Typhoid fever situation and Vi vaccine experience in Asia

84

Typhoid Fever and other SaLmonellosis Med

J

Indones

Tlphoid

fever situation and

Vi

vaccine experience

in

Asia

ss-3

D. Leboulleux*,

A.K.

Dutta**

Abstrak

Demam tifuid masih amat sering terjadi di barya1ç negara di Asia, terutama pada anak-anak, dengan peningkatan masalah resis-tensi terhadap berbagai antibiotika. Kami mempelajari kembali semua stucli tentang suatu vaksin baru, yang stdah dipublikasikan mau-pun yang belum, yang sudah terdaftar

di

1l

negara Asia, berisi polisakarida kapsul Vi dari Salmonella typhi, penyebab penyakit ini. Semua aspekvaksin ini, diberikan dalam tlosis tunggal25 1t"g telah diuji di Asia, termasttk efektivitas, imunogenitas tlan toleransi, bahkan pada anak keciL di bawah umur 2 tahun, serta proteksi jangka panjang. Dalam suatu penelitian luas di Nepal, pada kelompok ùtdividu berusia 5 sampai 44 tahun, didapatkan efektivitas vaksin

V

ini 72Vo. Suatu penelitian luas yang disponsori WHO di Indonesia mernasti-kan imunogenitas dan toleransi yang baik, sejak usia 12 bulan. Serokonversi yang baik, >98Vo, dan toleransi yang baik, dengan 3 sampai 77o demam 38"C, dikonfirmasikan pada penelitian yang tak dipublikasi di Pakistan dan Filipina. Suatu survei 3 talu,tn tent(tng orang berusia di atas 8 tahun yang divaksinasi mengkorfimasi hasil dari Afrika Selatan, dan perlunya yaksinasi ulang setelah 3

talun.

Vaksirt polisakarida Vi menryakan antigen yang terstandarisasi baik, yang lebih aman daripada vaksin seluruh kuman, amat imunogenik, efektif dalam dosis tunggal parenteral, terutama di daerah yang endemik. Hasil dari penelitian cli Asie sebanding dengan yang teLah dilakukan di bagian lain dunia dan memastikan bahwa vaksin ini mwtgkin lebih baik diberikan pada anak berusia 2 tahun aîau lebih.

Abstract

Typhoid fever is stilL highly prevalent in many countries in Asia, particularly in clildren, with an increasing problent of multi tlrug-resistance. We reviewed aIL published antl unpublishecl studies of a new vaccine, already registerecl in

1l

countires in Asfu, contposetl

of

tlte Vi capsular polysaccharide o/Salmonella typhi, the caLtsative agent of the disease.

All

aspects of the vaccine, given in ct single close

of 25 1tg, were lested in Asia, including efficacy, immunogenicity and tolerance, even in yomtg children below 2 years of age, und long term protection. Efficacy of this Vi vaccine was evaluated at 727o in a large trial in Nepal, in subjects aged 5 to 44 years. A large trial sponsored by WHO in Indonesia conJirmed the good itnmurtogenicity and tolerance, as front

l2

months of oge. Good serocont,ersion, >98Vo, and good tolerance, with 3 to 77o

offever

38oC, were confirmed in unpublishecl trials in Pakistan and Philippines. A

j

years surveys of vaccinated persons aged more than

I

years confirms the results from South Africa, ancl tlrc necessily to revaccinate after 3 years. Vi polysaccharide vaccine is a well-standarcliled antigen that is safer than whole-cell vaccin.e, highly imtnunogenic, effectitte in a sitxgle paretxteral dose, particularly in highly enelemic situation. The resubs of the stuelies performed in Asia are comparable to those conducted in other parts of the workl and confirm that this vaccines may be _favourably used in chiklren 2 years of age or older

INTRODUCTION

Typhoid fever is

contracted when people ingest

food

or water infected with Salmonella

typhi.It is

classi-cally

recognized

by the

sudden

onset

of

sustained

fe-ver (39-40"C),

severe headache, nausea, abdominal

discomfort,

hepatosplenomegaly

and

severe

loss

of

appetite.

Two complications, intestinal

perforation

and

haemorrhage,

occur in

0.5

to

IVo

of

cases.

In

In-donesia,

several forms have been described with

cerebral

dysfunction,

delirium

and

shockl.

Each

year,

about

16

to

33

million

cases

occur around the

world,

with

more than 600,000

deathsl'2.

Typhoid fever

re-mains

an

important public problem in

many

develop-ing countries,

with

an

estimated incidence

of 540

cases

per

100,000

people3.

*

_{Pasteur Mériew Corumught, Lyon Frcmce}

''+

Pastettr Mérieux lndia PW-LTD

For

a

long time, inactivated whole-cell vaccines

(Ty

21a) were

used.

However,

their

large-scale use

has

been hindered

by their high reactogenicity

and

vari-able

immunogenicity.

In

1989,

a

new injectable

vaccine,

Typhim

Vi@,

pro-duced

by

Pasteur

Mérieux

Connaught

(Lyon,

France),

was marketed

in

France,

containing

25

ltg

of

highly

purified

Salmonella

typhi (Ty2

strain)

Vi

capsular

polysaccharide.

This

vaccine can

be

given

in

one dose

from

2 years

of

age

onward,

and

provides

an

ex-cellent immunogenic

response

(80

to

1007o

serocon-version) that

lasts

3

years.

The safety

of

the Vi

vac-cine

can

be

assessed

from

about

20 immunogenicity

and

efficacy trials,

as

well

as

post-marketing

surveil-lance

data

from 40 countries

in

which

the

vaccine

is

Suppl

I

-

1998

subjects4's.

This

Vi

polysaccharide vaccine

is

now

available

in

63

countries,

including USA and

11

countries in

the

Asia-Pacific

region.

EPIDEMIOLOGICAL

SITUATION

IN

ASIA

In Asia,

in

some

high

endemic countries, the

typhoid

situation is

a cause for

concem.

Typhoid

fever affects

mostly young children

of

about

5

years

of

age or

less6-8, and the

risk of

complications

appears

to

be

higher

than Western countriesl,s.

Tâble

1

summarizes

recent

epidemiological

data from

various

Asian

coun-tries

and shows

that typhoid fever is a crucial public

health

problem,

particularly for young

children.

The

resistance

or

multi-resistance

of

Salmonella

ty-phi

strains

to

antibiotics,

mainly ampicillin,

co-tri-moxazole

and

chloramphenicol,

is

an increasing

and

important problem. Almost

all

strains

isolated from

children below 2years ofage in India

are

resistant to

multiple

antibioticstO, and

multidrug-resistant

strains

account

for

50

of all

strains

in Chinall,

75Vo

to

I00Vo

in

recent outbreaks

in

Vietnaml2,r3,

all50Vo

to

77Vo

in

Pakistanl4,ls.

In

Metro Manila

in

the Philippines,

from July 1993-April

1994,

252 multidrug-resistant

strains

were isolatedl6. Drug-resistant strains have

also

been

described

in Malaysiall.

Thbte

1.

Epidemiological data in some Asian countries

Country Epidemiology

Typhoid. Fever Prevention: RoIe

of

Vaccination

85

Vi

vaccine

is

immunogenic

in

children and

adults,

with

a seroconversion

rate (>4-fold

increase

in

anti-body titer)

from

68

to

I00Vo.

Post-vaccination

anti-body titers

observed

in Asia,

measured

with PHA or

RIA

methods,

are high and

comparable

to

other

stud-ies. Vi

Vaccine is

well

tolerated,

with only a2.6 to

12 Vo

incidence

of

fever.

Local

and general

reaction

are

always

mild and

transient.

In

Nepal,

in

high-endemic

situation,

Vi vaccine protected 72Vo

of

vaccines

against

typhoid injection. In Asia,

Vi

the

vaccine

ap-pears safe and immunogenic, and provides

a

high

level

of

protection.

DISCUSSION

Recent

data

confirm

that

Asia

remains

an

endemic

or

high-endemic

area

for

typhoid fever

with

increasing

multi-drug

resistance

of

Salmonella

typhi

strains.

Sanitation

and

improvement in

hygiene

are necessary measures

to control foodborne diseases,

but are

both

costly

and long-term.

In

reponse

to

this

situation,

many countries have

adopted

vaccination

strategies.

However,

the

inactivated

whole-cell

vaccines

(Ty

21a) previously used are

highly

reactive and have

variable immunogenicity.

The Vi"vaccine

recently manufactured

by

Pasteur

Mérieux Connaught (Typhim

Vir)

has been

devel-oped

in

Europe

and

USA.

Furthermore,

many studies

conducted

in Asia

have also shown

that

this

vaccine

is well

tolerated

and

immunogenic, both

in

children

and

adults.

In addition, this

vaccine is

particularly

ef-ficacious and protective

in

high-endemic

situations

and

although no strict

comparisons have been

made,

results

appear

better than those obtained

with

the

en-capsulated

oral vaccine'ly21.azo,zs

_"

Revaccination is

recommended

after 3

years, as

de-cribed

in studies

performed

in USA and

South

Africa,

consistent

with

long-term

follow-up

results

in

Ko-rea30,3 r.

All

the

results generated

in Asian

studies are

consis-tent

with

those obtained

from trials

in

other

conti-nents. Children from 2 years of age

onwards,

particu-larly

at

school-age,

but

also

working adults, military

personnel, exposed persons and foodhandlers

are

po-tentially at

risk

and

must be protected.

It

would be

significantly

advantageous

for

both private

practitio-ners

and

public

health

authorities in Asia to

consider

this

new

Vi

vaccine

as a

useful, immediate and

major

means

of

reducing the

morbidity

and

mortality of

ty-phoid

fever.

ThailandrT

Pakistanls'le

Indonesial,20

Papua New

Guinea2l.2 India22

Philippines23

Malaysia2a

Incidence

=

l2/10s. CFR

=

1%

In 1996 no major problem concerning

resistance to antibiotics

1990-1994: Estimation

of 150,000

cases

per year 48Vo are <5 years of age

Incidence = 350 to 810/105, Aftack rate of

positive blood culrure

=

10261105 >20.000

deaths per year. _{Age = 3} to 19 years

Incidence

=

1208/105.

All

age groups

affected, mostly in rural areas

Incidence _=7601105. <15 years of age.

CFR

=

1.1%

Several outbreaks per year in Metro Manila, 850 cases

in

1995

Incidence = 4.461105. _{CFR =} 0.88%

CFR: Cases

fatality

rate

Vt

VACCINE

IN

ASIA

A

significant part

of

the

development

of

the

pasteur

Mérieux Connaught

Vi

vaccine

has been conducted

in Asia. Efficacy, immunogenicity, long-term

protec-tion and

safety

studies,

conducted

in 5 different

86 Typhoid Fever and other Salmonellosis

Table

2.

Efficacy, immunogenicity and tolerance data from trials with Typhim Vi vaccine conducted in Asia

Med

J

Indones

Country/year

Age/N Design Results

Nepal 1996 Acharya25

5-44

years

efficacy

N=69,000

controls received Pneumo vaccine

o

72Vo of effieacy after 17 months of follow-up

Nepal 1986 Acharya2s

5-l4years

imunogenicity

N

=65

tolerance

a a

GMT

=

1 .89 pglml, 77Vo >4-fold increase (RIA)

no si gnificant side-effects

Nepal 1986 Acharya25

15-44

years

immunogenicity and tolerance N--43

GMT - 3.68 pg/ml

79% 4 - fold increase (RIA) no si gnifi cant side-effects O

a a

Indonesia

1986-90 Simanjuntak26

6-13

months

immunogenicity and tolerance

N=130

control group receive

meningococcal vaccine

7'1Vo with at least 4-fold increase after 28 days. Peak GMT 28 days after vaccination

=

12.5-fold

above the baseline GMT (RIA)

Mild side-effects in both vaccinated and control groups

Indonesia r986-90

Simanjuntak2T

l-12

years

immunogenicity and tolerance

N=268

controls receive pnuemo vaccine

>21 years

N=32

immunogenicity and tolerance

controls receive pneumo vaccine

90Vo >4-fold increase, GMT 28 days post-vaccination = 5.03

pdml

(RIA)

local reaction <75Vo,fever <3Vo,no severe reaction GMT ₌ 11.3 pg/ml, 68Vo 4-fold increase

pain - 29%, fever

=

l2Vo, no severe reaction

a a

Philippines

1991 Montalban2s

5-10

years

immunogenicity and tolerance

N=153-

47 tested before and after vaccination

l00Vo 4-fold increase, GMT=79.85 (PHA)

fever >38VoC=2.6Vo,Mild and transient local reactions, no severe reaction

a a

Pakistan 1988 Waheed2e

2-10

years

immunogenicity and tolerance

N=200

158 infants completed the study

98,7Vo seroconversion, _{GMT = 24,5 (PHA)} 4.6Vo local reaction, 7.ZVo fever >38'C, transient

a a

Korea

1991-93

8-16 years

Kim3o

N=64

immunogenicity

3 years follow-up

r

> 4-fold increase=987o at 1 month, l00%o at 3 months

GMT=69.4 and 49.2 respectively (PHA)

mean increases=28.6-fold and 20.2-fold, respectively

Korea

1991-93

20-28 years

Kim3o

N=85

immunogeniticity 3 years follow-up

o

>4-fold increases=88% at 1 month, 967o at 3 months

GMT=79.1 and 120.3 respectively (PHA)

mean increases=l1.9 fold and 18.1-fold respectively

GMT: geometric mean titer

PHA: passive hemagglutination method

RIA:

radio-immuno assoy method

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