Studies on immunity to measles

T h e J o u r n a l of P E D I A T R I C S

471

Studies on immunity to measles Studies on immunity to measles have been in progress since 1960. Primary infection with measles virus was followed by evidence o[ detectable antibody by the twelfth day; peak antibody titers were observed by the twenty-first to the twenty-eighth day. Subsequently, in most instances antibody persisted for at least four years at levels capable of completely inhibiting measles infection. However, when antibody declined to minimal or undetectable levels, exposure to measles virus was usually followed by an asymptomatic infection and a booster response; under these circumstances antibody was detectable by the seventh day and peak antibody levels were observed by the twelfth day. These studies confirm the observation that one attack of measles is [ollowed by lifelong immunity. They also provide strong support for the prediction that one inoculation of live measles-virus vaccine will confer permanent immunity.

Saul Krugman, M.D., ~ Joan P. Giles, M.D., r

Harriet Friedman, M.A.,

and Shirley Stone, M.D. NEW

YORK~

N.

Y.

THE COMPLETE LACK of immunity to measles in virgin populations has been well documented. In the Southern Greenland epidemic in 1951 the attack rate was 99.9 per cent? The following year, in an epidemic among Canadian Indians and Eskimos of the Eastern Arctic Region, more than 99 per cent of the population acquired measles. 2 In both areas the disease attacked persons

From the Department of Pediatrics, New York University School of Medicine, New York, and the Willowbrook State School, Staten Island. This work was supported by the Health Research Council of the City of New York under Contract No. U-1056. ~Address, Department of Pediatrics, New York University School of Medieine. 550 First Avenue, New York, N. Y. 10016. ~ N e w York City Health Research Council Career Scientist Awardee.

of all ages from early infancy to old age. So-called "natural immunity" to measles was nonexistent. In contrast, the epidemic of measles in the Faroe Islands in 1846 did not strike completely virgin soil because the disease had Occurred there in 1781. During 1846 approximately 6,000 cases of measles ~were recorded in the population of about 8,000 inhabitants. In his historic description of this epidemic, Panum a observed that all old people who had measles 65 years previously were protected against the disease. High attack rates occurred in all age groups from early infancy to 65 years. The experience in the Faroe Islands demonstrated that repeated exposure to the disease was not a necessary prerequisite for permanent immunity to measles.

4 72

K r u g m a n et aI.

In the United States and in other similar countries measles is an endemic or recurrently epidemic disease. The over-all attack rate ranges between 85 and 90 per cent. It is reasonable to postulate that 10 to 15 per cent of persons acquire their immunity following a subclinical infection or a mild illness which is not typical of measles. The modified disease m a y occur during early infancy under the cover of passively acquired maternal measles antibody or following an inoculation of g a m m a globulin. T h e propagation of meas!es virus in tissue culture by Enders and Peebles 4 provided the tools needed for the development of specific serologic tests as well as vaccines for the prevention of the disease. These new procedures and techniques have been extremely valuable for the study of mechanisms of immunity to measles. This report includes several studies in which serial observations were made on groups of infants and children whose immunity to measles was acquired as follows: (1) transplacentally at birth, (2) following natural measles, or (3) following vaccination with live attenuated measlesvirus vaccine, inactivated vaccine, or combined inactivated-live vaccine. The study population included the following three general groups: (1) institutionalized children at the Willowbrook State School, an institution for mentally defective children on Staten Island, New York; (2) home-dwelling children enrolled in the East Nassau Health Insurance Plan Group; and (3) home-dwelling infants who attended Bellevue Hospital Well Baby Clinic. During the course of our studies three types of measles vaccine were used: (1) live attenuated measles-virus vaccine, Edmonston B type,* (2) live attenuated measles-virus vaccine, further attenuated type,t and (3) formalin-inactivated measles vaccine.:~ The

*Live measles vaccine, Edmonston B type, was supplied by Dr. Maurice Hilleman, Merck Institute for Therapeutic Research, West Point, Pa. ~Live further attenuated vaccine was supplied by Dr. Anton Schwarz, Pitman-Moore Co., Indianapolis, Ind. ~Inactivated measles vaccine was supplied by Dr. Joel Warren, Chas. Pfizer & Co., Terre I-Iaute, Ind.

March 1965

study population and the characteristics of the vaccines have been described in detail in previous reports. ~s The studies on immunity to measles will be discussed in the following sequence: 1. The pattern of antibody response following measles infection: comparative sensitivities of complement-fixation (CF), hemagglutination-inhibition (HI) and neutralizing (NA) antibody tests. 2. Measles immunity during the first year of life. 3. A longitudinal study on the persistence of measles antibody following natural infection and vaccination. 4. Studies on the significance of undetectable measles antibody titers observed in children 1 to 4 years after natural infection or successful immunization with live attenuated measles-virus vaccine. These studies included the following observations: (a) clinical and serologic effects following intimate exposure to patients with measles; (b) clinical and serologic effects following revaccination with live attenuated measles-virus vaccine, Edmonston B type; and (c) reevaluation of the measles antibody studies utilizing a more sensitive H I antibody test. PATTERN OF ANTIBODY RESPONSE FOLLOWING MEASLES INFECTION. COMPARATIVE SENSITIVITIES OF CF, HI, AND NEUTRALIZING ANTIBODY TESTS

The serologic tests were performed by methods described in previous publications, s-l~ The drop technique of Fulton and Dumbell as modified by Svedmyr and associates ~~ was employed for the CF test. The procedure for the H I test was a modification of the method described by Rosen. 11 The neutralizing antibody tests were performed by Dr. Maurice Hilleman employing a technique which he described in a previous paper. 9 The development of measles antibodies was studied in 10 susceptible children following parenteral inoculation of live attenuated measles-virus vaccine, Edmonston B type.

Volume 66 Number 3

Four children received vaccine only and 6 received g a m m a globulin also. Serial determinations of measles CF, H I , and neutralizing antibodies were performed at frequent intervals from the fifth to the twenty-seventh day. The results of these studies are shown in Table I. The addition of g a m m a globulin did not alter the pattern of the antibody response. Measles CF antibody was first detectable on the fourteenth and fifteenth postvaccination days in 7 of the 10 children; it was detectable on the thirteenth day in one child and on the sixteenth day or later in 2 children. Thus, CF antibody was usually detectable by the fifteenth postvaccination day. Measles H I and neutralizing antibodies were both detectable by the twelfth postvaccination day as a rule. The earliest appearance of H I antibody was day 11, the latest was day 14. Neutralizing antibody was detectable as early as day 10 in one child and as late as day 14 in one child; in most children it was detectable on day 12. Comparative studies on the persistence of the three types of antibody for months and years after vaccination or natural infection revealed a close correlation between H I and neutralizing antibodies. They were detectable for longer periods of time than CF antibodies. Therefore, a negative H I or neutralizing antibody test was a more sensitive index of susceptibility than a negative CF test. The lack of sensitivity of the CF test was observed during the course of our early immunization studies with live attenuated measles-virus vaccine. During one study, 22 presumably susceptible children failed to respond to vaccination with live vaccine. Subsequently, detectable H I antibody was found in their prevaccination sera which were lacking in CF antibody. The comparative value of the CF and H I antibody determinations as tests of susceptibility was observed during an epidemic of measles in a building at the Willowbrook State School. Of 39 children who were presumed to be susceptible because of a negative CF test, 28 (72 per cent) contracted measles.

Immunity in measles

473

Of 19 children who had negative H I tests, 17 (90 per cent) acquired measles. These data indicated that about 18 per cent of the children were probably immune to measles in spite of no detectable CF antibody. These studies confirm and extend the observations of Cutchins 12 and Black and Rosen la who compared the relative sensitivities of the three tests. Measles H I and neutralizing antibodies appear earlier and persist longer than CF antibodies following vaccination or natural infection. The H I antibody test is the serologic procedure of choice for the study of measles immunity. I t has t h e following advantages: (1) It is a more sensitive indicator of the presence of antibody than the CF test; (2) it is equally as sensitive as the neutralizing antibody test; and (3) it is the simplest and most practical test to perform. In subsequent studies of this report, the H I antibody test will be used exclusively. MEASLES IMMUNITY DURING THE FIRST YEAR OF LIFE

M a n y epidemiologic and clinical surveys have indicated that measles rarely occurs in infants during the first 6 months of life. Immunity in early infancy has been closely correlated with the maternal past history of measles. Immunity during this period of life was studied in a group of 107 infants who attended the Bellevue Hospital Well Baby Clinic. Approximately 4 or 5 serial samples of blood were obtained from each infant from the first to the twelfth month of life. Maternal and cord blood samples were not available for this study. The results of serial determinations of measles H I antibody are shown in Fig. 1. The antibody titers of 51 infants, 1 month old, ranged from less than 1:8 to 1:512. Three infants (6 per cent) had no detectable antibody in this first month. By the fourth month of life 53 per cent of the infants did not have detectable H I antibody. After 6 months of age passively acquired antibody was no longer detectable. There was a good correlation between the height of the antibody titer and its persistence.

4 74

Krugman et al.

March 1965

T a b l e I. D e v e l o p m e n t of measles antibodies following i m m u n i z a t i o n of 10 children with live ( C F ) , b e m a g g l u t i n a t i o n - i n h i b i t i o n ( H I ) , a n d neutralizing (NA) antibodies

Day alter vaccination 5 6 7 8 9 10 11 12 13 14 15 16 21 27

1. C.L.

cF l nix t NA

t

2. M.R. CF, I HI I NA

<1 < 2 <2 <1 < 2 <2
m

m

m

m

i--8 [

32 64 128 128 256 128 64

3. M.H.

cF 1

<1 < 2 <1 < 2 <1 < 2 %1 < 2 <1 < 2 <8 <1%2 <8 2 <2 <8 ~4 <2 <8'. ~ 4 < 2 (I 16 16 < 2 J 64 18 4 64 32 32 256 32 64 128 64 64 --

I NA <1 <1 <1 %1 <1 <1
4.],F. CF I HI 1NA <2 <2 <2 <2 <2 <2 <2 <2 <2 2 2 2 512 1024

- - <1 - - <1 - - <1 - - <1 - - <1 < 8 <1 < 8 <1 < 8 <1 < 8 <1 8 1 32 2 64 8 512 ~64 256 64

5. D.H. CF t HI I NA <2 <1 <2 <1 <2 <] <2 <1 <2 <1 <2 <8 <1 <2 , 8!<1 <21 16 - 2 <2', 32 2 < 2 ', 64 ~4 2 128 ~4 64 256 16 128 256 64 256 256 64

Nos. 1 to 4 received vaccine only. Nos. 5 and 6 received vaccine plus gamma globulin~ 0.01 ml. per pound. Nos. 7 to 10 received vaccine plus gamma globulin, 0.02 ml. per pound.

D u r i n g the course of this study 8 infants had a greater t h a n fourfold rise in a n t i b o d y titer following a k n o w n or u n k n o w n exposure to measles. I t is of interest t h a t only 2 of the 8 infants had a n illness which was clinically compatible with a diagnosis of measles with rash. T h e r e m a i n i n g 6 infants had a modified disease or subclinical infection which could not be identified without specific serologic tests. T h e significant modification of the disease in these infants indicated t h a t measles antibody, though nondetectable, was present in adequate concentration to exert a " g a m m a globulin-like" effect. I n addition, these findings indicated that small a m o u n t s of passively acquired a n t i b o d y did not inhibit measles infection. A n "'all or n o n e " p h e n o m e n o n was not observed. T h e relatively high mortality rate of u n modified measles in infants u n d e r 1 year of age has been well documented. TM i5 T h e increased severity of the disease in this age group is well k n o w n to clinicians. T h e results of the present study highlight the broad spectrum of the clinical manifestations of measles in infancy, r a n g i n g from a n unrecog-

nizable subclinical infection to a severe fatal disease. A LONGITUDINAL

S T U D Y ON

THE PERSISTENCE OF MEASLES ANTIBODY FOLLOWING

NATURAL INFECTION VACCINATION

AND

I n the spring of 1960 a n extensive epidemic of measles occurred in the Willowbrook State School; more t h a n 600 cases were observed d u r i n g a 4 m o n t h period. Since 1960 about 95 per cent of 1,030 newly a d m i t t e d susceptible ~ i n f a n t s a n d children were successfully i m m u n i z e d with live a t t e n u a t e d measles vaccine. O n this regimen measles has been virtually eliminated from this institution. A l o n g i t u d i n a l study on the persistence of measles H I a n t i b o d y was initiated 4 years ago. This study has been conducted in a setting where there has been no o p p o r t u n i t y for repeated exposure to measles.

~Infants with a measles H I antibody t[ter o[ less thart 1:8.

Volume 66 Number 3

I m m u n i t y in measles

4 75

a t t e n u a t e d measles-virus vaccine, E d m o n s t o n B type. Serial d e t e r m i n a t i o n s of c o m p l e m e n t fixing

6. B.Z. CF I HI I NA

7. I.D. CF I HI I N A

<2 <2 <2 <2 <2 <2 <2

<8 <8

<2

<8

~- ?--

<2 <2 <2 <2 <2 <2 <2 <2

<8 <8 <8

<1 <1 <1 <1 <1 <1 <1 <1

4

<2

<8

~-

4 32 128 256 256

16 64 128 128 128

--

t

<2,

<21

16

32

< 2 'J 128 8 128 128 128 256 256

<1
~4 8 16 64 64

16 16 32 32 64

9. H.L. CF I HI I N A

8. R.N. t CF I HI t NA <2 -<2 -<2 -<2 -<2 --<2 <8 <2 32 i < 2 , 16 < 2 ', 32 64 64 128 256 256 256 1024 512 512 256

<1 <1 <1 <1 <1 <1

;<1_ 2 ~4 8

32 64 ~64 64

<2 <2 <2 <2 <2 <2 <2

---~ <8 <8 <8 <2 ,--8 < 2 ~ 16 16 --2 16 64 128 256 256 256 256 256

<1 <1 <1 <1 <1 2 2 2 4 ~4 16 32 64 ~64

10. A.S. CF 1 HI I N A <2 <2 <2 <2 <2

<1 <1 <1 <1 --

<2 <2


<1 --

<1

<2

<8

<1

<2

<8

',- 2

<2 i 8 <2 ] 8 <2,, 16 128 128 64 128

4 8 8 32 32

T a b l e II . Persistence of measles H I antibody two years after n a t u r a l infection or i m m u n i z a t i o n w i t h live a t t e n u a t e d measles-virus vaccine

Group i. 2. 3. 4. 5.

Natural infection Live Edmonston B vaccine Live Edmonston B vaccine plus gamma globulin Live further attenuated vaccine Live further attenuated vaccine plus gamma globulin

No. with antibody/ No. tested

% with antibody

Geometric mean antibody titer

92/96 52/55 39/41 74/90

96 95 95 80

84 53 30 16

8/12

66

12

T h e above data are based on studies performed with the H I antibody test described by R o s e n J x When the more sensitive I-II antibody test described by Norrby is, ~ was used, antibody was detected in 100 per cent of the children in all 5 groups.

Persistence of H I a n t i b o d y following natural infection. Serial samples of blood were obtained f r o m 60 children for a 4 y e a r period after onset of measles. T h e results of H I antibody d e t e r m i n a t i o n s are shown in Fig. 2A. A n t i b o d y was detectable 14 to 16 days after exposure, shortly after th e onset of rash. Peak antibody levels were observed a bout one m o n t h after exposure, titers ranging f r o m 1:16 to 1:1,024. T h e geometric m e a n antibody titer decreased f r o m 1:135 at 1 m o n t h to 1:50 at 4 years.

M o s t children h a d significant a n t i b o d y levels r a n g i n g f r o m 1:32 to 1:256, 4 years after onset of measles. H o w e v e r , it is of p a r t i c u l a r interest t h a t a small n u m b e r of the children h a d no detectable H I a n t i b o d y 1 to 4 years following infection. As i n d i cat ed in T a b l e I I , 4 per cent of 96 children h a d no detectable antibody 2 years after onset of measles. Persistence of H I a n t i b o d y following imm u n i z a t i o n with live a t t e n u a t e d measlesvirus v acci n e was studied in 3 groups of

476

Krugman et al.

March 1965

SERtAL DETERMINATIONS OF HEMAGGLUTINATION- INHIBITION (HAl) ANTIBODY m

_

_

|

| |

| @

|

|

| 3..

e

o

ooe~

ooo~

9

Qool 9 eo

o eo e

BIRTH

I

2

5

5

9

9 _ 9_

6

7

AGE IN MONTHS |

~

9 e

IJO

eo eeo 9 9 9 9 O l o o o e o o e e ot

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9 9

8

9

9

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9 eo

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o 6 1 e9 ooe 9 9 oee 9 fo 9 9 9 ol eoe 9 eo b

II

12

~0 4 FOLD RISE IN TITEB

Fig. 1. A longitudinal study of measles immunity during the first year of life. Each black dot represents one of the serial I-II antibody determinations performed by the method of Rosen. 11 Note the disappearance of detectable I-II antibody by 7 months of age. When aliquots of the serum specimens were tested by the more sensitive method of Norrby, 16, 17 antibody was detectable as late as 11 months of age; it was not detectable at 12 months of age. Of 8 infants @ who had a greater than fourfold rise in antibody titer after natural measles infection, 2 infants had the typical disease; the remaining 6 infants had a modified illness or a subclinical infection.

children. T h e first group received E d m o n ston B t y p e vaccine (Fig. 2B), the second group, E d m o n s t o n B t y p e vaccine plus g a m m a globulin (Fig. 2 C ) , a n d the third group, f u r t h e r a t t e n u a t e d type (Fig. 2D). Peak titers were d e t e c t e d 3 to 4 weeks after vaccination. T h e p a t t e r n a n d persistence of the a n t i b o d y response was similar to t h a t observed following n a t u r a l infection. As i n d i c a t e d in Fig. 3 a n d T a b l e I I , m o d i fication with g a m m a globulin or f u r t h e r att e n u a t i o n of the vaccine was followed b y a decrease in the geometric m e a n a n t i b o d y titer a n d an increase in the n u m b e r of vaccinees w i t h o u t d e t e c t a b l e a n t i b o d y 2 to 4 years a f t e r successful vaccination. C o m p a r a tive studies 2 years a f t e r disease or vaccination revealed the following: (1) no detectable a n t i b o d y in 5 p e r cent of children who h a d n a t u r a l measles or llve vaccine, E d m o n s t o n B type, with or w i t h o u t g a m m a globulin; a n d (2) no d e t e c t a b l e a n t i b o d y in 20 p e r cent of the children w h o received live f u r t h e r a t t e n u a t e d vaccine without

g a m m a globulin a n d in 33 p e r cent of a small g r o u p of 12 vaccinees w h o received f u r t h e r a t t e n u a t e d vaccine with g a m m a globulin. Significant i n d i v i d u a l variations have been observed in the persistence of a n t i b o d y following n a t u r a l infection a n d vaccination. This p h e n o m e n o n was d e m o n s t r a t e d b y 2 children whose d a t a are r e c o r d e d in Fig. 2B. Both children received live a t t e n u a t e d measles-virus vaccine, E d m o n s t o n B type; the H I a n t i b o d y response was 1:1,024 one m o n t h later. F o u r years later, it was still 1:1,024 in one child a n d 1:64 in the second child. D u r i n g the 4 y e a r p e r i o d of observation n e i t h e r child was exposed to measles. Persistence of H I a n t i b o d y following imm u n i z a t i o n with c o m b i n e d i n a c t i v a t e d - l i v e measles vaccine. A 7 m o n t h follow-up was available on two groups of children who received c o m b i n e d killed-live measles vaccine. T h e first group ~ of children over 1

~We are indebted to D r . Joel W a r r e n for providing us with allquots of serum specimens collected for this study.

Volume 66 Number 3

year of age received two inoculations of inactivated measles vaccine followed by one inoculation of live vaccine, Edmonston B type, all given at intervals of one month ( K K L group). The second group of infants received inactivated measles vaccine at monthly intervals, beginning at 1 to 2 months of age; live measles vaccine, Edmonston B type, was given after an interval of 8 to 10 months, at 12 to 14 months of age ( K K K - L group). As indicated in Table I I I , the geometric mean H I antibody titer one month post inoculation was 1:150 for 30 children in the K K L group and 1:192 for 16 infants in the K K K - L group. H I antibody was not detectable in any of the 16 infants in the K K K - L group before they received live vaccine. Seven months after live vaccine inoculation the geometric mean titer for the K K L group was 1:12 as compared with a significantly higher titer of 1:36 for the K K K - L group. The sigaaificant decline in measles antibody titer following the K K L vaccination regimen may be due to the suppressive effect of the antibody formed after the two inoculations of killed vaccine. A similar phenomenon was observed following administration of combined live attenuated measles vaccine and gamma globulin (Table I I ) . This suppressive effect was diminished when the interval between the last inoculation of killed vaccine and the inoculation of live vaccine was increased from one month ( K K L ) to 8 to 10 months ( K K K - L ) . During the course of these studies s 17 infants were exposed to measles after receiving three inoculations of inactivated vaccine at one-month intervals. Exposure occurred from 1 to 9 months after the third inoculation of vaccine. Of the 17 infants, only 2 had typical clinical manifestations of measles; 3 had a modified illness; and 12 had no apparent disease. All 17 infants had a fourfold or greater rise in antibody titer after exposure. Thus, immunization with inactivated measles vaccine appeared to be followed by a prolonged "gamma globulinlike" effect.

I m m u n i t y in measles

4 77

Table III. Hemagglutination-inhibition antibody response after combined inactivated-live measles-virus vaccine immunization

No, of children

Group

KKL KKK-L

Geometric mean HI antibody titer l month [ 7 months

30 16

150 192

12 36

K K L , infants over 1 year of age who received two inoculations of killed vaccine and one inoculation of live vaccine, all at one m o n t h intervaIs. K K K - L , infants who received three inoculations of killed vaccine at monthly intervals beginning at 1 to 2 months of age followed by live measles vaccine, Edmonston B type, at 12 to 14 months o1 age.

STUDIES

ON

THE

SIGNIFICANCE

OF NONDETECTABLE ANTIBODY

TITERS

MEASLES OBSERVED

IN CHILDREN 1 TO 4 YEARS AFTER NATURAL INFECTION OR SUCCESSFUL IMMUNIZATION WITH

LIVE

ATTENUATED

MEASLES-VIRUS

VACCINE

The longitudinal studies at the Willowbrook State School revealed that measles antibody may decrease to nondetectable levels 1 to 4 years after natural infection or successful vaccination with five attenuated measles-virus vaccine. This decline in antibody titer was observed most often in children who received further attenuated measles vaccine. Two years after receiving this vaccine in Willowbrook, 20 per cent of 90 children had no detectable antibody. During a comparable period of time only 5 per cent of a similar number of Willowbrook children had no detectable antibody following natural measles or vaccination with live Edmonston B type vaccine. The phenomenon of nondetectable antibody following natural infection and successful immunization posed a crucial question. Did this observation imply that children in this situation were no longer immune to measles? The following studies were designed to attempt to answer this important question: (1) clinical and serologic observa-

4 78

Krugman et al.

March 1965

MEASLES H I ANTIBODY RESPONSE AND PERSISTENCE IN 5 8 CHILDREN FOLLOWING N A T U R A L INFECTION

~

1o24

i

iii...~

i

!.

'/!ii" :/

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.,

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~

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:

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<~ DAyS- - J

L----

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MONTHS

IL - -

yEaRs _

_

J

INTERVAL FOLLOWING NATURALMEASLES

MEASLES H I ANTIBODY RESPONSE AND PERSISTENCE IN 52 CHILDREN FOLLOWING LIVE EDMONSTON B VACCINE 7

"

:.

.!

[____

DAYS _ _ j

[__

MQNTH~

Ii

-YEARS

-

]

-

INTERVAL FOLLOWING VACCINATION

tions following exposure of children with nondetectable antibody to patients with measles; (2) clinical and serologic observations following revaccination of children with nondetectable antibody; and (3) re-evaluation of the measles antibody studies by utilizing the highly sensitive H I antibody test described by Norrby. ~6, aT Effect of intimate exposure to patients with naturally acquired measles. T w o Willowbrook children received live further attenuated measles vaccine early in 1962 (Table I V ) . T h e H I antibody titer was < 1 : 8 before vaccination; one m o n t h post vaccination it was 1:32 in the first child (Lav.) and 1:256 in the second child (Cal.). A follow-up one and 2 years later revealed no detectable H I antibody ( < 1:8). Both children were intimately exposed to 14 patients with naturally acquired measles between Jan. 1 and Jan. t2, 1964. T h e y were asymptomatic and had no evidence of clinical measles during a 2 m o n t h period of observation after exposure. At the end of this 2 m o n t h period their H I antibody titers had risen from < 1 : 8 to 1:256 and 1:128, respectively. These observations revealed evidence of a booster type of phenomenon,

MEASLES ANTIBODY RESPONSE AND PERSISTENCE IN 45 CHILDREN FOLLOWING LIVE EDMONSTON "B" VACCINE + GAMMA GLOBULIN .

i

~

MEASLES HI ANTIBODY RESPONSE AND PERSISTENCE IN 52 CHILDREN FOLLOWING LIVE FURTHER ATTENUATED VACCINE

:

I024

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256

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,~176176

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Fig. 2. The pattern and persistence of the HI antibody response following: A, Natural infection. B, Live attenuated measles-virus vaccine, Edmonston B type. C, Live Edmonston B vaccine plus gamma globulin. D, Live further attenuated measles vaccine. Each black dot represents one of the serlaI HI antibody determinations performed by the method of Rosen.~1 Solid line indicates the geometric mean antibody titer,

YEARS-

Volume 66 Number 3

Immunity in measles

4 79

GEOMETRIC MEAN H E M A G G L U T I N A T I O N - I N H I B I T I O N ANTIBODY TITERS X--X NATURALMEASLES INFECTION 0--0 LIVE EDMONSTON "B" VACCINE O--Q LIVE EO~ " B " VACCINE + GAMMA GLOBULIN EJ--D LIVE FURTHER ATTENUATED VACCINE

512 ~ 13:: IJJ I--I"- 2'36

O v-_ z '~ 64 z

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MONTHS

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3 YEARS-

4 J

INTERVAL AFTER INFECTION OR VACCINATION

Fig. 3. Comparison of the pattern and persistence of the HI antibody response following natural infection and vaccination.

thereby supporting the hypothesis that antibody, though nondetectable, was indeed present. Additional confirmation of a booster effect was obtained in the following study. Two groups of children of comparable age received the same dose and lot number of live further attenuated vaccine. Group I included 90 children at the Willowbrook State School. These institutionalized children were not exposed to measles during the 2 year period of observation. Group II ineluded 42 children* in the East Nassau Health Insurance Plan Group. These homedwelling children were potentially exposed to measles during three "measles seasons" in 1962, 1963, and 1964. The results of measles H I antibody studies in the two groups of children are shown in Table V. A fourfold or greater antibody response was observed in all children in both groups one month after vaccination. However, 2 years later detectable H I antibody was observed in only 80 per cent of the

*These children received a small quantity of g a m m a globulin with the measles vaccine; the total dose was 0.2 ml., approximately 0.002 ml. per pound of body weight.

Willowbrook children as compared with 100 per cent of the Nassau children. The lower geometric mean H I antibody titer one month after vaccination of the Nassau children was probably due to the suppressive effect of gamma globulin given to this group. The higher geometric mean antibody titer in the Nassau children 2 years post vaccination was probably due to the booster effect following repeated exposures to children with measles. Effect of revaecination with live attenuated measles-virus vaccine, Edmonston B type. This study included 36 children at the Willowbrook State School. Live further attenuated measles vaccine was administered to 30 children; the remaining 6 children received live measles vaccine, Edmonston B type. The H I antibody titer of all 36 vaccinees rose from < 1:8 before vaccination to a level of 1:16 to 1:1,028 one month after the initial vaccination. These antibody titers declined to nondetectable or minimal levels ( < 1:8 - 1:8) 1 to 3 years later. At this time all 36 children were revaceinated with live attenuated measles vaccine, Edmonston B type. Clinical observations. All 36 children were

4 80

Krugman et al.

March 1965

asymptomatic during the 3 week period after revaccination. Clinical manifestations of measles were not present. Serologic observations. Measles H I antibody determinations were performed at frequent intervals from the third to the thirtyfifth day after revaccination. Serial samples of blood were obtained on the following postvaccination days: 3, 4, 5, 6, 7, 9, 10, 12, 21, and 35. The results of the serial H I antibody studies before and after initial vaccination and subsequent revaccination are shown in

Table IV. SeroIogic response of two children following vaccination with live further attenuated vaccine and subsequent exposure to naturally acquired measles Measles H I antibody titer Year and status

Lay.

1962 Before vaccination 1962 1 month after vaccination 1963 1 year after vaccination 1964 Exposed to measles 1964 2 months after exposure

I

Cal.

<8 (<8)

<8 (<8)

32 (128)

256 (256)

<8 (16)

<8 (16)

<8 (32)

<8 (-)

256 (~2048)

128 (~2048)

Both children were asymptomatic following exposure to measles. H I antibody titers method of Rosen. 11 H I antibody titers of Norrby. 1~, a7

without parentheses performed by

with parentheses performed by method

Table VI. The antibody titers listed without parentheses opposite each vaccinee were determined by the conventional H I antibody test described by Rosen. lz A booster type of response was observed in 25 of the 36 children. The H I antibody titers of the remaining 11 children were essentially unchanged. The significance of these observations becomes apparent when the data in Table I are compared with the data in Table VI. Following initial vaccination (Table I) with live attenuated measles vaccine, H I antibody generally was detectable by the twelfth postvaccination day. In contrast, after revaccination with Edmonston B vaccine (Table VI) H I antibody was detected on the seventh day in most children, and as early as the fifth or sixth postvaccination day in an occasional child. The pattern of the H I antibody response following initial vaccination and subsequent revaccination of children whose antibody titers had fallen to nondetectable levels is shown in Fig. 4. The antibody response following initial vaccination is represented by the geometric mean antibody titer of the 10 children listed in Table I. The response following revaccination is represented by the geometric mean antibody titer of the 25 children listed in Table VI. Following initial vaccination H I antibody was first detectable on the twelfth day and peak levels were observed on the twenty-first day. Following revaccination, H I antibody was detectable on the sixth or seventh day and peak levels were detected on the twelfth day.

Table V. Comparison of measles hemagglutination-inhibition (HI) antibody titers in two groups of children one month and two years after they received live further attenuated measles-virus vaccine % with detectable H I antibody

Group I II

Children 90 42

1 month

100 100

I

_. Geometric mean H I antibody titer

2 years

l month

80 100

112 72

I

2 years

16 36

Group I, children at the Willowbrook State School who were not exposed to measles during the 2 year period of observation. They received 800 TCID~0 of live further attenuated vaccine. Group II, children in the Nassau Health Insurance Plan group who were potentially exposed to measles during the 19621964 seasons. They received 800 TCIDs0 of llve further attenuated vaccine plus gamma globulin, 0.2 ml. intramuscularly.

Volume 66 Number 3

I m m u n i t y in measles

48 1

PATTERN OF HEMAGGLUTINATION- INHIBITION ( HI) ANTIBODY RESPONSE FOLLOWING INITIAL VACCINATION AND SUBSEQUENT REVACCINATION OF CHILDREN WHOSE ANTIBODY TITERS HAD FALLEN TONON-DETECTABLE LEVELS

256 H,[. ANTIBODYRESPONSE FOLLOWINGREVACCINATION

128

" -- - - ~ / - - -- -- -- -- -- o -- -- -- -- -- r

64 32 HI ANTIBODYRESPONSE FOLLOWINGINITIAL

/

/, o,//Io//

16

8 <8

,___o, 0

.

I

I

i

i

~

I

5

6

7

8

9

I0

DAY AFTER

l

II

I

I

I

I

1

I

l

12

13

14

Ib

16

21

27

INOCULATION OF LIVE ATTENUATED MEASLES-VIRUS VACCINE

Fig. 4. Comparison of the pattern of HI antibody response following initial vaccination with live attenuated measles-virus vaccine (solid line), and subsequent revaccination of children whose antibody titers had declined to nondetectable levels (interrupted line). Following the initial vaccination, antibody was detected first on the twelfth day and peak levels were observed on the twenty-first day. Following the revaccination, antibody appeared earlier, on the sixth day, and peak levels were reached by the twelfth day. Assay for HI antibody was performed by method of Rosen# z

The classical booster effect was observed in 25 (70 per cent) of 36 children who had nondetectable or minimal antibody titers ( < 1 : 8 or 1:8) prior to revaccination. A similar study was performed with a group of 6 children who had H I antibody titers of 1:16 or 1:32 before revaccination; only one child had evidence of a booster response. These findings suggest that reinfection followed by an early recall of antibody may occur when measles antibody falls to low or nondetectable levels. In contrast, high levels of antibody may suppress or prevent reinfection completely in most children. Effect of administration of live attenuated measles vaccine Edmonston B type, to children with nondetectahle antibody 4 years after natural measles. Six Willowbrook children were observed for 4 years after onset of measles in 1960. All six children had a significant antibody titer (1:32 or 1:64) one

month after measles. The H I antibody titer was less than 1:8 in all 6 children 4 years later. The results of vaccination with Edmonston B type vaccine are shown in Table VII. A booster type of antibody response was observed in 4 of the 6 children by the seventh postvaccination day. All 6 vaccinees were asymptomatic during the 3 week period of observation. A similar phenomenon was reported by Stokes and co-workers, 9 who observed 34 persons with serologic evidence of measles before their exposure during an epidemic. A fourfold or greater rise in neutralizing antibody titer was observed in 6 of 12 individuals whose pre-epidemic antibody titers ranged from 1:2 to 1:8. The remaining 22 persons had pre-epidemic antibody titers ranging from 1:16 to 1:256; no significant increases in antibody titer were observed in any of this group.

482

Krugman

et al.

March 1965

Table VI. Measles hemagglutination-inhibition ( H I ) antibody response following revaccination of virus vaccine, Edmonston B type (Ed. B.V.), or with live further attenuated measles-virus vaccine Hemagglutination-inhibition No. and name i. Aba.

Type of vaccine Ed. B. V.

Before initial vaccination <8

(<8) 2. Ell.

Ed. B. V.

3. H a r .

Ed. B. V.

4. Ols.

Ed. B . V .

5. Bov.

F. A. V.

6. Fal.

F. A. V.

7. Gar.

F. A. V.

8. H a r r ,

F. A . V .

9. How.

F. A. V.

10. Hus.

F. A. V.

11. K a u .

F. A . V .

12. Luc.

F. A . V .

13. Pat.

F. A. V.

14. Asa.

F. A. V.

15. Jay.

F. A. V.

<8 (16) <8 (8) <8 (--) <8 <8) <8 (--) <8 <8) <8 (--) <8 (<8) <8 (<8) <8 (<8) <8 (--) <8 (<8) <8 (<8) <8

(<8) 16. Patr. 1 7 .

W a l .

18. Wes. 19. T u r . 20. Ack. 21. H a g . 22. T h o .

Ed. B.

<8

Ed. B.

(16) <8

F. A . V .

(64) <8

F, A, V. F. A. V. F. A . V . F. A. V.

23. T u c .

F. A. V.

24. Leb.

F. A. V.

25. T i n .

F. A . V .

(<8) <8 (<8) <8 (<8) <8 (16) <8 (<8) <8 (<8) <8 (<8) <8 (<8)

Time after initial vaccination 1 month 64 (64) 64 (256) 256

(512) 256 (1024) 32 (128)

32 (256) 128 (128) 1 6

(128) 1 2 8

(1024) 82 (256) 64 (512) 32 (64) 16 (32-+) 16 (128) 16 (64) 16 (256) 16 (64) 64 (256) 32 (128) 3 2

I

1 year

3 years

(32)

(32) --

--

<8 (16)

--

<8

<8

--

(32) 8 (32) <8 (64) <8 (64) <8 (32)

(32) <8 (32) <8 (32)

< 8

- -

<8 (8) - -

(16) 16 (128) <8 (16)

<8 (32) <8 (16)

<8 (16) <8 (16) --

-- -

- -

-- -

- -

- -

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

16 (32) <8 (32) < 8

<8 (64) <8 (16) - -

--- -

(16) - -

<8

.--

(16) --

<8

-

-

-

-

(8) - -

(128) 256 (1024) 32

I

<8 (8) 16 ( 1 2 8 +- )

(256) 128

2 years <8 (16) <8 (32) <8

(64) 32

I

<8 (4) 8 (32) 8

<8

(8) - -

- -

<8

<8

(128)

(8)

64 (128)

8 (64)

- -

-

-

(4) - -

- -

HI antibody tlters without parentheses performed by method of Rosen) 1 HI antibody titers with parentheses performed by method tlon and a subsequent decline in titer one to 3 years later. After revaecination a booster type response was observed in the 25 children

Volume 66 Number 3

Immunity in measles

483

pre.iously immunized children. Initial immunization was performed with live attenuated measles(F. A. V.) antibody titer before and alter vaccination Day after revaccination with live Edmonston B vaccine 0 z2 3 t4 t 5 [ 6 I 7 1 9 1 1 0 <8 (16)

<8 (16) 8 (32) <8.

(8) <8

- -

- -

<

(16) <8

- -

(16) - -

- -

< 8

- -

.

.

.

(16) .

.

.

.

.

- -

- -

<

8

- -

.

.

.

(16) .

.

.

.

.

.

.

.

.

(16)

<8 (32) <8

8

(32) 8

- -

- -

1 6

<8 (8) <8 (4) <8 (32) <8 (8) <8 (16)

<8

(32) <8 (32) <8 (32) <8 (16) <8 (8) <8 (16)

<8 (16) <8 (16) <8 (16) <8 (4) <8 (32)

- -

(64)

(32) - -

- -

< 8

- -

(8) .

.

.

.

.

.

.

.

.

.

.

.

.

<8 (16) 8 (32) <8 (32) .

.

.

.

.

.

.

.

.

<8 (16) <8 (32) <8 (32) .

<8 (32) 8 (64) <8 (32) .

<8 (64) 16 (128) <8 (32)

16 (64) 16 (64) 8 (64) 8 (32) 64 (128) 16 (64) 64 (256) 16 (64) 64 (512) 16 (64) <8 (32) 32 (128) 16 (32) 16 (64) 64 (256) <8 (32) 8 (32) <8 (64) 16 (64)

128 (512) 64 (256) 64 (256) 64 (1024) 128 (256) 64 (256) 256 (1024) 64 (256) 64 (512) 16 (128) 128 (512) 64 (256) 512 (1024) ---8 (32) 16 (128) 64 (512)

- -

- -

--- -

---- -

- -

---16 (128) 64 (512) 16 (64) 16 (64) 16 (128) 128 (512)

I

2z

I

256 (1024) 128 (512) 128 (512) 512 52048) 64 (256) 64 (512) 512 ~2048) 64 (512) 64 (256) 16 (128) 256 1024) 64 (256) ~512 ~4096) 16 (128) 64 (256) 32

128 (512) 128 (512) 128 (256) 256 (52048) 64 (128) 64 (256) 256 (1024) 64 (256) 32 (256) 16 (64) 256 (1024) 64 (256) 1024 (~4096) 8 (64) 64 (256) 32

16 (64) 16 (128) 64 (256) --

16 (64) 16 (64) 64 (128) 32 (64) 128 (1024) 64 (256)

(128)

- -

- -

- -

- -

- -

(256)

1 6

(64) 16 (64) 32 (256)

35 128 (256) 64 (256) 64 (256) 256 (~2048) 64 (128) 32 (128) 128 (512) 32 (128) 32 (128) 8 (32) 256 (512) 64 (256) 1024 (~4096) ------32 (64) 64 (1024) 128 (128) 8

(64) 16 (64) 32 (128)

of Norrby,16, lr The total group included 36 children. They had a fourfold or greater rise in antibody titer following initial vaccinalisted above; the remaining 11 children had no significant change in titer.

484

March 1965

K r u g m a n et al.

Table VII. Serial measles hemagglutination-inhibition antibody titers in 6 children who had naturally acquired measles in April 1960; effect of inoculation of live attenuated measles-virus vaccine, Edmonston B type, in April 1964 Hemagglutination-inhibition antibody titer Time interval after disease Days alter vaccination No, and name

1. Mon. 2. Sel. 3. Shu. 4. Vor. 5. Lew. 6. c a .

1960 I too.

196l l yr.

1962 2 yrs.

64 (128)

8 (64)

(32)

I I963 3 yrs.

1964 4 yrs.

<8

<8

(32)

(32)

8

64

32

16

8

(123)

(32)

(32)

(32)

~8

(16)

1 0

5

7

I2

21

<8 (32)

'<8 (32)

8 (32)

16 (32)

16• (64)

<8 (16)

8 (16)

8 (16)

16 (32)

8 (16)

16 (64)

16 (64)

32 (128)

32 (128)

64

16

8

~8

~8

(128)

(64)

(64)

(32)

(32)

8• (32)

~8

<8

8

32

16

16

(32)

(32)

(32)

(32)

(64)

(64)

32

16

16

8

(512)

(64)

(64)

(64)

64

32

8

8

~8

<8

<8

8•

8•

<8

(256)

(64)

(32)

(32)

(16)

(16)

(16)

(32)

(32)

(32)

32

8

<8

<8

<8

<8

<8

<8

<8

<8

(128)

(32)

(16)

(16)

(8)

(8)

(8)

(16)

(8)

(8)

H I antibody titers without parentheses performed by method of Rosen. 7a H I antibody titers with parentheses performed by method of Norrby. aG,17

RE-EVALUATION OF THE MEASLES H I A N T I B O D Y STUDIES

U T I L I Z I N , G A MORE S E N S I T I V E HI A N T I B O D Y T E S T The method described by Rosen 11 was used to determine H I antibody in the preceding studies. This H I antibody test was shown to be equally as sensitive as the neutralizing antibody test in studies reported by Black and Rosen, 13 by Cutchins, 12 and by our data in Table I. Recently, however, Norrby TM ~ reported that the sensitivity of the test was increased by treating the measles antigen with Tween 80 and ether (T-E). The untreated antigen used in the conventional test contained nonhomogenous particles with considerable variation in buoyant density, in size, and in morphology. In contrast, the T-E-treated antigen had a homogeneous population of small hemagglutinin particles. The increase in sensitivity of the H I test performed with T-E-treated antigen was probably a reflection of the smaller amount of antibody required to inhibit one hemagglutinin unit. Norrby re-

ported that his test was 5 to 10 times more sensitive than the neutralizing antibody test or the H I antibody test performed with untreated antigen. The method described by Norrby was used to repeat the titrations of serial serum specimens collected from children who had nondetectable H I antibody 1 to 4 years following natural infection or successful vaccination with live attenuated measles virus vaccine. The antibody titers observed with this method are recorded in parentheses in Tables IV, VI, and VII. The results are very dramatic. Table I V shows the serologic response of 2 children following vaccination with live further attenuated vaccine and subsequent exposure to 14 children with naturally acquired measles. The H I antibody test performed with untreated antigen revealed no detectable antibody ( < 1 : 8 ) , 1 and 2 years after vaccination. In contrast, the more sensitive test with T-E-treated antigen revealed H I antibody titers of 1:16 and 1:32 in aliquots of the same serum specimens. After

Volume 66 Number 3

an intimate exposure to measles these H I antibody levels were boosted to a titer equal to or exceeding 1:2,048. A similar phenomenon was observed in the studies recorded in Tables VI and VII. The more sensitive H I test revealed evidence of detectable antibody in virtually all serum specimens obtained after vaccination or natural infection. A booster response was observed on the seventh day after revaccination with live attenuated measles vaccine, Edmonston B type. The study on persistence of measles H I antibody, 1 to 4 years after natural infection and vaccination, was re-evaluated with the more sensitive test. The following 43 convalescent serum specimens, previously lacking in detectable H I antibody, were available for retest: 6 following natural measles, 3 following live Edmonston B vaccine, 5 following live Edmonston B vaccine plus gamma globulin, 27 following live further attenuated vaccine plus gamma globulin. T h e more sensitive test revealed the presence of H I antibody in all 43 serum specimens; a titer of 1:16 was detected in most of these convalescent sera. The study on persistence of passively acquired measles immunity during the first year of life was re-evaluated. When the conventional H I antibody test n was used, passive antibody was not detectable after 6 months of age (Fig. I). However, the more sensitive test is, 17 revealed evidence of antibody as late as 11 months of age. Passively acquired measles antibody in low titer was observed in 20 per cent of 40 infants 9 months old, in 12 per cent of 54 infants 10 months old, and in 8 per cent of 48 infants 11 months old. There was no evidence of detectable measles antibody in sera obtained from 27 infants 12 months of age. DISCUSSION These studies have provided data which should clarify some of the questions regarding the mechanism and the persistence of immunity to measles following natural infection and vaccination. The following concept of the development of immunity to

I m m u n i t y in measles

485

measles is based upon our interpretation of the various studies reported in this paper. Infants whose mothers have had measles are born immune to the disease. Their passively acquired measles antibody may decline to nondetectable levels as early as 2 months or as late as 11 months of age. Infants with a high titer of transplacentally acquired antibody should be solidly protected if exposed to measles. The mechanism of protection is probably due to the prompt neutralization of wild measles virus and complete inhibition of infection. On the other hand, if exposure to measles occurs when passive antibody has declined to minimal or nondetectable levels, some multiplication of virus may take place in spite of the presence of antibody. These circumstances may lead to passive-active immunity which may follow a subclinical infection or a mild illness with or without rash. This passive-active type of immunity appears to be solidly protective and permanent. A similar type of immunity may be observed in older infants and children who receive gamma globulin shortly before or after an exposure to measles. After passive immunity has waned, exposure to measles will be followed by the classical unmodified disease with rash and the usual antibody response shown in Fig. 2A. Measles antibody may be detectable by the first day of rash, approximately 14 to 16 days after exposure. Peak antibody levels are observed about 2 weeks later, one month after exposure. In most individuals measles antibody persists for many years at a level capable of completely neutralizing measles virus acquired by intimate exposure to contagion. In a small number of persons the antibody titer may decline to minimal or nondetectable levels. Under these circumstances, adequate antibody may not be available for the prompt neutralization of measles virus. The consequent multiplication of virus provides an adequate antigenic stimulus to initiate the booster type of response illustrated in Fig. 4. The early appearance of antibody probably inhibits further multiplication and spread of measles

486

March 1965

Krugman et aI.

virus, thereby preventing the clinical disease. The infection which is inapparent can be detected only by serial serologic studies. The pattern and the persistence of the antibody response following a single inoculation of live attenuated measles-virus vaccine has been remarkably similar to the response following natural infection. The same recall phenomenon has been observed following reinfection with measles virus (Tables I V and V I and Fig. 4). Therefore, it seems reasonable to postulate that one inoculation of potent live attenuated measlesvirus vaccine will induce the same type of lasting immunity which follows the natural infection. H o w does one reconcile this hypothesis of the mechanism of immunity to measles with observations in patients with agammaglobulinemia? These patients are reported to develop normal immunity to measles in spite of their failure to produce neutralizing antibodies in discernible amounts. Black is has had an opportunity to test sera from 7 patients with agammaglobulinemia. These serum specimens were obtained before treatment was initiated with g a m m a globulin. Utilizing a highly sensitive plaque-reduction test for measles neutralizing antibodies, he demonstrated measurable titers in 3 of the 7 patients. Three of the negative reactors were young enough to have been nonimmune. In view of these observations, it is probable that patients with agammaglobulinemia may produce minimal or nondetectable quantities of antibody, adequate enough to provide immunity to measles. Studies have been initiated to determine the mechanism of immunity after vaccination with inactivated measles vaccine. The available data indicate that the antibody titers decline rapidly to low or nondetectable levels. Karelitz and associates 19 studied 49 children for persistence of neutralizing antibody 6 to 9 months after 3 doses of killed vaccine; neutralizing antibody was no longer detectable in 14 (28.6 per cent) of the children. Evidence has been presented which indicates that subsequent exposure to measles m a y be followed by an inapparent

infection, a mild modified disease, or a typical case of measles. I t is clear that antibod), though nondetectable, may be adequate enough to suppress disease without suppressing infection. Immunity to measles following inoculation with killed vaccine is dependent upon an adequate subsequent exposure to wild virus or live attenuated measles-virus. Studies in progress will attempt to clarify the mechanism of immunity associated with inactivated measles vaccine immunization and subsequent exposure to live measles virus. The studies in this report have provided data which support the observation that the height of the antibody titer following natural infection or vaccination with live vaccine was of no practical importance. The same durable type of immunity to clinical measles was observed in children with low antibody titers as well as in those with high antibody titers. These studies provide strong support for the well-known observation that one attack of measles is followed by lifelong immunity. These studies also provide strong support for the prediction that one inoculation of potent live attenuated measles-virus vaccine will be followed by lifelong immunity. SUMMARY

1. Studies on immunity to measles have been in progress since 1960. During the past 4 years serial serologic observations have been made on groups of children whose immunity to measles was acquired as follows: (a) transplacentally at birth; (b) following natural measles; or (c) following vaccination with live attenuated measles-virus vaccine, inactivated vaccine, or combined inactivated-live vaccine. 2. A comparison of the complement fixing (CF), hemagglutination inhibition ( H I ) , and neutralizing antibody response following an inoculation of live attenuated measlesvirus vaccine, Edmonston B type, revealed the following: (a) Neutralizing and H I antibody were both detectable by the twelfth day after vaccination; CF antibody appeared on the fifteenth day. (b) Peak titers of CF,

Volume 66 Number 3

H I , a n d neutralizing a n t i b o d y were observed by the twenty-first to the twenty-eighth day. (c) Neutralizing a n d H I antibodies persisted at detectable levels for longer periods of time t h a n C F antibodies. (d) T h e H I antibody test was the most sensitive a n d most p r a c t i c a l serologic p r o c e d u r e for the study of i m m u n i t y to measles. 3. A longitudinal study of measles imm u n i t y in 107 infants d u r i n g the first year of life revealed: (a) Passively acquired measles H I a n t i b o d y was detected in 94 per cent at 1 m o n t h , 47 p e r cent at 4 months, 26 p e r cent at 6 months, a n d none at 7 months. (b) O f 8 infants who were exposed to measles, 6 h a d a modified disease or subclinical infection with evidence of passiveactive immunity. 4. A longitudinal study on the persistence of measles a n t i b o d y 1 to 4 years following n a t u r a l infection a n d vaccination revealed: (a) T h e p a t t e r n a n d persistence of the H I antibody response was similar following natural infection a n d vaccination with live att e n u a t e d measles vaccine, E d m o n s t o n B type, and further a t t e n u a t e d type, with a n d without g a m m a globulin. (b) A d d i t i o n of g a m m a globulin a n d f u r t h e r a t t e n u a t i o n of live vaccine was followed b y a lower geometric m e a n a n t i b o d y titer a n d an increased per cent of children with low or n o n d e t e d t a b l e H I a n t i b o d y levels. (c) A f t e r a c o m b i n e d inactivated-live vaccine regimen the H I a n t i b o d y level was h i g h e r a n d persisted longer when the interval between the last killed vaccine inoculation a n d the live vaccine was increased from one m o n t h to 8 to 10 months. 5. C h i l d r e n with m i n i m a l or n o n d e t e c t able H I a n t i b o d y , 1 to 4 years after a successful v a c c i n a t i o n with live vaccine, were challenged b y exposure to measles or revaccination with live vaccine. N o clinical reactions were observed. A significant booster type of response o c c u r r e d in 70 p e r cent of the children; a rise in H I a n t i b o d y was detectable b y the sixth or seventh d a y a n d p e a k titers were r e a c h e d by the twelfth day. A booster response was not observed in children with high levels of antibody.

Immunity in measles

487

6. R e - e v a l u a t i o n of the measles H I antib o d y studies by means of a r e c e n t l y described m o r e sensitive H I a n t i b o d y test revealed evidence of a n t i b o d y in all serum specimens collected 1 to 4 years a f t e r n a t u ral infection a n d v a c c i n a t i o n w i t h live vaccine. A n a n t i b o d y titer of 1:16 was d e t e c t e d in most convalescent sera which were observed to h a v e no d e t e c t a b l e a n t i b o d y with the conventional H I test. Passively a c q u i r e d m a t e r n a l a n t i b o d y was detectable as late as 11 m o n t h s of age; it was not d e t e c t a b l e at 12 m o n t h s of age or older. 7. These studies provide strong s u p p o r t for the well-known observation t h a t one attack of measles is followed b y lifelong immunity. These studies also p r o v i d e strong s u p p o r t for the p r e d i c t i o n t h a t one inoculation of p o t e n t live a t t e n u a t e d measles-virus vaccine will be followed b y lifelong immunity.

We are indebted to Dr. Paul H. Hoch, New York State Commissioner of Mental Hygiene, to Dr. Jack Hammond, Director, and Dr. Harold H. Berrnan, former Director, Willowbrook State School, for their cooperation and help. The assistance of Mrs. Cass Lattimer and Mrs. Alma Bertolini is acknowledged with appreciation. The cooperation of the medical, nursing, and administrative staff of the East Nassau Health Insurance Plan Group is greatly appreciated.

REFERENCES

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