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Experience with rubella and rubella immunization in institutionalized children
July, 1973 The Journal of PEDIATRICS
51
Experience Mth rubella and rubella immunization in institutionalized children Serial monitoring o/rubella hemagglutination-inhibiting antibodies in institutionalized children revealed that 4 o / 1 6 nonvaccinated rubella-susceptible children had developed antibodies and 4 of 29 children immunized with Cendehill rubella vaccine had a fourfold or greater increase in hemagglutination-inhibiting antibodies between the second and fourth years a#er vaccination. Five of 19 naturally immune children had a fourfold or greater rise in antibody titer during the same 4 ')'ear interval. This apparent spread of wild virus occurred within three building with a population estimated to be 91 per cent "'immune." The vaccinees have shown a slight fall in hemagglutination-inhibiting antibody titers over t h e / o u r years, and both the vaccines and naturally immune children who experienced the "'booster" response had titers lower than the others. These observations cast doubt on the ability of "herd immunity" to prevent the spread of wild rubella virus.
John D. Farquhar, M.D., P h i l a d e l p h i a , Pa.
T H E P R E S E N T policy in this country t o control the spread of rubella and prevent the congenital rubella syndrome is to immunize all young children to produce a herd immunity and thereby reduce the exposure of women of childbearing age? This indirect approach was considered necessary because of the understandable concern about administering a live virus vaccine to the target g r o u p - - w o m e n of the childbearing a g e - because a certain number of pregnant women might be vaccinated inadvertently.
From the Presbyterian-University of Pennsylvania Medical Center, and the " Department of Pediatrics, University of Pennsylvania. Supported in part by Research Grant CC 00623 from the C e n t e r / o r Disease Control, Atlanta, Ga. Reprint address: 3910 Powelton Ave., Philadelphia, Pa. 19104.
Evidence is accumulating which challenges the wisdom of this approach? -s From a practical point of view, it is highly improbable that 90 per cent of the population could be immunized against rubella. The follow-up observations have not been carried out long enough to know whether antibodies, induced by the presently licensed rubella vaccines given in early childhood, will persist long enough to protect women of childbearing age. Experience has shown that the HPV-77 and Cendehill vaccines are limited in their ability to produce a booster response. '~-~e Recent observations suggested that the presence, of hemagglutination-inhibiting ( H A I ) antibodies does not prevent the spread of the rubella virus through an institutional population. 2~ The experience to be described indicates that rubella virus Vol. 83, No. 1, pp. 51-56
52
Farquhar
The Journal o[ Pediatrics l u ~ 1973
T a b l e I. Results of serial rubella H A I a n t i b o d y tests over four years Interval alter vaccination
No. o[ children tested
Vaccinees 7-9 mo. (1969) 1 yr. (1969) 2 yr. (1970) 4 yr. (1972)
29 30 30 29
Naturally immune children (not vaccinated) 0 (1967) 19 4~2 yr. (1972) 19
Reciprocals o[ geometric mean titers
No. o[ children with a [our[old or greater tiler rise
49 49 38 42 (34*)
-0 0 4
62 100 (86*)
-5
Nonvaecinated, rubeUa-susceptible children 0 (1967) 17 2 yr. (1970) 8 4 89 yr. (1972) 16
< 8 -< 8 -12 children < 8 -4 children 215 4 XGeometric mean HAI liters after omitting subjects who had a fourfold or greater rise in antibodiesin the fourth year.
spread through an institutional p o p u l a t i o n in which 91 per cent of the residents h a d a measurable titer of H A I antibodies. MATERIALS
AND METHODS
Subjects. T h e children p a r t i c i p a t i n g in this study were mentally retarded, but their physical condition was stable and reasonably good. Most of the children were not ambulatory and were confined to their beds. These children were housed in three different buildings, and each building had app r o x i m a t e l y equal numbers of boys and girls. This group of children was included in earlier publications on the use of rubella vaccines?a, 14 T h e institution is filled, a n d there have been very few changes in the p o p ulation during this interval. L a b o r a t o r y procedures. Blood specimens were collected by v e n i p u n c t u r e ; the sera were p r o m p t l y separated a n d frozen until tested. T h e rubella h e m a g g l u t i n a t i o n - i n h i b iting antibody test as described by Stewart a n d associates 1'~ was employed. T h e H A I tests on all the sera collected at the specified intervals from vaccinees, n a t u r a l l y i m m u n e children, a n d the nonvaccinated rubellasusceptible children were done simultaneously as a single procedure. Experience indicates that there is no significant loss of a n t i b o d y titer in sera stored in frozen state.
Clinical procedure. I n N o v e m b e r a n d December, 1967, all the children from 1 to 10 years of age housed in three buildings were surveyed for serum rubella antibodies using the h e m a g g l u t i n a t i o n - i n h i b i t i n g antibody test. T h e children were identified as rubella susceptible on the basis of an H A I antibody t i t e r of less t h a n 1:8. T h e y were given the Cendehill rubella vaccine in 1968, a n d their H A I antibody titers have been monitored regularly t h r o u g h 1979. T h e results of this monitoring form the basis of this report. As a means of controlling o u r observations with the vaccinees, a group of 19 naturally i m m u n e children a n d 17 rubella-susceptible children, who were not vaccinated, were monitored during the same time interval. RESULTS
F r o m a total of 238 children in the age group of 1 to 10 years, it was d e t e r m i n e d that 25 p e r cent lacked rubella hemagglutination-inhibiting antibodies. Parental permission was obtained, a n d 38 of the 59 seronegative children were given the Cendehill rubella vaccine subcutaneously. T h e remaining 21 seronegative children were not vaccinated which resulted in a resident population with 91 per cent i m m u n e and 9 per cent susceptible children. A total of 50 nursing and p a r a m e d i c a l staff members were
Volume 83 Number 1
Experience with rubella immunization
53
Table II. Rubella H A I antibody titers (reciprocals) of subjects showing a booster response
SubjectNo. Vaccinees 157 292 1521 1543 GMT ~
0 8 8 < 8 8 < 8
Interval alter vaccination I 7-9mo. (1969) I 1 yr. (1969) I 2 yr. (1970) 256 32 16 32 45
Naturally immune children 185 128 178 16 163 32 173 32 170 8 GMT ~ 28
128 16 8 32 27 h
m
u
m
m
64 16 < 8 32 19
I 4 yr. (1972) 256 256 64 128 150 512 256 128 128 32 145
*Geometric m e a n H A I antibody titers.
tested with the H A I antibody test, and all had rubella antibodies. The rubella HA'I antibody titers were done on sera collected from the vaccinees at 7 to 9 months, 1 year, 2 years, and 4 years, respectively, after vaccination, after 4 years in the case of the naturally immune children, and after 2 and 4 years in nonvaccinated, rubella-susceptible children. These results are shown in Table I. The H A I antibody titers among the recipients of the Cendehill rubella vaccine have been fairly stable over the past four years. However, if the assumption is accepted that the four vaccinees who had a fourfold rise in H A I titer between the second and fourth years experienced this boost from exposure to natural rubella and these are eliminated, the "corrected" geometric mean titer suggests a gradually falling antibody level. Four of the 29 vaccinees and 5 of 19 naturally immune children had' a fourfold or greater rise in H A I antibody titers suggesting subclinical reinfection with natural rubella virus. This suggestion is strengthened by the observation that 4 of 16 previously seronegative, nonvaccinated children developed H A I antibodies between 1970 and 1972. These children had not.been out of the institution during this time. The individual H A I antibody titers for
those vaccinees and naturally immune children who had a fourfold or greater rise are listed on Table II. These H A I tests were performed simultaneously in a single procedure. The H A I tests were performed also in 1971--three years after immunization-on all the vacinees and the nonvaccinated, rubella-susceptible children, but sera were not available for the repeat simultaneous testing. Results of the 1971 H A I tests supported the current results and indicated that natural rubella existed in the institution between 1970 and 1971. DISCUSSION
Admittedly, this experience in an institution for mentally retarded children may not be reproducible in the open community, but it should alert us to the possibilities involved. The seroepidemiologic evidence strongly suggests that natural rubella spread through the three pediatric buildings of this institution in spite of the fact that about 90 per cent of the population was "immune." The nine children who had the "booster" antibody response and the four rubella-susceptible children who developed rubella antlbodies during this interval were divided among the three buildings approximately in proportion to the population of those build-
54
Farquhar
ings. These children were not aggregated in one building, which would have suggested a single source of infection. The existence within the institution of one or more infants with the congenital rubella syndrome who were shedding virus and acting as the source of the infection is a possibility. However, all the "new" admissions were one year of age or older on admission and had been residents for two years prior to this experience, so it is unlikely that they were shedding virus at this time. Regardless of the source of the natural virus, it appears that wild rubella virus spread through the institution. At the end of the second year the geometric mean H A I titer of the four vaccinees who experienced the serologic "booster" response was lower than the mean for the vaccinees who did not respond (1:19 versus 1:42), but there was some overlap which suggests a quantitative as well as a qualitative difference in antibodies. Similarly, the naturally immune children who had a "booster" response had a lower initial titer than those who did not (1:28 versus 1:82). The experience of others 2, 1G-21indicates that there is a lower incidence of reinfection among naturally immune subjects than among recipients of the HPV-77 or Cendehill vaccines on exposure to wild rubella virus, and that this is related in part to the level of H A I antibodies. Immunity to rubella may be more closely related to serum antibodies other than H A I antibodies and to local secretory antibodiesY 2 The antibody response induced by RA 27/3 rubella vaccine more closely simulates that of natural rubellaY a With the relatively small numbers of subjects studied, the attack rate did not differ in the various groups--the naturally immune, the vaccinees, and the nonvaccinated susceptible children. Perhaps the attack rate among the susceptible children would have been higher if 91 per cent of the population had not been "immune," but the numbers involved are too small to be conclusive. If there is such a thing as "herd immunity" against rubella, it may possibly reduce, but
The Journal o[ Pediatrics July 1973
not prevent, the spread of natural rubella virus through an institutional population. This experience supports the results reported recently in a similar institution, 24 in which over 99 per cent of the population had rubella H A I antibodies in their sera. Results of annual monitoring of H A I antibody titers revealed that between the second and third years after vaccination, 24 of 93 Cendehill vaccinees, 2 of 58 RA 27/3 vaccinees, and 1 of 40 naturally immune children had a fourfold or greater rise in antibody titers. Although these sera were not paired, as was done in the present study, the results, at least, suggested that natural rubella virus had spread through this "immune" population. In both instances the booster antibody responses occurred largely among those with low H A I antibody titers. The prime purpose of rubella immunization is to prevent the congenital rubella syndrome. If "immunized" women do not experience a viremia on reinfection--a question not adequately answered at the present time--the reinfection phenomenon may not lead to fetal infection and actually may be beneficial in maintaining protective antibodies. Judelsohn and WylF ~ recently reported the termination of an epidemic of rubella in Bermuda by a mass vaccination campaign using Cendehill rubella vaccine. They have shown again that rubella vaccine will prevent the clinical manifestations of rubella. Mass immunization in a rubella epidemic is worthwhile, since individuals with clinical rubella do excrete larger quantities of virus and are a greater threat to spread the disease. Although, as the authors noted, the epidemic was waning as the program began, the relatively high antibody titers occurring two to three weeks after vaccination would be expected to stop clinical rubella and perhaps subclinical infection for several months. However, we do not know the incidence of subclinical infection or reinfection or whether women of childbearing age--the target population--were protected. The mass vaccination program simply reduced the number of children susceptible to
Volume 83 Number 1
clinical rubella. I t m a y be t h a t these vacc i n a t e d c h i l d r e n will h a v e their i m m u n i t y reinforced by wild virus in this situation. A recently reported e p i d e m i c of r u b e l l a o n a n o t h e r island, K a u a i , stopped spont a n e o u s l y w i t h o u t the use of r u b e l l a vaccine. 26 S e c o n d a r y cases d i d n o t t r a n s m i t rubella to n o n v a c c i n a t e d rubella-susceptible contacts. T h e i m p o r t a n t p o i n t is that in o r d e r to p r e v e n t the c o n g e n i t a l r u b e l l a s y n d r o m e - o u r u l t i m a t e o b j e c t - - w e should c o n c e n t r a t e on p r o t e c t i n g y o u n g w o m e n directly. Perhaps at times we will n e e d to i m m u n i z e preschool c h i l d r e n to p r e v e n t such epidemics, b u t we should v a c c i n a t e regularly 12- to 14year-old girls to m a x i m i z e their i m m u n i t y closer to the t i m e w h e n p r o t e c t i o n is needed. It is i n t e r e s t i n g t h a t the m a j o r i t y of cases in the B e r m u d a e p i d e m i c o c c u r r e d in adolescents a n d y o u n g adults, so if p r e a d o l e s c e n t girls h a d b e e n iml~nunized regularly, this large reservoir of i n d i v i d u a l s w o u l d have b e e n greatly r e d u c e d . W h i l e H P V - 7 7 a n d C e n d e hill vaccines h a v e been relatively ineffective as booster vaccines, i n f o r m a t i o n to be p u b lished indicates t h a t R A 2 7 / 3 v a c c i n e given i n t r a n a s a l l y is highly effective. REFERENCES
1. Recommendatiori of the Public Health Service Advisory Committee on Immunization Practices, Morbidity Mortality Weekly Rep. 18: 124, 1969. 2. Horstmann, D. M., Liebhaber, H., LeBouvier, G. L., et al.: Rubella: Reinfection of vaccinated and naturally immune persons exposed in an epidemic, N. Engl. J. Med. 283: 771, 1970. 3. Beasley, R. P.: Dilemmas presented by the attenuated rubella vaccines, Am. J. Epidemiol. 92: 158, 1970. 4. Neff, J. M., and Carver, D. H.: Rubella immunization: Reconsideration of our present policy, Am. J. Epidemiol. 92: 162, 1970. 5. Chang, T. W., DesRosiers, S., and Weinstein, L.: Clinical and serologic studies of an outbreak of rubella in a vaccinated population, N. Engl. J. Med. 283: 246, 1970. " 6. Lehane, D. E., Newberg, N. R., and Beam, W. E., Jr.: Evaluation of rubella herd immunity during an epidemic, J. A. M. A. 213: 2236, 1970. 7. Chang, T. W.: Strategy of rubella vaccination, J. Infect. Dis. 123: 224, 1971. 8. Detels, R., Kim, K. S. W., Gal, J. L., and
Experience with rubella immunization
9.
10.
1 I.
12.
13.
14.
15.
16.
17.
18.
I9.
20.
21.
55
Grayston, J. T.: Viral shedding in Chinese children following vaccination with HPV-77 and Cendehill-51 live attenuated rubella vaccines, Am. J. Epidemiol. 94: 473, 1971. WylI, S. A., Herrmann, K. L., Abrutyn, E., Murphy, G. D., III, and Witte, J. J.: Rubella booster immunization: Serologic response to a second dose of vaccine, J. A. M. A. 216: I451, 1971. Schiff, G. M., Rauh, J. L., Rotte, T., and Trimble, S.: Two-year follow-up of rubella vaccinees in a public school system, Am. J. Dis. Child. 123" 193, 1972. Goldblum, N., Swartz, T. A., Klingberg, W., et al.: Immunization with live attenuated rubella virus vaccine (HPV-77): Clinical and serological results in children and adolescents in Israel, Am. J. Dis. Child. 118: 190, 1969. Karchmer, A. W.~ Herrmann, K. L., Friedman, J. P., et ai.: Comparative studies of rubella vaccines, Am. J. Dis. Child. 118: 197, 1969. Farquhar, J. D., Plotkin, S. A., and Schoengold, R. S.: Clinical and laboratory evaluation of the Cendehill rubella vaccine, Proceedings of the Twenty-third Symposium on Microbiological Standardization: Rubella vaccines, Basel, Switzerland, 1969, S. Karger AG, pp. 331-336. Farquhar, J. D., Plotkin, S. A., and Schoengold, R. J.: Cendehill strain of rubella vaccine: Clinical evaluation, J. PEmATR. 75: 412, 1969. Stewart, G. L., Parkman, P. D., Hopps, H. E., Douglas, R. D., Hamilton, J. P., and Meyers, H. M.: Rubella virus hemagglutination-inhibition test, N. Engl. J. Med. 276: 554, 1967. Meyer, H. M., Jr., Parkman, P. D., Hobbins, T. E., et al.: Clinical studies with experimental live rubella virus vaccine (strain HPV-77): Evaluation of vaccine induced immunity, Am. J. Dis. Child. 115: 648, 1968. Meyer, H. M., Jr., Parkman, P. D., Hobbins, T. E., et aI.: Attenuated rubella viruses: Laboratory and clinical characteristics, Am. J. Dis. Child. 118: 155, 1969. Schiff, G. M., Donath, R., and Rotte, T.: Experimental rubella studies. I. Clinical and laboratory features of infection caused by the brown strain rubella virus. II. Artificial challenge studies of adult rubella vaccinees, Am. J. Dis. Child. 118: 269, 1969. Wilkins, J., Leedom, J. M., Portnoy, B., et al.: Reinfection with rubella virus despite live vaccine induced immunity: Trials of HPV-77 and HPV-80 live rubella virus vaccines and subsequent artificial and natural challenge studies, Am. J. Dis. Child. 118: 275, 1969. Detels, R., Grayston, J. T., Kim, K. S. W., et al.: Prevention of clinical and subclinical rubella infection; efficacy of three HPV-77 derivative vaccines, Am. J. Dis. Child. 118: 295, 169. Davis, W. J., Larson, H. E., Simsarsian, J.
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Farquhar
P., et aI.: A study of rubella immunity and resistance to reinfection, read before the Seventh Annual Immunization Conference, National Communicable Disease Center, Atlanta, Ga., March 24, 1970. 22. LeBouvier, G. L., and Plotkin, S. A.: Precipitin responses to rubella vaccine RA 27/3, J. Infect. Dis. 123: 220, 1971. 23. Liebhaber, H., Ingalls, T. H., LeBouvier, G. L., and Horstmann, D. M.: Vaccination with RA 27/3 rubella vaccine, Am. J. Dis. Child. 123: 133, I972.
The Journal o[ Pediatrics July 1973
24. Farquhar, J. D.: Follow-up on rubella vaccinations and experience with subclinical reinfection, J. PEDIATR. 81: 460, 1972. 25. Judelsohn, R. G., and Wyll, S. A.: Rubella in Bermuda, J. A. M. A. 223: 401, 1973. 26. Hattis, R. P., Halstead, S. B., Herrmann, K. L., and Witte, J. J.: Rubella in an immunized island population, J. A. M. A. 223: 1019, 1973.
51
Experience Mth rubella and rubella immunization in institutionalized children Serial monitoring o/rubella hemagglutination-inhibiting antibodies in institutionalized children revealed that 4 o / 1 6 nonvaccinated rubella-susceptible children had developed antibodies and 4 of 29 children immunized with Cendehill rubella vaccine had a fourfold or greater increase in hemagglutination-inhibiting antibodies between the second and fourth years a#er vaccination. Five of 19 naturally immune children had a fourfold or greater rise in antibody titer during the same 4 ')'ear interval. This apparent spread of wild virus occurred within three building with a population estimated to be 91 per cent "'immune." The vaccinees have shown a slight fall in hemagglutination-inhibiting antibody titers over t h e / o u r years, and both the vaccines and naturally immune children who experienced the "'booster" response had titers lower than the others. These observations cast doubt on the ability of "herd immunity" to prevent the spread of wild rubella virus.
John D. Farquhar, M.D., P h i l a d e l p h i a , Pa.
T H E P R E S E N T policy in this country t o control the spread of rubella and prevent the congenital rubella syndrome is to immunize all young children to produce a herd immunity and thereby reduce the exposure of women of childbearing age? This indirect approach was considered necessary because of the understandable concern about administering a live virus vaccine to the target g r o u p - - w o m e n of the childbearing a g e - because a certain number of pregnant women might be vaccinated inadvertently.
From the Presbyterian-University of Pennsylvania Medical Center, and the " Department of Pediatrics, University of Pennsylvania. Supported in part by Research Grant CC 00623 from the C e n t e r / o r Disease Control, Atlanta, Ga. Reprint address: 3910 Powelton Ave., Philadelphia, Pa. 19104.
Evidence is accumulating which challenges the wisdom of this approach? -s From a practical point of view, it is highly improbable that 90 per cent of the population could be immunized against rubella. The follow-up observations have not been carried out long enough to know whether antibodies, induced by the presently licensed rubella vaccines given in early childhood, will persist long enough to protect women of childbearing age. Experience has shown that the HPV-77 and Cendehill vaccines are limited in their ability to produce a booster response. '~-~e Recent observations suggested that the presence, of hemagglutination-inhibiting ( H A I ) antibodies does not prevent the spread of the rubella virus through an institutional population. 2~ The experience to be described indicates that rubella virus Vol. 83, No. 1, pp. 51-56
52
Farquhar
The Journal o[ Pediatrics l u ~ 1973
T a b l e I. Results of serial rubella H A I a n t i b o d y tests over four years Interval alter vaccination
No. o[ children tested
Vaccinees 7-9 mo. (1969) 1 yr. (1969) 2 yr. (1970) 4 yr. (1972)
29 30 30 29
Naturally immune children (not vaccinated) 0 (1967) 19 4~2 yr. (1972) 19
Reciprocals o[ geometric mean titers
No. o[ children with a [our[old or greater tiler rise
49 49 38 42 (34*)
-0 0 4
62 100 (86*)
-5
Nonvaecinated, rubeUa-susceptible children 0 (1967) 17 2 yr. (1970) 8 4 89 yr. (1972) 16
< 8 -< 8 -12 children < 8 -4 children 215 4 XGeometric mean HAI liters after omitting subjects who had a fourfold or greater rise in antibodiesin the fourth year.
spread through an institutional p o p u l a t i o n in which 91 per cent of the residents h a d a measurable titer of H A I antibodies. MATERIALS
AND METHODS
Subjects. T h e children p a r t i c i p a t i n g in this study were mentally retarded, but their physical condition was stable and reasonably good. Most of the children were not ambulatory and were confined to their beds. These children were housed in three different buildings, and each building had app r o x i m a t e l y equal numbers of boys and girls. This group of children was included in earlier publications on the use of rubella vaccines?a, 14 T h e institution is filled, a n d there have been very few changes in the p o p ulation during this interval. L a b o r a t o r y procedures. Blood specimens were collected by v e n i p u n c t u r e ; the sera were p r o m p t l y separated a n d frozen until tested. T h e rubella h e m a g g l u t i n a t i o n - i n h i b iting antibody test as described by Stewart a n d associates 1'~ was employed. T h e H A I tests on all the sera collected at the specified intervals from vaccinees, n a t u r a l l y i m m u n e children, a n d the nonvaccinated rubellasusceptible children were done simultaneously as a single procedure. Experience indicates that there is no significant loss of a n t i b o d y titer in sera stored in frozen state.
Clinical procedure. I n N o v e m b e r a n d December, 1967, all the children from 1 to 10 years of age housed in three buildings were surveyed for serum rubella antibodies using the h e m a g g l u t i n a t i o n - i n h i b i t i n g antibody test. T h e children were identified as rubella susceptible on the basis of an H A I antibody t i t e r of less t h a n 1:8. T h e y were given the Cendehill rubella vaccine in 1968, a n d their H A I antibody titers have been monitored regularly t h r o u g h 1979. T h e results of this monitoring form the basis of this report. As a means of controlling o u r observations with the vaccinees, a group of 19 naturally i m m u n e children a n d 17 rubella-susceptible children, who were not vaccinated, were monitored during the same time interval. RESULTS
F r o m a total of 238 children in the age group of 1 to 10 years, it was d e t e r m i n e d that 25 p e r cent lacked rubella hemagglutination-inhibiting antibodies. Parental permission was obtained, a n d 38 of the 59 seronegative children were given the Cendehill rubella vaccine subcutaneously. T h e remaining 21 seronegative children were not vaccinated which resulted in a resident population with 91 per cent i m m u n e and 9 per cent susceptible children. A total of 50 nursing and p a r a m e d i c a l staff members were
Volume 83 Number 1
Experience with rubella immunization
53
Table II. Rubella H A I antibody titers (reciprocals) of subjects showing a booster response
SubjectNo. Vaccinees 157 292 1521 1543 GMT ~
0 8 8 < 8 8 < 8
Interval alter vaccination I 7-9mo. (1969) I 1 yr. (1969) I 2 yr. (1970) 256 32 16 32 45
Naturally immune children 185 128 178 16 163 32 173 32 170 8 GMT ~ 28
128 16 8 32 27 h
m
u
m
m
64 16 < 8 32 19
I 4 yr. (1972) 256 256 64 128 150 512 256 128 128 32 145
*Geometric m e a n H A I antibody titers.
tested with the H A I antibody test, and all had rubella antibodies. The rubella HA'I antibody titers were done on sera collected from the vaccinees at 7 to 9 months, 1 year, 2 years, and 4 years, respectively, after vaccination, after 4 years in the case of the naturally immune children, and after 2 and 4 years in nonvaccinated, rubella-susceptible children. These results are shown in Table I. The H A I antibody titers among the recipients of the Cendehill rubella vaccine have been fairly stable over the past four years. However, if the assumption is accepted that the four vaccinees who had a fourfold rise in H A I titer between the second and fourth years experienced this boost from exposure to natural rubella and these are eliminated, the "corrected" geometric mean titer suggests a gradually falling antibody level. Four of the 29 vaccinees and 5 of 19 naturally immune children had' a fourfold or greater rise in H A I antibody titers suggesting subclinical reinfection with natural rubella virus. This suggestion is strengthened by the observation that 4 of 16 previously seronegative, nonvaccinated children developed H A I antibodies between 1970 and 1972. These children had not.been out of the institution during this time. The individual H A I antibody titers for
those vaccinees and naturally immune children who had a fourfold or greater rise are listed on Table II. These H A I tests were performed simultaneously in a single procedure. The H A I tests were performed also in 1971--three years after immunization-on all the vacinees and the nonvaccinated, rubella-susceptible children, but sera were not available for the repeat simultaneous testing. Results of the 1971 H A I tests supported the current results and indicated that natural rubella existed in the institution between 1970 and 1971. DISCUSSION
Admittedly, this experience in an institution for mentally retarded children may not be reproducible in the open community, but it should alert us to the possibilities involved. The seroepidemiologic evidence strongly suggests that natural rubella spread through the three pediatric buildings of this institution in spite of the fact that about 90 per cent of the population was "immune." The nine children who had the "booster" antibody response and the four rubella-susceptible children who developed rubella antlbodies during this interval were divided among the three buildings approximately in proportion to the population of those build-
54
Farquhar
ings. These children were not aggregated in one building, which would have suggested a single source of infection. The existence within the institution of one or more infants with the congenital rubella syndrome who were shedding virus and acting as the source of the infection is a possibility. However, all the "new" admissions were one year of age or older on admission and had been residents for two years prior to this experience, so it is unlikely that they were shedding virus at this time. Regardless of the source of the natural virus, it appears that wild rubella virus spread through the institution. At the end of the second year the geometric mean H A I titer of the four vaccinees who experienced the serologic "booster" response was lower than the mean for the vaccinees who did not respond (1:19 versus 1:42), but there was some overlap which suggests a quantitative as well as a qualitative difference in antibodies. Similarly, the naturally immune children who had a "booster" response had a lower initial titer than those who did not (1:28 versus 1:82). The experience of others 2, 1G-21indicates that there is a lower incidence of reinfection among naturally immune subjects than among recipients of the HPV-77 or Cendehill vaccines on exposure to wild rubella virus, and that this is related in part to the level of H A I antibodies. Immunity to rubella may be more closely related to serum antibodies other than H A I antibodies and to local secretory antibodiesY 2 The antibody response induced by RA 27/3 rubella vaccine more closely simulates that of natural rubellaY a With the relatively small numbers of subjects studied, the attack rate did not differ in the various groups--the naturally immune, the vaccinees, and the nonvaccinated susceptible children. Perhaps the attack rate among the susceptible children would have been higher if 91 per cent of the population had not been "immune," but the numbers involved are too small to be conclusive. If there is such a thing as "herd immunity" against rubella, it may possibly reduce, but
The Journal o[ Pediatrics July 1973
not prevent, the spread of natural rubella virus through an institutional population. This experience supports the results reported recently in a similar institution, 24 in which over 99 per cent of the population had rubella H A I antibodies in their sera. Results of annual monitoring of H A I antibody titers revealed that between the second and third years after vaccination, 24 of 93 Cendehill vaccinees, 2 of 58 RA 27/3 vaccinees, and 1 of 40 naturally immune children had a fourfold or greater rise in antibody titers. Although these sera were not paired, as was done in the present study, the results, at least, suggested that natural rubella virus had spread through this "immune" population. In both instances the booster antibody responses occurred largely among those with low H A I antibody titers. The prime purpose of rubella immunization is to prevent the congenital rubella syndrome. If "immunized" women do not experience a viremia on reinfection--a question not adequately answered at the present time--the reinfection phenomenon may not lead to fetal infection and actually may be beneficial in maintaining protective antibodies. Judelsohn and WylF ~ recently reported the termination of an epidemic of rubella in Bermuda by a mass vaccination campaign using Cendehill rubella vaccine. They have shown again that rubella vaccine will prevent the clinical manifestations of rubella. Mass immunization in a rubella epidemic is worthwhile, since individuals with clinical rubella do excrete larger quantities of virus and are a greater threat to spread the disease. Although, as the authors noted, the epidemic was waning as the program began, the relatively high antibody titers occurring two to three weeks after vaccination would be expected to stop clinical rubella and perhaps subclinical infection for several months. However, we do not know the incidence of subclinical infection or reinfection or whether women of childbearing age--the target population--were protected. The mass vaccination program simply reduced the number of children susceptible to
Volume 83 Number 1
clinical rubella. I t m a y be t h a t these vacc i n a t e d c h i l d r e n will h a v e their i m m u n i t y reinforced by wild virus in this situation. A recently reported e p i d e m i c of r u b e l l a o n a n o t h e r island, K a u a i , stopped spont a n e o u s l y w i t h o u t the use of r u b e l l a vaccine. 26 S e c o n d a r y cases d i d n o t t r a n s m i t rubella to n o n v a c c i n a t e d rubella-susceptible contacts. T h e i m p o r t a n t p o i n t is that in o r d e r to p r e v e n t the c o n g e n i t a l r u b e l l a s y n d r o m e - o u r u l t i m a t e o b j e c t - - w e should c o n c e n t r a t e on p r o t e c t i n g y o u n g w o m e n directly. Perhaps at times we will n e e d to i m m u n i z e preschool c h i l d r e n to p r e v e n t such epidemics, b u t we should v a c c i n a t e regularly 12- to 14year-old girls to m a x i m i z e their i m m u n i t y closer to the t i m e w h e n p r o t e c t i o n is needed. It is i n t e r e s t i n g t h a t the m a j o r i t y of cases in the B e r m u d a e p i d e m i c o c c u r r e d in adolescents a n d y o u n g adults, so if p r e a d o l e s c e n t girls h a d b e e n iml~nunized regularly, this large reservoir of i n d i v i d u a l s w o u l d have b e e n greatly r e d u c e d . W h i l e H P V - 7 7 a n d C e n d e hill vaccines h a v e been relatively ineffective as booster vaccines, i n f o r m a t i o n to be p u b lished indicates t h a t R A 2 7 / 3 v a c c i n e given i n t r a n a s a l l y is highly effective. REFERENCES
1. Recommendatiori of the Public Health Service Advisory Committee on Immunization Practices, Morbidity Mortality Weekly Rep. 18: 124, 1969. 2. Horstmann, D. M., Liebhaber, H., LeBouvier, G. L., et al.: Rubella: Reinfection of vaccinated and naturally immune persons exposed in an epidemic, N. Engl. J. Med. 283: 771, 1970. 3. Beasley, R. P.: Dilemmas presented by the attenuated rubella vaccines, Am. J. Epidemiol. 92: 158, 1970. 4. Neff, J. M., and Carver, D. H.: Rubella immunization: Reconsideration of our present policy, Am. J. Epidemiol. 92: 162, 1970. 5. Chang, T. W., DesRosiers, S., and Weinstein, L.: Clinical and serologic studies of an outbreak of rubella in a vaccinated population, N. Engl. J. Med. 283: 246, 1970. " 6. Lehane, D. E., Newberg, N. R., and Beam, W. E., Jr.: Evaluation of rubella herd immunity during an epidemic, J. A. M. A. 213: 2236, 1970. 7. Chang, T. W.: Strategy of rubella vaccination, J. Infect. Dis. 123: 224, 1971. 8. Detels, R., Kim, K. S. W., Gal, J. L., and
Experience with rubella immunization
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Grayston, J. T.: Viral shedding in Chinese children following vaccination with HPV-77 and Cendehill-51 live attenuated rubella vaccines, Am. J. Epidemiol. 94: 473, 1971. WylI, S. A., Herrmann, K. L., Abrutyn, E., Murphy, G. D., III, and Witte, J. J.: Rubella booster immunization: Serologic response to a second dose of vaccine, J. A. M. A. 216: I451, 1971. Schiff, G. M., Rauh, J. L., Rotte, T., and Trimble, S.: Two-year follow-up of rubella vaccinees in a public school system, Am. J. Dis. Child. 123" 193, 1972. Goldblum, N., Swartz, T. A., Klingberg, W., et al.: Immunization with live attenuated rubella virus vaccine (HPV-77): Clinical and serological results in children and adolescents in Israel, Am. J. Dis. Child. 118: 190, 1969. Karchmer, A. W.~ Herrmann, K. L., Friedman, J. P., et ai.: Comparative studies of rubella vaccines, Am. J. Dis. Child. 118: 197, 1969. Farquhar, J. D., Plotkin, S. A., and Schoengold, R. S.: Clinical and laboratory evaluation of the Cendehill rubella vaccine, Proceedings of the Twenty-third Symposium on Microbiological Standardization: Rubella vaccines, Basel, Switzerland, 1969, S. Karger AG, pp. 331-336. Farquhar, J. D., Plotkin, S. A., and Schoengold, R. J.: Cendehill strain of rubella vaccine: Clinical evaluation, J. PEmATR. 75: 412, 1969. Stewart, G. L., Parkman, P. D., Hopps, H. E., Douglas, R. D., Hamilton, J. P., and Meyers, H. M.: Rubella virus hemagglutination-inhibition test, N. Engl. J. Med. 276: 554, 1967. Meyer, H. M., Jr., Parkman, P. D., Hobbins, T. E., et al.: Clinical studies with experimental live rubella virus vaccine (strain HPV-77): Evaluation of vaccine induced immunity, Am. J. Dis. Child. 115: 648, 1968. Meyer, H. M., Jr., Parkman, P. D., Hobbins, T. E., et aI.: Attenuated rubella viruses: Laboratory and clinical characteristics, Am. J. Dis. Child. 118: 155, 1969. Schiff, G. M., Donath, R., and Rotte, T.: Experimental rubella studies. I. Clinical and laboratory features of infection caused by the brown strain rubella virus. II. Artificial challenge studies of adult rubella vaccinees, Am. J. Dis. Child. 118: 269, 1969. Wilkins, J., Leedom, J. M., Portnoy, B., et al.: Reinfection with rubella virus despite live vaccine induced immunity: Trials of HPV-77 and HPV-80 live rubella virus vaccines and subsequent artificial and natural challenge studies, Am. J. Dis. Child. 118: 275, 1969. Detels, R., Grayston, J. T., Kim, K. S. W., et al.: Prevention of clinical and subclinical rubella infection; efficacy of three HPV-77 derivative vaccines, Am. J. Dis. Child. 118: 295, 169. Davis, W. J., Larson, H. E., Simsarsian, J.
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P., et aI.: A study of rubella immunity and resistance to reinfection, read before the Seventh Annual Immunization Conference, National Communicable Disease Center, Atlanta, Ga., March 24, 1970. 22. LeBouvier, G. L., and Plotkin, S. A.: Precipitin responses to rubella vaccine RA 27/3, J. Infect. Dis. 123: 220, 1971. 23. Liebhaber, H., Ingalls, T. H., LeBouvier, G. L., and Horstmann, D. M.: Vaccination with RA 27/3 rubella vaccine, Am. J. Dis. Child. 123: 133, I972.
The Journal o[ Pediatrics July 1973
24. Farquhar, J. D.: Follow-up on rubella vaccinations and experience with subclinical reinfection, J. PEDIATR. 81: 460, 1972. 25. Judelsohn, R. G., and Wyll, S. A.: Rubella in Bermuda, J. A. M. A. 223: 401, 1973. 26. Hattis, R. P., Halstead, S. B., Herrmann, K. L., and Witte, J. J.: Rubella in an immunized island population, J. A. M. A. 223: 1019, 1973.