Jpn. J. Infect. Dis., 53, 98-106, 2000
To see an article, click this [PDF] link.
Review
A Proposal for Safety Standards for Human Use of Cholera Toxin (or Escherichia coli Heat-Labile Enterotoxin) Derivatives as an Adjuvant of Nasal Inactivated Influenza Vaccine
Shin-ichi Tamura* and Takeshi Kurata
Department of Pathology, National Institute of Infectious Diseases,
Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
(Received June 15, 2000. Accepted July 28, 2000)
SUMMARY: Cholera toxin (CT) and Escherichia coli
heat-labile toxin (LT) are not only the causative agents of diarrhea
but are also strong mucosal adjuvants which enhance immune responses
to mucosally coadministered bystander antigens. One of the most
promising applications of these toxins would be as mucosal adjuvant
of nasal influenza vaccine. In comparison to current inactivated
vaccines, the nasal vaccine provides
superior cross-protection by inducing production of cross-reacting
anti-viral IgA antibodies in the respiratory tract even when the
vaccine strain is different from the epidemic strain. On the use
of the toxins as mucosal adjuvants in humans, toxicity and allergenicity
of the toxins are problems which impinge on safety. To resolve
these problems, various approaches have been attempted to produce
less toxic and less allergenic CT (or LT) derivatives. We now
propose the following standards for human
use of safer CT (or LT) derivatives as an adjuvant of a nasal
influenza vaccine. Thus, CT (or LT) derivatives can be administered
intranasally together with a current inactivated influenza vaccine,
provided they meet the following criteria. 1) A single dose of
the derivatives, administered intranasally by spraying, should
be around 100 ƒÊg/adult in a volume of less than 0.5 ml. 2) CT
(or LT) derivatives should retain the properties of the native
CT (or LT), i.e., the ability to augment secretory IgA and serum
IgG Ab responses to viral surface glycoproteins, when administered
intranasally together with an inactivated influenza vaccine. 3)
CT (or LT) derivatives should not induce IgE Ab responses to the
vaccine, as well as to the CT (or LT) itself. 4) The CT (or LT)
should be nontoxic; the toxicity of the derivatives, as determined
by the Y-1 adrenal cell assay, should not exceed 1/100 EC50 of the native CT (or 1/1000 ECi of the native
CT). 5) CT (or LT) derivatives should not cause serious disease
in guinea pigs when administered intranasally or intraperitoneally
at the dose used in humans (around 100 ƒÊg).
*corresponding author: Tel:+81-3-5285-1111, Fax:+81-3-5285-1189, E-mail: stamura@nih.go.jp
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