# CHOLERA--PATHOGENESIS AND IMMUNOLOGY

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 1993 · $234,345

## Abstract

The goals of this research are to contribute to the understanding of the
pathogenesis of cholera, an epidemic diarrheal disease caused by Vibrio
cholerae 01, at both the organismal and the molecular levels, with the
expectation that this information will lead to the development of rational
and effective means of immunoprophylaxis.  As cholera is the prototype of
an expanding number of diarrheal diseases which are mediated by
enterotoxins which are structurally, functionally and immunologically
related to the cholera enterotoxin(s), the observations are pertinent to
the larger global problem of the billions of cases and millions of deaths
annually from diarrheal diseases especially in children in the Third World.
Cholera enterotoxin (CT) was discovered in 1959 and it was purified and
partially characterized in 1969.  In the ensuing period, expectations that,
as with diptheria and tetanus, a toxoid vaccine would prevent the disease
have not been fulfilled despite early encouraging experimental
observations.  It is now known that the disease, cholera, is an effective
immunizing process in which the human host is presented with a consortium
of products elaborated by the cholera vibrios growing in vivo in/on the
small bowel.  In addition to the enterotoxin, these include colonization
factors, such as toxin-coregulated pili (TCP), other surface components
including lipopolysaccharide (LPS) and outer membrane proteins, HA/protease
and other soluble factors, the cell-associated mannose-sensitive
hemagglutinin of the E1 Tor biotype, the flagellum and, possibly, other
factors.  The solid immunity evoked in people by the disease has not yet
been duplicated by non-living preparations, administered parenterally or
perorally, or by living attenuated mutants, administered perorally,
although some degree of protection has been attained -- even in the absence
of toxin antigen.  Results of studies with toxin antigen by itself have
been even more disappointing.  This proposal addresses some of the reasons
for previous failures of toxoid vaccines; it addresses the development of a
new cholera vaccine to consist of a non-toxic conjugate of de-lipidated LPS
and cholera toxin; and, in addition, it will continue to address other
factors which may contribute to the virulence and immunogenicity of wild-
type cholera vibrios in vivo.  The technology includes the synthesis and
analysis of sequential continuous overlapping peptides comprising the
immunologically dominant B-subunit protein of CT and the use of site-
specific mutagenesis to create a V. cholerae strain which produces a CT
which is not toxic but expresses the major epitopes of the holotoxin.  This
CT will also be cross-linked to LPS oligosaccharide to form a conjugate
vaccine which will stimulate both antibacterial and antitoxic immunity.  We
will further examine and define the role of HA/protease and the mannose-
sensitive hemagglutinin in attachment and/or detachment of cholera vibrios
and examine the signific...

## Key facts

- **NIH application ID:** 3127141
- **Project number:** 5R01AI017312-13
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **SAM.gov UEI:** SZPJL5ZRCLF4
- **Principal Investigator:** Richard A. Finkelstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $234,345
- **Award type:** 5
- **Project period:** 1980-04-01 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3127141

## Citation

> US National Institutes of Health, RePORTER application 3127141, CHOLERA--PATHOGENESIS AND IMMUNOLOGY (5R01AI017312-13). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3127141. Licensed CC0.

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