VACCINES FOR THE PREVENTION OF ENCAPSULATED BACTERIAL DISEASES: CURRENT STATUS, PROBLEMS AND PROSPECTS FOR THE FUTURE JOHN

B. ROBBINS

Bureau of Biologics, 8800 Rockville

INTRODUCTIOY It

is an honor for me and my colleagues to participate in this colloquium acknowledging the scientific accomplishments and the special contribution of Professor Michael Heideiberger to the vaccine program of the Bureau of Biologics. When, as a medical student I first became interested in infectious diseases and immunology, the late Dr. Chandler A. Stetson urged me to read Lectures in fmmun~ehemi.~tr~ by Michael Heidelberger (Heideiberger, 1956). These accounts of the introduction of quantitative chemical and physical measurements to the study of immunity was my introduction to the accomplishments of this remarkable man. His discoveries and continued attention to unanswered questions of the structure of carbohydrates and the immune response they elicit in humans remain stimulating to scientists in many disciplines. Recent FDA activities have been concerned with the regulation of new bacterial poiysaccharide vaccines. Many of our decisions were aided by publications and conversations with this gifted and giving individual. For example, the establishment of reference anticapsular pofysaccharide antisera for pneumococcal, meningococcal and Haemophilus irtj7uenzae radioimmunoassay required quantitation of human precipitating antibody described by Professor Heideiberger (Heidelberger & MacPherson, 1943). Professor Heideiberger is an author of at least one of the references for each of the 14 pneumococcal polysaccharides cited in the FDA brochure describing minimum requirements for the currently licensed vaccine (Federal Register). One cannot approach the subject of standardization ofcapsular polysaccharides without ret&ring to him or his associates’ work. The first references in the FDA’s General Bibliography for Pneumococcai Vaccine Licensure is The Sofubfe Specif;c Substance of Penumococcus by Heideiberger and Avery in the Journal 01‘ Experimental Medicine (Heideiberger & Avery, 1923, 1924; Heidelbcrger, Avery CL Goebei, 1929). More recently, we used reference by Heidelberger and Nimmich (1976) to point out the potential for pneumococcal capsular poiysaccharide vaccine to prevent septicemia caused by Kfebsieflu species (Heideiberger & Nimmich, 1972, 1976). The only published structural study of 839

Pike,

Bethesda.

MD 20011. U.S.A

pneumococcus type 25 is dated 1977 and has as an author Dr. Heideiberger (Das, Heidelberger & Brown, 1976). Dr. Heidelberger’s discovery of the pyruvate content of pneumococcal type-4 poiysaccharide was published in 1972 (Heidelberger. Gotschlich & Higginbotham, 1972). One of Professor Heideiberger’s contributions was the development of a multivalent pneumococcal capsular polysaccharide vaccine. This effort, together with those of Drs. MacLeod, Hodges, dilapi, Siegel and Walters, resulted in the awarding of a license to the E. R. Squibb Company in 1945 (MacLeod et ui., 1945). The increasing development and use of antibiotics resulted in this company withdrawing their license without prejudice in 1947. Thereafter, largely through the persistence and broad scientific avenues taken by Dr. Robert Austrian and his associates. the need for preventation of pneumococcal disease was reconsidered (Austrian & Gold, 1964; Mufson et ul.. 1974; Austrian, 1975) and resulted in the production. study, standardization and recent iicensure of a I4 talent pneumococcal polysaccharide vaccine (Smit ef al., 1977). This effort was aided by the simultaneous, rapid development of a meningococcal vaccine composed of Group A and Group C capsular polysaccharides (Gotschiich et af., 1969; Artenstein t-‘f al.. 1970; Wong et al., 1977). PREVENTION RATHER THAN TREATMENT FOR CONTROL OF ENCAPSULATED BACTERIAL DISEASE

The view that we have achieved effective control of encapsulated bacterial diseases has been challenged. Encapsulated bacterial diseases, including those caused by pneumococci, meningococci, ~u~~rn~~ph~fu.~ injluenzae type b, Group B streptococci, Escherichiu coli, Salmonella typhosa, Klehsiella penumoniae and S~aph~fococ~us aureus, remain substantial public health threats. For example, the mortality and morbidity of one disease caused by these organisms, bacterial meningitis, although successfully ‘cured’ in most patients by antibiotics, is unacceptably high. The overall mortality of pneumococcal meningitis has been reported to be about 307; (Baird, Whittle & Greenwood, 1976). A long-term follow of 6000 ‘cured’ meningococcal meningitis patients revealed significant central nervous system problems in about IO”,, (WHO.

.1OHY I3

s-lo

1077). The

lnorbidity

meningitis.

measured

of ‘cured‘

type-b

H. ir~fl~vrxw

by tixcd central nervous deficit.

Ip/~o\tr ha\c comparatively structures. Sialic acids arc frcqucnt simple components of disease-us~ociatsd capsules. Thib Encapsulated gram-positive or gram-negative monosaccharide is found in 9 01‘the 3 I bacteria listed bacteria cause ;I variety of clinical diseases with in Table I. However. their presence. per \c. doe5 not septicemia as a common pathogenic factor. The explain the disease potential of these hactcrla. l-01 capsules of thesepathogens. which confer this invasive example. E. c,o/i strains with the K93 capsularproperty. share several properties: (I) they are surface polysaccharide. u linear +iallc acid homopol~mc~- uith structures in direct contact with the host; (2) all are linkages similar to those of mmlngococc;II Group5 B polymers composed mostly of monosaccharides. They and C, and E. c,o/i K I capsular polq~accll~trld~2. arc’ ma> be linear homopolymers of a single saccharide infrequently associated with dixca\e (Cilodc C/ ol.. such as meningoccal Groups A. B and C‘ and 1977: Egan . Got~chlich and LILI halt po\tulatcd that two or more monosaccharides such as pneumococcal the molecular size ofpurified capsular poly~accharide~ types 3 and 8. multi-chained branched copolymers solution was due to multi chain in aqueous composed of at least five monosaccharides and aggregation (LIU c’t N/., 1977). Their prclimlnal-k Mark additional moieties such ah pyruvic acid or as suggests that this aggregation is due to m~celle pneumococcal type 4. or contain phosphodiester formation consisting of polysaccharlde chains of bonds such as H. i~~//wnrrw type b and pneumococcal about 40.000. A glycolipid. attached by ;I pho\phatc type 6 (Table I ): (3) all purltied capsular diester joining the reducing monoaccharldc of Groups polqsacchurides are antigenic. and probably all are A. B and C meninpococcal polysaccharidc. 15 immunogenic although meningococcal Group B and composed of a phosphate and glycerol \uh\tltuteJ E c,o/i K I. a~, prepared to date. fail to induce serum with two Cl2-I4 fatt) acids 1s the molcty forming thih antibodies in most adult5 (W,y!c C/ (I/.. 1972): (4) the micellar structure. This glycol~p~d moiet! could he antlpenicity and immunogeniclty of several capsular Of tt1c capslllar~ involved in the attachment polysaccharides have been shown to be directly related polysaccharides to the intact bacteria. Detailed to their mol. wt (probably valid for all) (Martin it [I/.. analysis of these capsules irl ti/lc on the bacteria and in 1956: Kabat & Bezcr. 195X: Howard ef (I/.. 1971: solution will be required for characteriration of their Gotschlich. 1974); (5) the virulence of some virulence and immunogenic propertie\. cncapsulatcd bacteria is directly related to the amount per bacterial cell and to the mol. wt of their capsular polysaccharides (MacLeod & Krauss. 1950; Shin et P\\EI \lOC’O(‘( I r/l.. 1969: Smith & Wood. 1969: Kaijser. 1973: Glynn e/ Pneumococci cause a variety of diseases with ol., 1977). This is seemingly contradictory to the observation that immunogenicity (presumably a different frequencies in different age groups. In adult\. protective propert>) and mol. wt are directly related. pneumonia is the most common scrlous disease. while However. increasing mol. wt may confer In infants. pneumococci are the most common cause 01‘ serious and rc-occurring otitls media (Heffron. characteristics that permit both activation of immunocyte surfaces and responsiveness as well as 1939: Kamme et rrl.. 1970: Slo)c~- VI o/.. 1974). interference with effective binding and inactivation of Pneumococcal meninpitis occur\ at all ages. In sonic protective components such as complement proteins African and Asian countries. pncumococcal dlseasc is (Wood. 1941; Wood & Smith. 1949). The best a leading public health problem (Delltt & Douglas explanation by which capsular polysaccharides confer 1973; Odouri & Shah, 1973). Patients with del’ectiic invasiveness through an anti-phagocytic mechanism splenic function. ofwhich sickle cell anemia ISthe mo\t (Wood. 1941; Wood & Smith. 1949: Johnston P/ ul.. common. areespecially susceptible to \e\crc and often overwhelming pneumococcal dlscase dcsplte antl1969; Shin (‘I u/.. 1969; Roberts. 1970: Stossel 1’1al., microbial therapy (Pearson. 1977). 1973). The cell wall mucopeptide of gram-positive and the lipopolysaccharide of gram-negative bacteria can Following the Tillctt and Francis obscr\:ttion that

.IOHN

s-l7 puritied

capsular

antibody

in humans.

polysaccharides belton

type-spcclfic

disease

injected

types

with

(k-rancis,

1034:

Induced

(11(I/. showed

protection

I

in

and II capsular

krancis

&

Tillett,

H. ROBBlhS

serum

in the 1930s

CCC‘

recruits

system

Ekwurzel

(‘I

Because ofextcnsivc

pneumococcal accoi-ding

polysaccharidcs 1930;

polysaccharides.

polysaccharides

to :I serological

designated

al.. 1938: I-rlton. 103X). .4 group headed by MacLeod, Includine I’rofeaor Heldelburger. showed IOO”,,

example.

cl‘ficacq ?or

26. respectivelv.

caused

types

I. 2. 5 and

b> these

organisms

earl>

I urthel-.

these in\estipators

111 WWII

01‘ individuals

soldiers.

Thiz

c;trrlagc using

was

prorect~on elderIF

cpidcmiological National

Discascb

Institute

pi-olect~\‘c and other South

Al‘rican

bacterial

high

attack

rate

01‘ their

divided

hark.

equal

groups

pneumococc~rl

\ accine.

saline

These

placebo.

antibody inlo

~;is

;I multivalent

Austrian.

capsular

and

1977.

Smlt

c’/ r/l..

1977).

or meningococcal

did not occur. There

were no significant

in the vaccine recipients. in ;I rural

population

1077).

A prcllmlnary

chlldrcn

Mith

sickle

Guinea

shoued

control

due

to

type\

capsular

itrc S3 zcrologlcallq

poll xxcharides

1970:

C/ 01..

and

to bc solbed discax

distinct

(Kaufman

IO7 I ).

Lund.

In

other bel’orc can

be

pnc~~mococc~~I discahe (X0-90”,,) types.

Accordingly.

contain

at lcast

I4 capsular

signiticant

pneumococcal

chrce variables

arc related Isolates.

disease

;frca. Types 111 ;I

45(72)

Africa

recent

in

vaccine I’ormulationh geographic ol‘dlsease. to

the number

account

for

Ibrtunately. II)

of types to one

have been I‘ound only in

Type

Egypt. To

least

and

absorption

prepared

remaining

for their

IOO”,, coLerage

types in the laccinc will.

rhe

\arlable

is thee\aluation

cro\kreacti\it\i

01‘

with

(Krishnomurthy

monosaccharide I9A(S7).

I -rhamnose

rabbit

acti\#ities.

un-

ofsurveillance pneumococcal

to know

the

their

against It will

causing

disease.

of multiple

This

discasc

(Appelbaum

ha\c utilized

type

with

more accurateI! ih emphazi;lctl resistant

isolatch

rrom

01 (II..

(includlnr chlor-

.lohannesburg.

1977).

Our

curl-cnt

19).

(3) The time-related change in the praalencc pncumococcal type5 in disease isolates. empha\i/cd Lund

and

unexplained Barnes.

Finland.

remains

phenomenon

1977). isolates and 40s.

Types

;I

(Lund.

I’a\cinating 1970:

U.S.

t\\o

and

types

Europe

xc

Kc

among

during

\Irtually

01’ h) and

Finland

3 and 5 were prominent

in the

These

h! t;pc

cephalothtn

tetraqcline~.

I9F(

from

to serotype

methicillin.

ampicillin.

Africa

Laccines

bc

~111

immunitcd

antibiotic

clindamycin. erythromgcln. amphenicol and cotrimosia)le) South

in

it

for this liner type

those

the organisms

G.

induced

related lypcs

be important

from

pncumococcl

and I)-

to Identil!,

H vaccine prepared serologically

\acc~nc to character102

peniclllm

19A(57)

l’or thl\ cro\\-

are

the world

and especially

IO) and

II-glucose,

cross-protcctlic:

antibodies

throughout

disco\cr)

the

type

genetic basis

pneumococcal rcccnt

al-c

in

gluco\amine

polysuccharides.

the I9 group.

There

lOF(

be necessary

whether

protect

disease Isolates speciticitl

will

these

puriticd

thcsc two

197X).

whereas

to characterize

When by

betuecn

of

plus

and

pol~saccharides

galactosamlne.

and possible

and

humans

work

of whole

similarltles

phosphate.

Further

reactivit)

within

;I nd

thcsc I’our moieties

galactose.

antisera

ili.jection

relation

19Fcontamz and

I‘rom ussa)

w#hole organisms

composition

Type

;md

IO gi-oup

t:\idencc

C/ ol.,

dil‘l’ercnces

:I\;

I9U(5X)

and agglutination

intracenous

organisms

U.S..

I9 antixra

01‘ this

hyperimmunc

a close serological

1930s

pneumococcal

lG30”,,

ol’

by multiple

sub-types

disease

or capsular

IYA(57).

indicate

Thus.

approach

W,,

using Qucllung

All

I9A(57).

isolates

isolate

are classitied

antisera.

19).

art

111 Ihc

isolates

disease

19) and

studies

29 was a maJor isolate

have to double.

(2) Another data

the

At

types arc limited

may have to be adjusted

destination.

I4

to achieve

immunity.

to the distribution

Some

and Asia.

seriou\

i\ caused by about

polysaccharides

and 46(73)

sur\ey

most

an elf‘ecti\e vaccme must disease

among

pneumococcal

(‘I rrl.. 1960: Lund.

However.

capa&ir

Southern

l9F(

I9t(

most

cast

In

isolates

In children.

typing

types

arc X0”,, earlier

lOA(57)

There

with

one lqpe uill

(Rile>

available

7 qpc 6

and SH(26).

disease

another

to

t>pcs has not

6A(6)

of

XV’,, ofdiscasc

In the U.S..

important

considered.

( I)

react

For

19c‘(59).

were obtained

disease elficxy

01‘ pncumococcal

approximately

adverse effects

c’t t/l.. 1977).

thcrc arc‘ \c\craI problems

complete

6B(26).

the structural

C/ i/i.. 1976:

anemia

ccl1

(Ammann

degree of

capsular

XV’,,

The

relation

I-01. instance,

both

and 20”,, are 6B(26). type

contains

mcningococcal

results

111 Neu study

hcmoflohinopathlc~ )‘a.

Similar

poly-

Dlscase

pneumococcal

or

Incorporation

was achicvcd (Austrian

with

approximately

major

the serum

and a high

pneumococcal

protcctlon

other

\ accinc

by their

formulation

capsular-specific ~IWIW

individual

al‘kcted

were

multl\alent

that

t-act

formalinized

sekrral

miners

menmgococcal

to

not

the first

investigated.

will

adults.

vaccine-induced

later more prectse assays with purilicd

pneumonia

recruit

showed

in

has an

encapsulated

rcceiking

studies

response

accharides

within The

the

vaccines

pncumococcal

mcningitib

mine

into

Infectious studied

populalion 01‘

been thoroughly

laboratnrles

tvpcs as sinplc cntitlcs.

between these cross-reacti\c

antiserum

i-or

;I\ 6A

these types as 6 and antlscra.

immunity

uill

and

denotes

available

and

based

(21(I/.. 1960).

basis

clinical

and

system With

Danish

two types rccognired

cross-reactive

type I9 with

& Dohmc This

including

In

groups

chemical

are

(21(I/. and others.

01‘ Allerpy

will identify

The

types within (Kaulhnan

6 contains

U.S.

care hospital

cf’fects ol‘multicalent

2nd meningococcal months

the

and 6B. The

6A(6)

hacterimia

a chronic

miners.

disease

Kauffman. type-specific

and

Sharp

injected

a decreased

showed

recruit

extraordinary

these

and. hence. a lower

01‘ Austrian

and later Merck

1945).

immunity‘

to

Following

studies

Forces

(I/..

colleagues.

attendIng

1947).

(Kauflinan.

troops

pneumoniu

individuals

cf

with

vaccine.

against

Armed

attributed

unimmunizcd

Iri\iilenl

pneumonia

a ‘herd

interacting

el‘ltict

ofthcir ;I

U.S.

bho~

in the immunired

exposure

the

in

(MacLcod

recruits cl‘kct

7 against

Group

classification.

capsular

upon thiscross-reactivity

cross-reactivity,

have been designated

the

absent from recent sur\cys. C’ontinued aur\eillancc MIII be necessary 10 dctermlne uhethcr the appearance 01’ some pneumococcal types will bc ta~ored bq ~acc~nc’ usage. (3) Age-related diflrrences in the distrlbutlon 01‘ pneumococcal types and sub-types are imporkmt 111 determining the multlcalcnt \acc~nc I’ormulation.

Vaccines

Against

Encapsulated

Types 6,9, 14, 19F( 19) 23 and I8C(56) predominate in CSF and purulent otitis media isolates from otherwise healthy infants and from the blood and CSF of infants and children with absent or defective spleen function (72). Curiously. there is a direct relation between infant disease type and the low immunogenicity of these types in this age group (73). Types I, 2,3,4.8 and 12 which are more frequently associated with serious disease in adults are more immunogenic in infants (Austrian. 1977; Borgono er al.. 1978). This inverse relation between immunogenicity and virulence of pneumococcal types associated with disease is an important theoretical and practical problem for pneumococcal and other bacterial disease prevention with significant attack rates in this a& group. Pneumococcal otitis media poses a special problem for immunoprophylaxis. That otitis media constitutes a serious cause of immediate morbidity and acquired hearing loss has only recently been appreciated by the medical community. Studies are under way to evaluate vaccine-induced prevention of pneumococcal otitis media. The data suggests that with our current vaccines. infants under two years of age will not respond to those pneumococcal types most frequently associated with disease. Further, it is possible that external secretory mechanisms in addition to serum antibodies, have to be induced to prevent otitis media. The type-specific inhibition upon nasopharyngeal acquisition induced by the pneumococcal polysaccharide vaccine suggests that an immunogenic vaccine

Bacterial

in the infant age group will be protective against otitis media. Dr. Heidelberger has reported extensive crossreactivity between pneumococcal capsular polysaccharides. including vaccine types. and Klebsiella and E. coli (Avery rt cd., 1925: Heidelberger pt cd.. 1968; Heideiberger & Nimmich, 1972; Robbins et ul.. 1972: Heidelberger & Nimmich, 1976: #rskov et ul.. 1977). Both Klebsiella and E. coli are common in hospital associated infections. Cross-immunity to these organisms may be induced with pneumococcal vaccines and this possibility should be studied.

There are at least seven meningococcal capsular polysaccharides designated Groups (Table 2). Most meningococcal disease is caused by Groups A, B and C. W I35 and Group Y have been recentlv shown to comprise approximately IO”/,, of disease -isolates in some countries (WHO, 1976). Epidemiologic characteristics of meningococcal disease can be related to the Group. Group A is usually associated with acute epidemics or high levels of endemic disease (Gold & Lepow, 1976). Outbreaks and occasionally smaller epidemics have been associated with Groups B and C. The sudden emergence of severe meningococcal epidemic in Brazil, especially Sao Paulo. from 1972 to 1974 was originally caused by Group C and then by

Table ?. C‘ross-reacting antigens of pharyngeal and’or enterlc organisms Invasive

Pathogen

Cross-reacting organism

Pneumococcus Type I

to capsukrr

polywccharldes

Meningococcus Group A

ol

bacteria Cross-reacting

structure

Extracellular polysaccharidc. not characterized K7 capsular polysaccharrdc acid component Extracellular polysaccharrdc. acid component

Type 3

Group

x43

Drseases

structure r,-glucuronic n-glucuronic

J~-acetyl-p-mannosamine phosphate component ofextracellular polysaccharide ,Y-acetyl-u-mannosamine phosphate component ofextracellular polysaccharide O-acetyl + and O-acetyl - form variants of K I capsular polysaccharide. cz 2-X linked ,V-acetyl neuraminic actd K92 capsular polysaccharide, :V-acetyl neuraminic acid homopolymer with alternating J 2-8, 2-9 linkages

C

E.whrric~hia di Staphylococcus aureu. Bacillus pumilis. Bacillus sub t ilis Locrohacillus plantorum Pneumococcus

K IO0capsular polysaccharlde, +3)-/I-t,Chose (1 + 2) ribitol-S-phosphate + Polyribitol phosphate component of cell wall teichotc acrd Type 26 (VIB), 29 and 30 capsular polysaccharide ribitol phosphate component ,v-acetyl galacturonrc acid component extraccllular polysaccharide

ol

both Groups A and C. The recent epidemic of meningococcal meningitis in Finland, first observed in young army recruits and then in the general population. was due to Group A (Makela C/ ~1.. 1975). Outbreaks of’ meningococcal Group B disease habe occurred in Belgium. England and Norway (Mumford rt 01.. 1974: B@vrc t”t (II., 1977: Griffiss clt (11.. 1977: Jacobson c’t L/I.. 1977). Success in prevention 01‘ Groups A and C meningococcal meningitis in older children and adults has been achieved with capsular polysaccharidc vaccines (WHO. 1976: Peltola (‘I crl.. 1977). These vaccines are now licensed products in the U.S. and other countries and under manulhcture by at least five countries. At least four problems prcvcnt complete vaccinecontrol ofmeningococcal disease. I-lr\t it is the lesser immunogenicity of polysaccharides in infants that group with the highest attack rate (Gold & Lepow,, 1976). Data l‘rom Finland and the immunogenicity studiesconducted in the U.S. indicate that prevention ofGroup A disease can bc achieved bq two injections initiated at three months and then again at six months of age (XX). Group c‘ has not been shown to be fully protcctivc under the age 01‘two years and this correlates well with its lesser immunogenicity m this age group. Important information regarding the human infant immune response to Group A in contrast to Group C menmgococcal polysaccharidcs has been developed by Gold. LepoM and Gotschlich (89). Injection of Group A polysaccharide into infants 3 months of‘ age induced no antibody response. A slight response was elicited in individuals older than 6 months and this increased with arc (Gold (‘I o/.. 1975. 1977). Booster immunization showed inlants. who received Group A vaccine at 3. 7 or I? months. responded significantly greater than int’ants who had received only one inJectIon. This booster ellt-ct was no longer demonstrable in individuals o\er IX months. These tindings were utilized to prcvcnt Group A meningococcal disease in Finnish children (Peltola 1’1 cl/.. 1977). In contrast. Group c’ meningococcal polysaccharide induced 21significant (but probably not sufficiently high to be protective) antibody response as early as 3 months of age. With Increasing age the response increased but the mean antlbod) concentration achieved at 1 year was approximately 1’10th that ofolder children and adults. In contrast to the anamestic response induced by Group A meninpococcal polysaccharldc in infmts up to IX months. Group C exert ;I supprcstic effect ~lpon reimmunization of this age group. One approach to ;i solution to this problem of :I non-protective response to Group C‘ meningococcal polysaccharidc has been studied by Glade (‘I u/.. (1976). These workers utilized a Group C‘ meningococcal polysaccharide var’lant lacking Oacetyl (Apicella. 1974). This capsular polysaccharidc variant comprised about IO”,, of disease isolates (Apicella & Feldman. 1976). The Group C capsule was purified and was found to induce higher levels of antibodies compared to the O-acetyl positice vaccine in young adult volunteers (Glade (‘I (I/.. 1979). Antibodies induced by the O-acetyl negative variant were bactericidal for the O-acet>l positibr organisms. Further studies to characterize 11s immunogenlcity in younger individual\ arc under \\a!

A second hurdle is that vaccines for the so-called minor groups have not been tested. Because of their low disease attack rate it is unlikely that one clinical trial will be able to verify their disease efficacy. relation the direct between the However. immunogenicit? and disease efficacy of groups A and c‘ polysaccharldes suggests these Groups can be included in the multivalent vaccine if they are shown to induce serum antibodies with biologic activity, such as complement-dependent bactericidal reaction (Gotschlich (‘t t/l., 1969). Preliminary studies suggest Groups 29E. WI35 and Y are immunogenic and induce bactericidal antibodies (Farquhar c’f ul.. 1977). A third problem is that the duration of vaccineinduced immunity is not yet known (Lepow C/ r/l.. 1977). Some worker\ suggest that re-immunization may be necessary 3-3 years later. even in the adult group. to restore antibodies to their maximum level and to retard their rate of decline observed after initial immunization (94). Fourth. the Group B capsular polysaccharide (and I? cali K I ) has not proved to be an effective immunogcn (Wyle C/ al.. 1972: Kasper ~‘1 (I/.. 1973). Two approaches to this problem have provided Important new information regarding the physiology of encapsulated bacteria/host interaction. The tirst. advocated by Frasch and others. is the study ofanother surface structure. the outer membrane proteins of meningococci (E‘rasch & Gotschlich. 1974; Frdsch. tY77: Mumford ot al.. 1974: Zollinger & MandrelI. 1977). There is a polymorphic system. presumably controlled at ;I Tingle locus, of antigenially related proteins. These outer membrane proteins have been designated ~s~vv/~~x’sand have many characteristics that support their use as vaccines. (a) Using hyperimmune rabbit antisera. prepared by multiple injections of whole bacteria. serotype-specific reagents have been prepared (Frasch & Chapman. 1973). The serotyping reagent prepared with Group B strains has been shown to react with outer membrane proteins among meningococcal Groups B. c‘. I’. W I35 and 29E (Frasch & Friedman. 1977). It is interesting that Group A and 29E strains. which do not contain sialic acid. do not react with these antisera. (b) To-date. IS variants have been identified. The serotype distribution of these scrotypes among isolates from discused or healthy individuals resembles that of the capsular polysaccharides. For example. disease is associated with onI1 some serotyprs. Some scrotypcs have been associated only with carriage and some are associated with carriage and ‘or disease (Frasch. 1977). Scrotypinp prohidcs a tool for assessing the disease potential of isolates tn an outbreak or epidemic (Jacobson CI (I/.. 1977: Mumford c’t rrl.. 1974). (c) The serotype protems can be prepared in highly purified form free from significant contamination by other cellular components especially endotoxin. Injection of animals with the purified serotypc proteins elicits bactericidal antibodies and a protective effect in several animal models (Frnsch & Robbins. 1978). Further, anti-serotype protein antibodies and antipolysaccharide antibodies exert a synergystic protective effect (Frasch CI cl/.. 1976). This important finding suggests that immuniration with both the serotypc protein and capsular polysaccharide could provide ;I longer duration of immunity since the protective effect of these two antibodies may be

\:accinea Against Encapsulated Bacterial Diseases greater than their sum. Since only several serotype proteins are associated with disease among the Groups B, C, Y and W I35 stramb a serotype protein vaccine may require only several components. It should be noted that the Group C epidemic in Brazil was caused almost exclusively by serotype 2. These findings provide the impetus for studying outer membrane proteins and other surface antigens such as pili (attachment factors) of other encapsulated bacteria. Investigators have shied away from studying other surface structures because it has been assumed that capsules formed a non-penetrable covering. Antibodies to the 0 antigen of gram-negative bacteria exert a protective effect although with a lower specific activity than that of anti-capsular antibodies. Noncapsular antibodies may exert a bactericidal effect (Muschel, 1960: Osawa & Muschel, 1964). Kabat and Heidelberger showed that absorption ofhyperimmune antiserum, prepared by repeated injection of whole bacteria. with either encapsulated or unencapsulated variants of the immunizing strains. removed antibodies to non-capsular antigens indicating that the latter were available for interaction with serum antibodies in both bacterial preparations (Pittman, 1931).

Although thcrc arc 51x capsular types of H. irzfluenxr. most serious disease is caused by type b (Parke ef ul., 1977). This organism is the leading cause of bacterial meningitis in the U.S.. Sweden and Finland (Johnson & AlLin. 1971; Peltola L’I(I/.. 1977~). H. i~~flucwxc~ type b also causes other serious diseases including epiglottitis. septic arthritis and pneumonitis with empyema (Smith & Robbins, 1974). Until recently, only deaths due to H. in/lucwx~e type b have been reported. Bused upon limited surveys. it has been estimated that there are about 12.000 cases per year in the U.S. Several workers have reported that about one third of ‘cured’ patients have significant permanent CNS deficits (Sell c’t uI.. 1972; Lindberg c/ ul., 1977). One of the important observations regarding the pathogenic role of the H. in/1u(wxw type b capsule was reported by Heidelberger and Alexander (Alexander et ul.. 1944). These workers showed that the protective element in hyperimmunc rabbit therapeutic antisera could be removed by absorption with purified type b capsular polysaccharide. Efforts to-date to prevent H. ir@rnxc type b disease by inducing type by antibodies with capsular polysaccharide vaccines can be summarized: the type b capsule can be prepared in non-toxic high molecular form with trace amounts of protein. nucleic acid und endotoxin contaminants (Smith CI al.. 1975: Parke C’I(I/.. 1977). Injection of these preparations into adults induced long-lived serum antibodies with bactericidal. opsonic and mouse-prbtective activity. In.jection of children of between 18 months and 5 years resulted in ;t serum antibody response which was protective but shortlived (Robbins tz/ r/l.. 1973: Smith PI ul.. 1975). Todate, disease efficacy has been established for children after the age of IX months injected with the purified capsular polysaccharide (Peltola et rrl., 1977~). However, current prcparatlons induce only a shortlived immunity in older infants and little or no

x45

proteclion in the lounger infants. those uith the highest attack rate (Parke ct ul., 1977: Smith rt rrl.. 1975). Based upon these studies as well ilS analyses ol individuals x-linked with hypogammaglobulinemia rccciving effective passive immunotherapy with pooled immunoglobulin it has been estimated that a protective serum anti-type b level ranges about 0.2 /cg,rnl (Robbins (‘/ ul., 1973). Thus. a protective effect of a polysaccharide vaccine can be predicted. Current programs involve the study of protein-polysaccharide complexes and the use ol cross-reacting organisms. Another method proposed for induction of serum antibodies has been deliberate colonization with E.sc/rc~ric~/~itrc,o/i K 100 strains containing a capsular polysaccharide antigenically and immunogenically related to H. iyflucnxe type b (Schnecrson & Robbins. 1975). The capsular polysaccharide is composed ofequlmolar amounts of ribosc. ribitol and phosphate. “C NMR studies shorn a different. though yet not completely characterized linkage (Branefors-Hclandcr CI ul.. 1976: Egan (‘I t/l.. 1978).

It ha5 been known for many years that home serotypes are found more often among E. co/i isolates from blood, CSF and urinary tract as compared to their frequency in stools of healthy individuals (Sjostedt. 1946: @rskov ct c/l.. 1971: Mabeck c’f u/.. 1970; Clrskov V/ rrl.. 1977~). Adircct correlation was made between the presence of acidic capsular polysaccharides (K antigens) and E. co/i strains isolated from extragastrointestinal sites such as the blood. urinary tract or CSF (C)rskov c’f(I/.. 1977u).Two invasive E. co/i diseases are prominent in humans and have been associated with capsular polvsaccharides. These are childhood urinary tract inyections and neonatal septicemia and meningitis. Capsular polysaccharide (K) antigens have been shown to exert an important role in determining the disease potential of E. co/i invasive for the renal parrnchyma as contrasted to those confined to the lower urinary tract (Mabeck c,tu/.. 1970: Hanson, 1973; Glynn cjtul.. 1977; Glynn & Howard, 1970; Kaijser 1’1 (I/.. 1977). Although there are 100 K antigens observed to date. E. c,o/i isolates from urinary tract infections of children and young adults are caused almost exclusively by tive K types. The E. co/i isolated from the renal parenchyma have K antigens of higher mol. wt and higher concentration per bacterial cell than those confined to the bladder and gastrointestinal tract (Kaijser, 1973; Glynn cutul.. 1977). Reinfection may be related to the finding that serum antibodies to the K capsular polysaccharide appear infrequently and in low levels following convalesence from urinary tract infection (Hanson, 1973). In contrast. antibodies to the CJ and H antigen appear in high concentration. It has been shown that antibodies to the K polysaccharide have a higher specific protective activity than antibodies to the 0 antigen (Kaijser o/ ul., 1972: Kaijser 6i Ahlstedt, 1977). Considering their frequency. reoccurrence and potential for permanent Injury, vaccines containing the most frequently encountered E. c,o/i K antigens should be studied for prevention of E. w/i urinary tract infections.

the cast‘ 01 neonatal

For

lcast X0”,, ofthe been shown (Robbinz K I

organisms

to possess

c’/ t/l..

the K

1074).

and

Group

study

01‘ neonatal

revealed

many

observed

in

meningitis

caused

I’catures

C/

Anticap>ular

concentration (I/..

of

2 highly

ausccptibilit~

crlticial

to

assay.

antibody susceptiblllty. unusual

that E.\c,/~ic,/fitr suggesting

Study

of

There

problem

aspect 01‘ K I capsular ,E. c,oli Kl

phenomenon ohserced

I’orm \ariatlon intensltles 011

antiserum properties

i\ due

to

;I

polqsaccharide the j~-acctyl dihtributcd

has

c,o/i K

:lgkll

and

by

The

indicate

that

the

new

antlgcnic

in

immunogenic

than

position

Bacterial

positi\c

the O-acctyl

is ;I major 1964:

nieninglti\ cuusc

Baker.

is

polysaccharides to Group

( I

antigens

to be directed

to type-specitic

GI-oup

H (Lancetirld

(‘I t/l..

III.

type\ ofhpccific All

disease.

antigens

1075).

Landy.

from

poor types

prognosis la

and

has been shown III.

Another

capsular

able to show preparation

conl‘erred

;I challenge

model

long-lived.

extracted in

has been within

are at least la. lb. II and with

clinical

to

disease. with

a

due to \.ariant.

loucr

from.

the

mouse

human

assay

vacclnc

shown

to

have

against

S.

/J~&SU

induce al..

incomplete

1974:

moiety

and

higher than

among

is

anti

.S.

an equivalent

more

active

antibodies

bactericidal

0 antibodies

whole

bacterIaI are highly

immunity

various

purified

acetone-inactivated Vi

C/ c/i.. 1970). the

This than

specific

protection. of their

Hornick

c’/

C./ic~urztlii

from

IO times

preparations.

1964). Typhoid

and the duration

antigens

1954: Hornick

is 20 times more active

bvhole.

Vi

and

mol. wt than the Vi preparation

01‘ the

Citrobactcr

Muschel.

extracted

in

fed S

has been re-

polqsaccharide (Landq.

preparation

bacterial-cell

were

by this

to primates

problem

protection

dosage

induced volunteers

.5‘. /.~pl~o.\n TY-2.

/~~/~/Io.scI Vi antigen

antibodies

to be largely

using Vi capsular

(I/.. 1970). 7he VI antigen

among

sepsis

this

they

was incomplete

this protection

a

also as E.

extracts.

to human

With extracted

38 (referred

antibodies

by newer methods

ofconslderably

preparation

53%

Rcccntlq.

l9S4;

In the late 1950s.

some protection

and

O-acetyl

01‘ Vi antigen.

bacterial

strum

that

/~pho.str. Howsever.

according

activities

f~~r~clii

with a capsular

associates isolated and compositlon. immuno-

polysaccharide

C‘i/~&c~/c~

from

(Kauflinan,

1956).

and

Isolates

:V-acetyl,

antigen)

C/ r/l..

c,o/i) by acid-treatment

cell-wall

onset

acid (Vi

Vi

and the

surfaces

in some hosts.

are encapsulated

Martln

fever, the

H. and

S. /~./~~zo.suis an

mucosal

01‘

effect

01‘ differentiation

and typhoid

components.

composed

genic and protectibc similar

N/..

antigens

An carlq clinical characteri~tlcs. characterircd by sevel-c overwhelming

1954:

in\estlgatcd

There

distribution

in\ariablq

FEXEH)

mice and humans

Landy. Webster and their characterlrcd the chemical

more

are caphules and all have been associated but ha\c ;I unique

in

fever. Part

to .5‘. /~~~/Io.Yu. 0.

bacterial

pol~palacturonic

on

(Eickhoffrt

dcsignatcd

in rcactivitc

typhoid

lack

carriage

between laboratory

prepared

models

to the

polysaccharide

s

protective

bc due

ma>

the blood

variant.

specific

in animal

this

This

B Streptococcus

shown Ibur

plasma

of non-immune

in preventing

been

i\ randomly

is

antibodies

stream

capsular

classitication

upon

(I 36). However.

antibodies.

( 1.1 I’HOID

the blood

or absence

ncgati\e

O(‘O(

Ciroup

B Streptococcus

in

to measure

the protective

enters

colonies

and

due to Group

based

Studies

regarding

B. A

poly%aharide

ofdisease111new horns 1977).

Streptococci

capsular

B type III

that penetrates

of the O-acetyl

determinants

I’ I{ s1 Hk:l~l

III

this serum

I \ i .\r\;l’l(;k.\

between asymptomatic

not (;Hot

with IgG

with human

organism

I antisera.

the

acid monomer

O-acctql

streptococcal

type

data).

entcric

on thcc‘7 and CU. Prcliminaryc.xperlments

confers

mothers

population

to be immunogenic

administered

is controbcrsy

lack of purilicd

differential

co/i K

change

an

01‘ halo

I

by the presence

ncuraminic

and

or by active Immunization

dill‘erences

which

~a/(I/.. 1977).

E.

of 01

Group

variation

single

\tructur;iI

moictie\.

01‘ O-acotyl

Ibrm

with some E.

conferred

ofant+Vi

I’or precention

can be detcctcd b) dil’l~rences

agplutinatlng

H

el‘l?ct 01‘ Group

.S II. \lO \&/.I. 1 ~~/‘t/O.Y

host

polyzaccharidc

K I (Ursko\

surrc)undlng

grown It

as

tI. co/i

in In

are in profrrys.

disease

haz revealed

and mcnlngococcu\

known

in the

mothers

disease

to

may pro\ ~dc ;I new ;ikenuc for research of both

8

There

problems

antibodies

ol‘ this

ncwjborns

ih insufficient

technical

K I

B

Group

(unpublished

wjhether passively

co/i

that

determinant

unreholccd

adults

to be absent

without

has been shown

& by

er LI/., 19770).

colonited

mothers

Puritied

the protective

in

of

type III (Baker

measured

B type III

babies

almost

to becapsular

An at risk

for Group

born

due

type-specific

01‘ newborns

B streptococci.

polysaccharlde

capsular Group

Z&30”,,

antibodies.

;I\

disease (Baker

identifying

organism,

\el-otypcs I’ound in the

common

surveys.

is B

component

have been shown

who contracted

young

main

septicemia,

including

Antibodies.

has been defined

by repeated effect

acid as their

by

Group

type antigens

19761~).

disease

1975).

The

ha\e been shown

All

Group

with

prognosis

Ill.

of disease

late onset birth)

rat model (Robbinz

(Sarl‘l‘ c’r explain the development of age-related immune response to capsular polysaccharide vaccine by postulating an increasing reservoir of differentiated B cells induced by crossreacting bacteria. Serum antibodies are only one component of host resistance. Their importance is illustrated by the remarkable susceptibility to repeated and severe disease with encapsulated bacteria suffered by patients with x-linked hypogammaglobulinemia (Rosen bz Janeway, 1964). C‘omplemcnt component deficiencies, defective splenic function and as yet unknown host genetic factors predispose to encapsulated bacterial diseases (Alper rt ol.. lY70: Whisnant ct (I/., 1975; Pearson. 1977; Johnston (‘1 trl.. 1978).

There is an increasing interest in prevention of human diseases due to encapsulated bacteria. The virulence of encapsulated bacteria is related to their capsular polysaccharides. This virulence is most probably mediated by their anti-phagocytic effect. Other bacterial surface components, such as outer membrane proteins of Group B and other meningococcal groups. may be related to virulence but the mechanism of this relation has not yet been characterized. Anti-capsular antibodies mediate immunity by activation of complement. Evidence indicates that IgM and IgG antibodies are protective moieties. Information from animal models, and from unusual disease susceptibility states in humans.

Vaccines

Against

Encapsulated

indicate that in the spleen, genetic control of immunoglobulin synthesis and the complement system are required for effective resistance. Capsular polysaccharides may be prepared in highly purified form with no serious reactogenicity. Most capsular polysaccharides are immunogenic and have been effective in preventing serious diseases due to their homologous organism in individuals older than 2 years. Theoretically, it should be possible to prepare a multivalent capsular polysaccharide vaccine for all common species,

invasive

organisms.

For pathogenic

bacterial

such as pneumococci with many capsular types, immunization has not resulted in emergence of other capsular types as pathogens. A preventative immunization program with our existing vaccines cannot yet achieve the goal of elimination of all encapsulated bacterial disease because most capsular polysaccharide vaccines studied to-date do not induce effective disease prevention in infants and young children. Methods to increase the immunogenicity of our current vaccines and to develop immunigens against meningococcal Group B and E. coli Kl are needed. The mechanism by which only some of the many bacterial capsular polysaccharides confer invasiveness is not known. Some evidence indicates that both the chemical (composition) and physical (mol. wt) properties may be important variables related to virulence. Further understanding of these characteristics might provide opportunities to supersede polysaccharide-specific immunity. Incorporation of a new vaccine into current public health programs requires continued surveillance by Public Health agencies to insure its effectiveness as well as to prepare for any unpredicted adventitious reactions. Surveillance for these bacterial diseases requires serological reagents and trained personnel. It is worthwhile to mention problem of pneumococcal type identification. Other causes of vaccine failures may be due to genetic or acquired deficiencies in host resistance. The study of pneumococcal and later other capsular polysaccharides lead to the discovery of immune tolerance. DNA as the transforming principle and hence the genetic information, identification of gamma globulins as antibodies and their molecular heterogeneity. quantitative methods for the measurement 01 antibodies and complement, virulence mechanisms of human pathogens and important probes for immunologic studies. There is every hope that studies of these interesting molecules, although appearing ‘applied’ will continue to reveal important ‘basic’ scientific information. REFERENCES

Alexander H. E.. Heidelberger M. & Leidy G. (1944) The protective or cur;Ltive element in type b H. infl~rr~ac~ rabbit serum. y~lc J. Biol. Med. 16, 425-438. Alper C. A.. Abramson N., Johnston R. B. Jr.. Jandl J. H. & Rosen F S. (1970) Increased susceptibility to Infection associated with abnormalittes of complement-functions and of the third component of complement (C3). ,v,srzs LXXXIX, 184-194. Austrian R. &Gold J. (1964) Pneumococcal hacteremia with especial reference to bacteremlc pneumococcal pneumonia. Ann. inrern. Mrd 60, 759-776. Avery 0. T.. Heidelberger M. & Goebal W. F. (lY75) The soluble specific substance of Friedlander‘s bacillus. Paper II. Chemical and immunological relationship\ ol pneumococcus type II and of a strain of Friedlander’s bacillus. J. e.x-p Med. 42, 709-725. Baird D. R.. Whittle H. C. & Greenwood B. M. (1976) Mortality from pneumococcal meningitis. Ltrnc,er II, 1344-1346. Baker C. J. (1977) Summary of the workshop on perinatal infections due to group B Srr~,~~roc,oc,c,u.\.J mfwr. Di.c 136, 137. Baker C. J. & Kasper D. L. (1976~) Microcapsule of type III strams of Group B .xrrrptococ~c~\: production and morphology. Infwr. Immun. 13, I X9-lY4. Baker C. J. & Kasper D. L. (1976h) Identification of slalic acid in polysaccharide antigens of Group B .sIT(‘~,I)Io(‘o(‘L’II.,. fnfecr. Immm. 13, 284-288. Baker C. J.. Kasper D. L.. Tager 1. B., Paredcs A.. Alpert S.. McCormack W. M & Goroff D. (1977~) Ouantitntlve determination of antlhody to capsular polqs&haride in infection with Type III strains Group B S/r.c,~/~,~.oc,c.lc\.J. clirr. Inw.s/ 59, 8 l&8 18.

850

JOHN

B. ROBBINS

Baker P. J.. Morse H. C., Gross S. C.. Sta\hak I’. W. & Studies on the mechanlw of the Immunologvxl paralysis I’l-c~cotl B. ( I Y77h) Maturation 01. regulator) factor\ induced in mice by pncumococcal polyaaccharidea. J. ~nllurnc~ng magnitude of antibody response to capa~la~ Itttmrr,~. 74, 17-26. polysaccharide of type I I I .Tt,.c,ptoc.oc,c,rr.v /~rt~~/rr,torrirtc,. .I I-inland M. (1973) Excursionr Into epidemiology, wlected irzfcc,t.Di.v.136, S23. studies during the past four decades at Boston c‘itj Baltimore R. S., Kaaper D. L.. Baker C. J. Xc Goroff D. K. Hospital. J i/r/w~. ni.\ 128, 76-l 24. (1977) Antigcnic specificity of opsonophagocytlc Finland M. & Barnes M. W. (1977) Changes in occurrrncc of antlboda in rabblt antIsera to group B streptococci. J cnpsular serotqpcs of Strcptocouuspw~v~~~~~t~icrc~ at Boston /t?v?lUn. 118, 673-67X. City Hospital during selected years between I935 and 1974. Borgono J. M.. McLean A. A.. Vella P. P.. Woodhour A. I-.. J. c,/in. .4limhio/. 5, 154-l 66. Canepa 1.. Da\td\on W. L. & Hlllcman M. R. (197X) Fintand M. & Shuman H. L. (lY42) The type-specific Vaccination and revaccination with pol~ralcnt agglutinln response of children uith pneumococcal pneumococcal polysaccharide vaccine? in adults and pneumoniah. J. fmtttwt. 45, 2 15-242 infants. Proc,. Sot, cx,j. Biol. :Mrt/. 157, 14X-I 54. Francis T. (1934) Antigenic action of the hpecitic BQvre K., Holtrn E.. Vik-Mo H.. Brondbo A.. Bratlid D.. polqsaccharidr of pncumococcus Type I In man. Pwc Bjark P. & Moe P. J. ( 1977) &‘rv.c.w~o rmwirt,qit~t/i,~ SM C’Yp Bid Med. 31, 493-495 infectIons in northern Norway: an epidemic in 1976lY75 I.rancis T Jr. & Tillctt W. S. (1930) C‘utancous reaction\ in due mainly to Group B organlm\. J IU/saccharidcs. Frasch C’. E., Parka I... McNcilis R. M. & Gotschhch E. C. .w?t/. J 4 MS/I, 4Y-51. ( 1976) Protection against Group B mrningococcal disease. Dowling H. I-. (1973) The rise and I’all of pneumonia-control I. C‘omparlson of group-specific and type-specific programs. J. infwt Di.c 127, 201-206. protection in the chick embryo model. .f. KY/>.Mcri. 144. Egan W.. I_lu T.-Y.. Dorrow D., Cohen J. S., Robbins J. D.. 3 I Y-32’). Gotschlich E. c’. & Robbins J. B. (1977) Structural studies Frasch C. E. & Robbins J. D. ( 1978) ProtectIon against group on the slalic acid polymer antigen of ~.s~~/wrrc~hrtrw/i strain B meningococcal disease III Immunogenicity ofserotype BOS-I 2. Bioc~/rcwi\rr~~ 16, 3687-3697. 2 vaccines and speaticitl of protection 1n a guinea pig Egan W. M.. Tsui F. P.. Liu T.-Y.. Schneerson R. (lY78) model. J. c\f’. ,Mcc/. 147, 62%644. Structural studies of the KIOO capsular polysaccharide Glode M. P.. Robbins B., Liu T.-I’., Gotschlich E. C.. Orskoc I. 8: Orsko\ F. (1977) C‘ro\s-antigenicity and antigen of E~ch~ri~~hiu w/i. Submitted for publication. immunogcniaty between capsular polysaccharides of Exkhoff T. C.. Klein J. O., Daly A. K.. Ingall D. & Finland M. (1964) Neonatal sepsis and other infections due to group C ~Vria.wicr nwnir~,~ific/,.\ and of Ew/wric,hicr w/i K92. Group B beta-hemolytic streptococa. h’c,n, OI,~/ J ,tlct/. J it1frc7 f1i.c. 135, 94-l 02. Glade M. P.. Schiffcr M. S.. Robbins J. B.. Khan W.. Battle 271, 1221-1128. Ekwuvel G. M.. Simmons J. S.. Dublin L. I. & Felton L. D. S. ti. & Armenta E. (lY76) An outbreak of Haem~f~f~i/u.t in/lwttruc~ type b meningitis is an enclosed hospital (1938) Studies on the immunizing substances in pneumococci. VIII. Report on lirld tests to determine the population. J Pdicrt. 88, 3&40. Glade M. P. Lewin E. B.. Sutton A.. Lc. C. T., Gotschlich value of a pneumococcus antigen. Puhl. H/t/?Rep., I~h.th. E. C. & Robbins J. B. (1979) Comparatice immunogen53, 1877-1893. icity of Group C h’ciwritr nlcwrn~rrrclic O-acetyl positive Farriles J. S.. Dickson W.. Greenwood E.. Malhotra T. R.. and 0acetyl negative variants and E.cc/wri&ia w/i K92 Abbot J. D. Cyr Jones D. M. (1975) Meningococcal capsular polysaccharides in adult volunteers. J. infwt. Div., infectlons in Bolton. 1971-1977. Lunwt II, 118-120. 111prca Farquhar J. D., Hankms W. A.. DeSanctis A. N., DeMeto & Metzgar D. P. (1977) Clinical and serological evaluation of Glynn A. A. (lY69) The complement lysorymc sequence 111 purified polysaccharide vaccines prepared from ~ei.swritr immune bacteriolysis. /wnww/o~~~ 16, 463-471. t~~~wft~gttttli.~ Group \I’ Pro. SIN c\f~. Rwl ~21~~1155. Glynn A. A.. Bruintitt W. & Howard C. J. (1077) K antigens of ,%heric~hicr w/i and renal involvement in urinary tract 453-45s infections. Luncrt II, 5 14-5 16. Felix A. & Pitt R. M. (1951) The pathogenic and Glynn A. A. & Howard C. J. (lY70) The sensitivity to immunogenic activities of Sa/mone//cr tyth in relation to its complement of strains of &&ri&i~~ c,ofi related to their K antigenic constituents. J. H>,g.. C‘onth. 49, 92-l IO. antigens. fmrnum/o~~~ 18, 331-340. Felton L. D. (I 930) The variables in the mouse protection test Gold R.. Lepow M. L.. Goldschneider 1.. Draper T. L. & of antipncumococcus serum. J. fm0wl. 19. 485-509. Gotschlich E. C. (1975) Clinical evaluation of Group A Felton L. D. (1938) Studies on immunizing substances in and Group c‘ menmgococcal polyaaccharide vaccines in pneumococci VII. Response in human beings to antigenic infants. J. C./M frtw.st. 56, l53&1547. pneumococcus polysaccharides. types I and II. Pub/. Hlth Gold R.. Lepow M. L.. Goldschneider I. & Gotschlich E. C. Rep , U’mk. 53, 1855-1877. (1977) Immune response of human infants to Felton L. D.. Kauffmann G.. Prescott B. &Ottinger B. (1955)

Vaccines Against

Encapsulated

polysaccharlde vaccines of Groups A and c‘ A’eixwitr r,wning;r;cl;.\. J it&c I II;.\. 136, S31-S35.. .I. i,~fwr. Div 136, suppl. S3 I. Gold R. & Lepow M. L. (lY76) Present status of caccines in preventIon of the polqsaccharide meningococcal disease. .-ldv Pcdirrr. 23. 71-93. Gold R. J.. Wmkrlhake L.. Mars R. S. & Artenstein M. S. c1971) Identification 01‘ an epidemic strain ol’ Group C \ CI.~‘TICI wrwinr~~ic/i.\ by bacterlal \erotyplng. J. infwf IIt\ 124, 50%1597. C;~,ld R. J Xr Wyle F. A. (1970) New classification of .~~iv.wr~crwcwirr~rtc/i.\ by means 01‘ bactericidal reactions. /rl/eC 1.Imn1w. I, 4Y7-484. Gotschlxh E. C‘. (IY74) Proposal forcollaborative studies l’or the laboratory cxaluation ol’ meninfococcal polysaccharade vaccine. U’HO Twh. Rep SW. BD CSM) 74. I I. Gotschlxh E. C‘., Rcy M.. Etienne W. R.. Sanborn R.. Triau B. & C‘ce.jtanovic B (1972) Immunological response observed in field studies In Africa with meninyococcal vaccines. Prog Ivvr~~rrfohir~l..C/~rrwl.5, 4X5-90 I. Gotschllch E. c‘.. Rcy M.. Triau R. & Sparks K. (lY77) Quantitative determination of the human immune response to immunization with meningococcal vaccines. J. pe-hpecltic polywxharldea. .I. CY,~I. ,Zlc~/. 82. 303-320. Heldclbcrgcr M. & MacPherron C. l-. c’ (1943~ QuantItatI\c mwo-estimation of antlbodles in the st’ra 01‘ man and other anlmills .SCwhew 97. 405-406. Heidelbergcr M. & Nimmich W. (1971) Additional immunochemlcal relatlon\hips 01‘ capsular pol\iraccharIda 01‘ Klebsiella and pneumococci. ./ I~,I~I 109. 1337-1344

Heldelbcrger M. & Pederwn K. 0. (lY37) ‘lhc moIecuI;Ir acight 01’ antlbodles. .I. of I.‘. ~,r,/i K antigen\ 111 urtnary-tract infection5 in chlldrcn. I_trw~ai I, 663-663. Kaljser B.. Holmgren J. & Hanwn I.. A. ( 1972) The protective effect against L-. w/, of 0 and K antlbodlrs 01’ different immunoglohulin cla\x~ .Swtll/ .I /rrr,~rfiw,/ I. 27-32. Kamme C.. Ageberg M. & Lundgrrn K. (1970) Dl\trlhutwn of Diploc~oc~~u.rp,~c’~rr,rr~,~,~rc’ in acute otitls media in chlldrcn and the influence on the clinical courw in Penicillin \ therapq. S~rorcl. J. i,l/cv t /Iis 2, 18.3-190. Karakawa W. W. & Kane A. J. (1975) It~~munochem~cal analysis of a surfax anttgcn of ;i Smith-llke antiwn lsolatcd from two human \traln\ ol’.Y~rrl~h~l,w~c~cII) awci,.>. .1. fwv~lwl 1IS. 564-568. Kasper D. L., Winkelhake J. L.. Zolltngcr W. I).. Brandt B. Kr Artenstein M. S. (1973) Immunological \tmllarlty bctwcen polysacchsride antIsen\ of &C /wr.ic Iri~r CC)// 07:K I :(N M J and Group B meningococcl. ./ /w,,rwr 1IO. 262-268. Kauffman P. (1947) Pneumonia in old age .-Irr /I.\ i,lcvffl MC,d. 79, 51x-513. Kauffman F., Lund E. & Eddy B. (1960) Pneumococcal nomenclature. Irll Blrli. Utr~/ .Vmrvn ToI IO, 3 l-40. Krishnamurthq T.. Lee c‘. J.. Henrichsen J.. C’arlo D. J.. Stoudt T. M. Kr RobbIns J. B. (1979) (‘har~tcteri/atlon 01 the cross-reactlon hctuccn pneumococcal capsular polysaccharides tyc\ l’)l.( I’)) ;1nd l’JA(57). I Compositional anal>a~s and ~mmun~~lo~~c rclatl~>il dctcrmlncd \\~th rahhit typing antiwr;~ /~I/c,cI //,~,tr~u.. in press. Kurone T.. Peltola H., Not-h T & Mahela P. ti. (1977) Adverse reactIon and cndotou1n con1cnt 01 polysaccharide \accincb. /)(‘I, B/C)/ .Srtrrrr/ 34, I 17-175 Lancefield R. c’.. McC’arty M. & E\rrlJ W. h. (1975) Multiple mouse-protective .Intlbodlc\ dlrcctcd agaln\t group B streptococci. J. c’_\,J .%/CC/.142, 16-l 7’). Lady M. (1954) Studleh on the VI antlgcn VI Immuni/atlon ofhumans wth purified Vi antigen. ..1n1 .I //l,q 60. 52-62 Larm 0. & Lindherg B. (1977) The pncumococcal polysaccharide~, a re-c\lllliin;ltlol1. ic.553, li/\, C‘LI)./IO/I I,(/ Xc\ 34, 295-322. Mawr I>. t.. Lldi\ar h. M.. C;oldin$h 11.. Mend J.. Scher I. Lepow M. L.. GoldschneIder I.. Gold R.. Randolph M. & & Paul W. E. (1077) I-ormatlon ofantibod! In the newborn Gotschlich F. C’. (1977) Pcrsi\tencc of antlhod> follon~ng moux stud! 01’ T-cc11 tndcpendent antIhod> response. ./ immunvatlon of children ulth Group\ A and C’ /,rfrt I Dl\ 1.36.Sl&S10. meningococcal pol)~,uccha~-DDE. Special rcl~rencc to Muf\on M. A. Kru\\ I). hl Wavl R. I:. & Metrger D. antibodles effecttvr against protan antlpcn\. ( 1974) C‘apwlar tqw and outconic 01‘ bacteremla Lenin D. M.. Wang K-tl.. Rcqnold\ tl. \r’ Sutton 4. & pncumococc;~I diw;t;c 111the antihlotic era. .4rci1,in/cwr Northrup R. S. ( 1975) VI antiwn from .S~ri~~uvr~~//~~ II~~I~I~O 24CCl 134. X)5$5 IO. and Immuntt) aguinrt tqphold le\cr. II. Salety and antigenicity in human\. /,7fwr /,rrnrrr,r 12, I X!-I X)4 Lim D . Gewur/ A.. Lint 1 t-.. (I1 heat and phenol. J. ir~/i~c~/. Di.\. 129. 501-506. Wood W. B. (1941) Studies on the mechanlams ofrcco%erv In pncumococcal pneumonia. I. The action of type-specific antibody upon the pulmonar] lehlon of expcrlmental pneumonia. J. c\,>. Merl. 73, 201-222. Wood W. B. & Smith M. R. (1949) The inhlbition ofrurfacc phagocytosis by the capsular slime layer ofpneumococcu? type III. J. c\p MN/. 90, X5-96. U’right J. & Fotherpill L. D. I 1033) Influcwal meningitis. The relation of age to the bactericidal pov,cr of blood against the causal organl\m. J. /~WUWI.24, 273-284. Wqle F. A.. Artcnstein M. S., Brandt B. L.. Tramont t. C Kasper D. L.. Altierl P. L.. Berman S. L. & Louenthal J. P. (1972) Immunologic responses of man to Group B meningococcal polysaccharidc caccincb. J rrrfrc~r.Dt.s. 126, 51+522. Yosliida K. ( 1971) Demonstration of serologlcally diffcrcnt capsular types among straina of .Stcry/~~~/~/c~~,c~~,~~.s NII~UJ by the serum-soft agar tcchnque. /rf/cc,r /ww~~. 3, 535-539. Yount W. J.. Dorner M. M.. Kunkel H. & Kabat E. A. (196X) Studies on human antibodies. VI. Selective variations in subgroup composition and genetic markers. .I. ~a.\-p.Meal. 127, 633-646. Zollinger W. 1). oi Mandrel1 R. E. (1977) Outer-Membrane protein and lipopolysaccharide serotyping of .Vc~ir.veria trrcr~irrgitid.\ by inhlbition of a wlid-phase radiotmmunoassa4. /U/CCI /mr~fwl 18, 414-433.

Vaccines for the prevention of encapsulated bacterial diseases: current status, problems and prospects for the future.

VACCINES FOR THE PREVENTION OF ENCAPSULATED BACTERIAL DISEASES: CURRENT STATUS, PROBLEMS AND PROSPECTS FOR THE FUTURE JOHN B. ROBBINS Bureau of Biol...
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