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Development of serum antibodies of the immunoglobulin G class and subclasses against the capsular polysaccharide of Haemophilus influenzae type b in children and adults with invasive infections

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Copyright© 1988,American SocietyforMicrobiology

Development of Serum Antibodies of the Immunoglobulin G Class

and

Subclasses

against

the

Capsular

Polysaccharide of Haemophilus

influenza

Type b in Children and Adults with Invasive Infections

BO A. CLAESSON,1* TERESA

LAGERGÂRD,2

ANDBIRGER TROLLFORS3

Departments of Infectious

Diseases,'

MedicalMicrobiology,2 andPediatrics,3 University ofGoteborg, East

Hospital,

S-416

85

Goteborg,

Sweden

Received 9 May1988/Accepted 8 September 1988

Thedevelopment of totalimmunoglobulin G(IgG) antibodies and antibodies of the fourIgGsubclasses in serum againstHaemophilusinfluenzatype b capsular polysaccharide (CPS) was studied in 24 children and 11 adults with invasive Haemophilus influenza type b infections, by using an enzyme-linked immunosorbent assay. None of the 8 children aged 10 months or younger had increases in theIgG class or in any of theIgG subclasses. In contrast, 14 of 16 children between 10 months and 6 years of age and 10 of 11 adults had

significant increases in total IgG, IgGl, orIgG2 antibodies invarious combinations, but none of them had increases in IgG3 or IgG4 antibodies. The increases in IgGl and IgG2 antibodies in the childrenwereofsimilar magnitudes.

0f

l1 adult patients, 9 hadsignificantincreasesinIgG2 antibodies,whileonly4 had increases in

IgG1antibodies. In conclusion, this study shows that children younger thanapproximately1year havenoIgG

response to H.influenzaetype bCPS, while individuals above this age haveamixedIgGlandIgG2 response.

Theserumantibodyresponse to thecapsular polysaccha-ride (CPS) ofHaemophilus influenza type b isage depen-dent. Infants show

little

or noincrease inimmunoglobulin G (IgG) antibodies afterinvasive infections, while most

chil-dren older than 1 to 2 years and adults develop an IgG

response (3, 11, 15, 27). The subclass composition of IgG antibodies against H.

influenza

type b CPS and other

bacterial CPSs hasbeencharacterized in vaccinated

individ-uals and shown to be composed of both

IgGl

and IgG2 antibodies (4, 10, 16, 18, 23, 30), incontrast to some other

reports, suggesting thatthe IgG antibodiestocarbohydrate antigensaremainly composed of IgG2 antibodies (2, 24, 35).

The

development of

H.

influenza

type

b CPS antibodies

of

thedifferent IgG subclasses has,to ourknowledge, notbeen

studied in

patients after invasive

H.

influenza

type

b

infections. In the present study, we have analyzed the

antibody responses of the IgG class and the four IgG subclasses, IgGl, IgG2, IgG3, and IgG4, in children and

adults with invasive H.

influenza type

b

infections.

MATERIALS ANDMETHODS

Patients. A total of35patients, 14males and 21females, with invasive H. influenzatype b infections wereincluded

inthe study.H.

influenza

type bwas isolated from blood,

cerebrospinal fluid,

or both in all patients. There were 24

children, aged 3months to 6years (Table 1), and 11 adults,

aged 22 to 64 years (Table 2). Of the children, 18 had

meningitis and 6 hadepiglottitis. One child (patient 1) with

H.

influenza

type b meningitis at the age of 3 months was

born at a gestational age of 30 weeks. None of the other

children had any known condition that would predispose them to infection. Manifestations ofthe infections in the adults are shown in Table 2. Four of the adult patients had

underlying conditions of possible importance as

predispos-ing factors for infection; pregnancy week 35 (patient 25),

alcoholism (patient 26), transient hypogammaglobulinemia (patient 29), and sarcoidosis (patient 32). All patients

sur-*Corresponding author.

vived. H. influenza type b anticapsular antibodies ofthe IgG, IgM, and IgA classesin19ofthechildren(patients1to 15, 17,and19 to21)andfive ofthe adults

(patients

25,29to 31, and 33) have been reportedpreviously (3, 15).

Serumsamplingintervals aredescribedinTables 1 and 2. Serum

samples

were storedat -20°C until analyzed.

Informedconsent wasobtained fromthe adultpatientsor theparentsof the childrenparticipating inthe study, which

wasapprovedby theEthical Committee oftheUniversityof

Goteborg.

Healthyadults. Serum samples from10adult blood donors

were analyzed.

Serological methods. Antibodies ofthe IgGclass and IgG subclasses to H. influenza type b CPS were measured by

indirect enzyme-linked immunosorbent assay (ELISA) (4, 31).Microtiter plates (Dynatech,Novakemi, Enskede,

Swe-den)werecoatedwithbiotinylatedH. influenzatypeb CPS afterprecoatingwithavidin. Murine monoclonalantibodies specific for human IgG (HP6045), IgGl (HP6069), IgG2 (HP6002), IgG3 (HP6050), and IgG4 (HP6025) were kindly

donatedby CharlesB.Reimer, Centers for Disease Control,

Atlanta, Ga. (9, 14). The affinityconstants were similarfor

the four IgG subclass-specific antibodies. The affinity con-stants, Ka- were 7.5 X 107, 6.5 X

107,

5.0 x

107,

and

10.0x

107

forIgGl, IgG2, IgG3, and IgG4, respectively (21). The

reactivities and specificities of the monoclonal antibodies werereverifiedby titration (ELISA) with myeloma proteins

ofkappa and lambda light chains, representing each sub-class. The myelomaproteins were kindly donatedby Rich-ard Wistar (U.S. Naval Medical Research Institute,

Be-thesda, Md.) and Peter Schur (Harvard Medical School, Boston, Mass.). Peroxidase-conjugated rabbit immunoglob-ulin to mouse

immunoglobulin,

adsorbed with human

immu-noglobulin (Dakopatts, Copenhagen, Denmark), wasusedin all assays. The optimal concentrations ofmonoclonal anti-bodies and

conjugates

were tested by checkerboard titra-tions.Antibody concentrationsareexpressed as the negative

loglo

value of the highest serum dilution showing an extinc-tion of 0.5 (IgG) or 0.2 (IgG subclasses) above the

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TABLE 1. TotalIgG, IgGland IgG2serumantibodies against

H.influenza typebCPS in children withinvasive infections

Age No. ofdays

patient Disease (o afteronset

(mo) of

1 Meningitis 3 1

13

2 Meningitis 3 1

8 17 38 103

3 Meningitis 3 3

33 75

Antibodylevel'

IgG IgGl IgG2

<1 <1 <1 1.0

<1 <1 <1 <1 <1

<1 <1 1.1

4 Meningitis 4 0 <1

10 <1

5 Meningitis 6 1 <1

10 <1

16 1.0

<1

<1

<1 <1 <1 <1

<1 <1 <1

<1

<1

<1 <1 <1

<1

<1 <1 <1

<1 1.0 <1 <1

<1 <1 <1 <1 <1 1.0

6 Meningitis 7 2 <1 <1 <1

10 1.2 <1 <1 18 <1 <1 <1

7 Meningitis 9 0 <1 <1 <1

8 1.0 <1 <1

8 Meningitis 10 2 1.1

24 1.1

120 <1

9 Meningitis il 0 <1

8 1.7

15 1.9b

30 1.8b

10 Meningitis 13 2 1.5

26 1.3

il Meningitis 19 0 <1

5 1.8b

10 2.4b

12 Epiglottitis 20 0 <1

6 1.2

23 1.2

13 Meningitis 22 4

il 17

14 Meningitis 23 1

9

23

15 Meningitis 26 0

29

168

16 Meningitis 32 3

10

17 Epiglottitis 35 4

6

39

<1 <1 <1

<1 1.1 1.0

1.4

1.4 1.2

<1

2.9b

2iéb

3.1"

<1 1.2

1.8b

1.8 <1 1.8 1.4

2.1 1.1

2.0 1.5

2.4 1.7

1A ')d;b

1.5 2.7b

2.3b

1.8

1.9

1.8

2.3 2.2

<1

2.

2.

1. 1.

2.

2. 3.

<1 <1

<1

<1 <1 <1

1.0

<1 <1

<1 <1 <1

<1 <1 1.1

<1 1.8b

1.8b

<1

1.5b , lb

TABLE 1-Continued

Age No.ofdays Antibody level'

Patient Disease

(ge)

afteronset

ofsymptoms IgG

IgGl

IgG2

18 Meningitis 35 1 1.5 <1 <1

6 1.7 <1 <1

il 1.7 1.0 <1

32 1.7 1.5 <1

19 Meningitis 37 0 1.6 1.8 2.0

23 2.1 2.1 2.8

20 Epiglottitis 50 0 1.6 <1 <1

2 2.0 1.2 2.6b

16 3.2b 2.7 3.3

21 Epiglottitis 56 0 1.5 <1 <1 2 1.5 <1 <1

14 2.0 1.4 1.5b

22 Epiglottitis 70 1 1.4 <1 <1 7 1.5 <1 <1

28 1.9 2.3 3.0

91 1.9 2lb 3 ob

23 Meningitis 73 2 1.5 1.0 1.1

17 3.0b 2.4b 2.7b

24 Epiglottitis 74 1 1.2 1.6 <1

6 2.3 2.4 3.0

aForunits of antibody levels, see Materials and Methods.

bSignificant increase compared with the firstserumsample.

ground. Values below 1.0 (correspondingtoaserumdilution

of1:10) are considerednegative. The U.S. Food and Drug

Administration (Bethesda, Md.) immunoglobulin standard forIgG (170 ,ug/ml)was usedasthe reference in allassays.

Inourassays,thevalues for theIgG fraction were4.0, 2.6,

3.6, 1.3, and 1.6 for total IgG, IgGl, IgG2, IgG3, and IgG4, respectively. Apostvaccination serum sample froma child

vaccinated with H. influenza type b CPS conjugated to tetanus toxoid (4) was used as a second standard. This

sample had titers of 6.0, 5.0, 2.5, 1.6, and 1.8 for total IgG, IgGl, IgG2, IgG3, andIgG4, respectively. In thetwo

previ-ous reports of H. influenza type b anticapsular serum

antibodies in some of these patients, antibodieswere

mea-sured by direct ELISA (3, 15). Values of IgG antibodies measured by direct and indirect ELISAagreed well. Indirect ELISA was used hereto determine total IgG because IgG subclasses are determined by indirectELISA. An increase in total IgG, IgGl, IgG2, IgG3, or IgG4 antibodies of0.6 (fourfold)wasconsideredasignificant antibodyresponse(3).

RESULTS

Children. None of the 8 youngestchildren, aged 3 to 10

1 o

months,

had

significant

increases in

IgG

antibodiesor inany

4b 2b2" of the four

IgG

subclasses

(Table 1).

Only

seven serum

.2b 2.2b samples had detectable levels of IgG antibodies, and only

twoserumsampleshad detectable levels ofIgG2antibodies.

.3 <1 None haddetectableantibodies of the IgGl, IgG3, and IgG4

.4 1.2 subclasses.

Of the16olderchildren,aged 11monthsto6years(Table o0 <1

*8b

24"

1),

14

developed

significant

increases inatleastone

antibody

*2b

3.1b isotype. Specifically, 6 of the older children had

increases

in

*______

* total

IgG

antibodies,

10 had increases in the

IgGl

subclass,

Continued and10 had increasesin theIgG2 subclass;7hadincreasesin

Pi

Z.4 Z.

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both IgGl and IgG2. The youngest child with a significant increase in total IgG antibodies was 11 months old, and the

youngest children, who developed significant increases in IgGl and IgG2 antibodies, were 19 and 22 months old, respectively. Increases in total IgG, IgGl, and IgG2 antibod-ies which did not reach the level of significance in the

individualpatient were seen in nine, five, and three children, respectively, while only one child (patient 10) had slightly

decreasing IgG and IgGl antibodies. In one of the two

children who did not develop significant increases in IgG,

IgGl,or IgG2antibodies (patient 16), the timing of the serum samples was not optimal.

In the last serumsample from patient 15, a low level (1.2)

of IgG3 antibodies was detected, and in the last serum sample from patient 20, low levels (1.1 to 1.3) of IgG3 and IgG4 antibodies were detected. None of the other serum

samples from the children had detectable IgG3 or IgG4

antibodies.

Adult patients. Ofthe 11 adult patients, 7 had significant

risesintotal IgG antibodies(Table2). Only4of11adults had

significant increases in antibodies ofthe IgGl subclass, while 9had significantincreases in the IgG2 subclass. All patients, who responded in the IgGl subclass, also had significant

tises inthe IgG2 subclass. Patient 33 had nosignificant rises intotal IgG antibodies or in any IgG subclass but showed a

good response inantibodies oftheIgA and IgM classes(15).

Whenevaluatingtheantibodyresponse in the adults, it must be noted that the first serum sample available was obtained 5to 6days afterthe onsetofsymptoms in three adults. From theinitial valuesforpatient 31, theremightwell have been a responsein both total IgG and IgGl antibodies. None of the serum samples from the adult patients had detectable

anti-bodies ofthe IgG3 and IgG4 subclasses.

Healthy adults. All 10 adult blood donors had detectable

anti-H. influenza type b CPS antibodies of the IgG class

(median value, 1.3) andof theIgG2 subclass(median value, 3.1), but only 5 of 10 had IgGl antibodies (median value, 1.0). IgG3 and IgG4antibodies could not bedetected inany

of these sera.

DISCUSSION

Serum levels ofthe four IgG subclasses are age

depen-dent. Afteraninitial decline inantibodies ofmaternalorigin

inallfour IgGsubclasses duringthefirst 3 months, agraduaI increase is seen after this age. IgGl antibodies increase

rapidly, reaching levels comparable with adult levels at the age of3 to 4years, while IgG2 antibodies, although present inchildren fromtheageof3 months, increaseslower and do not reach adult levels until about the age of 12 to 14 years.

IgG3 and IgG4 antibody levels increase with age but are much lower thanIgGl andIgG2 antibody levels throughout life (19, 20, 28, 29, 33).

IgG antibodies against carbohydrate antigens have been

considered toberestricted to the IgG2 subclass in adults (8, 24, 35), which is supported by one report of adults

immu-nized with pneumococcal CPS, in which the antibody re-sponses were mainly in IgG2 and to a lesser extent in IgG3, butnot inIgGlantibodies (2). Other

studies

have, however,

shownthathealthyadults have bothIgGlandIgG2 antibod-ies against pneumococcal CPS (7) and children predomi-nantly have IgGl antibodies (7, 8), which agrees with a report showing that adults immunized with pneumococcal

CPS responded with both IgGl and IgG2 antibodies (16). Also, inadults immunized with the CPS ofNeisseria

men-ingitidisgroup A, a mixedIgGland IgG2response was seen

(23).

TABLE 2. TotalIgG, IgGl, and IgG2 serum antibodies against

H.influenzatypebCPS in adults with invasive infections

Age No. ofdays Antibody level

Patient Disease Age after onset

(yr) of symptoms IgG IgGl IgG2

25 Meningitis 22 2 1.0 <1 <1

Sinusitis 57 2. lb 17b 20ob

26 Pneumonia 24 6 <1

41 1.3

27 Epiglottitis 25 1 1.2

12 2.6

37 1.6

44 1.3

28 Epiglottitis 29 0

3 6

29 Epiglottitis 29 1

4 20 150 171

30 Epiglottitis 31 2

s

15

31 Meningitis Sinusitis

32 Meningitis Phlegmon

33 Sinusitis

1.2 1.gb 1.8b

1.0

1.gb 3.1" 3.Ob

1.2 1.1

2.1b

43 6 2.3

13 2.0

19 2.2

27 1.9

64 1.7

91 1.7

44 4 1.2

94 3.0"

46 5 1.2

10 1.2

21 1.2

53 1.2

<1 <1

<1

1.gb

1.4 1.3

1.4

2.8b 2.9b

1.0 2.2b 3.Ob

3 Ob

3.2b

<1

<1

<1

1.7

1.7 1.5 1.3 <1 <1

<1 <1

<1 <1 <1 <1

<1

2.1b

<1 3.3b 3.3b 3 BOb

1.0

3.3b

3.1"

<1 1.0

3.4b

3.5b 3.3b

<1 1.0 1.4

2.0 2.1

2.2

2.1 2.7b 1.5

<1 2.5b

<1 <1 <1 <1

34 Pneumonia 48 4 <1 <1 <1

7 1.5b <1 2.4b

35 Meningitis 64 4 <1 <1 <1

Pneumonia 12 1.1 <1 1.5"

17 1.4 <1 1.6

53 1.2 <1 1.2

"Forunits of antibody levels, see Materials andMethods.

bSignificant increasecompared withthefirstserumsample.

Only limited data are available concerning the IgG sub-class distribution of naturally acquired anti-H. influenza

typeb CPS antibodies (5, 22). Most ofour knowledge on the human IgG response to H. influenza type b CPS is derived fromimmunization studies using purified H. influenza type b CPSalone or conjugated to a protein. After immunization of adults with H.influenza type b CPS alone or conjugated to a carrier protein, antibodies have been shown to be of both the IgGl and IgG2 subclasses (10, 18, 30). In 18- to 23-month-old children immunized with the pure H. influ-enzae type b CPSaloneorconjugated to tetanus toxoid, the antibody responses were mainly in the IgGl subclass (4). In this and other studies, the antibody responses toconjugales have been more pronounced than the responses to pureH.

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influenza type b CPS in both children and adults, but the differences are more quantitative than qualitative (4, 18, 30). IgG3 and IgG4 antibodies have been considered to be oflittle importance for the total IgG response to polysaccharide antigens (2, 4, 7, 8, 18, 23, 24, 35), but results from one study, comparing convalescent-phase-serum antibodies of children with invasive H. influenza type b disease with

antibodies ofa control population, suggested that specific anti-H.influenzatypeb CPS IgG4antibodies mightdevelop

afterinvasiveH.

influenza

typebdisease (22).

Thepresentstudy shows that theyoungestchildren donot

develop IgG antibodies against H.

influenza

type b CPS after invasive infections. None of the 8 children aged 10

monthsor youngerhadincreases in total IgG antibodiesorin

any of the four IgG subclasses. These results agree with

studies of children who showed little or no IgG response,

when

vaccinated with H.

influenza

type b CPS

before

the

age

of 1

year (12, 13, 17).

H.

influenza type b CPS,

like

other CPSs, are considered to be T-cell-independent

anti-gens, towhichyoungchildren usuallyhave a poorantibody

response(25, 34). Onlywhen the H. influenzatype bCPS is conjugated to a protein does there seem to be an antibody

responseinIgGantibodiesinchildren under1yearofage (1,

6, 12, 17), since conjugation ofH. influenza type bCPSto

a

protein

confersT-cell-dependentpropertiestothe

polysac-charide component (26, 34).

In the children between 11 months and 6 years studied here, therewasusuallya mixed

IgGl

andIgG2responseof similarmagnitude. Of16children, 7hadsignificant increases in both

IgGl

and IgG2 antibodies, 3 had increases in IgGl antibodies alone, and another3 had increases only in IgG2 antibodies. The number ofpatients studied is too small to

allow for comparisons of the responses in different age groups. Sincemanychildrenwith nosignificant increasesin

IgG,

IgGl,

or IgG2 antibodies already haddetectable

anti-bodies of these isotypes in the first serum sample, it is

possible

that they had developed an antibody response,

which couldhave been detected withsome othertiming for

the

collection ofserumsamples. This mixed

IgGl

and IgG2

response is incontrastwiththeviewthatantibodiestoCPS

antigens

are restricted to the IgG2 subclass (2, 24, 35) but

agrees well with studies of children and adults vaccinated withdifferent CPS vaccines (4, 10, 16, 18, 23, 30).

In the adults, on the other hand, the IgG2 response seemed tobemore pronouncedthan the

IgGl

response. Of

11 adults, 9 had increases in IgG2 antibodies, while only4 hadincreases in

IgGl

antibodies. Oneadult(patient 33)had noincreases in anyofthefour IgG subclasses and had low

levels of total IgG antibodiesin severalconvalescent-phase

sera, but increases in IgM and IgA antibodies have

previ-ously

been demonstrated in this

patient (15).

The more

pronounced IgG2 responsein theadult

patients

agreeswith

the subclass distribution ofthe IgG antibodies

against

H.

influenza

type b CPS in the blood donors studiedhereand

in pregnant womenstudied

previously

(5). Inbothgroupsof healthy adults, more individuals were found with anti-H.

influenza

type

b

CPS

IgG2

than with

IgGl

antibodies.

Concerning

the

antibody

response

against

H.

influenza

type

bCPSin adultsafter invasive

infections,

itmustbe

pointed

outthatinvasiveH.

influenza

type b infections in adultsare rare (32), and that the infected individuals

might

have an abnormal immune response.Ofthe 11adults described

here,

4 had

underlying conditions,

which

might

have

changed

or

altered theantibodyresponse.

In thepresentstudy, therewas noevidence that

IgG3

and

IgG4

antibodies

play

an important role in the

antibody

response afterinvasive H.influenzatype b infections in any age group,which is in contrast to a previous study, suggest-ing that IgG4 antibodies against H. influenza type b CPS

develop in

children

after invasive H.

influenza

type b disease (22). In a study of children vaccinated with H.

influenzatypeb CPS aloneorconjugatedto tetanustoxoid,

therewas no increase in IgG4 antibodies and only a slight increase in IgG3 antibodies (4).

Inconclusion, infants below approximately 1 yearofage have no response in total serum IgG antibodies or in any of thefour IgG subclasses after invasive H. influenza type b infections. Childrenabove this age have a mixed IgGl and IgG2 response of similar magnitude. In adults, the response in IgG2 antibodies seems to predominate over the IgGl

response.

ACKNOWLEDGMENTS

This workwassupported by grants from the Petter Silfverskiold MemorialFoundation, theWilhelm and Martina Lundgren Founda-tion for Scientific Research, and the Faculty of Medicine, University ofGoteborg, Goteborg, Sweden.

WethankCharlesB.Reimer forproviding monoclonal antibodies, John B.Robbins and Rachel Schneerson for valuableadvice, and Marianne Svensson for skillful technical assistance.

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