Kansas State University College of Veterinary Medicine
Diagnostic Medicine/Pathobiology, Manhattan, KS 66506.
Ph.D. (1996) Iowa State University, Ames, Iowa.
E. coli associated diarrheal disease pathogenesis,
Vaccines development for enterotoxigenic E. coli (ETEC)
associated diarrhea and other enteric diseases.
Weiping Zhang was trained as a molecular evolutionary biologist. His Escherichia coli research and vaccine development career began in 2003 when he studied virulence significance of individual enterotoxins produced by enterotoxigenic E. coli (ETEC) in diarrheal disease using gnotobiotic (germ-free) piglets. By challenging gnotobiotic piglets with isogenic E. coli strains that express heat-labile toxin (LT) or a heat-stable toxin (STa, STb, or EAST1) and analyzing clinic outcomes, he developed a gnotobiotic pig challenge model for ETEC diarrheal disease research and vaccine development.
Zhang’s another contribution toward ETEC vaccine development is the application of toxoids as safe vaccine antigens and the innovation of toxoid fusion antigens to induce protective antitoxin antibodies against ETEC diarrhea. An effective ETEC vaccine needs to protect against enterotoxicity of LT and STa toxins because it is these two toxins that cause fluid hyper-secretion and watery diarrhea. It was once considered an unachievable task for vaccines to include safe STa antigens and to induce protective antibodies against STa toxin. But by introducing a single mutation, his laboratory identified STa mutants that maintain STa antigenic integrity but abolish enterotoxicity. Moreover, when these STa toxoids were genetically fused to a novel mutant LT monomer, he generated monomeric LT-STa toxoid genetic fusions that are not only safe but also induce strong antibodies neutralizing LT and STa enterotoxicity and protecting against ETEC diarrhea in a pig challenge model. Application of STa toxoids and safe LT-STa toxoid genetic fusion for protective antibodies against STa is hailed as a major breakthrough in ETEC vaccine development.
His most recent innovation is structure-based MEFA - multiepitope fusion antigen for development of broadly protective multivalent ETEC vaccines. Different ETEC strains produce immunologically heterogeneous bacterial adhesins to attach host cells and colonize in small intestines, initiating ETEC diarrheal disease. Heterogeneity of ETEC adhesins is another major challenge in ETEC vaccine development. His group created the MEFA structural vaccinology approach by identifying an adhesin backbone and mimicking antigenic presentation of epitopes from 6 to 8 other important ETEC adhesins and also LT and STa toxins. A single MEFA protein induces anti-adhesin antibodies broadly protecting against 7 or 9 ETEC adhesins and also antitoxin antibodies against both ETEC toxins.
His research is largely supported by NIH, USDA, EVI/PATH/Bill & Millender Gates Foundation, and other private or governmental funding agencies. He serves on review panels of NIH, DOD, USDA, and other public and private funding agencies. He also serves as journal editorial board member and ad-hoc reviewer for more than 30 peer-review journals.
(selected from 64; * indicted corresponding author)
- Nandre R., X Ruan, T. Lu, DA Sack, W. Zhang*. 2018. Enterotoxigenic Escherichia coli (ETEC) adhesin-toxoid MEFA (multiepitope fusion antigen) CFA/I/II/IV-3xSTaN12S-mnLTG192G/L211A derived antibodies inhibit adherence of seven adhesins (CFA/I, CFA/II & CFA/IV), neutralize enterotoxicity of both toxins (LT & STa), and protect piglets against diarrhea. Infect. Immun. In Press (doi:10.1128/IAI00550-17).
- Duan QD, JC Huang, N. Xiao, H. Seo, W. Zhang*. 2018. Neutralizing anti-STa antibodies derived from enterotoxigenic Escherichia coli (ETEC) toxoid fusions with heat-stable toxin (STa) mutant STaN12S, STaL9A/N12S or STaN12S/A14T show little cross-reactivity with guanylin or uroguanylin. Appl. Environ. Microbiol. 84(2): e01737-17).
- Duan, QD, KH Lee, RM Nandre, C Garcia, J Chen, W. Zhang*. 2017. MEFA (multiepitope fusion antigen)-novel technology for structural vaccinology, proof from computational and empirical immunogenicity characterization of an enterotoxigenic Escherichia coli (ETEC) adhesin MEFA. J. Vaccines Vaccin. 8(4):1000367.
- Wenzel H, RW Kaminski, KA Clarkson, M Maciel Jr., MA Smith, W. Zhang, EV Oaks. 2017. Summary of the workshop “Improving chances for successful clinical outcomes with better preclinical models”. Vaccine 35(2017):6798-6802.
- Duan, QD, W. Zhang*. 2017. Genetic fusion protein 3xSTa-ovalbumin is an effective coating antigen for ELISA to titrate anti-STa antibodies. Microbiol. Immunol. 61(7):251-257.
- Lu, T, W. Zhang. 2017. Identifying immuno-dominant and neutralizing epitopes from K88 fimbriae of enterotoxigenic Escherichia coli (ETEC). Kansas AES Res. Rep. 3(7):e54.
- Rausch, D., X. Ruan, R. Nandre, Q. Duan, E. Hashish, TA Casey, and W Zhang*. 2017. Antibodies derived from a toxoid MEFA (multiepitope fusion antigen) show neutralizing activities against heat-labile (LT), heat-stable toxins (STa, STb), and Shigella toxin 2e (Stx2e) of porcine enterotoxigenic Escherichia coli (ETEC). Vet. Microbiol. 202(2017):79-89.
- Nandre, R.M., Q. Duan, Y. Wang, and W. Zhang*. 2016. Passive antibodies derived from intramuscularly immunized toxoid fusion 3xSTaN12S-dmLT protect against STa+ enterotoxigenic Escherichia coli (ETEC) diarrhea in a pig model. Vaccine 35:552-556.
- Nandre, R.M., X. Ruan, Q. Duan, and W. Zhang*. 2016. Enterotoxigenic Escherichia coli heat-stable toxin and heat-labile toxin toxoid fusion 3xSTaN12S-dmLT induces neutralizing anti-STa antibodies in subcutaneously immunized mice. FEMS Microbiol. Let. 363 (21):1-6.
- Nandre, R. M., X. Ruan, Q. Duan, D.A. Sack, and W. Zhang*. 2016. Antibodies derived from an enterotoxigenic Escherichia coli (ETEC) adhesin tip MEFA (multiepitope fusion antigen) against adherence of nine ETEC adhesins: CFA/I, CS1, CS2, CS3, CS4, CS5, CS6, CS21 and EtpA. Vaccine 34 (2016):3620-3625.
- 11. Zhang W*, DA Sack. 2015. Current progress in developing subunit vaccines against enterotoxigenic Escherichia coli (ETEC) associated diarrhea. Clin. Vaccine Immun. (Editorial invited minireview article). 22(9):983-991.
- Ruan X, Sack DA, and W Zhang*. 2015. Fusing a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retains broad anti-adhesin and antitoxin immunogenicity. PLoS One 10(3):e0121623.
- Ruan X, D.C. Robertson, J.P. Nataro, J.D. Clements, and W Zhang* & the STa Toxoid Vaccine Consortium Group. 2014. Characterization of heat-stable (STa) toxoids of enterotoxigenic Escherichia coli fused to a double mutant heat-labile toxin (dmLT) peptide in inducing neutralizing anti-STa antibodies. Infect. Immun. 82(5):1823-1832.
- Ruan X., D. E. Knudsen, K. M. Wollenberg, D. A. Sack, and W. Zhang*. 2014. Multiepitope fusion antigen induces broadly protective antibodies that prevent adherence of Escherichia coli strains expressing colonization factor antigen I (CFA/I), CFA/II, and CFA/IV. Clin. Vaccine Immun. 21(2):243-249.
- Zhang, W*. 2014. Perspective of use of vaccines for preventing enterotoxigenic Escherichia coli diarrhea in humans. P273-301, Chapter 15, in Morabito S (ed) Pathogenic Escherichia coli: Molecular and Cellular Microbiology. Caister Academic Press, Norfolk, England.
- Zhang W*. 2014. Progress and challenges in vaccine development against enterotoxigenic Escherichia coli (ETEC)-associated porcine post-weaning diarrhea (PWD). J. Vet. Med. Res. 1(2):1006.
- Zhang, C., D. E. Knudsen, M. Liu, D. C. Robertson, and W. Zhang*, & the STa Toxoid Vaccine Consortium Group. 2013. Safety & immunogenicity of enterotoxigenic Escherichia coli heat-labile and heat-stable toxoid fusion 3xSTaA14Q-LTS63K/R192G/L211A in a murine model. PLoS ONE. 8(10):e77386.
- Hashish E, C. Zhang, X. Ruan, D. E. Knudsen, C. C. Chase, R. E. Isaacson, G. Zhou, and W. Zhang*. 2013. A multi-epitope fusion antigen elicited neutralizing antibodies against enterotoxigenic Escherichia coli (ETEC) and homologous bovine viral diarrhea virus (BVDV) in vitro. Clin. Vaccine Immun. 20(7):1076-1083.
- Ruan, X., and W. Zhang*. 2013. Oral immunization of a live attenuated Escherichia coli strain expressing a holotoxin-structured adhesin-toxoid fusion (1FaeG-FedF-LTA2:5LTB) protected young pigs against enterotoxigenic E. coli (ETEC) infection. Vaccine 31(2013):1458-1463.
- W. Zhang*, and D. A. Sack. 2012. Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans. Expert Review of Vaccines. 11(6):677-94.
- Ruan X., Crupper S.C., Schultz B.D., Robertson D.C., and W. Zhang*. 2012. Escherichia coli expressing enteroaggregative heat-stable toxin 1 (EAST1) did not cause an increase of cAMP or cGMP levels in cells, and no diarrhea in 5-day old gnotobiotic pigs. PLoS ONE. 7(8):e43203.
- Liu, M., X. S. Ruan, C. Zhang, S. Lawson, D. Knudsen, J. P. Nataro, D. C. Robertson, and W. Zhang*. 2011. Heat-labile (LT) and heat-stable (STa) toxoid fusions (LTR192G-STaP13F) of human enterotoxigenic Escherichia coli elicited neutralizing antitoxin antibodies. Infect. Immun. 79(10): 4002-4009.
- Ruan, X., M. Liu, T. Casey, and W. Zhang*. 2011. A Tripartite Fusion, FaeG-FedF-LT192A2:B, of Enterotoxigenic Escherichia coli (ETEC) Elicits Antibodies Neutralizing CT Toxin, Inhibiting Adherence of K88 (F4) and F18 Fimbriae, and Protecting Pigs against K88ac/LT ETEC Infection. Clin. Vaccine Immun. 18(10): 1593-1599.
- Liu M., C. Zhang, K. Meteo, JP Nataro, DC Robertson, and W. Zhang*. 2011. Modified heat-stable toxins (hSTa) of enterotoxigenic Escherichia coli lose toxicity but display antigenicity after being genetically fused to heat-labile toxoid LT(R192G). Toxins. 3:1146-1162.
- Zhang, C., and W. Zhang*. 2010. Escherichia coli K88ac fimbriae expressing heat-labile and heat-stable (STa) toxin epitopes elicited antibodies that neutralize cholera toxin and STa toxin and inhibit adherence of K88ac fimbrial E. coli. Clin. Vaccine Immun. 17(12): 1859-1867.
- *Zhang, W., and D. H. Francis. 2010. Genetic fusions of heat-labile toxoid (LT192) and heat-stable toxin b (STb) of porcine enterotoxigenic Escherichia coli (ETEC) elicit protective anti-LT and anti-STa antibodies. Clin. Vaccine Immun. 17(7):.1223-1231.
- *Zhang, W., C. Zhang, D. H. Francis, J. Nataro, and D. C. Robertson. 2010. Genetic fusions of pLTAB and pSTa toxoids of enterotoxigenic Escherichia coli (ETEC) induce protective anti-LT and anti-STa antibodies. Infect. Immun. 78(1):316-325.
- *Zhang, W., Y. Fang, and D. H. Francis. 2009. Characterizing the Binding Specificity of K88ac and K88ad Fimbriae of Enterotoxigenic Escherichia coli by Constructing K88ac/ad Chimeric FaeG Major Subunits. Infect. Immun. 77:699-706.
- Zhang, C., D. Rausch, and W. Zhang*. 2009. Heat-labile and heat-stable toxin genes of enterotoxigenic Escherichia coli strains isolated from diarrheal pigs show little heterogeneity. Appl. Environ. Microbiol. 75(19): 6402-6405.
- *Zhang, W., D. Robertson, C. Zhang, W. Bai, M. Zhao, and D. Francis. 2008. Escherichia coli constructs expressing human or porcine enterotoxins induce identical diarrheal disease in a piglet infection model. Appl. Environ. Microbiol. 74(18):5832-5837.
- *Zhang, W., M. Zhao, L. Ruesch, A. Omot, and D. Francis. 2007. Prevalence of virulence genes in Escherichia coli strains isolated from young pigs with diarrhea in North Central U.S. Vet. Microbiol. 123:145-152.
- Zhang, W., J. Freeling, E. Berberov, R. Moxley, and D. Francis*. 2006. Contribution of heat-stable and heat-labile enterotoxins in the pathogenesis porcine colibacillosis. Infect. Immun. 74:3107-3114.