James E Galen

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Development of a Live Oral Cholera Vaccine

James B Kaper

1 January 1983 - 30 June 2011
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

The long-term objective of this project is the development of a safe and highly efficacious live oral cholera vaccine. Previous work funded by this project has resulted in the development of an attenuated live oral cholera vaccine, Vibrio cholerae CVD 103-HgR, which confers strong protective immunity after a single dose. Although this vaccine is highly protective against experimental challenge in North Americans, it has a mixed record of success in conferring protective immunity in citizens of developing countries. An improved cholera vaccine that colonizes the intestine more avidly and engenders a stronger immune response than CVD 103-HgR would be desirable. However, better colonizing and more immunogenic vaccine strains have usually caused side effects in North Americans including mild to moderate diarrhea. During the past period of support, we have used in vivo expression technology (IVET) in a volunteer study to identify genes that are activated during the course of human infection. We have also generated new insights into intestinal inflammation caused by these reactogenic cholera vaccines by using gene arrays of epithelial cell transcriptional responses. In the next period of support, we will pursue four specific aims. The first aim will be to examine the role of flagellin in TLR5 activation and IL-8 production by V. cholerae. The second aim will be to characterize the involvement of TLR5 in the reactogenicity of many live attenuated cholera vaccines. The third aim will be to characterize the human immune response to in vivo-induced V. cholerae proteins identified in the IVET volunteer study. The fourth aim will be to develop a V. cholerae vector system for expression of foreign antigens based on in vivo induced promoters. The proposed aims will yield important information about the interaction of V. cholerae with the innate immune system, insights into the reactogenicity caused by ctx V. cholerae mutants, novel information regarding human immune responses to in vivo expressed antigens, and a promising new vector system for expression of heterologous antigens. Lay summary: Vibrio cholerae is a bacterium that causes cholera, a severe diarrheal disease that can often cause death. This project will develop improved vaccines for the prevention of cholera.

57 Resulting Publications

• 1.

  2010

  Greta Caburlotto; Maria M Lleò; Tamara Hilton; Anwar Huq; Rita R Colwell; James B Kaper

  Effect on human cells of environmental Vibrio parahaemolyticus strains carrying type III secretion system 2.

  Infection and immunity 2010;78(7):3280-7.

• 2.

  2010

  Rogeria Keller; Tamara D Hilton; Hernam Rios; Edgar C Boedeker; James B Kaper

  Development of a live oral attaching and effacing Escherichia coli vaccine candidate using Vibrio cholerae CVD 103-HgR as antigen vector.

  Microbial pathogenesis 2010;48(1):1-8.

• 3.

  2009

  Cara E Morin; James B Kaper

  Use of stabilized luciferase-expressing plasmids to examine in vivo-induced promoters in the Vibrio cholerae vaccine strain CVD 103-HgR.

  FEMS immunology and medical microbiology 2009;57(1):69-79.

• 4.

  2008

  Lisa M Harrison; Prasad Rallabhandi; Jane Michalski; Xin Zhou; Susan R Steyert; Stefanie N Vogel; James B Kaper

  Vibrio cholerae flagellins induce Toll-like receptor 5-mediated interleukin-8 production through mitogen-activated protein kinase and NF-kappaB activation.

  Infection and immunity 2008;76(12):5524-34.

• 5.

  2007

  Mary-Jane Lombardo; Jane Michalski; Hector Martinez-Wilson; Cara Morin; Tamara Hilton; Carlos G Osorio; James P Nataro; Carol O Tacket; Andrew Camilli; James B Kaper

  An in vivo expression technology screen for Vibrio cholerae genes expressed in human volunteers.

  Proceedings of the National Academy of Sciences of the United States of America 2007;104(46):18229-34.

• 6.

  2005

  James B Kaper; Vanessa Sperandio

  Bacterial cell-to-cell signaling in the gastrointestinal tract.

  Infection and immunity 2005;73(6):3197-209.

• 7.

  2005

  C G Osorio; J A Crawford; J Michalski; H Martinez-Wilson; J B Kaper; A Camilli

  Second-generation recombination-based in vivo expression technology for large-scale screening for Vibrio cholerae genes induced during infection of the mouse small intestine.

  Infection and immunity 2005;73(2):972-80.

• 8.

  2004

  Neil R Stokes; Xin Zhou; Stephen J Meltzer; James B Kaper

  Transcriptional responses of intestinal epithelial cells to infection with Vibrio cholerae.

  Infection and immunity 2004;72(7):4240-8.

• 9.

  2004

  Xin Zhou; Da Q Gao; Jane Michalski; Jorge A Benitez; James B Kaper

  Induction of interleukin-8 in T84 cells by Vibrio cholerae.

  Infection and immunity 2004;72(1):389-97.

• 10.

  2002

  Caiyi C Li; D Scott Merrell; Andrew Camilli; James B Kaper

  ToxR interferes with CRP-dependent transcriptional activation of ompT in Vibrio cholerae.

  Molecular microbiology 2002;43(6):1577-89.

• 11.

  2001

  D S Merrell; C Bailey; J B Kaper; A Camilli

  The ToxR-mediated organic acid tolerance response of Vibrio cholerae requires OmpU.

  Journal of bacteriology 2001;183(9):2746-54.

• 12.

  2001

  D K Karaolis; R Lan; J B Kaper; P R Reeves

  Comparison of Vibrio cholerae pathogenicity islands in sixth and seventh pandemic strains.

  Infection and immunity 2001;69(3):1947-52.

• 13.

  2000

  C C Li; J A Crawford; V J DiRita; J B Kaper

  Molecular cloning and transcriptional regulation of ompT, a ToxR-repressed gene in Vibrio cholerae.

  Molecular microbiology 2000;35(1):189-203.

• 14.

  2000

  J Hacker; J B Kaper

  Pathogenicity islands and the evolution of microbes.

  Annual review of microbiology 2000;54():641-79.

• 15.

  1999

  S Sozhamannan; Y K Deng; M Li; A Sulakvelidze; J B Kaper; J A Johnson; G B Nair; J G Morris

  Cloning and sequencing of the genes downstream of the wbf gene cluster of Vibrio cholerae serogroup O139 and analysis of the junction genes in other serogroups.

  Infection and immunity 1999;67(10):5033-40.

• 16.

  1998

  M Trucksis; J Michalski; Y K Deng; J B Kaper

  The Vibrio cholerae genome contains two unique circular chromosomes.

  Proceedings of the National Academy of Sciences of the United States of America 1998;95(24):14464-9.

• 17.

  1998

  J A Crawford; J B Kaper; V J DiRita

  Analysis of ToxR-dependent transcription activation of ompU, the gene encoding a major envelope protein in Vibrio cholerae.

  Molecular microbiology 1998;29(1):235-46.

• 18.

  1998

  D K Karaolis; J A Johnson; C C Bailey; E C Boedeker; J B Kaper; P R Reeves

  A Vibrio cholerae pathogenicity island associated with epidemic and pandemic strains.

  Proceedings of the National Academy of Sciences of the United States of America 1998;95(6):3134-9.

• 19.

  1997

  M Trucksis; T L Conn; A Fasano; J B Kaper

  Production of Vibrio cholerae accessory cholera enterotoxin (Ace) in the yeast Pichia pastoris.

  Infection and immunity 1997;65(12):4984-8.

• 20.

  1997

  A E Fiore; J M Michalski; R G Russell; C L Sears; J B Kaper

  Cloning, characterization, and chromosomal mapping of a phospholipase (lecithinase) produced by Vibrio cholerae.

  Infection and immunity 1997;65(8):3112-7.

• 21.

  1997

  A A Franco; L M Mundy; M Trucksis; S Wu; J B Kaper; C L Sears

  Cloning and characterization of the Bacteroides fragilis metalloprotease toxin gene.

  Infection and immunity 1997;65(3):1007-13.

• 22.

  1996

  V Sperandio; C Bailey; J A Girón; V J DiRita; W D Silveira; A L Vettore; J B Kaper

  Cloning and characterization of the gene encoding the OmpU outer membrane protein of Vibrio cholerae.

  Infection and immunity 1996;64(12):5406-9.

• 23.

  1996

  C L Sears; J B Kaper

  Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion.

  Microbiological reviews 1996;60(1):167-215.

• 24.

  1996

  L E Comstock; J A Johnson; J M Michalski; J G Morris; J B Kaper

  Cloning and sequence of a region encoding a surface polysaccharide of Vibrio cholerae O139 and characterization of the insertion site in the chromosome of Vibrio cholerae O1.

  Molecular microbiology 1996;19(4):815-26.

• 25.

  1995

  V Sperandio; J A Girón; W D Silveira; J B Kaper

  The OmpU outer membrane protein, a potential adherence factor of Vibrio cholerae.

  Infection and immunity 1995;63(11):4433-8.

• 26.

  1995

  F Raimondi; J P Kao; J B Kaper; S Guandalini; A Fasano

  Calcium-dependent intestinal chloride secretion by Vibrio parahaemolyticus thermostable direct hemolysin in a rabbit model.

  Gastroenterology 1995;109(2):381-6.

• 27.

  1995

  A Fasano; C Fiorentini; G Donelli; S Uzzau; J B Kaper; K Margaretten; X Ding; S Guandalini; L Comstock; S E Goldblum

  Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro.

  The Journal of clinical investigation 1995;96(2):710-20.

• 28.

  1995

  M Nishibuchi; J B Kaper

  Thermostable direct hemolysin gene of Vibrio parahaemolyticus: a virulence gene acquired by a marine bacterium.

  Infection and immunity 1995;63(6):2093-9.

• 29.

  1995

  L E Comstock; D Maneval; P Panigrahi; A Joseph; M M Levine; J B Kaper; J G Morris; J A Johnson

  The capsule and O antigen in Vibrio cholerae O139 Bengal are associated with a genetic region not present in Vibrio cholerae O1.

  Infection and immunity 1995;63(1):317-23.

• 30.

  1995

  J B Kaper; J G Morris; M M Levine

  Cholera.

  Clinical microbiology reviews 1995;8(1):48-86.

• 31.

  1994

  J B Kaper; J Michalski; J M Ketley; M M Levine

  Potential for reacquisition of cholera enterotoxin genes by attenuated Vibrio cholerae vaccine strain CVD 103-HgR.

  Infection and immunity 1994;62(4):1480-3.

• 32.

  1993

  J Michalski; J E Galen; A Fasano; J B Kaper

  CVD110, an attenuated Vibrio cholerae O1 El Tor live oral vaccine strain.

  Infection and immunity 1993;61(10):4462-8.

• 33.

  1993

  J M Ketley; J Michalski; J Galen; M M Levine; J B Kaper

  Construction of genetically marked Vibrio cholerae O1 vaccine strains.

  FEMS microbiology letters 1993;111(1):15-21.

• 34.

  1993

  M Trucksis; J E Galen; J Michalski; A Fasano; J B Kaper

  Accessory cholera enterotoxin (Ace), the third toxin of a Vibrio cholerae virulence cassette.

  Proceedings of the National Academy of Sciences of the United States of America 1993;90(11):5267-71.

• 35.

  1993

  J A Johnson; J G Morris; J B Kaper

  Gene encoding zonula occludens toxin (zot) does not occur independently from cholera enterotoxin genes (ctx) in Vibrio cholerae.

  Journal of clinical microbiology 1993;31(3):732-3.

• 36.

  1992

  M Nishibuchi; A Fasano; R G Russell; J B Kaper

  Enterotoxigenicity of Vibrio parahaemolyticus with and without genes encoding thermostable direct hemolysin.

  Infection and immunity 1992;60(9):3539-45.

• 37.

  1992

  J E Galen; J M Ketley; A Fasano; S H Richardson; S S Wasserman; J B Kaper

  Role of Vibrio cholerae neuraminidase in the function of cholera toxin.

  Infection and immunity 1992;60(2):406-15.

• 38.

  1991

  R H Hall; G Losonsky; A P Silveira; R K Taylor; J J Mekalanos; N D Witham; M M Levine

  Immunogenicity of Vibrio cholerae O1 toxin-coregulated pili in experimental and clinical cholera.

  Infection and immunity 1991;59(7):2508-12.

• 39.

  1990

  K Yamamoto; A C Wright; J B Kaper; J G Morris

  The cytolysin gene of Vibrio vulnificus: sequence and relationship to the Vibrio cholerae E1 Tor hemolysin gene.

  Infection and immunity 1990;58(8):2706-9.

• 40.

  1990

  J M Ketley; J B Kaper; D A Herrington; G Losonsky; M M Levine

  Diminished immunogenicity of a recombination-deficient derivative of Vibrio cholerae vaccine strain CVD103.

  Infection and immunity 1990;58(5):1481-4.

• 41.

  1990

  K Richardson; L Nixon; P Mostow; J B Kaper; J Michalski

  Transposon-induced non-motile mutants of Vibrio cholerae.

  Journal of general microbiology 1990;136(4):717-25.

• 42.

  1990

  H Marcus; J M Ketley; J B Kaper; R K Holmes

  Effects of DNase production, plasmid size, and restriction barriers on transformation of Vibrio cholerae by electroporation and osmotic shock.

  FEMS microbiology letters 1990;56(1-2):149-54.

• 43.

  1989

  D P Sharma; C Thomas; R H Hall; M M Levine; S R Attridge

  Significance of toxin-coregulated pili as protective antigens of Vibrio cholerae in the infant mouse model.

  Vaccine 1989;7(5):451-6.

• 44.

  1989

  K Richardson; J B Kaper; M M Levine

  Human immune response to Vibrio cholerae O1 whole cells and isolated outer membrane antigens.

  Infection and immunity 1989;57(2):495-501.

• 45.

  1988

  M M Levine; J B Kaper; D Herrington; J Ketley; G Losonsky; C O Tacket; B Tall; S Cryz

  Safety, immunogenicity, and efficacy of recombinant live oral cholera vaccines, CVD 103 and CVD 103-HgR.

  Lancet 1988;2(8609):467-70.

• 46.

  1988

  E R Vimr; L Lawrisuk; J Galen; J B Kaper

  Cloning and expression of the Vibrio cholerae neuraminidase gene nanH in Escherichia coli.

  Journal of bacteriology 1988;170(4):1495-504.

• 47.

  1988

  R H Hall; P A Vial; J B Kaper; J J Mekalanos; M M Levine

  Morphological studies on fimbriae expressed by Vibrio cholerae 01.

  Microbial pathogenesis 1988;4(4):257-65.

• 48.

  1988

  N F Pierce; W C Cray; J B Kaper; J J Mekalanos

  Determinants of immunogenicity and mechanisms of protection by virulent and mutant Vibrio cholerae O1 in rabbits.

  Infection and immunity 1988;56(1):142-8.

• 49.

  1988

  M M Levine; J B Kaper; D Herrington; G Losonsky; J G Morris; M L Clements; R E Black; B Tall; R Hall

  Volunteer studies of deletion mutants of Vibrio cholerae O1 prepared by recombinant techniques.

  Infection and immunity 1988;56(1):161-7.

• 50.

  1987

  N F Pierce; J B Kaper; J J Mekalanos; W C Cray; K Richardson

  Determinants of the immunogenicity of live virulent and mutant Vibrio cholerae O1 in rabbit intestine.

  Infection and immunity 1987;55(2):477-81.

• 51.

  1986

  K Richardson; J Michalski; J B Kaper

  Hemolysin production and cloning of two hemolysin determinants from classical Vibrio cholerae.

  Infection and immunity 1986;54(2):415-20.

• 52.

  1986

  M M Baldini; J P Nataro; J B Kaper

  Localization of a determinant for HEp-2 adherence by enteropathogenic Escherichia coli.

  Infection and immunity 1986;52(1):334-6.

• 53.

  1986

  J B Kaper; J P Nataro; N C Roberts; R J Siebeling; H B Bradford

  Molecular epidemiology of non-O1 Vibrio cholerae and Vibrio mimicus in the U.S. Gulf Coast region.

  Journal of clinical microbiology 1986;23(3):652-4.

• 54.

  1985

  N F Pierce; J B Kaper; J J Mekalanos; W C Cray

  Role of cholera toxin in enteric colonization by Vibrio cholerae O1 in rabbits.

  Infection and immunity 1985;50(3):813-6.

• 55.

  1984

  H A Lockman; J E Galen; J B Kaper

  Vibrio cholerae enterotoxin genes: nucleotide sequence analysis of DNA encoding ADP-ribosyltransferase.

  Journal of bacteriology 1984;159(3):1086-9.

• 56.

  1984

  J B Kaper; H Lockman; M M Baldini; M M Levine

  Recombinant nontoxinogenic Vibrio cholerae strains as attenuated cholera vaccine candidates.

  Nature 1984;308(5960):655-8.

• 57.

  1983

  H Lockman; J B Kaper

  Nucleotide sequence analysis of the A2 and B subunits of Vibrio cholerae enterotoxin.

  The Journal of biological chemistry 1983;258(22):13722-6.

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