Jpn. J. Infect. Dis., 53, 181‑188, 2000

Invited Review

Current Status of Cholera and Rise of Novel Mucosal Vaccine
Tatsuo Yamamoto *Deparlment of Bacteriology, School of Medicine. Niigata UniversiO!,
Ichibanchou 75 7, Asahimachidori, Niigata 951‑851 0. Japan(Received November 2, 2000)
SUMMARY: Three serious cholera epidemics have threatened the world during仇e last 1 0 years. As a countermeasure against such cholera epidemics, three vaccines, CVD 1 03‑HgR, WC/rBS, and Vietnamese WC, showed
good performance･ CVD I 031HgR is a recombinant attenuated live vaccine for travelers, and its highly safety

and protective emcacy have been demonstrated in volunteers in advanced countries. WC/rBS, which consists orheat‑ and formalin‑killed bacteria and cholera toxin B subunit･ protects the vaccin.ees (>5 years old) fromcholera for 6 months. Vietnamese WC, a heat‑ and formalin‑killed vaccine, is inexpensive and effective even forl to 5‑yearl01d children･ Additionally, irradiated WC vaccines and new serotype (0139) vaccines are being
developed･ Regarding lnteStinal immunity, secretory lgA has been mainly examined. In addition, mucosal lgG,

as induced by the irradiated WC vaccine, should also be investigated. Development ofmucosaladjuvant, such as
holotoxin‑type mutants of cholera toxin and related Escherichia coli heat‑labile enterotoxin, has been actively
undertaken. Diverse custom‑made vaccines may be one countermeasure for the changlng Situations in endemic
countries or areas and for "barriers" agalnSt live vaccines in such areas.

infection is controllable if humans are protected by immu‑

1. Introductionnity (which can be induced by vaccines) (9).

Since Robert Koch succeeded in the pure culture of Vibrio

In the last 15 years, three cholera vaccines have received

cholerae (called Kommabazillen at thattime) in I 884, cholera

high evaluations for their propertiesand effectiveness. These

epidemics moved from the fifth to the sixth cholera pandemic,

vaccines have been studied in volunteers in the United States

then, the seventh cholera pandemic have been occumngfrom(US) and Swedenand in the field in epidemic countries. Two

1961 to date (1) (Fig. 1). The sixth cholera pandemic wascaused by V. choleraewith classical biotype, while theproducts have become commercially available.
In this manuscript, We summarize the current status ofcausative agent in the seventh pandemic is EI Tor biotype (V.

cholera and recent trends in cholera vaccine research.

cholerae Ol biotype EI Tor). V. cho/erae 01 includes two

serotypes, Ogawa and Inaba, which are used as markers in

2. Infection and symptoms

epidemiological analysis (2, 3).

The cholera toxin (CT) that Robert Koch speculated on in

Unlike Helicobacter pylori, V. cholerae 0 1 can actively

1884 was purified in 1969 (4)･ In 1999, it was r.eported that V･

move in river water at environmental temperature (1 0), andcholerae 01 contains two types of lysogenelC Phages, anddoes not moat away, which causes fecal‑Oral infection in thethe bacteria exhibit the patbogenlClty uSlng these two pro‑contaminatedriver basin.
The bacteria that are orally ingested colonize in the small

phages (5, 6). One is designated CTX￠ having the cholera

toxin genes (ctxA, ctxB), and the other is designated VPIO
having the TcpA coat protein gene. TcpA constructs TCP pin

with H. jD}lori is high. Chronic gastritis induced by persistent(type IV pili), which play a role in仇e intestines as a coloniza‑

infection of H. pylori causes hypochlorhydria, which makes

intestine (I 1 , I 2). In developing countries, the infection ratetion factor, and also serve as a receptor for CTXO phage. The

infectionwith gastric hydrochloric acid‑susceptible V.

whole V･ cholerae 01 genomでwas determined in 2000 (7)･

cholerae 01 easy (13). Personswith type 0 blood have also

The chromosome was approxlmately 4 Mbp in length, andbeen reported to be a high risk group for severe illness (14).

had A@3,885‑estimated genes. The chromosome has beenshown to consist of two circular replicons or approximately

The latent period varies from 6 h to about 3 days, dependingon the amount of bacteria Ingested. Theinitial symptom is an

3 and 1 Mbpin size.

unpleasant feeling in the abdomen, and the main symptoms,

Desplte Such accumulation of knowledge, people's lives

severe dia汀hea and vomltlng, develop. Symptoms are some‑are stiH threatened by cholera in some areas on the earth.

times accompanied by muscular palm. Fever is generally

Cholera is a human disease. Although V. cholerae 0 1 excreted

absent (15‑18).

in feces can survive in the environment (e.g., inrivers) (8),Usually, the mo叩hology of the intestinal mucosa does notchange, and water retention starts in theintestine. This diarrhea
consists of a large volume of white turbid watery stool*Corresponding author: Tel: +8 1 ‑25‑227‑2050, Fax: +8 1 ‑25‑227‑

described asrice‑washed water, and is excreted in a hquid0762, E‑mail: tatsuoy@med.niigata‑u.ac.jp

stream. Five liters of diarrhea is usually excretedwithin 24 hafter onset, and the volume reaches 8‑10 liters in a day.

ThisarticleisanlnvitedReviewbasedonalecturepresentedat
the10thSymposiumoftheNationallnstituteoflnfectiousDia汀hea may continue fb∫ 6 days or longer. Dia汀hea stool
becomes yellowish, then the color changes to a black一green

Diseases,Tbkyo,19May2000.

like that ofbilimbin (1 5‑18).

181

Fig. 1. The seventh cholera pandemic and major Cholera epidemics in the last 10 years.

by outflow ofNa+ and water) in crypt cells located in thelower reglOn Ofthe villi.
In children, the feca) potassium ion (K') level is high (〜30

mEq/1). Abdominal extension is considered to be due toparalytic ileus caused by hypopotassemia.

3. Epidemiology
Three large scale cholera epidemics occu汀ed during thelast 10 years in the world (Fig. 1). In 1991, cholera suddenly
occu汀ed in Peru in South America, where an epidemic had
not been recorded fわr 100 years. The epidemic was charac‑terized by over 1,700 cases per day on average; 391,220 per
year; and 4,002 patients died (19, 20).

In 1992, V･ cholerae belonging tP a new serotype (0139)

emerged in India (21), and the prevlOuS Cholera vaccine Yas
not effective; the epidemic spread to neighboring countnes,

Fig･ 2l Facial appear甲ce ofO139 cholera patient (supplied by Dr･ G･BI
Nair, National lnst血te of Cholera and Enteric Diseases, India).

including Thailand and Bangladesh (22, 23). At the beginning,cholera specialists were concemed about "an eighth pandemic"
Diarrhea is categorized by the degree of nuid loss (ratio to(24), but it is now considered to have been a subtype epidemic

body weight) as mild (<5%)･ moderate (5‑10%), and sev.ere

in the seventh cholera pandemic.

diarrhea (>1 0%). In a dehydrated state, the ups dry, the patlent

In 1994, a serious cholera outbreak occurred in Rwandanfeels thirsty, the skinloses elasticity, the cheek and eyes sink,and the eyeballs are rolled back (Fig. 2). When water loss
reaches 1 O% or more of body weight, the condition becomes

refugees in Zaire (Goa) in Africa (25). The mortality brieny
reached 17% (26).

serious. In children (especially those under 5 years old),

never been abroad and the source of infection became an issue

although dehydration is observed, a large volume of watery(27).

In 1997 in Japan, cholera occurred in 36 Japanese who hadstool is retained in the intestine, causlng marked abdominal

In 1999, 61 countries were reported by the World Healthextension, and watery stool may not be excreted until a probe

Organization (WIIO) to be contaminatedwith V. cholerae.

is inserted in the rectum.

The number of patients was 254,3 10, and 9,175 patients died,showing a mortality rate of3.6% (28).

A characteristic orthe watery stools in cholera is a highPoncentration of sodium ion (Na') (〜1 30 mEq/1) and chlorineton (Clー) (‑100 mEq/I), at the same levels as those in the

4. Attenuated live vaccine

serum. When CT acts on the target cells, the intracellularcyclic AMP (CAMP) level increases. The increased CAMP is

A hve vaccine, developed by recombinant DNA technology

considered to inhibit absorption of Cl‑ and Na'inepithelial
cells ofvilli, and to facilitate secretion ofCl (accompaniedin the US, becam? available fわr use by travelers in 1994 (9,28‑30). This vacclne is attenuated V. cholerae 01 classical182

biotype lnaba serotype (569B strain), and is called CVD IO3‑

1n addition to these vaccines, Other attenuated live vaccines

HgR. The attenuated bacteria were prepared by deletlng 94%
of the cholera toxin A subunit gene (ctxA), conser.vhg the B

are being developed using V. cho/erae 01 from Peru(35) andV. cholerae serotype 01 39 (36).

subunit gene (clxB), and destroying the hemolysln gene byinsertlng the mercury resistance gene.

5. Killed vaccine

ln仇e US study in volunteers, oral administration ofa single

dose was possible. The protective effect began 8 days afteradministration, and continued for 3 months in 95% for classi‑
cal cholera and 65% for EI Tor cholera (28).

(1) WC/rBS va.cfine
A vaccine contalnlng amixture of heat‑ and formalin‑killedbacteria and the cholera toxin 良 subunit (CTB) (whole cell/

The examples fTrom the US study in volunteers are shown

B subunit, or WC/BS) was developed by a Swedish groupin Table I. An increase in the serum vibriocidal antibody titer,(28, 30, 37, 38) (Table 2). The vaccine contained 2.5 × 101｡

which is used as an index ofestablishment of immunity against

each orheat‑killed classica一 lnaba strain (Cairo 48), heat‑killedcholera, was observed in 90% or more of subjects vaccinated.

classical Ogawa strain (Cairo 50), formalin‑killed EI Tor lnaba
strain (Phil 6973), formalin‑kil)ed classical Ogawa strain

When EI Tわr lnaba strain (105 CFU) was challenged 3 months

after vaccination, 91% ofmi1d and severe diarrhea (3 liters(Cairo 50), and I mg orCTB. The a subunit (rBS) obtained
from recombinant ctxB has been used in experiments afteror more ordiarrhea stool) caused by the bacteria challenged
was prevented. Shedding of the challenged bacteria into fTeces

1992 (39, 40). WC/BS and WC/rBSLdo not differ in the(colonizing bacteria) was decreased to lO 4 or lower (29).

immune respon.se (39)･

A field study ofCVD 103‑HgR vaccine, which has been
well examined in volunteers, was perfbmed in the epidemic

three doses orthe vaccine were administered 6 Weeks apartregion (north Jakarta) in Indonesia (3 I ) (Table 1)･ An increase(37). However, since a similar effect (increases in vibriocidalln the vibriocidal antibody titer was observed in 65%, asantibody titer) could be expected by two doses of WC/rBS

expected. Even in children aged 5 years or younger, the literwith a 21Week interval (38), the effect of two doses.wasincreased in 78%. However, the 4‑year long‑tらm protection

investigated in later studies in Pe川 (41 , 42) and other reglOnS.

was observed only ln 14%, showlng that the vaccine was noteffective against Cholera in this reglOn. Studies on the short‑term efficacy ofa slngle oral dose and long‑term efficacy byno adverse effects were observed (30). The protection was

At the beginnlng Orthe BS‑WC vaccine study in Bangladesh,Jn field studies in Bangladesh, Columbia, Peru, and Sweden,
observed 1 week after the second vaccination, and a hightwo doses are planned.

protection emcacy of 85‑90% was obtained fわr 4‑6 months

As a cause of the ineffectiveness in north Jakarta, a "bamier"after vaccination.

for hve vaccine in children in developlng countries is being

ln the studyinBangladesh (1985‑1988) (37, 38), the protec‑

considered. Actually, to establish immunlty With a hightion efⅥcacy was 60% at 2 years and 50% at 3 years, anddefensive index (a high serum vibriocidal antibody titer ≡ aalmost all effect disappeared at 5 years after vaccination. Inhigh ser?conversion rate) in children in developing countrleS,

children 51yearS Old or younger (215 years Old), the protec‑

vaccination With a large dose ofCVD 103‑HgR (5 × 109 CFU)

tive effect was weak. The absence ofprevlOuS immunlty Was

was necessary. This amount or bacteria corresponds to I 0
times the experimental value (5 × 108 CFU) in North Ame空aconsidered to be the cause. The long‑tem protection was also
weak in subjects of blood type 0. During 4‑6 months afterand Europe (32). Bacterial overgrowth in the intestine lS

administration, WC/rBS was clearly superior to WC, and theconsidered to be the "ba汀ier''mechanism (33).

direction or later studies was established.

Mixed administration with another attenuated vaccine

ln a field study ofWC/rBS vaccine in Peru initiated indeveloped separately (CVD 1 1 1) has been investigated (34)1993, a marked protective effect was confirmed for the first 4(Table I). CVD Ill is attenuated V. cho/erae 01 EI Tor
biotype, Ogawa serotype (N161 17 strain), in which the CT

Ponths or longer alter administration (4 I ) (Table 2)･ However,gene was removed and ctxB and mercury resistance gene were

the second vaccination (42). Based on these findings, it has

inserted in the hemolysln gene. A mixed vaccine orCVD

been suggested that EI Tor Ogawa straln, Which is frequently

103‑HgR and CVD 1 l 1 increased the semm vibriocidal anti‑
body titer, but an adverse effect (diarrhea) ofCVD 1 I 1 was athat three doses may be necessary (booster may be necessary

large obstacle. Further attenuation is necessary fわr CVD 1 1 1

after 1 year) (42).

1n another study, the protective effect was not conflrmed after

isolated worldwide, should be added to WC/rBS vaccine, and(34).

Table I. Results ofvolunteer and field studies of attenuated live cholera vaccine (CVD 103‑HgR)
Study period Study content

Results

ⅥlCCineReference(study place) (adlllinistration)
CVD103‑HgR

1 999

(USA)

Volunteer study for EI Tor cholera(single dose)･ Defense index of immunity (vibriocidal antibodies) increased

29(after 3 months): 91% in the vaccine group vs. 2% in the placebo
grOup･

Protection in 91% (after 3 months)
The maximal bacterial excretion: 4.9 X 102 CFU/g ln thevaccine group vs･日× 107CFU/g in the placebo group.

CVDIO3‑HgR

Filed study for EI Tor cholera

Defense index of imlllutlity (vibriocidal antibodies) increased(Indonesia)(single dose)(after 10 days): 65% in the vaccine group (78% at 2‑4 years old,
60‑74% over 5 years old) vs. 2% in the placebo group.

1999

Immune response test in volunteers

Defense index of illl111unity (vibriocidal antibodies) increased:(single dose)

tllixed vaccine > smgle vaccine

1993‑1 997

31

Protection in 14% (for 4 years)
Mixture or

CVDIO3‑HgR(US facility

and CVD 1 1 1 in Panama)

Adverse event orCVD 1 1 I (dia汀hea): 8%

183

34

Table 2. Results of filed, volunteer, and animalstudies of killed cholera vaccine
vaccine(Ssttuuddyy

P,霊coe3

Killed bacteriaa ‑B subunit

1 9851 I 988(WC/BS=first generation)(Bangladesh) (three doses)

Killed bacteriaa (WC)1 9851 1 988(satdu慧nci器,tact:in)

Results

ReferenceProtection in 85% (for 4‑6 months)
Protective efrlCaCy decreased to 50% after 3 years

Filed study for EI Tor cholera(26% at 2‑5 years old, 63% over 5 years old)Protection in 58% (for 4‑6 months)

Filed study for EI Tor cholera

Protective efrlCaCy decreased to 52% after 3 years(Bangladesh) (three doses)(23% at 2‑5 years old, 68% over 5 years old)
Killed bacteriaa ‑rB subunit

1 992(WC/rBS=second generation) (Sweden)

Illlmune response test in volunteers

Defense index of immunity (vibriocidalantibodies) increased:(two, three doses)

WC/BS = WC/rBS

39

two doses = three doses

Killed bacteriaa ‑rB subunit

1 992(WC/rBS)(Columbia) (twodoses)

Defense index of immunity (vibriocidal antibodies) increased:

Field immune response test

40

44% in the vaccine group vs. 9.2% in the placebo group･Weak response under 4 years old
Weak response in blood type 0

Killed bacteriaa ‑rB subunit

1 994(WC/rBS)(Peru)

Killed bacteriaa ‑rB subunit

199311994(WC/rBS)(Penl)

Protection in 86% (for 1 8 weeks)

Filed study for EI Tor cholera(twodoses)

Filed study for Et Tor cholera(two

PTOteCtion in 4% (for 1 year)

doses)

Protection in 61% (for I year)
Protection in 68% even in children aged 1‑5 years(three doses)

Killed bacteriaa

I 992‑ I 993(Vietnamese WC)(Vietnam)

Filed study(for 8‑I 0 months)(two doses)

Protection in 66% over 5 years old(for 81IO months)
Killed bacteria一2000(Imdiated WC)(Japan)1mcreased protection, compared with the previous WC･

Rabbits

UnpublishedHigh levels of intestinal lgA and lgG･

(three doses)

data

aKilled by heat/ formalin treatment.
b Killed by 60co‑in･adiation.

also lgG antibodies in the intestinal tract, unlike the heat‑ Or(2) WC vaccine
In an achievement of technology transfer, an inexpensive

formalin‑killed WC (Fig. 3), and the irradiated WC showed avaccine (cost: 0.1 dollars) was prepared in Vietnam, andremarkably higher protection agalnSt Challenge than that of

examined in a filed study in 1992 (43) (Table 2). The vaccine

the heat‑ Or formalin‑killed WC. Furthermore, the vibriOcidal

compositions are 2.5 × 1 010 of each of the followlng: heat‑killed

antibodies were detected in intestinal julCe Of rabbits thatclassical lnaba strain (Cairo 48), heat‑killed classical 0gawastrain (Cairo 50), formalin‑killed EI Tor Inaba strain (Philreceived the i汀adiated WC.

6973), and formalin‑killed classical Inaba strain (569B). This

Therefわre, mucosal immunlty induced by i汀adiated WC may

Vietnamese WC vaccine differs from the Swedish WC

include the killing of V. cholerae Ol, in addition to, for

IgG is a vibriocidal antibody, while lgA is not (44)･vaccine in the use of the 569B strain, which expresses well

example, the inhibition of the bacterial colonization andthe colonization factor, TCP pilli. Two doses of the vaccine

neutralization or toxin. The immune response to i汀adiatedwere administered at a 2‑week interval. A good result was

WC vaccine may qualitatively differ from that to the previous

obtained, and the low protective efficacy ln younger Children,heat‑ or fbmalin‑killed WC vaccines. Two fbms, i汀adiatedthe disadvantage or Swedish vaccine (WC/rBS, WC), was

WC and irradiated WC plus adjuvant, are being developed.

overcome (Table 2).

(3) Irradiated WC vaccine

6. Mucosal lgG

Heat and fbmalin treatment denatures proteins on thebacterial cell surface and destroys bacterial cell surface func‑

The main component of mucosal immunlty lS SeCretOry

tions such as motility and adhesion. In conbTaSt, 60Co irradiationlgA (45). However, mucosal lgG has been attracting atten‑

first destroys macromolecular chromosomal DNA. Therefore,tion in recent years. For example, when Haemophilus

the bacteria could be killed, preservlng the celt surface func‑

injluenzae type b oligosaccharide conjugated to diphtheria

tions such as motility and adhesion by controlling the i汀adia‑

toxoid vaccl.ne (‖ib‑DT) in a formulation containing 1 α , 25‑

tion conditions.

dihydroxy vltamin D3 (mucosaladjuvant) was subcutaneously

Irradiation at 1.5 × 103 Gy (1.5 × 105 一ad) destro≠S 90%

Injected tomice, anti‑diphtheria toxin lgG antibody appeared

or more of200 kbp plasmid DNA. Under this condition, no

in feces (46). It hasalSo been shown that the passive admin‑

viable bacteria are detected. However, 5‑38% of the bacteria

istration oHgGl monoclonal antibody prevented simian‑

still swim at 4‑39 〝m/S; the hemagglutinatlng aCtivlty

human immunodeficiencyvirus (SIV) infection in pregnant(detected with human erythrocytes) is observed in 6‑50%;
and adhesion to M cells in human Peyer's patches is observedin 43‑65% (unpublished data).
This new irradiated WC vaccine was examined for immun0‑

macaques, and仇at仇e neonatal macaques仇at received lgGl

monoclonal antibody administration were resistant to oral SIV

infection (47). This suggests the potential protective effect oflgG on mucosa) mother‑to‑infant HIV infection (48).

10glCal properties and protection agalnSt Challenge in rabbits(RITARD model). The vaccine contained 2.5 X 1 OIO of bothclassicalInaba strain (C13) and EI Tor Ogawa strain (EO8).
As the controls, heat‑killed C13 and EO8 and fbmalin‑killed

In 1992, V. cho/erae O139 that produces CT emerged in

CI3 and EO8 were used. EO8 was used as the challenge strain.

0 1 cholera epidemic region, India (仙en soon in Bangladesh),

The i汀adiated WC induced the secretion of not only lgA but

overcoming V. cholerae 01, which also produces CT (21,

7. Mystery ofOI choJera and 0139 cholera

184

H20

60Co‑irradiated

C ド

VaCCIne
Adju

短療:̲=

l

17

l

蒜

/

㌔:.

"

★

nt

b

劔主をi::i

椶

i.

L'F

≠

璽
Mucosal membranes㌧ーし,濫準一一‑Gadrointe剖inal tract>

Upper respiratory tract

Genilourinary tract
Antigen･sampfing Peyerls patch
Fig. 3. Ⅰ汀adiated WC vaccine and mucosal immunity mechanism (hypothesis).

22). Since most 01 39 cholera patients were adults, who mightstrong, and the mucosal adjuvant effect ofCT is more potent

have acquired immunity by previousinfTectionwith V. cholerae(51, 52). This is considered also to be the case fわr the similar

0 1 and therefわre possessed some degree ofanti‑CT antibody,toxin (LT) of ETEC (52)･ Analysis. of the relationshipthe infection was expected to cause only slight diarrhea.

between retrograde transport of the toxln and adjuvant effTect

However, many 0139 cholera patients developed severe

is awaited.

The details of the action on CD41POSitive cells differdia汀hea in these regions (49).
lt was, therefわre, hypothesized that anti‑CT immunlty lS

between CT and IJ (56). CT inhibits Thl subset by inducing

not useful in preventlng infection. Indeed, when CVD IO3‑

apoptosis, which results in the induction orTh2 subset, andHgR was administered to rabbits (two doses) and V. cholerae

IL‑4, IL‑5, and IL‑6 cytokines promote the differentiation of
B cells to lgA plasma cells, by which lgA production is

01 (569B strain) or 0139 was challenged after 3 weeks,colonization of V. cholerae 0 1 and diarrhea were prevented,
but the effects of V. cholerae 0139 were not prevented (49).

increased. ln contrast, LT induces both Thl and Th2 subset(57). Both CT and LT enhance the expression of co‑stimulatory

In contrast, in a field studyinBangladesh, WC/BS vaccine

molecules (87‑2) orAPC in Peyer's patches (56) (Fig. 3).

provided a shorトtem protection in叩prOXimately 70% agalnSt

CT and LT are very toxic. In volunteers, oral administra‑

infection with enterotoxigenic Escherichia coli (ETEC) (59),tion of5 LLg ofCT inducedト6 liters of diarrhea (58). How‑

which produces heatllabile enterotoxin (LT) similar to CT and

ever, CTB is very safe, as described above, and oral adminis‑

induces cholera‑like watery dia汀hea.

tration of I mg does not induce diarrhea (59). The safety ofWith regard to both of the above cases, experiments must
be conducted to investigate whether BS (rBS) in WC/BS (rBS)mCT needs to be examined in volunteers.

vaccine acted as antigen (26) or non‑specific adjuvant (5 1 ).

9. Countermeasures for epidemiCs
For the contro一 or cholera epidemics, treatment with oral

8. Mucosal adjuvant effect of cholera toxin

nuid sTPPlement (ORS); aヲupply ofclean drinking water;

The mucosal adjuvant effect of CT is non‑specific. The

hygienlC instruction on sanltation, etc.; and environmenta一

improvements are effective.
Chemotherapy with tetracyclines, new qulnOlones, andmacrolides is also effective fTor reducing diarrhea or shortenlng

actions.in mucosa are diverse (52‑54), such as the facilitationof passlng through the epithelial ba汀ier or antlgenS, aCtiva‑tion of antigen presentation orAPC (antigen‑presenting cells)
including macrophages and dendritic cells, promotion orclassthe dia汀hea period, and fわr shortenlng the bacteria‑shedding

switch斤om lgM十prOducing to lgA‑producing cells, induction

period, and has been applied in epidemic regions aS a Supple‑ofTh2 cells by inhibition ormacTOphage cytokine IL 1 2, andmental therapy (1 8). Case‑fatality rate (CFR) is controlled toactivation of macrophages and lymphocytes by macrophage

1 % Or below if the countemeasures are appropriate (30).
Cholera v?ccine (28, 30) may be used in people who m?ve

cytokine lL‑IB. The toxin exhibits a strong adjuvant effectfrom epidemlC areas, and for the control ofcholera epidemlCS

even by subcutaneous administration (55).

that may occur in people (refugees) who move into epidemic

The mucosal adjuvant effect ofB subunit is weak･ The
mucosaI adjuvant effect of the holotoxin type mutant toxin

areas. lt has been proposed that stores of vaccines fわr two(mCT) With a slight residual toxin activity ofA subunit ismillion people should be prepared fわr emergency use. The

185

use ofWC/rBS vaccine (oral administration twice with a l‑

8. Lobitz, a., Beck,し., Huq, A., Wood, B., Fuchs, G.,

week interval) is considered when an epidemic is expected

Famque, A. S. G. and Colwell, R. (2000): From仇e cover:to occurwithin 6 months. Vietnamese WC vacclne (oraladministration twicewith a 1‑week interval) has currently

chmate and infectious disease: use of remote senslng fordetection of Vibrio cholerae by indirect measurement･been approved only in Vietnam. CVD 103‑HgR vaccine

Proc. Natl. Acad. S°i. USA, 97, 1438‑1443.

9. Levine, M. M. and Kaper, J. B. (1993):Live oral vaccines(single ora) dose) may be available for travelersinadvanced
countries.

agalnSt Cholera: an update. ⅥlCCine, 1 1, 207‑212･

10. Tsutsui, N., Taneike, I., Ohara, T., Goshi, S., Kojio, S.,

Iwakura, N. , Matsumaru, H., Wakisaka‑Saito, N., Zhang,

10. Conclusion

H. M. and Yamamoto, T. (2000): A novel action of theIn vaccine development, three vaccines have made steadyproton pump inhibitor rabeprazole and its thioether

derivative agalnSt the motility of He/icobacter pylori.

progress during the last 1 5 years, and irradiated WC vaccine isfollowing. Secretory lgA has been mainly examined in regard

Antimicrob. Agents･ Chemother･, 44, 3069‑3073 ･

to mucosal immunlty agalnSt bacterial infection. Additional
investigation of the role ofmucosal lgG is necessary･ Diverse

1 1. Nelson, E. T., Clements, J. D. andFinkelstein, R. A. (1976):

custom一made vaccines that can deal with the changlng S血a‑mental cholera: electron microscopic Studies. Infect.

Vibrio cholerae adherence and colonization in experi‑

tions in endemic countries or areasmight be required in the

Immun., 14, 527‑547.
1 2. Yamamoto, T. and Yokota, T. (1988): Electron microscopic

2lst century for the "barriers" agalnSt live vaccines in suchstudy of Vibrio cholerae 0 1 adherence to the mucus coatareas.

andvi11us surface in the human small intestine. Infect.
Immun., 56, 2753‑2759.

AC KNOWLEDGM ENTS

13. Clemens, J.,Albert, M. J., Rao, M., Qadri, F., Huda, S.,

The development of irradiated WC vaccine is underway,

Kay, B., van Loon, F. P., Sack, D., Pradhan, B. A. and
Sack, R. B. (1995): Impact of infection by Helicobacterand is supported by a grant (97‑1) from the Organization for
Pharmaceutical Safety and Rese?rch (OPSR), Japan･ I thankYoshifumi Takeda, National Instltute of Infectious Diseases,

pylori on the risk and severity of endemic cholera. J･
Infect. Dis., 171, 1653‑1656.
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