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 diseases mechanism,
Vaccines against enterotoxigenic E. coli (ETEC).
Weiping Zhang was trained as a molecular evolutionary biologist and his Escherichia coli pathogenesis and vaccine research and development carrier began in 2003 when he studied molecular pathogenesis 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 his application of toxoids as safe vaccine antigens and his innovation of toxoid fusion antigens to induce protective antitoxin antibodies against ETEC diarrhea. An effective vaccine needs to protect against enterotoxicity of LT and STa toxins because these two toxins are the virulence determinants in ETEC diarrhea. It was 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 monomeric LT toxoid, he generated monomeric LT-STa toxoid genetic fusions that are not only safe but also induce strong antibody responses against both toxins and against ETEC diarrhea in the pig challenge model. Application of STa toxoids and safe LT-STa toxoid genetic fusion for induction of protective antitoxin antibodies is hailed as a major breakthrough in ETEC vaccine development.
His most recent innovation is 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 approach by identifying an adhesin backbone and substituting backbone surface-exposed peptides with antigenic epitopes from 6 or 8 other important ETEC adhesins and both LT and STa toxins, to create a single recombinant protein that induces anti-adhesin antibodies broadly protecting against 7 or 9 ETEC adhesins and also antitoxin antibodies against both ETEC toxins. With inclusion of another adhesin MEFA, his subunit vaccine is potentially able to induce antibodies against both toxins and up to 15 prevalent ETEC adhesins, thus effectively protecting against ETEC diarrhea.
His research is 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 serve as journal editorial board member and ad-hoc reviewer for more than 20 peer-review journals.
(selected from 52; * indicted corresponding author)
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Harshish 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Zhang, C., and W. Zhang*. 2010. Escherichia coli K88ac fimbriae expressing heat-labile and heat-stable (STa) toxin epitopes elicited antibodies that neutralize cholerae toxin and STa toxin and inhibit adherence of K88ac fimbrial E. coli. Clin. Vaccine Immun. 17(12): 1859-1867.
16. *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.
17. *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.
18. *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.
19. 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. Micorbiol. 75(19): 6402-6405.
20. *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.
21. *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.
22. *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.