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THE RESPONSE OF PREMATURE INFANTS TO INFECTION WITH ATTENUATED POLIOVIRUS

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N EWBORNINFANTS, especially those born prematurely, are thought to be more susceptible to infection than older infants. Although there are only a few recorded ob servations of virus infections in newborn premature infants, both unusually severe and inapparent infections assuredly do oc cur.'-4

The development of attenuated strains of poliovirus as vaccines made available agents that could be used for the induction of experimental enteric virus infections, so that it became possible to explore system atically ways in which premature infants are infected with poliovirus and their sub sequent immunologic responses.5 This study, which complements our observations in full-term infants,68 focuses on the neo natal period, for it is in early life that physi ologic anomalies such as transitory hypo gammaglobulinemia and deficient immuno logic responses seem to occur.9'1°

Consequently we have studied the re sponses of premature infants to infection with living attenuated poliovirus vaccine soon after birth.@'@4 By showing that pre mature infants are readily infected with poliovirus, we were able to infer that the tendency to resist infection with attenuated poliovirus that occurs transiently after birth in some full-term infants is probably not due solely to immaturity of the intestinal receptor cells.7 Also presented here are ob servations on the rate of decay of trans placentally acquired poliomyelitis anti bodies and their influence on the response to attenuated virus in premature infants. Finally, the state of immunity induced by

the feeding of attenuated virus as tested by the re-exposure of infants to the same virus is examined.

METHOD OF STUDY

Subiects; Attenuated Poliovirus

The study was carried out in the nursery for premature infants at the Philadelphia General Hospital between January, 1959, and April, 1960. Sixty-five premature in fants, ranging in weight from 879 to 2,220 gm, were given 5.7 log,0 tissue-culture in fectious doses50 (TCID50) of CHAT type 1 live poliovirus vaccine (Koprowski) by ga vage with each infant's formula on the third day of life.15 The infants received a variety of artificial and natural foods, and none was breast-fed. All but two of the infants weighed less than 2,000 gm at birth. Seven teen infants with birth weights of 1,191 to 1,900 gm were not given virus and were retained as a control group. Infants were studied for the duration of the hospital stay (4 to 10 weeks) and in the outpatient clinic thereafter up to the age of 6 months. In a few cases additional studies were done 8 to 20 months after birth.

Specimens

Specimens of feces collected twice weekly in the hospital and kept at —¿20°C were tested in monkey-kidney tissue-culture cells for cytopathogenic effect; viruses isolated from the feces were identified by type specffic neutralization tests.16

Blood specimens were taken from the umbilical cord at birth and by heel punc ture at monthly intervals up to 4 to 6 This investigation was supported in part by a PHS grant (E-1799) from the National Institute of

Allergy and Infectious Disease, U. S. Public Health Service.

ADDRESS; (J.S.P.) Institutionen for Virusforskning, Karolinska Institutet, Box 764, Stockholm 1, Sweden.

PEDIATRICS, May 1962 794

THE RESPONSEOF PREMATUREINFANTS TO INFECTION

WITH ATTENUATEDPOLIOVIRUS

Joseph S. Pagano, M.D., Stanley A. Plotkin, M.D., Donald Comely, M.D., Walter Leuterer, M.D., and Hilary Koprowski, M.D.

(2)

Infant

NumberBirth Weight (gm)Virus

in Feces

(days)Cord-Blood

Antibody

TiterPost-vacdnationAntibody

Titers*21198522+<8<8(4)32(14)32(2)..3299040832

(4)32 (3)32 (4)32

(44)701892Ot12832(1)<8(14)<8(24)<8(4)27185024+<8<8(1)..<8(3)<8(5)79124713+<8<8(1)<8(2)..<8(44)

months after birth. Neutralizing antibody

titers were determined in pairs of sera from each infant in a modffied immune-inactiva tion test.7 Titers of 8 (i.e., %; reciprocals of the serum dilutions are used throughout) or more were considered significant.

Twofold or greater increases in titer were counted as positive antibody responses; in fants in whom the antibody titer decreased to and remained <8 were considered to have a negative response; other post-vacci nation antibody patterns were called equiv ocal. This classification of responses was selected to circumvent the difficulties of interpretation arising from the presence of transplacentally acquired antibodies in most of the infants.

Re-administration of Attenuated Poliovirus

Thirty-one infants selected at random

were given a second feeding of the same dose of CHAT virus (5.7 log TCID50) 2 to 5 months after the first administration; four stool specimens were collected at home during the 2-week period after the re administration of virus. Three infants were given a third dose of CHAT virus after a further interval.

RESULTS

General Observations

Sixty-five infants were given CHAT type 1 living attenuated poliovirus; most ex creted the virus in the feces, and all of them did so without symptoms and with out evidence of transmission of the virus

to the four unvaccinated infants in adjoin ing bassinets from whom feces were col lected twice weekly. Morever none of the unvaccinated control infants had an in crease in antibody titer, and fecal speci mens obtained from infants before they

were fed the virus were without cytopatho genic effect.

In Table I typical responses to the virus feedings are shown. Infant 21, given CHAT virus on the third day of life, began to

excrete poliovirus within 2 days and was

still excreting the virus at the time of dis charge from the nursery 22 days later. Al though no antibody response was evident one-half month after birth (titer of <8), within 1% months the type 1 antibody titer had risen from the cord-blood level of <8 to 32. Infant 32 also was readily infected, excreting virus for some 6 weeks, despite the presence of homotypic transplacentally acquired antibody in low titer (8) at the

time of the virus feeding. There was a

prompt immunologic response in this in fant, the titer increasing in less than a month from 8 to 32, where it was main tained up to 4%months.

Infant 70 was not infected, and the de crease in titer of antibody of maternal ori gin from 128 to 32, then to <8, was as

expected. Infants 27 and 79 provide ex amples of a dissociation between infection

and antibody response, in that these in fants were infected and excreted poliovirus for more than 13 and more than 24 days, respectively, without, however, at any time

TABLE I

TYPICAL PATTERNS OF INTESTINAL INFEcTION AND ANTIBODY RESPONSES IN PREMATURE INFANTS

GIVEN CHAT ATTENUATED POLIOVIRUS ON THE THIRD DAY OF LIFE

*Months after birth in parentheses.

(3)

Frequency of Intestinal infection after Feeding of VirusFrequency

of Antibody Response in the Infected and NoninfectedinfantsAntibody

Response-Outcome

No.Infants

TestedPositiveNegative

—¿Equivocal%No.%

No. %

Birth WeightInfants InfectedDuration

of Es cretion of Virus

in Feces(gin)—-No.

%Mean* Range

(wk) (wk)980—1,2009/9

10044(5) 2—61,201—1,80029/31

9444(11) 2—71,801—2,10020/23

8734(10) 14—9

796

PREMATURES AND POLIOVIRUS

TABLE II

INFECTION AND ANTIBODY RESPONSE WITH CHAT VIRUS IN PREMATURE INFANTS

Infected 59 92 22 59* 15 41* 18t

Not infected 5 8 0 0 4 100 1

Total 64 100 .. .. ..

* The denominators for these percentages are the 37 infants with either positive or negative antibody responses. Positive, negative, and equivocal antibody responses are defined in the text.

t In four additional infected infants the antibody titers were not determined. showing an antibody response when tested

Up to 5 months after birth.

In 92% of the infants the multiplication of poliovirus was induced, as evidenced by re

peated isolations of type 1 poliovirus from

fecal specimens beginning within a day of virus feeding (Table II). Only five infants (8%) were not infected; from one of them Coxsackie B-5 virus was isolated (courtesy of Dr. Klaus Hummeler, Children's Hos pital of Philadelphia). As indicated earlier, an antibody response did not necessarily

follow infection; among the infants who

excreted poliovirus only 59% had a definite detectable antibody response (Table II). Finally, 18 infants were infected but had neither a significant increase or decrease in titer during the time they were studied; their responses were considered to be equiv ocal (Table II).

Birth Weight and Multiplication of Virus There was no notable relation (Table III) between birth weight and the multiplica tion of attenuated poliovirus in the intes tine, as indicated by the similar percentages of infants that were infected in each weight group and by the duration of excretion of virus in the feces. Excretion regularly began within 1 or 2 days after administration of the vaccine and continued for an average of about 4 weeks regardless of the size of the infant.

Transplacentally Acquired Poliomyelitis Antibodies

Eighty-six per cent of the infants had significant levels of homotypic antibodies (titers of 8 to 512 or more) at birth. There was no obvious relation between birth

weight and the antibody titers in the cord blood of the infants (Table IV). The 78

infants ranged in weight from 980 (approxi

mately the seventh fetal month) to 2,100 gm; the distribution of titers in the cord blood sera of the infants at the time of birth appeared to be a random one. Lacking the ratio of the maternal to cord-blood antibody titer, we could not tell whether the size of

the infant determined the amount of anti body transferred to it.

TABLE III

BIRTH WEIGHT AND INTESTINAL INFECTION

WITH CHAT VIRUS

(4)

Birth Weight

(gm)Infants Tested

(no)Cord-blood

Antibody Titer (Type 1)512—9156128—6@

32—168—<8Number

of Infants980—1,200902

251,201—1,80041138

1191,801—2,1002888 48Total782118

1722*

Type

AntibodyPaired Serum

Determinations

(no.)AntibodyHalf-lifeRange(days)GeometricMean (days)I337—6826II398—5822III325—5620Total1045—6823 TABLE IV

DISTRIBUTION OF TRANSPLACENTALLY ACQUIRED POLIOMYELITIS ANTIBODIES AT BIRTH ACCORDING TO BIRTH WEIGHT

* Eleven with titers of <8.

life estimated from cord-blood sera paired with sera taken more than 101 days after birth equaled 35 days (Table VI).

On the other hand, there appeared to be no relation between the initial antibody titer and the rate of decline of the anti bodies (Table VII). The mean half-life of poliomyelitis antibodies of maternal origin was about the same (21 to 25 days) in infants with high, low, and intermediate cord-blood titers. There was no relation be tween birth weight and antibody half-life.

Transplacentally Acquired Antibodies and Infection

Almost all the infants were infected with the attenuated virus despite the presence of circulating homotypic poliomyelitis anti bodies (Table VIII). The extent of multipli

TABLE V

HALF-LIFE OF TRANSPLACENTALLY ACQUIRED PoLIo MYELITIS ANTIBODIES IN PREMATURE INFANTS

Half-life of Transplacentally Acquired Antibodies

We estimated the rate of decline of the three types of poliomyelitis antibodies in the unvaccinated infants, as well as of type 2 and type 3 antibodies in the infants who had been fed the type 1 CHAT virus. Anti body decay was expressed in terms of half life derived from paired sera—the cord blood and one or more later specimens from the same infant by dividing the num ber of days between the paired determina tions by the number of twofold drops in antibody titer. There were 104 paired deter minations in infants examined up to 220 days after birth (Table V); 56 were in the unvaccinated control infants (Table VI).

(5)

Interval after Birth

(days)GeometricMeanAntibody

Half-life,in Days,by Type*1

—¿__________________11 —¿__________________111I, II,illVacc.Unvacc.Vacc.tUnvacc.Vacc.fUnvacc.All15—40

41—70

71—100

>101

All..

.. .. .. ..15

(5)

24 (9) 22 (7)

41(12)

2613

(5)

22 (4) 26 (8)

27 (7)

2214

(5)

30 (4) 25 (4)

38(2)

2215

(9)

22 (3) 23 (9)

32 (3)

2010

(4)

30 (1) 48 (2)

55(1)

2118

25 25

35

23

Cord-blood Antibody

Titer*Infants

Infected

-% No.Duration

of Excretion of Virus in FecesMean

Range (wk)@ (wk)

512—256t9313/148(5)14—7128—648012/155(6)3—932—169212/134(4)14—68—<810018/1834(8)2—7

Cord-blood

Antibody TiterDetermi nations

(no.)Geometric

Mean

Antibody Half-life

(days)2,048—1,0241321512—2563924128812164—32142216—8625Total10323

TABLE VI

HALF-LIFE OF TRANSPLACENTALLY ACQUIRED POLIOMYELITIS ANTIBODIES AS DETERMINED AT INTERVALS AFFER BIRTH

* Number of determinations in parentheses.

t With type 1 only.

cation of the attenuated poliovirus in the intestine, as indicated by the duration of virus excretion, did not seem to be influ enced by the pre-existing antibody titer. Infants with the highest titers encountered (512-256) had a mean duration of excretion of about 3 weeks, and infants with the low est titers (8- <8) excreted virus for 3% weeks on the average. The mean duration of virus excretion in infants with intermediate titers (128-16) was not significantly greater than this, and the range of excretion encountered in individual infants was similar in each group. The one infant with an extremely high prevaccination titer (2,048) was in fected.

Transplacentally Acquired Antibodies and Antibody Response

Antibody responses to infection with the

TABLE VII

LACK OF RELATION BETWEEN CORD-BLOOD TITER OF TRANSPLACENTALLY ACQUIRED ANTIBODIES

AND THEIR RATE OF DECLINE

attenuated virus occurred in infants with relatively high prevaccination antibody titers as well as in those with low titers of maternal antibodies (Table IX). Perhaps the higher prevaccination titers tended to have an inhibitory effect on active immuno logic responses, but no clear demarcation was apparent, possibly because many re sponses had to be classed as equivocal. Most of the infants with high cord-blood antibody titers and few serial antibody de terminations may well have had masked antibody responses.

Antibody Response to Infection

There were three categories of antibody responses in infants who were infected after

TABLE VIII

LACK OF INFLUENCE OF TRANSPLACENTALLY ACQUIRED ANTIBODIES ON INTESTINAL INFECTION

* Type 1 titers before vaccination.

f Includesone infant with cord-bloodtiter of 2,048 that excreted virus for 14 weeks.

(6)

Cord-blood

Antibody

Titer5infants (no.)Antibody

Response after Infection

Positive Negative Equivocal

(no.) (no.) (no.)512—256131

2t 10128—64123

3 632—16128

2 28—<81810

7 1

Antibody ResponseAntibody

Titer

.

before Vaccination5.

.

Antibody Titer aft.er *

VaccinationAge

in Months01284-6Positivet

Negativef18

(22)

29(14)83

(17)

9(12)32

(14)

9(5)32

(10)

6(7)15

(14)

5(12)Unvaccinated

Equivocalf91

(17)

166 (18)26

(10) 68 (17)30

(10) 50 (3)10

(12) 40 (3)10

(12)

..

TABLE IX

TRANSPLACENTALLY ACQUIRED ANTIBODIES

AND ANTIBODY RESPONSE

equivocal had the highest mean cord-blood antibody titer of the three groups (166); in these infants there was a decrease in anti body titer that apparently continued for at least 3 months, but because of the high initial titers and the brief follow-up the eventual outcome was not resolved.

Later Antibody Determinations

Six infants were available for the deter mination of antibody levels 8 to 20 months after having received CHAT virus (Table

XI). The two infants who were not infected

(Infants 9 and 10) had no detectable type 1 antibodies 10 to 15 months later. The other four infants all had significant titers, ranging from 8 to 128, 8%to 20 months later. Infant 53 had been classed as having an equivocal antibody response because the titer had decreased from 128 to 32 in 3% months. However, the antibody titer at 11 months was still 32, when it should have decreased to <8. This indicated that an active immunologic response, probably to the vaccine, had indeed taken place but had been masked by the passively acquired antibodies; coincidental natural infection could not be excluded in this case. Infant 7 was the only infant in the entire series in whom the antibody titer, once having fallen to <8 (4 and 4% months after birth), later increased to significant levels (8 and 128).

TABLE X

* Type I titers before vaccination.

t Oneinfanthada cord-blood

titerof2,048.

receiving attenuated poliovirus: those with a positive response, those with no response detectable, and those with an equivocal response (Table X). In infants with a posi tive response the geometric mean antibody titer increased from 18 to 33 one month after feeding of the virus, remained at the same level for 2 or more months, and then declined somewhat. In contrast, the titers of infants with a negative response had de clined by two-thirds (from 29 to 9) after a month, a decline comparable to that in the control infants who were not fed the at tenuated virus (from 91 to 26). The mean titer in infants without an antibody re sponse decreased to a low level (6) by 3 months. Infants in whom the response was

MEAN ANTIBODY TITERS BEFORE AND AT INTERVALS AFTER VACCINATION

AT BIRTH AND IN UNVACCINATED INFANTS

* Geometric means; titers of <8 taken as 4 (number of determinations in parentheses).

(7)

Cord-blood Antibody

TiterInfected

after Post-vaccination Antibody Titers at Intervals after Birth* Feeding

800

TABLE XI

LATER ANTIBODY DETERMINATIONS

128 (1)

32(14) 32(14)

64(1)

5 512 Yes

53 128 Yes

7 64 Yes

38 <8 Yes

10 128 No@

9 128 No

128 (20)

32 (34) .. 32 (11)

8(3) <8(4)f 8(5l) 128(184)

8(84) <8(15)

<8(10) .. <8(14)

* Months after birth in parentheses.

t <8 also at 4@months.

@ Infected naturally with Coxsackie B-S virus.

Diet

The infants were assigned various diets at random (as part of a project of Paul Gyorgy, @s'I.D.,and Walter Omans, M.D.) with, in general, either a high (4.2%) or a low (1.5%) protein content. Although the diets have quite different effects on the pH and the bacterial flora of the bowel,hi no obvious differences were observed in the rates or duration of viral infection in the infants receiving the various diets. Nor did the diets seem to affect the capacity to form antibodies.

RE-ADMINISTRATIONOF ATFENUATED VIRUS

The Immunized Infants

Twelve infants who responded to pri mary infection with CHAT virus with a significant increase in antibody titer were re-fed CHAT in the same dose 2 to 6 months later (Table XII). The majority (In fants 28, 32, 39, 44, 55, 100, & 101) ap peared to be relatively resistant to re-infec tion. Re-infection, when it did occur, was of variable duration—usually brief—and often stimulated an increase in the existing anti body titer. However, there were only two clear instances of apparently complete re sistance to re-infection with this dose of virus (Infants 32 & 39), for even two of the infants in whom virus was not detected in the feces (Infants 55 & 101) must have been re-infected transiently, as indicated by the increase in antibody titer in each of them.

The Uninfected Infants

Table XIII shows that only three of the five originally uninfected infants were in fected after the second feeding of CHAT virus 2% to 15 months after birth, and only one (Infant 10) was successfully immunized. This group seemed to be both resistant to infection and to form antibodies poorly. After a third feeding of CHAT (Table XIV) one of the infants (Infant 15) again re mained uninfected, and one of them (Infant 49) was at last infected.

Lack of Re-infection Soon after

Primary Infection

Two infants (Table XV) were re-exposed to CHAT virus soon after the termination of the primary infection with CHAT at about the time (age 2 months) the infants had reached the chronologic equivalent of full-term infants. Despite the low anti body titer (8) at the time of the second ex posure to CHAT, in neither infant was de tectable infection or an increase in antibody titer induced. Infant 82 was given a third feeding of CHAT when it was 8 months old (Table XIV). It then appeared to be fully susceptible to infection, responding with the formation of antibodies (titer of 128) just as did the infants described in Table XVI.

Immunologic Tolerance

(8)

First Feeding5Second FeedingCord-blood

Virus

Infant Antibody

Number Antibody in Feces

Response Titer (days)Antibody

Virus

Antibody Titer Age

Titer before in Feces

after Re-feedingf (mo) Re-feeding

(days)28

<8 13 Yes

32 8 40 Yes

39 512 28+ Yes

44 128 22 Yes

55 128 62 Yes

66 <128 22+ Yes

77 32 16+ Yes

84 <8 30+ Yes

87 <8 26 Yes

91 8 30+ Yes

100 8 30 Yes

101 32 36 Yes5

8 4 1918(917)

45 32 0 391(48,75,270)

8 (118)

55 32 0 32(21)

34 1918 4 91,048(69)

512 (96)

3 1918 0 5191(50)

4 8 14+ 32(43)

5 8 12+ 8 (30)

4 32 15+ 128 (120)

5 8 8+ 128 (80)

6 128 4+ Not obtained

2 <391 0 8(28,58)

5 1918 0 5191

(110)*

Third day of life.

t Days in parenthesis.

TABLE XIII

RE-EXPOSUREVIRUSFirstOF INFANTS RESISTANT TO PRIMARY INFECTION WITH CHAT

Feeding5Second FeedingCord-blood

Virus

Infant Antibody

Number Antibody in Feces

Response Titer (days)Antibody

Virus Antibody Age

Titer before in Feces Titers after (mo)

Re-feeding (days) Re-feedingf9

128 0 No

10 128 0@ Equivocal

15 9156 0 No

49 32 0 No

70 128 0 No14

<8 14+ <8(25)

15 <8 + 512 (30)

5 <8 0 <8 (32—*2910)

24 <8 0 <8 (914—÷66)

4 <8 19+ <8(26)

TABLE XII

RELATIVE RESISTANCE TO RE-INFECTION OF IMMUNIZED INFANTS WHEN RE-EXPOSED TO THE SAME VIRUS

* Third day of life.

f Days in parenthesis.

(9)

Infant NumberAge at Virus Feeding (mo)Pre-vacci

nation Antibody TiterVirus

in Feces

(days)Post-vaccination Antibody Titers*150

5

12256

<8 <80

0 0256

(30)f—@<8 (150) <8 (32) —¿@<8 (220) <8(25)490

24 1032

<8 <80

0

7+<(78)

<8(24)—*<8 (305) Not

obtained820

2 88

8 <835

0 12+8

(30)—@ 8 (60) 8 (6) —¿*<8(240) 128 (40)

Infant NumberBirth

.

Weight

(gui)Duration of Excretion

.

of Virus in Feces

(days)Antibody

Titers at Intervals afterBirth.

Age, in Days

66 86

12603060*156170821,10635888*8

<8 <8<8<88598510<378288@8

f ttt

TABLE XIV

THREE SUCCESSIVE EXPOSURES TO CHAT ATTENUATED P0LI0vIRUs

* After the feedings serial post-vaccination blood specimens were obtained. Days are given in parentheses.

sponse to intestinal infection with CHAT virus (Table II). This group was of special interest because of the possibility that ex posure of immature infants to a viable anti gen before they were immunologically re sponsive might render the infants incapable of responding with the formation of polio myelitis antibodies on subsequent exposures to poliovirus. The eight infants described in Table XVI had all been subjected to active intestinal infection with the CHAT virus,

yet at no time after the first virus feeding

had they been stimulated to produce de tectable titers of type 1 antibodies. More over, five of the infants had had maternal antibody titers of <8 at the time of the first feeding. When re-exposed to the same virus 4 to 6 months later, all eight infants were readily infected and excreted polio virus as long as the feces were tested (5 to 25 days), unlike some of the successfully

immunized infants in Table XIII. There was no suggestion of resistance to re infection in this group. Most important, all the infants tested after the second exposure to the CHAT virus were then found to have significant antibody titers, ranging from 8 to 512 (Table XVI).

COMMENT

Virus Infection in Premature Infants

The intestine of the premature infant seems fully capable of supporting the growth and multiplication of poliovirus dur ing the neonatal period. Receptor cells in which virus multiplication is presumed to occur must be present in abundance; their presence does not appear to be correlated with the stage of maturity—as gauged by birth weight—of the viable fetus. In their ready susceptibility to infection with at

TABLE XV

LACK OF AN ACCELERATED RESPONSE ON RE-FEEDING Two INFANTS HAVING Low ANTIBODY TITERS

* Each infant re-fed CHAT at this point; neither excreted poliovirus after re-feeding.

(10)

First Exposure5SecondExposureDuration

of

Infant Cord-blood Excretion of Post-vaccination Number Antibody Titer Virus in Feces Antibody Titer

(days)Minimum

Duration

Age when Antibody

Re fed of Excretion of

- Virus in Feces Titer after

(mo) Re-feeding

(days)916

<8 27 <8

27 <8 914+ <8

40 <8 10 <8

52 1918 25 <8

58 .. 911 <8

79 <8 191 <8

81 391 49 <8

103 <8 18 <85

12+ 512

5 12+ 5191

5 7+ t

4 5+ 5191

5 7+ 391

5 14+ 128

6 915+ 8

4 5+ 5191

TABLE XVI

LACK OF IMMUNOLOGIC TOLERANCE ON RE-EXPOSURE TO ATTENUATED P0LIOvIRUS

* Third day of life.

t Not determined.

tenuated poliovirus premature infants are comparable to full-term infants during the neonatal riul2 It is apparent that in infants gastric acidity does not have an im portant effect in reducing susceptibility to infection with the amount of attenuated poliovirus ordinarily used for immunization, for both full-term and premature infants usually have free acid in the

@

Susceptibility to infection with the same dose of the same strain of poliovirus

CHAT—appears to extend from late pre

natal life to early adulthood with little

variation.8'19'20 The only gap in the spec

trum of susceptibility seems to be some transitory resistance in infants 1 to 10 weeks old. However, infants in this age group are only relatively resistant to attenuated polio virus, there being but 20 to 30% fewer in testinal infections.12

What stops the multiplication of virus in infected subjects? The usual view is that infection wanes as the immunologic re

sponses are activated.u1 But there may be

other factors, particularly of cellular and

humoral origin, which account for the ter mination of infection without involving the

systemic immunologic functions. Whether

such factors were at play in some of the infants under study is difficult to know;

however, it is certain that a number of in

fants stopped excreting poliovirus without

ever attaining what are usually considered

signfficant levels of antibodies.

The further question of whether the mu!

tiplication of the CHAT virus in the infant, both in the presence and in the absence of maternal as well as of actively formed antibody, affects the genetic or antigenic constitution of the virus must be answered qualifiedly until more tags of strain identity are available. The intratypic serologic dif ferentiation test (1ST) and the growth char acteristics of the excreted virus at different temperatures (t marker) have proved to be the most reliable methods of checking on the genetic stability of attenuated polio virus. Using these identifying marks, we found that the virus strain fed to and the strain excreted by premature infants did not

differ.22

Poliomyelitis Antibodies in the Premature lnfant—Passively Acquired

“¿Inman the antibody supply is.. . pre

natal. •¿â€œ23Maternal poliomyelitis anti

bodies are transferred from mother to in fant during gestation at least as early as the second trimester and, after the thirtieth week, probably in a mother-to-infant ratio

of one to one.2325 Our observations that the

quantity of passively transferred antibody

could not be correlated with the birth

(11)

PREMATURES AND POLIOVIRUS

transplacental transfer of poliomyelitis anti bodies is virtually complete in fetuses ma ture enough to survive outside the uterus.26

The rate at which antibodies of maternal origin disappear from the infant's circula tion appears to vary from infant to infant. In full-term infants the half-life of such antibodies has been variously estimated as between 2% and 4 weeks and thought to parallel the decline of passively acquired

27 28 In comparing two of our series of infants, we found that the average antibody half-life was 23 days in premature infants and 18 days in full-term infants.@ The globulin half-life in children may be longer than in adults.27

What can we infer about the protection against poliomyelitis afforded by passively acquired antibodies? Certainly they do not prevent infection with attenuated poliovirus in infants with a wide range of titer of homologous antibody: up to 512 and 1,024.8 Nor does their presence appear to enhance active immunologic responses to living poliovirus. On the other hand, there is as yet little proof that transplacentally ac quired antibodies interfere significantly with active antibody formation, except when they are present in unusually high titers.29'3° Although there is no question that clinically manifest poliomyelitis can occur in infants less than 6 months old,31 the incidence of polimyelitis in infants does seem to correlate with the waning and dis appearance of maternal antibodies around the sixth month of life; presumably, circu lating passively acquired antibodies block the access of poliovirus to the central nerv ous system.3° However, because infection with poliovirus can probably take place with ease in early life, and many factors besides circulating antibodies influence the incidence of disease, we cannot assume that transplacentally acquired antibodies are solely responsible for protection against poliomyelitis.32

Actively Formed Antibodies

Premature infants are relatively deficient in their ability to form antibodies in re

sponse to bacterial antigens,3335 although the ability to form macroglobulin anti bodies, for example to typhoid vaccine, may be present at birth.36 Our findings show that many premature infants do respond to a viral antigen with the formation of anti bodies, as observed in assorted natural virus infections.@ Perhaps a strong, continuous antigenic stimulus is required.37 However, many newborn infants do not form detect able antibodies, and the mean antibody titers reached are less than in infants 2 or 3 months old.7

This is not to say that the failure to de tect antibodies with the techniques we used means that none was formed. Even in chil dren with hypogammaglobulinemia, ex tremely low levels of neutralizing antibodies to poliomyelitis—presumably specific—can be detected with especially sensitive meth ods.38 Yet when 23 pairs of sera from some of the infants in our studies thought not to have an antibody response were retested with the sensitive unmodified immune-in activation test,39 only one additional infant with a possible response was found, al though higher pre-vaccination and post vaccination titers were usually found.

The comparatively deficient immunologic responses of premature infants are similar to those of full-term infants during the neo natal period.40'12'35 The last 2 or 3 months of gestation seem to improve the ability to form antibodies only slightly if at all. On the other hand, the extrauterine maturation of newborn infants is associated with in creasing ability to form circulating anti bodies,7'40'36 perhaps because of exposure to the environment of common microbial antigens.

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ma-cell proliferation in human @

and weak responses to Salk vaccine in chil dren with hypogammaglobulinemia have been demonstrated.@@ In any case, the de gree of hypogammaglobulinemia in new born infants is less than in the pathologic states.26

Although full-term and premature infants may be relatively deficient as a group in their ability to produce antibodies, we do not think they are quite comparable to children with the pathologic gamma globu lin deficiency states. Newborn infants, both premature and full-term, vary greatly in their ability to produce antibodies in re sponse to infection with attenuated polio virus, but the fact is that antibodies can be and are produced by most infants, without relation to the duration of multiplication of the virus. A rather erratic antibody-forming mechanism, in existence some time before gestation is complete, develops rapidly in the early postpartum months; it becomes reliable after about 3 months.

Immunity and Tolerance

Current speculations on the nature of immunity detract from the significance of circulating antibodies and assign primary importance to “¿theimmunologically com petent cell.―46We have generally considered that infants are immune to poliomyelitis when two conditions are fulfilled: one, there has been an active infection with poliovirus; and two, a significant titer of circulating homologous antibody can be detected. When the immunity of such in fants is tested by re-exposure to the same agent, susceptibility to infection seems to

be lost or diminished, in that the duration of multiplication of virus tends to be brief

or fleeting; in some cases re-infection does not even take place. Frequently, there is an increase in antibodies on re-exposure to homotypic poliovirus.12'47

If cells and not antibodies determine im

munity—as, for example, in children with

agammaglobulinemia who are resistant to

re-infection with measles@°—then all that

would be required to produce immunity to

poliomyelitis is the multiplication of polio virus in the host. Hence the group of in fants described in Table XVI, who were in fected with poliovirus but did not form de tectable antibodies, should possess immu nity to homotypic poliovirus. This did not seem to be SO; there was no evidence of resistance to re-infection in infants without antibodies even though they had been pre viously infected.

Although immunologic tolerance to tissue and cellular antigens and to ovalbumin is readily induced experimentally in animals, the induction of tolerance to subcellular structures such as viruses appears to be far more difficult. It is unlikely that the unusual severity of certain viral diseases in the pre natal and the neonatal period is a clinical reflection of a form of immunologic toler ance or ar2 for antibodies seem to

be produced in such infections.48 Moreover,

there are reports of the induction of only partial immunologic tolerance to bacterial antigens—shigella—in chickens and in mice.49 Tolerance to a virus has never been recorded.5052 The primary requirements for the induction of immunologic tolerance—in timate (if not systemic) exposure to a viable antigen during the prenatal or neonatal period—were fulfilled in this study. Further more, the failure of some infected infants to produce antibodies approximated a state superficially like that of immunologic tol erance. But it was clear on re-exposing these infants to poliovirus that the usual antigen

antibody relation had not been disturbed.

SUMMARY AND CONCLUSIONS

Sixty-five premature infants were given

CHAT type 1 live poliovirus vaccine. Seven teen other infants were retained as controls.

Although 92% of the infants were infected with the attenuated poliovirus, only 59% of infected infants had a definite antibody

response. The size of the infant did not seem to influence the duration of intestinal infection.

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mated at 23 days. Moderately high titers of homotypic maternal antibodies in the in fants did not interfere with infection, nor was there obvious inhibition of active im munologic responses.

Thirty-one of the infants were given a second feeding of the CHAT virus 2 to 5 months after the first administration. The primarily immunized infants were rela tively, but seldom completely, resistant to re-infection. In contrast, infants that did not form antibodies after the primary infection seemed to be fully susceptible to re-infec tion. Moreover, there was no evidence of immunologic tolerance to poliovirus in these infants, for after the second infection polio myelitis antibodies were invariably found. We concluded that, while premature in fants are highly susceptible to infection with CHAT poliovirus, their immunologic responsiveness—just as in newborn full-term infants—is distinctly less than in infants 2 or 3 months old, but that exposure to polio virus in early life does not impair later im munologic functioning.

REFERENCES

1. Hodes, H. L.: Coxsackie virus infection of

childhood,in ViralInfectionsof Infancy and

Childhood, edited by H. M. Rose. New York, Hoeber, 1960, pp. 22-32.

2. Van Creveld, S.: Virus myocarditis in infancy —¿Acutephase and possible late sequels, in Viral Infection of Infancy and Childhood, edited by H. M. Rose. New York, Hoeber, 1960, pp. 33-54.

3. Eichenwald, H. F., and Kotsevalov, 0.: Im munologic responses of premature and full

term infants to infection with certain viruses.

P@wrmcs, 25:829, 1960.

4. Benirschke, K.: Routes and types of infection

in thefetusand thenewborn.J.Dis.Child.,

99:714, 1960.

5. Koprowski, H.: Tin anniversary of the develop ment of live virus vaccine. J.A.M.A., 174:

972, 1960.

6. Koprowski, H., et al.: Immunization of infants

with living attenuated poliomyelitis virus:

investigations of alimentary infection and

antibody responsein infantsunder six

months of age with congenitally acquired

antibodies.J.A.M.A.,162:1281,1956.

7. Pagano, J. S., Plotkin, S. A., and Koprowski, H.: Variations in the responses of infants to living attenuated poliovirus vaccines. New EngI. J. Med., 264:155, 1961.

8. Plotkin, S. A., Koprowski, H., and Stokes, J., Jr. : Clinical trials in infants of orally ad ministered attenuated poliomyelitis vaccines. PEDIATRICS,23: 1041, 1959.

9. Finkel, K. C., and Haworth, J. C. : Clinical trial

to assess the effectiveness of gamma globulin in acute infections in young chil

dren. PirniAnucs, 25:798, 1960.

10. Smith, R. T. : Immunity in infancy. Pediat. Clin. N. Amer., 7:269, 1960.

11. Pagano, J. S., et al.: Experimental infection with attenuated poliovirus in premature in

fants. Clin. Res., 8:223, 1960.

12. Pagano, J. S., Plotkin, S. A., and Koprowski, H.: Variation of response in early life to vaccination with living attenuated poliovirus

and lack of immunologic tolerance. Lancet,

1:1224, 1960.

13. Pagano, J. S., at at.: Experimental infection with CHAT attenuated poliovirus in prema

tare infants, in Second International Confer

ence on Live Poliovirus Vaccines (Wash ington, D.C., 6-10 June, 1960). Scientific Publication 50. Washington, D.C., Pan American Sanitary Bureau, 1960, pp.

287-293.

14. Koprowski, H., et at.: Behavioi of attenuated

strains of poliomyelitis virus in relation to

age, familial spread, and duration of im

munity, in First International Conference on

Live Poliovirus Vaccines, Washington, D.C., 22-26 June, 1959). Scientific Publication 44.

Washington, D.C., Pan American Sanitary

Bureau, 1959, pp. 159-171.

15. Koprowski, H.: Discussion of Sabin, A.: Prop erties of attenuated polio-viruses and their behavior in human beings. N.Y. Acad. Sc. (Spec. Pub.), 5:113, 1957.

16. Koprowski, H., et at.: Clinical investigations on

attenuated strains of poliomyelitis virus: use as a method of immunization of children with living virus. J.A.M.A., 160:954, 1956. 17. Gyorgy, P.: Unpublished data.

18. Ames, M. D.: Gastric acidity in the first ten

days of life of the prematurely born baby.

J. Dis.Child.,100:252,1960.

19. Pagano, J. S., at at.: Routine immunization with orally administered attenuated poliovirus. J.A.M.A., 173:1883, 1960.

20. Koprowski, H.: Historical aspects of the de

velopment of live virus vaccines in polio myelitis. Brit. Med. J., 2:85, 1960. 21. Good, R. A., Bridges, R. A., and Condie,

R. M.: Host-parasite relationship in pa tients with dysproteinemias, in Nonspecffic Resistance to Infection. Bacteriol. Rev., 24: 115, 1960.

22. Koprowski, H., at at.: The application of genet

ic markers to the development and control

of live poliovirus vaccine, in Second Inter

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cines (Washington, D.C., 6-10 June, 1960).

Scientific Publication 50. Washington, D.C., Pan American Sanitary Bureau, 1960, pp.

53-65.

23. Vahlquist, B.: The transfer of antibodies from

mother to offspring: Advances in Pediatrics, Vol. 10, edited by S. Z. Levine. New York, 1958, pp. 305-330.

24. Brown, G. C., and Carroll, C. J. : Antibody re

sponse of pregnant women to poliomyelitis vaccine and passive transfer to infants.

J. Immunol.,

81:389,1958.

25. Edsall, C. : Active and passive immunity of the

infant. Ann. N.Y. Acad. Sc., 68:32, 1956.

26. Pratt, E. L. : Electrophoretic analysis of serum

proteins in premature infants. Pznwriucs, 10:527, 1952.

27. Dixon, F. J., et at.: The half life of homologous

gamma globulin in several species. J. Exp.

Med., 96:313, 1952.

28. Gelfand, H. M., et at.: Studies in the develop ment of natural immunity to poliomyelitis in Louisiana: V. Passive transfer of polio-anti

body from mother to fetus and natural de

dine and disappearance of antibody in the

infant. J. Immunol., 85:46, 1960.

29. Lepow, M. L., et at.: Effect of Sabin type 1 poliomyelitis vaccine administered by mouth

to newborn infants. New Engl. J. Med., 264:

1071, 1961.

30. Bodian, D., and Nathanson, N.: Bull. Johns

Hopkins Hosp., 107:143, 1960.

31. Grat, L. S.,and Peat,A. A.: The epidemiology of the firstpoliomyelitisepidemic (Jamaica,

1954). West Indian Med. J., 6:257, 1957.

32. Nonspecific resistance to infection. Bacteriol.

Rev., 24:1, 1960.

33. Donald W. D., and Coker, J. W.: The roleof hemophilus influenzae in respiratory infec tions of premature infants. Amer. J. Dis. Child., 94:272, 1957.

34. Stulberg,C. S.,and Zeulzer,W. W.: Infantile diarrhea due to Escherichia Coli. Ann. N.Y. Acad. Sc.,66:90, 1956.

35. Vahiquist, B., and Nordbring, F.: Studies in diphtheria: VI. The effect of diphtheria im munization of newborn prematures. Acta Paediat., 41:53, 1952.

36. Smith, R. T.: Response to activeimmunization of human infantsduring the neonatalperiod, in Symposium on Cellular Aspects of im munity edited by, C. E. W. Woistenholme, and M. O'Connor, Boston, Ciba Foundation, 495 pp. 1960.

37. Thorbecke, C. J.: Gamma globulin and anti body formation in vitro: I. Gamma globulin

formation in tissues from immature and nor

mal adult rabbits. J. Exp. Med., 112:279,

1960.

38. Barnett, E. V., et at.: Antibodies to entero

viruses in hypogammaglobulinemic patients. New EngL J. Med., 262:563, 1960.

39. Card, S. : Immuno-activation of poliovirus.

Arch. Ces. Virusforsch., 7:449, 1957.

40. Dancis, J., Osborn, J. J., and Kunz, H. W.: Studies of the immunology of the newborn infant: IV. Antibody formation in the pre mature infant. Psnwrsucs, 12: 151, 1953. 41. Bridges, R. A., et at.: Morphologic basis of

antibody formation development during the neonatal period. J. Lab. Clin. Med., 53: 331-357, 1959.

42. Smith, R. T. : Immunity in infancy. Pediat. Clin. N. Amer., 7:269, 1960.

43. Good, R. A.: The morphological basis of the

immune response and hypersensitivity in

host-parasite relationships in living cells. Springfield, Ill., Thomas, 1957.

44. Silverstein: Cited in Thorbecke.―

45. Baron, S., et at.: Antibody response of hype gammaglobulinemic patients given poliomye ifs vaccine (Abstract) J. Dis. Child., 100: 566, 1960.

46. Bumet, F. M. : The new approach to immunol

ogy. New Engl. J. Med., 264:24, 1961.

47. Plotkin, S. A., et a!.: Vaccination of families

against poliomyelitis by feeding and by con tact spread of living attenuated virus. Acta

Paediat., 49:551, 1960.

48. Steigman, A. J., and Lipton, M. M.: Active

antibody production by the newborn with Coxsackie B-3 viremia and encephalitis (Ab

stract). J. Dis. Child., 100:537, 1960.

49. Freidman, H., and Gaby, W. L.: Immunologic unresponsivenessin mice followingneonatal exposure to Shigellaantigens.J. Immunol.,

85:478, 1960.

50. Burnet, F. M. Theories of immunity. Perspect. Biol.Med., 3:447, 1960.

51. Smith, R. J.,and Bridges,R. A.: Immunologi cal unresponsiveness in rabbits produced by neonatal injection of defined antigens. J. Exp. Med., 108:227, 1958.

52. Burnet, F. M.: In Immunity and Resistanceto Infectionin Early Infancy: Report to the 29th Ross Pediatric Research Conference. Columbus, Ohio, 1959, p. 71.

Acknowledgment

We are indebted to Paul Gyorgy, M.D., for permission to carry on this study, and to Jane

Sitnek, R.N., Walter Omans, M.D., Thomas Nor

ton, Toby Coldschneider, Barbara Cohen, and Su zanne Richardson, R.N., for their help, as well as to Elizabeth Davies, R.N., and the nursing staff in the Division of Nurseries of the Philadelphia General Hospital for the feedings and the collection

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1962;29;794

Pediatrics

Koprowski

Joseph S. Pagano, Stanley A. Plotkin, Donald Cornely, Walter Leuterer and Hilary

ATTENUATED POLIOVIRUS

THE RESPONSE OF PREMATURE INFANTS TO INFECTION WITH

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1962;29;794

Pediatrics

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Joseph S. Pagano, Stanley A. Plotkin, Donald Cornely, Walter Leuterer and Hilary

ATTENUATED POLIOVIRUS

THE RESPONSE OF PREMATURE INFANTS TO INFECTION WITH

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Figure

TABLE IXequivocalantibody
TABLE XVILACK OF IMMUNOLOGIC TOLERANCE ON RE-EXPOSURE

References

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