United States

Chairman

Dr. Richard L. Guerrant
(1991- , Member 1984-1990)
University of Virginia
School of Medicine
Department of Geographic Medicine
Box 485
Charlottesville, Virginia 22908

Japan

Chairman

Dr. Kazunobu Amako
(1993-   , Member 1988-1993)
Professor
Faculty of Medicine
Kyushu University
3-1-1 Maidashi, Higashi-ku
Fukuoka 812, Japan

Panel Members

Dr. John D. Clemens (1992-1995) Chief, Epidemiology Branch
National Institute of Child Health and Human Development
National Institutes of Health
6100 Executive Boulevard - Room 7B03
Bethesda, Maryland 20892

Dr. Dennis Kopecko (1993-1996) Chief, Enteric and Sexually Transmitted Diseases
Food and Drug Administration
HFM 440
Building 29/420
8800 Rockville Pike
Bethesda, Maryland 20892

Dr. John Mekalanos (1992-1995) Department of Microbiology and Molecular Genetics
Harvard Medical School
Building D1, Room 517
200 Longwood Avenue
Boston, Massachusetts 02115

Dr. R. Bradley Sack (1985-   )
Division of Geographic Medicine
School of Public Health
Johns Hopkins University
615 N. Wolfe Street - Room 5031
Baltimore, Maryland 21205

Dr. Hiroshi Asakura (1995-   )
Professor
Faculty of Medicine
Niigata University
754 Ichiban-cho, Asahimati-dori
Niigata 951, Japan

Dr. Toshiya Hirayama (1995-   )
Professor
Research Institute of Tropical Medicine
Nagasaki University
1-12-4 Sakamoto
Nagasaki 852, Japan

Dr. Takeshi Honda (1993-    )
Professor
Research Institute for Microbial Diseases
Osaka University
3-1 Yamadaoka, Suita
Osaka 565, Japan

Dr. Haruo Watanabe (1991-   )
Director
Department of Bacteriology
National Institute of Health
1-23-1 Toyama, Shinjuku-ku
Tokyo 162, Japan

Guidelines

Cholera and Related Diarrheal Diseases Panels USJCMSP

Although goals have been modified and expanded during the life of the Panels, the highest priorities have changed little. The first goal, stated in 1965, was that "the highest priority in the overall program should be assigned to the development of an effective vaccine that consistently confers long-term immunity against cholera." Other major goals have included the study of the pathogenesis and treatment of cholera, and basic microbiological and ecological studies. In 1970, the priorities of the Cholera Panels were expanded to include cholera-like diarrheal diseases such as those caused by enterotoxigenic Escherichia coli. These general goals remained relatively unchanged until 1987 when it was decided to further extend them to include other acute bacterial diarrheal diseases. It was then that the Panel name was officially changed to "Cholera and Related Diarrheal Diseases." "Related diarrheal diseases" are those that involve the secretory pathways or imbalances in them as seen with cholera. Imbalances in the secretory pathways may result from the direct effect of bacterial toxins or indirectly by effecting cytokines or other cell signalling pathways. The expanded goals of the Panels came about because of the realization that many diarrheal diseases share pathogenic mechanisms and that the strategies for developing vaccines, based on recognized virulence antigens, are also closely related.

Although the Panels now include investigations in the broad range of cholera and related diarrheal diseases, the primary emphasis remains on cholera. The following areas have been assigned a high priority:

1. Methods of immunization. Improvements of whole cell vaccines, including live attenuated vaccines; development of effective adjuvants; isolation and purification of protective antigens; and development of an effective toxoid
2. Pathogenesis and treatment. Purification of responsible exotoxins, studies of mechanisms of action of toxins, and development of pharmacologic means of rapidly blocking the action of toxins; related investigations of basic mechanisms of secretion and absorption of water and electrolytes in the small intestines

3. Microbiologic investigations. Studies of those properties of Vibrio cholerae and related diarrheal producing microorganisms that are essential to multiplication in the gut of the susceptible host, and of those properties of the host that render him vulnerable to infection by these organisms
4. Ecology. Investigations of factors in the environment (e.g., food and water) outside the human host that influence population, distribution, growth rate, and virulence of cholera vibrios or related organisms.

Five-Year Summary

Broad Goals

The Panels support a broad range of investigations on cholera and related diarrheal diseases with primary emphasis on cholera. Goals include vaccine development, basic microbiological and ecological studies, and studies of pathogenesis and treatment.

The annual meetings of the Panels have been attended by a growing number of investigators as they have become the major international forum for scientific exchange on topics ranging from epidemiology to the molecular biology and ecology of cholera and related diarrheal diseases.

Progress/Accomplishments

During the past 5 years, significant progress has been made in understanding the molecular pathogenesis of cholera and related diarrheal diseases. The development of an effective cholera vaccine has become a realistic goal. Four of the most important advances made in the area of cholera and related diarrheal diseases during the last 5 years are:

1. The importance of adequate rehydration (i.v. or p.o.) therapy for patients suffering from cholera gravis has been established. This was demonstrated in the Latin American extension of the 7th Pandemic during 1992 and 1993 and more recently in the large outbreak of cholera in Rwandan refugees in Goma, Zaire. With respect to the latter, fatalities were approaching 50 percent at the height of the epidemic. Rehydration attempts with plain water, or sugar water, were inappropriate and ineffective as was the administration of proper i.v. solutions with inadequate 26-gauge needles. Once proper oral rehydration therapy was initiated and larger gauge needles were used to administer i.v. solutions, fatalities dropped to less than 1 percent. It should be noted that this treatment was effective under the worst possible conditions, e.g., extreme crowding, out in the open, with no sanitation, poor drinking water, and a high attack rate by the cholera vibrio.
2. An oral, killed whole cell/B subunit vaccine has been developed and tested. Although it was shown to induce about 50 percent protection over three cholera seasons, only 25 percent protection was demonstrable in target pediatric populations. This vaccine is undergoing modification to include killed O139 cells to protect against both O1 and O139 serotypes. Live, oral, attenuated vaccines also are under development. CVD 103HgR has been field tested and found to be about 70 percent protective after a single dose; a large field trial of this vaccine is underway in Indonesia. Additional live vaccines against O1 El Tor and the new O139 strain are now in Phase I/II trials as well. The collaboration among Japanese, Indian, Bangladeshi, and U.S. investigators led to the identification and rapid genetic characterization of the new O139 serotype. During the process of developing these vaccine strains much has been learned about the genetics and expression of virulence factors of V. cholerae. This knowledge will make the development of additional attenuated vaccine strains easier and more rapid in the future.
3. Much progress was made in elucidating new emerging enteric pathogens and their mechanisms of pathogenesis. Advances also were made in the clinical diagnosis of such infections. Among such pathogens are enterohemorrhagic Escherichia coli (EHEC) and enteroaggregative E. coli. Much has been learned about how this microorganism attaches to mucosal tissues, induces lesions in the small bowel, and invades the intestinal epithelium. Progress is being made in understanding the mechanism of the hemolytic uremic syndrome (HUS) associated with EHEC disease in children.
4. A new level of understanding has been attained with respect to the mode of action and structure of the toxins produced by these enteric pathogens. Crystallographic structural studies have suggested new approaches to yield nontoxic molecules that still possess adjuvanticity. Such molecules would have obvious uses in vaccine formulations. Also, much has been learned about adhesions and invasions that are involved in the attach-ment and invasion of target cells. Such knowledge is providing new insights into the pathology of these infections and may result in the development of new and more effective therapies.

Future Goals

Goals for the future have changed little from those of the past. An effective vaccine against cholera is still needed; it is now within sight. The U.S. Panel constitutes an advisory group to the National Institute of Allergy and Infectious Diseases (NIAID) at NIH that will help implement a coordinated, multi-center effort designed to evaluate vaccines and new approaches to treatment of cholera and related diarrheal diseases. Emphasis will remain on basic studies of pathogenesis, epidemiology, and the ecology of these organisms.

Selected References

1. Jertborn M, Svennnerholm AM, Holmgren J. Evaluation of different immunization schedules for oral cholera B subunit-whole cell vaccine in Swedish volunteers. Vaccine 1993; 11:1007-12.
2. Levine MM, Kaper JB. Live oral vaccines against cholera: An update. Vaccine 1993; 11:207-12.
3. Mekalanos JJ, Sadoff JC. Cholera vaccines: Fighting an ancient scourge. Science 1994; 265:1387-9.
4. Mahan MJ, Slauch JM, Mekalanos JJ. Selection of bacterial virulence genes that are specifically induced in host tissues. Science 1993; 259:686-8.
5. Lima AA, Soares AM, Freire JE, Guerrant RL. Cotransport of sodium with glutamine, alanine and glucose in the isolated rabbit ileal mucosa. Braz J Med Biol Res 1992; 25:637-40.

1. Ramamurthy T, Garg S, Sharma R, Bhattacharya SK, Nair GB, Shimada T, Karasawa T, Kurazono H, Pal A, Takeda Y. Emergence of novel strain of Vibrio cholerae with epidemic potential in southern and eastern India. Lancet 1993; 341:703-4.
2. Yoshino K, Miyachi M, Takao T, Bag PB, Huang H, Nair GB, Takeda T, Shimonishi Y. Purification and sequence determination of heat-stable enterotoxins elaborated by cholera toxin producing strain of Vibrio cholerae 01. FEBS Lett 1993; 326:83-6.
3. Kondo K, Takade A, Amako K. Morphology of the viable but nonculturable Vibrio cholerae as determined by the freeze fixation technique. FEMS Microbiol Lett 1994; 123:178-84.
4. Yamamoto T, Kaneko M, Changchawait S, Serichantalergs O, Ijuin S, Echeverric P. Actin accumulation associated with clustered and localized adherence in Escherichia coli isolated from patients with diarrhea. Infect Immun 1994; 62:2917-29.
5. Tobe T, Yoshikawa M, Sasakawa C. Deregulation of temperature-dependent transcription of the invasion regulatory gene, vir B, in shigella by rho mutation. Mol Microbiol 1994; 12:267-76.