2 Booster in Adults Older than 55 Years. N Engl J Med. doi: 10.1056/NEJMoa2213082.

4. Kurhade et al. 2022. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by parental mRNA vaccine or a BA.5-bivalent booster. Nat Med. doi: 10.1038/s41591-022-02162-x.

5. Kee et al. 2022. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature. 610(7931):381-388. doi: 10.1038/s41586-022-05282-z.

6. Ku et al. 2022. Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth. Nat Commun. doi: 10.1038/s41467-022-33284-y.

7. Richards et al. 2022. The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection. Science. doi: 10.1126/science.abn5648

8. Liu et al. 2022. The N501Y spike substitution enhances SARS-CoV-2 infection and transmission. Nature. doi: 10.1038/s41586-021-04245-0.

9. Xia et al. 2022. Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARS-CoV-2. Cell Host Microbe. doi: 10.1016/j.chom.2022.02.015.

10. Zou et al. 2022. Neutralization against Omicron SARS-CoV-2 from previous non-Omicron infection. Nat Commun. doi: 10.1038/s41467-022-28544-w.

11. Liu et al. 2021. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature. doi: 10.1038/s41586-021-03693-y.

12. Falsey et al. 2021. SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3. N Engl J Med. 385(17):1627-1629. doi: 10.1056/NEJMc2113468

13. Ku et al. 2021. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature. doi: 10.1038/s41586-021-03673-2.

14. Sahin et al. 2021. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. doi: 10.1038/s41586-021-03653-6.

15. Zhang et al. 2021. A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence. Cell. doi: 10.1016/j.cell.2021.02.044

16. Liu et al. 2021. BNT162b2-Elicited Neutralization against New SARS-CoV-2 Spike Variants. N Engl J Med. doi: 10.1056/NEJMc2106083.

17. Chen et al. 2021. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. doi: 10.1038/s41591-021-01294-w

18. Xie et al. 2021.Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. Nat. Med. doi: 10.1038/s41591-021-01270-4

19. Liu et al. 2021. Neutralizing Activity of BNT162b2-Elicited Serum. N. Engl. J. Med. doi: 10.1056/NEJMc2102017.

20. Plante et al. 2020. Spike mutation D614G alters SARS-CoV-2 fitness. Nature. doi: 10.1038/s41586-020-2895-3.

21. Walsh et al. 2020. Safety and Immunogenicity of two RNA-Based COVID-19 Vaccine Candidates. N Engl J Med. doi: 10.1056/NEJMoa2027906.

22. Xie et al. 2020. A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19. Nature Commun. 11(1):5214.

23. Mulligan et al. 2020. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 586(7830):589-593.

24. Sahin et al. 2020. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T-cell responses. Nature. 586(7830):594-599.

25. Xia et al. 2020. Evasion of type-I interferon by SARS-CoV-2. Cell Rep. 33(1):108234.

26. Xia et al. 2020. A cocrystal structure of dengue capsid protein in complex of inhibitor. PNAS. 117(30):17992-18001.

27. Shan et al. 2020. A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission. PNAS. 117(33):20190-20197.

28. Giraldo et al. 2020. Envelope Protein Ubiquitination Drives Zika Virus Entry and Pathogenesis. Nature. 585(7825):414-419.

29. Muruato et al. 2020. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nature Commun. 11(1):4059.

30. Xie et al. 2020. An Infectious cDNA Clone of SARS-CoV-2. Cell Host Microbe. 27(5):841-848.e3.