CLINICAL RESPONSE TO IMMUNIZATION WITH CENDEHILL STRAIN RUBELLA VACCINE

(1)

(Received March 5; revision accepted for publication June 12, 1970.)

ADDRESS: (K.D.R.) Department of Community Medicine, School of Medicine, University of

Pitts-burgh, Pittsburgh, Pennsylvania 15213.

PEDIATRICS, Vol. 47, No. 1, Part I, January 1971

ARTICLES

CLINICAL

RESPONSE

TO

IMMUNIZATION

WITH

CENDEHILL

STRAIN

RUBELLA

VACCINE

K. D. Rogers, M.D., George Ramirez, M.D., Manuel Cortez, M.D., Richard Michaels, M.D.,

Michael Savin,

M.D.,

Robert Montgomery, M.D., Thomas Welty,

M.D.,

Floyd Taylor, Sc.D., and Robert A. Hingson, M.D.

From the Department of Community Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

ABSTRACT. Approximately 1,100 institutionalized Costa Rican children and young women were ob-served daily for 25 days following immunization with Cendehill strain rubella vaccine or placebo. Observations were made double blind by specially trained public health nurses supervised by a physi-cian.

Three subgroups were identified: preimmuniza-tion seropositive subjects receiving vaccine (S+); preimmunization seronegative subjects receiving vaccine (5-); and preimmunization seropositive and seronegative subjects receiving placebo (P). The 25 day observation time was divided into 5-day periods. For both sexes, two age groups, and each time period the number of days was recorded on which was present one or more of 13 signs and

symptoms considered likely to reflect vaccine re-action. 5- and P,S+ groups were compared statis-tically for each symptom or sign, time interval, and age sex subgroup.

Most post-immunization signs and symptoms were not severe or disabling, of high prevalence, or usually more common in 5- than P,S+ sub-jects. There were significantly higher frequencies of posterior auricular, posterior cervical, and occip-ital lymphadenopathy in 5-. than P,S+ children less than 15 years of age. Females had higher fre-quencies of headache and arthralgia than did the

males studied, but frequencies in 5- and P,S+ groups did not differ significantly. Pediatrics, 47:7, 1971, CENDEHILL, RUBELLA, VACCINE, CLINICAL RE-ACTION.

C

UNICAI. trails of Cendehill vaccine have differed in the reported fre-quency of clinical signs and symptoms

oc-curring

in the post-vaccination period.19

“None” or few to as high as half or more subjects have been reported to show post-vaccination fever, joint pains, rash, lyinphad-enopathy, or upper respiratory tract infec-tion. Differences may in part be explained by small numbers of observations in some reports, failure to use placebos and double blind design in some trials, and varied fre-quency and methods of observation. Clini-cal observations in some studies have been

made

daily

by physicians

while

in others

they have consisted only of volunteered re-ports from patients or their families. Sev-eral observers have noted that signs and symptoms considered to result from rubella vaccination are seen in nonsusceptible or

unvaccinated subjects with similar

fre-quency,”3’6’1#{176} but usually quantitative sub-stantiation of

such

statements has not been made.

The clinical trial reported here was un-dertaken to determine the frequency and character of reactions of children and adults to Cendehil strain rubella vaccine.

The

study

used placebo controls, a double

blind design, and daily clinical observation of subjects for 25 days post-immunization.

Subjects

MATERIALS AND METHODS

The

study was performed under the

sponsorship

of the Ministry of Public

(2)

TABLE I

PLACEBO CONSTITUENTS AND PERCENTAGES

Placebo Constituents Percentages

Sodium Chloride, Reagent, Baker 0.8300 Sodium Phosphate, Dibasic, Reagent, 0. 070

Anhydrous, Baker

Potassium Phosphate, Monobasic, 0.0018 Reagent, Baker

Phenol Red (Reagent) Fisher Scientific 0.0009 Sodium Hydroxide Solution (% W/V) 0.1500 V/V Sodium Phosphate Monobasic Solution 0. 3q50 V/V

(Q.5% W/V)

Water for Injection (Abbott) q.s. ad. 100.00

who were in convents and prisons. All sub-jects were presumably well, and there was no evidence of naturally occurring rubella or rubella-like illness at the time of the study.

Vaccine and Placebo

The vaccine contained the Cendehill strain of rubella virus attenuated by serial

passages

in

primary

rabbit

kidney

cells.3

Each

dose contained 3,000 PFU (TCID50),

and

vaccine was reconstituted from its fro-zen, lyophilized form with 0.5 cc of sterile

water

immediately

before

injection.

The

placebo

consisted of sterile water

with trace amounts of salts and phenol red

(Table I). The vaccine or placebo was in-jected subcutaneously in

the

left

deltoid

area.

Subjects were assigned numbers prior to

study,

and

10% of these were randomly

chosen to receive a placebo while the re-mainder received vaccine.

Antibody Determinations

Immediately before injection of rubella vaccine or placebo, 10 cc of venous blood were collected. Blood samples were centri-fuged and sera separated and frozen for later assay of rubella hemagglutination in-hibiting (HI) antibody by a semiauto-mated microtiter procedure.14

From 95 to 104 days following

immuniza-tions, another sample of 10 cc of venous blood was obtained from all (332)

origi-nally

seronegative

subjects

who

were

avail-able. Blood samples also were obtained

from 224 originally seropositive subjects. These latter subjects were not specially se-lected but represented all seropositive sub-jects in the larger institutions studied.

Sec-ond blood samples were tested for rubella HI antibody in the same manner as the first.

Observations

In the 25 days after immunization,

sub-jects were

observed

daily

by

specially

trained public health nurses. They followed

a standard protocol which described the daily examination procedures in detail and

gave criteria for reporting findings. Nurses

were supervised by a physician whom they

consulted when they needed assistance with

TABLE II

NUMBER OF SUBJEC’rs BY AGE, SEX, AND VACCINE STATUS OBSERVED

FOUR OR MORE DAYS IN EACH FIVE DAY TIME PERIOD

Male Female

Time 1 yrs and less 15 yrs and over 14 yrs and less 15 yrs and over

Penod

--P 8+ 8- P S+ 8- P 8+ 8- P 8+

8-I 33 04 116 14 108 5 31 11 140 18 86 59

II 30 194 116 H 96 0 31 H6 139 17 80 56

III 31 176 108 H 93 15 3 119 140 15 75 5

IV 8 156 97 11 75 16 31 119 138 15 77 5

(3)

TABLE III

PREIMMUNIZATION RUBELLA Ill ANTIBODY TITER

Data

Age in Years

Total

.

Subjects

Under 5 5-9 10-14 15-19

-20+

Males

Total 8 H8 257 109 3 560

Percent negative 63 56 30 1 34 187

Mean positive titer 03 153 13 177 181 373

Females4

Total 8 125 167 158 80 .538

Percent negative 88 64 33 49 4 38

Mean positive titer 56 174 196 156 161 300

* Two females, age unknown, titers were negative and 1: 56.

their observations or judgments. The physi-cian visited each nurse at least weekly to review her records and to ascertain her ad-herence to the study protocol. The nurse’s daily observations consisted of oral temper-ature; palpation of lymph nodes (posterior auricular, posterior cervical, occipital, ante-nor cervical) for enlargment and tenderness; inspection of skin for evidence of exanthem

(

head,

chest, arms, legs); inspection of vac-cine injection site for evidence of inflamma-tion and tenderness; and determination by direct question of presence of arthralgia,

headache,

cough, nausea, and vomiting or

other untoward symptoms.

Oral temperature above 38#{176}Cwas

con-sidered

elevated,

and observation

of any of

the other

signs and symptoms was recorded

as either present or absent without respect to severity or extent. Nurses amplified their observations in explanatory notes which were used by

the

supervising physician in final decisions as to whether a sign or symp-tom should be recorded as present or absent. All observations were double blind with

respect

to preimmunization antibody and

vaccine or placebo status.

Not all

subjects

were available for

obser-vations on each of the 25 days post-immu-nization or for second bleeding. In some instances subjects were transferred or dis-charged from their institution even though

the original selection of subjects had been on the basis of those expected to be institu-tionalized for 90 days or more after immu-nization. In some instances subjects were not available for observation on given days because institutional programs prevented

their being available,

e.g., travel outside

the

institution.

Data Analysis

The 25 days of patient observations were divided into five periods of 5 days each. If

the patient

had

been observed on at least 4

of the 5 days in a given period, data for that period were used.

Subjects were grouped according to pre-immunization antibody status (antibody less

than 1:8 and antibody

1:8

or greater), immunization received (vaccine or pla-cebo), sex,

and age

(14 years or younger and 15 years or older).

Within

each

age and

sex

group,

three

groups

were observed: (1)

preimmuniza-tion seropositive subjects who received vac-cine (S +); (2) preimmunization seronega-live subjects who received vaccine (S -); and (3) preimmunization seropositive and seronegalive subjects who received placebo

(4)

10

RUBELLA

IMMUNIZATION

TABLE IV

POST-IMMUNIZATION RUBELLA HI ANTIBODY OF

PREIMMUNIZATION SERONEGATIVE SUBJECrS

1)020

Poe t-irnmu nizoiio n Titer

-<1:8 1:8 1:16 1.3k 1:64 1:1S 1:t’56

-Greater

Vaccine 7 14 39 103 103 7 5

N98

Placebo 31 1

N 35

and so forth) was positive. Table II records the number of subjects observed for 4 or more days in each 5-day time period (I-V), age, sex, vaccine group.

Statistical evaluation of the effects of the vaccine in the various subgroups was made using the H-statistic. This statistic is a dis-tribution-free test based on ranks. It is a general test of identity of distribution among two or more groups and does not de-pend entirely either on the use of difference in location or dispersion.’ The H-statistic was applied to the reported frequency of a given symptom during a 5-day interval. Comparisons were made on a pair-wise ba-sis for each symptom or sign and for each time interval within each age and sex sub-group.

RESULTS

Preimmunization Status

As noted in Table III, preimmunizalion

rubella HI antibody seronegativity tended to decline with age except in females aged

TABLE V

POST-IMMUNIZATION RUBELLA HI ANTIBODY OF

PREIMMUNIZATION SaaoPosxTzvE SUBJECrS

Post-immun izalion .Ini ibody Titer Mean Titer

Data Preimmu- Poet.

Unchanged lncrea.,cd Decreased nization ir*mu-ni;ciion

Vaccine 98 68 43 180 199

N =09

Placebo 9 8 1 155 I8

N-iS

15 to 19 years. More than half the children younger than 10 years were seronegalive (titer less than 1 :8) and females had higher rates of seronegativity than males.

Post-immunization Status

Fifty

placebo-injected subjects and 507

vaccine-injected subjects were rebled ap-proximately 100 days after initial bleeding and injection (Tables IV and V) .

Ninety-seven percent of the seronegalive vaccine-injected subjects showed antibody rise-al-most all at levels 1 : 16 or higher. One of

the seronegative placebo-injected subjects

showed an antibody rise; the remainder stayed seronegative. For both the placebo-and vaccine-injected groups, approximately

90% of the initially seropositive subjects had titers on rebleeding that were within one tube dilution of their preinjection sta-tus. Of second antibody titers not identical with first ones, more were increased than were decreased. Response to vaccine was not age related for subjects with the similar preimmunization titers.

Symptoms and Signs

Data were analyzed to test the hypothesis

that the originally seronegalive subjects

who received vaccine

(

S-

)

would have

more reactions than the seropositive

sub-jects who received vaccine (S +) or any of the subjects who received a placebo (P). H-statistic paired analyses were made for

each of 13 symptoms or signs, each of five

time periods, two vaccine groups [sero-negative vaccine subjects (S

-)

and all placebo subjects combined with

seroposi-live vaccine subjects (P, S

+)},

two age

groups (less than 15 years and 15 years and over), and two sex groups. Thus, there were 520 paired analyses (13 X 5 X 2 X 2

X 2). Of these, 20 were at a level of

statistical significance of p = .01 or less.

Nineteen of these were consistent and one

inconsistent with the hypothesis.

The frequency with which various signs and symptoms were observed is shown in

Table VI both as the average for all five

(5)

pe-nods. In Table VII is shown the time pe-nod and age/sex group in which S-

sub-jects showed a statistically higher fre-quency of specific signs and symptoms than did P and S + subjects.

The first eight signs and symptoms listed in Tables VI and VII were relatively infre-quent. Generally, they were not more com-mon at statistically significant levels in S

-than P,S + subjects except in the four in-stances noted in Table VII. Cough was more frequent in all time periods in females under age 15 than in males and older fe-males, but its frequency was not statisti-cally different in any time period between S- and P,S+ groups.

Postauricular adenopathy, while more commonly observed in younger than older subjects, had a maximum prevalence of

only 21% in any sex/age/vaccine/time subgroup. It was more common at statisti-cally significant levels in young S- subjects

of both sexes than P,S + ones in time peri-ods II and III and in older male S- subjects

in periods III and V.

Postcervical and occipital adenopathy were observed frequently-more often in younger than older subjects and among

younger subjects about twice as frequently in S- than P,S + ones. These latter

differ-ences were at statistically significant levels and were seen in four of the five time pen-ods. Postcervical and occipital adenopathy were observed in approximately three quan-tens of young S- subjects during at least one

time period.

Submaxillary adenopathy was seen com-monly in all time periods and in both sex and age groups. Only in one time/age/sex subgroup was this sign observed more fre-quently in S- than P,S + subjects.

Headache and arthralgia, while not more

frequent in S- than P,S + subjects were

more common in females than males and in older than younger females. In females

under age 15, P,S + subjects had a

statis-tically significantly higher frequency (p =

<.01) of headache in period II than did

S- subjects. This was the only instance in

which the hypothesis was not supported that S- subjects would have more reaction

than P,S+ ones.

Because adult females have been re-ported16’17 to be more likely than other age-sex groups to have arthralgia following immunization with rubella vaccine, the

ob-TABLE VI

AVERAGE AND RANGE oi PERCENTAGE OF SYMPTOMS AND SIGNS PRESENT ONE I)AY OR MORE PER PERIOD

Symptom or Sign

Male Female

lye 1.e.t.t Than 1.5 Year., lye 1.5 Fears and More Age less Than li Years lye 15 Years and Mccc Pond 8+ 8- PandS+ .S- PandS+ 5- PandS+

5-Nauseaandvomiting Injection site

induration Injection site

tenderness

.1% (0-1) .4%(0-1)

.3 (0-i) .4 (0-5)

2 (1-3) 1 (0-3)

.4% (0-1) 0% (0)

.4 (0-1) 0 (0)

5 (0-5) 0 (0)

.4% (0-5) .4% 0-1)

1 (0-1) .4 (0-1)

2 (2-3) 1 (0-5)

1%(0-2) 1% (0-5)

.4 (0-1) 2 0-4)

1 (0-2) 4 (2-10)

Fever Cough F.xanthem extremities Exanthem (head) I)xanthem (trunk) Adenopatby (post.auricular) Arthralgia headache Adenopathy (post-cervical occipital) Adenopathy (submaxillary)

1 (0-3) .5 (1-9)

0 (0) .4 (0-1)

5 (0-7) 3 (0-9)

2 (0-6) 5 (0-6)

3 (2-7) 7 (5-11)

6 (2-9) 13 (9-21))

3 (1-8) 2 (1-4)

1 (0-5) 1 (0-3)

36 (59-48) 65 (41-77)

43 (35-56) 48 (36-59)

2 (0-3) 2 (0-10)

1 (0-3) 0 (0)

.4 (0-1) 0 (0)

.5 (0-iS) 4 (0-14) 1 (0-3) 6 (0-20)

5 (0-10) 7 (6-1.5)

3 (0-7) 2 (0-7)

1 (0-3) 0 (0)

52 (10-43) 20 (4-38)

.54 (48-60) .54 (44-64)

1 (0-4) 5 (0-3)

15 (5-17) 8 (5-10)

3 (3-7) 6 (i-IS)

4 (1-7) 2 (0-5)

7 (1-11) 11 (2-15)

6 (5-8) 11 (4-21)

13 (9-17) 10 (8-11)

18 (13-22) 10 (6-13)

34 (28-49) 55 (41-68)

39 (25-57) 41 (20-63)

5 (0-3) 0 (0)

.4 (0-1) 3 (5-6)

3 (1-7) 4 5-7)

1 (0-15) 7 5-12)

7 (2-14) 7 (?13)

3 (0-7) 4 (0-6

17 (10-58) 24 1.5-36)

30 (20-39) 21 (13-31

15 (7-18) 19 (11-31

(6)

TABLE VII

SIGNS AND S &P’MS OBSERVED WITH STATISTICALLY SIo?mrIcAir GREATER

FREQUENCY IN S- THAN P, S+ SUB.TECTS

Age Less Than 15 Years Age 15 Years and More

Symptom or Sign

Time Period Time Period

iH

w

JfF if F M F M F MFMFMFMFMFMF

x

Nausea and vomiting Injection site

induration Injection site

tenderness Fever Cough Exanthem

(extremities) Exanthem (head) Exanthem (trunk) .&denopathy

(post-auricular) Arthralgia Headache Adenopathy

(post-cervical occipital) Adenopathy

(submaxillary)

X=p= .01

XX=p= .001

XXX=p= .0001

x

x xxxxxxx x

x

xxx

x

xx

x

12

RUBELLA

IMMUNIZATION

servation of this symptom was of special

in-terest. As noted in Table VIII, arthralgia (history of joint ache, pain, or stiffness in preceding 24 hours) was present in young as

well as older females although it was more

frequent in the latter group. There was no discernible association of arthralgia with

time following immunization, and there were no statistically significant differences in its frequency in S +, S-‘ and P groups in

different time periods.

In summary, most of the signs and symp-toms observed did not occur with high fre-quency in any subject group in any lime period and were not significantly more fre-quent in S- than in P and S + subjects.

Signs and symptoms were not severe nor

disabling. The most marked and consistent

response was in children less than 15 years

who showed significantly higher

frequen-cies of posterior auricular, posterior cervi-cal, and occipital adenopathy in S- as

com-pared to P and S + subjects. Most of these occurred from day 6 through 25. Females,

especially those 15 and older, had higher

frequencies than males of headache and

arthralgia, but these symptoms did not dif-fer in frequency between the S- and P

and S+ groups.

Further Analyses of Reactions

In subsequent analyses the seropositive vaccinated (S +) and the placebo (P)

(7)

sero-1. years and less

S+

15 years and over

5- P

flme S+

-

5- P

---

-

---

-

---No. Symptoms No. Symptoms

.0 .0

.Vo. Symptoms

...(/

#{149}/(

No. Symptoms No. Symptoms No. Symptoms

- (

/ /0 /0

No. Observed .Vo. Observed

I 11/110 10 13/17 10

.V0. Observed No. Observed No. Observed No. Observed

3/8 11 0/86 3 1/59 36 9/18 50

11 14/11) H 15/H4 12 5/31 16 13/80 16 13/56 3 6/17 35

III 18/119 15 16/140 11 7/3 7/75 9 10/5 19 /15 13

IV 16/1 19 13 15/138 11 6/3! 19 9/77 1 14/5 17 4/15 7

V o/103 10 11/131 8 6/30 0 9/71 13 8/53 15 1/17 6

11 18 15

Average All Periods

TABLE VIII

FEMALES REPORTING ARTHRALGIA (By AGE AND VACCINE SUBGROUPS)

positive subjects had reacted to the vac-cine, they would have maximum chance of being identified, e.g., reactions in which S + > P. There were no instances in which this occurred.

As in the other analyses, most of the sig-nificant differences were in the greater fre-quency of posterior auricular, posterior cervical, and occipital adenopathy in the S- than in other subjects.

DISCUSSION

Observations in this study must be viewed with respect to special conditions which make it difficult to identify separate effects of age, sex, and observer bias. Be-cause subjects were institutionalized, per-sons of the same sex and similar age were grouped. Nurse observers were assigned to individual institutions. Thus, what might appear to be an age or sex associated preva-lence of a sign or symptom, could be a consequence of greater or lesser sensitivity

of different observers or the concomitance of symptomatic disease in a specific institu-tional population.

Many of the findings of the Costa Rica study were consistent with those of other rubella immunization studies. These in-cluded increased frequency of naturally ac-quired seropositivity with increasing age,

and development of HI antibody in almost all seronegative immunized subjects. The

absence of antibody rise in seronegative placebo recipients living with immunized subjects was consistent with previous obser-vations of failure of Cendehill strain vac-cines to infect susceptible subjects.

The special characteristic of the study re-ported here was the double blind careful daily clinical observation by trained nurses following a standard protocol. Signs and symptoms suggesting vaccine reaction were reported more commonly in this than in other studies. This high prevalence

prob-TABLE

ix

HYPOTHETICAL EXAMPLE OF DISTRIBUTION OF

O13.sERv.tTIoNs IN 79 SUIUECTS

Days

Charac-teristic

Observed

----P

1mm on izalion. Group

---S- Total

5+

0 10 5 17

1 10 11

5 3 1

3 0 4 0 4

4 0 0 4 4

5 1 0 1

(8)

14

ably was a consequence of the detailed ob-servation rather than a genuinely higher reaction rate. The frequent occurrence of signs and symptoms in the P and S+ groups as well as in the S- group

mdi-cated their probable unrelatedness to the vaccine. Even those reactions showing high-est association with vaccine were not uniquely observed in S- subjects. About

25%

S

- as compared to approximately 1

vs -4-

subjects exhibited posterior auricular

adenopathy at some time

post-immuniza-tioii. About 75% 5- and 40% P,S+ subjects

were observed to have posterior cervical and occipital lymphadenopathy.

Of interest was the observation that prey-alence of arthralgia was not vaccine re-lated, did not vary significantly from one time period to another, was much more fre-quent in females than males of all ages, and was reported by about 20% of younger and 40% of older females. These findings, while differing from those of Cooper, et al.b6 and

Horstmann, et al.,17 agreed with reports of Marshall, et al. and Gold, et al.18 although

prevalence rates in the present study were higher. The disagreement concerning the association of Cendehill vaccine immuniza-tion with arthralgia and arthritis may be ex-plained in part by study design and age of subjects. Studies, including the present one, in which arthralgia was not considered vac-cine associated, employed some kind of control populations, whereas studies report-ing associations observed only immunized susceptibles. When arthritis and arthral-gia have been reported following Cen-(lehill or other rubella vaccines, rates have been higher in older women. Almost all women in the Costa Rican trial were less than 30 years of age and most were under 25.

ADDENDUM

The El-statistic is a rank randomization test for identical populations which is sensitive to differ-ences in location. In this study, each subject in (acl1 time period could have from 0 to 5 days in which he exhibited a certain characteristic. Table IX is a hypothetical example of the distribution of

hservations in 79 subjects. The rank of each

mdi-vidual in the total group is determined with re-spect to number of days in which a characteristic is

observed. In the example in the table, 79 ranks are possible. There are 17 subjects with “0” days-an

average rank of 8.5. Ranks 18 through 40 are

sub-jects who have one day on which the characteristic was observed-an average rank of 34. Ranks 41 through 69 are those with 2 days of positivity, and so forth.

The H-statistic is modified to take into account the presence of tied values, i.e., those individuals with the same average rank. Subsequent to correc-tion, the H-statistic is compared to the appropriate Chi Square value.

If there were no differences in subgroups P,S+ and S- with respect to frequency of occurrence of a given characteristic, the ranks of subjects should be randomly distributed in each subgroup. The H-statistic determines this. if ranks are not randomly distributed, the null hypothesis (that the groups are not dissimilar ) is rejected at whatever level of probability is selected, e.g., p = .05, .01,

and so forth.

SUMMARY

Approximately 1,100 institutionalized

Costa Rican children and young adults given Cendehill strain rubella vaccine in a

double blind vaccine-placebo study were observed daily for clinical evidence of

reac-tion during 25 days post-immunization.

Many signs and symptoms which logically might have been considered related to im-munization were observed. However, most

were no more common at statistically

sig-nificant levels in vaccinated seronegative

than in vaccinated seropositive subjects or placebo recipients. Arthralgia, in particular.

was not vaccine related. Only posterior

au-ricular, posterior cervical, and occipital lymphadenopathy were more frequent at statistically significant levels over periods of 10 or more days in vaccinated seronegative subjects. This difference was approximately two-fold and was seen in children under

age 15 but not in older persons. No serious

or disabling reactions were observed in any

of the immunized subjects.

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Acknowledgment

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analy-1971;47;7

Pediatrics

Montgomery, Thomas Welty, Floyd Taylor and Robert A. Hingson

K. D. Rogers, George Ramirez, Manuel Cortez, Richard Michaels, Michael Savin, Robert

RUBELLA VACCINE

CLINICAL RESPONSE TO IMMUNIZATION WITH CENDEHILL STRAIN

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