J Pediatr 89:662-668, 1976. 8. Monson RR, Rosenberg L, Hartz SC, et al: Diphenylhydantoin and selected congenital malformations. N Engl J Med 289:1049-1052, 1973. 9. Speidel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2:839-843, 1972. 10. Hill RM, Verniaud WM, Horning MG, et al: Infants exposed in utero to antiepileptic drugs: A prospective study Am J Dis Child 127:645-653, 1974. 11. Fedrick J: Epilepsy and pregnancy: A report from the Oxford record linkage study. Br Med J 2:442-448, 1973. 12. Lowe CR: Congenital malformations among infants born to epileptic women. Lancet
1:9-10, 1973.
13. South J:
sants. Lancet
Teratogenic effects of
anticonvul-
2:1154, 1972.
14. Meyer JG: The teratological effects of anticonvulsants and the effects on pregnancy and birth. Eur Neurol 10:179-190, 1973. 15. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285-290, 1975. 16. Hill RM: Drugs ingested by pregnant women. Clin Pharmacol Ther 14:654-659, 1973. 17. Seip M: Growth retardation, dysmorphic facies and minor malformations following massive exposure to phenobarbitone in utero. Acta Paediatr Scand 65:617-621, 1976. 18. Martin HP: Microcephaly and mental retardation. Am J Dis Child 119:128-131, 1970. 19. Watson E, Lowrey G: Growth and Develop-
ment of Children. Chicago, Year Book Medical Publisher Inc, 1967, pp 82, 419. 20. Lemire RJ, Loeser JD, Leech RW, et al: Normal and Abnormal Development of the Human Nervous System. New York, Harper & Row Publishers Inc, 1975, pp 390-391. 21. Starreveld-Zimmerman AAE, van der Kolk WJ, Elshove J, et al: Teratogenicity of antiepileptic drugs. Clin Neurol Neurosurg 77:81-95, 1974. 22. Waziri M, Ionasescu V, Zellweger H: Teratogenic effect of anticonvulsant drugs. Am J Dis Child 130:1022-1023, 1976. 23. Dronamraju KR: Epilepsy and cleft lip and palate. Lancet 2:876-877, 1970. 24. Meadow SR: Congenital anomalies and anticonvulsant drugs. Proc R Soc Med 63:48-49, 1970. 25. Sabin M and Oxorn H: Epilepsy and pregnancy. Obstet Gynecol 7:175-179, 1956. 26. Soifer JD: Convulsions and coma in pregnancy. Am J Obstet Gynecol 84:623-626, 1962. 27. Janz D, Fuchs U: Are antiepileptic drugs harmful when given during pregnancy? Ger Med Mon 9:20-23, 1964. 28. Baptisti A: Epilepsy and pregnancy: A review of the literature and a study of 37 cases. Am J Obstet Gynecol 35:818-824, 1938. 29. Pritchard JA, Scott DE, Whalley PJ: Maternal folate deficiency and pregnancy wastage. Am J Obstet Gynecol 109:341-346, 1971. 30. Bjerkedal T, Bahna SL: The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 52:245-248, 1973.
31. Burnett CWF: A survey of the relation between epilepsy and pregnancy. J Obstet Gynecol 53:539-556, 1946. 32. Knight AH, Rhind EG: Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 16:99-110, 1975. 33. Goodwin JF, Lawson CW: Status epilepticus complicating pregnancy. Br Med J 2:332-333, 1947. 34. McClure JH: Idiopathic epilepsy in pregnancy: Summary of the literature and clinical study of 20 patients. Am J Obstet Gynecol 70:296\x=req-\ 301, 1970. 35. Klein MD, Goodfriend MJ, Shey IA: Status epilepticus and pregnancy. Am J Obstet Gynecol 72:188-190, 1956. 36. Suter C, Klingman WO: Seizure states and pregnancy. Neurology 7:105-118, 1957. 37. Orringer CE, Eustace JC, Wunsch CD, et al: Natural history of lactic acidosis after grandmal seizures. N Engl J Med 297:796-799, 1977. 38. McCrann DJ, Schifrin BS: Fetal monitoring in high-risk pregnancy. Clin Perinatol 1:229\x=req-\ 252, 1974. 39. Ramsay RE, Strauss RG, Wilder BJ, et al: Status epilepticus in pregnancy: Effects of phenytoin malabsorption on seizure control. Neurology 28:85-89, 1978. 40. Dimsdale H: The epileptic in relation to pregnancy. Br J Med 2:1147-1150, 1959. 41. Brown GW: Berkson fallacy revisited: Spurious conclusions from patient surveys. Am J Dis Child 130:56-60, 1976.
Immunity After
Rubella and Measles Viral Vaccines
the early stages of clinical trials with live attenuated rubella vaccines about a decade ago, two
During
important questions
were
paramount
in the minds of those responsible for those trials. The first was concerned with the possible communicability of the vaccine virus and the second with the duration of immunity. It must be accepted that any new vaccine poses problems, both general and specific, but as far as rubella vaccines were
concerned, these
importance.
were
of
special
The first question arose from the original trials in a small group of susceptible children carried out by Parkman et al1 and Meyer et al2 with their high passage virus (HPV-77) prepared in monkey kidney cell cultures. They had shown that intermittent excretion of rubella vaccine virus occurred in the majority of vaccinated individuals. The question was simple.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
If vaccinees excreted virus in the
nasopharynx, could infection be transmitted to susceptible contacts and, more important, if the contact was a pregnant virus
woman, could the vaccine damage to the fetus?
cause
Fortunately, for one reason or another, possibly due to the fact that the vaccine virus in the nasopharynx was usually excreted in low titer, transmission of infection to suscepti¬ ble contacts could not be detected.
This fact was fully confirmed by the extensive trials of other live rubella vaccines between 1967 and 1969.M Nevertheless, at the time it was the most important potential drawback to the licensure of live rubella vaccines which, although attenuated in the sense that they produced very little clinical disease, had the propensity of spreading and could by no yardstick be regarded as attenuated or nonteratogenic for the human fetus that they
designed to protect. All current immunization programs against ru¬ bella are based on the fact that the vaccine is safe to administer to chil¬ dren and young adults and that no restrictions need be placed on them for fear of transmitting infection to their mothers or others with whom they might come into contact. The second question, that of the duration of immunity, was, and still is, a far more difficult one to answer. Many natural infections, including were
smallpox, yellow fever, poliomyelitis, measles, and rubella, give rise to a life-long immunity in that clinically and virologically proved second at¬
tacks are very rare events. It used to be taught that live attenuated vac¬ cines, such as smallpox and yellow fever, were to be preferred to inacti¬ vated vaccines because they gave rise
life-long immunity (which they clearly did not). Revaccination against smallpox was a statutory requirement to
for travellers for many years so that immunity could be maintained. Draw¬ ing a distinction between life-long and long-term immunity is not just a matter of semantics, there is an important difference. Only careful and continued surveillance of immu¬ nized populations can answer the question as to whether vaccines cur¬ rently in use against poliomyelitis, measles, and rubella for example, can confer the same effective immunity that follows natural infection. The present success with measles vaccine in the United States reported by Krugman" is encouraging, but it would be foolhardy to assume that success with a measles vaccine is necessarily going to be the same as with a rubella vaccine. First of all, the two viruses are different, the vaccines are different and the two diseases are
different. Measles is essentially a disease of early childhood capable of causing severe disease, particularly in the presence of malnutrition, whereas rubella is a disease of older children and adolescents in whom it causes little serious disease unless it occurs in pregnancy. The purpose for which measles and rubella vaccines are administered is therefore all impor¬ tant. Measles vaccine is administered to confer direct protection to the indi¬ vidual; rubella vaccine is administered to confer protection indirectly to an unborn fetus at some later stage in the life of the individual. The two vaccines do not necessarily have to be administered together, though it may be convenient to do so if combined vaccines are available. The procedure now recommended in the United States is to offer rubella vaccine to all children, both boys and girls from approximately 15 months of age to puberty.7 This would have the dual objective of conferring immunity on a large proportion of the childhood population before they ac¬ quired natural infection and also of suppressing or otherwise controlling the reservoir of infection. In theory, elimination of wild virus from the community by mass vaccination would remove the main source of the cause of congenital rebella defects, but it would also remove the most effective means of maintaining immunity in vaccinated communities. Unless there is a very high acceptance-rate of vaccine, rubella will continue to occur in vaccinated communities. This has already been reported in several areas in the United States with outbreaks of rubella occurring mainly in unvaccinated susceptible individuals.8 In Brit¬ ain and many European countries, selective immunization is used for
schoolgirls aged 11 to 14 years, leaving boys unvaccinated. Most countries
recommend immunization of ado¬ lescent girls and women if serological tests indicate that they are suscepti¬ ble. This then is the essential differ¬ ence between the so-called American and British schemes to control con¬ genital rubella defects—for this after all is what rubella immunization is all about. The crucial question to be answered now
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
with respect to rubella is whether vaccine-induced immunity is as effec¬ tive and durable as immunity from the natural disease. On this depends the whole question of the age at which the vaccine is best administered. As for natural immunity, there is good evidence that primary infection in childhood leads to immunity lasting for many years but it is not known with certainty how immunity is main¬ tained. It could be that humoral immunity persists for prolonged peri¬ ods after the primary stimulus to the immune mechanism, or that periodic reinfection occurs producing a booster or reinforcing effect to immunity. In this situation, one would expect the secondary type response to be asso¬ ciated with the rapid appearance of antibody of the IgG type. Horstmann and her colleagues9 have shown that reinfection occurs much more fre¬ quently after vaccination than after natural infection. In one study in mili¬ tary recruits,9 the reinfection rate after administration of Cendehill vac¬ cine was 80% compared with 3.9% in naturally immune individuals. Rein¬ fection was entirely asymptomatic and it is generally assumed that viremia does not occur in a reinfec¬ tion. Several reports have recently ap¬ peared that indicate that immunity after vaccination may not be as longlasting as originally anticipated. Dr Dorothy Horstmann carried out a surveillance of rubella vaccines on several hundred children immunized in 1968, with the HPV-77 duck embryo vaccine (HPV-77 DE5).1" Several im¬ portant points emerged from the study. First, the number of children with low antibody titers (1:8 to 1:16) was higher in the vaccinated group (30%) than in those naturally immune and a further 60% of the vaccinated group had hemagglutination inhibi¬ tion antibody levels in the median range. Second, there was a noticeable difference in the number of children who had lost antibody after vaccina¬ tion when tested three to five years later. Of the vaccinated group, 26% had no detectable antibody and this was mainly in the group that showed a poor initial response. Of these, asymp¬ tomatic reinfection developed in 12%,
whereas none of those who were natu¬ rally immune or who had high initial titers did so. In the original trial, it seemed that there was rather a large number of "vaccine-failures"; 118 children were so classified because there was no detectable antibody two months postvaccination. However, it is now well known that if the first postvaccination sample is collected too early, that is to say six to eight weeks after vaccination, then the percentage of seroconverters will be lower than when the second sample is collected eight to 12 weeks after vaccination. The percentage of seroconverters will then be in the region of 959c to 98%. Of the children designated as vaccinefailures, and retested,1" 82% were found to have detectable antibody three years after, and from the type of antibody response, it looked as if these had in fact responded to the administration of the vaccine rather than a naturally acquired immune response having developed. A later report published in a recent issue of the Journal (132:573-577, 1978) by Doctors Balfour and Amren from the University of Minnesota, Minneapolis, has shown a substantial¬ ly high serological failure rate in chil¬ dren given rubella, measles, and mumps vaccines, either as a monoval¬ ent vaccine or in a combined form. It is difficult to be certain that these were true vaccine-failures or nonseroconverters since antibody tests were not carried out after vaccination in as much as this was part of a routine primary health care program. It is possible that some children labelled as vaccine-failures had lost antibody, possibly in cases, as Horstmann found, where the initial antibody response was low. On the other hand, the number of seronegative children was higher in those groups immunized between 11 and 13 months than in the 14- to 16-month group, suggesting that residual amounts of maternal antibody could have the same suppressive effect as occurs when measles vaccine is administered at too early an
age."
Altogether, 58 of 159 children (36%) had no detectable rubella hemaggluti¬ nation inhibition antibodv at a mean
age of 4.7 years postvaccination. With measles vaccine, the same pattern was observed; the overall serological fail¬ ure rate was 18% (31/168 children) and here again, the age of immunization seemed to be a determining factor in
achieving sion
a
satisfactory
seroconver-
The failure-rate with vaccine was only 9%. It could mumps be that some of these children had very low levels of rubella antibody undetectable by standard tests and who were in fact immune. Krugman" found this to be the case in a study of a number of children in whom measles antibody had declined after a period of 11 years. When given a second inoculation 14 years later, a typical booster response with rapid appear¬ ance of antibody developed. Balfour and Amren have considered various possibilities to explain these unusual events. Loss of potency in the vaccine is one possibility, but several batches of vaccine were used over a period of time. Although this cannot be ruled out, it is well known that measles and rubella vaccines are labile products sensitive to heat and light and unless meticulous attention is paid to the details of storage, particu¬ larly when reconstituted, potency can be rapidly lost. This might occur more frequently when large numbers of children are being immunized in clin¬ ics as opposed to the somewhat differ¬ ent setting of a clinical trial. In a sense, these findings are not dissimilar from those of Horstmann1" from which two supplementary ques¬ tions arise. If such a high proportion of children are found to be seronega¬ tive four to five years after rubella vaccination, whatever the cause, what will be the position 20 to 25 years later when these vaccinated children will have reached the age of child-bearing? Will they continue to respond to rein¬ fection with an asymptomatic, nonviremic illness? After passage of time, will the effect of the primary antigen¬ ic stimulus cease to be effective, in which case could reinfection be asso¬ ciated with symptomatic disease, viremia, and a risk to the fetus? One way to answer this question is to revaccinate a group of these seronega¬ tive children to determine the type of immune response. This would seem rate.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
more reasonable than to challenge them with wild virus to try and deter¬ mine the presence or absence of viremia which would be an extremely difficult procedure to evaluate. These are questions that require urgent answers and until they are evaluated, the question of reimmunization of children vaccinated in early childhood will have to be kept open. In any case, there does seem to be an important message of practical impor¬ tance that reinforces the recommen¬ dation of the American Academy of Pediatrics that measles and rubella vaccines should not be given before the age of 15 months (except in the case of measles vaccine where indi¬ cated in the first year of life). But are 15 months and early childhood still too early for rubella vaccination, bearing in mind that the threat to be averted lies many years in the future? J. ALASTAIR DUDGEON, MD Department of Microbiology Hospital for Sick Children Great Ormond Street London WC1N 3JH, United
Kingdom References 1. Parkman PD,
Meyer
HM Jr, Kirschstein
et al: Attenuated rubella virus: I. Development and laboratory characterization. N Engl J
RL,
Med 275:569-574, 1966. 2. Meyer HM Jr, Parkman PD, Panos TC, et al: Clinical studies with attenuated rubella virus, in First International Conference on Vaccines Against Viral and Rickettsial Diseases of Man. Pan American Health Organization Scientific Publication No. 147, 1967, pp 390-398. 3. International symposium on rubella vaccines, Proceedings of the 23rd symposium organized by the Permanent Section of Microbiological Standardization, Nov 18-20, 1968, in Immunobiological Standardization. New York, S. Karger, vol 11, 1969. 4. Dudgeon JA, Marshall WC, Peckham CS: Rubella vaccine trials in adults and children. Am J Dis Child 118:237-242, 1969. 5. Krugman S (ed): International conference of rubella immunization. Am J Dis Child 118:2\x=req-\ 400, 1969. 6. Krugman S: Present status of measles and rubella immunization in the United States: A medical progress report. J Pediatr 90:1-12, 1977. 7. Steigman AJ (ed): Report of the Committee on Infectious Diseases, ed 18. Evanston, Ill, American Academy of Pediatrics, 1977. 8. Center for Disease Control Rubella Surveillance, No 3. Atlanta, Center for Disease Control, October 1971. 9. Horstmann DM, Liebhaber H, Le Bouvier GL, et al: Rubella: Reinfection of vaccinated and naturally immune persons exposed in an epidemic. N Engl J Med 283:771-778, 1970. 10. Horstmann DM: Controlling rubella: Problems and perspectives. Ann Intern Med 83:412\x=req-\ 417, 1975.
1:9-10, 1973.
13. South J:
sants. Lancet
Teratogenic effects of
anticonvul-
2:1154, 1972.
14. Meyer JG: The teratological effects of anticonvulsants and the effects on pregnancy and birth. Eur Neurol 10:179-190, 1973. 15. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285-290, 1975. 16. Hill RM: Drugs ingested by pregnant women. Clin Pharmacol Ther 14:654-659, 1973. 17. Seip M: Growth retardation, dysmorphic facies and minor malformations following massive exposure to phenobarbitone in utero. Acta Paediatr Scand 65:617-621, 1976. 18. Martin HP: Microcephaly and mental retardation. Am J Dis Child 119:128-131, 1970. 19. Watson E, Lowrey G: Growth and Develop-
ment of Children. Chicago, Year Book Medical Publisher Inc, 1967, pp 82, 419. 20. Lemire RJ, Loeser JD, Leech RW, et al: Normal and Abnormal Development of the Human Nervous System. New York, Harper & Row Publishers Inc, 1975, pp 390-391. 21. Starreveld-Zimmerman AAE, van der Kolk WJ, Elshove J, et al: Teratogenicity of antiepileptic drugs. Clin Neurol Neurosurg 77:81-95, 1974. 22. Waziri M, Ionasescu V, Zellweger H: Teratogenic effect of anticonvulsant drugs. Am J Dis Child 130:1022-1023, 1976. 23. Dronamraju KR: Epilepsy and cleft lip and palate. Lancet 2:876-877, 1970. 24. Meadow SR: Congenital anomalies and anticonvulsant drugs. Proc R Soc Med 63:48-49, 1970. 25. Sabin M and Oxorn H: Epilepsy and pregnancy. Obstet Gynecol 7:175-179, 1956. 26. Soifer JD: Convulsions and coma in pregnancy. Am J Obstet Gynecol 84:623-626, 1962. 27. Janz D, Fuchs U: Are antiepileptic drugs harmful when given during pregnancy? Ger Med Mon 9:20-23, 1964. 28. Baptisti A: Epilepsy and pregnancy: A review of the literature and a study of 37 cases. Am J Obstet Gynecol 35:818-824, 1938. 29. Pritchard JA, Scott DE, Whalley PJ: Maternal folate deficiency and pregnancy wastage. Am J Obstet Gynecol 109:341-346, 1971. 30. Bjerkedal T, Bahna SL: The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 52:245-248, 1973.
31. Burnett CWF: A survey of the relation between epilepsy and pregnancy. J Obstet Gynecol 53:539-556, 1946. 32. Knight AH, Rhind EG: Epilepsy and pregnancy: A study of 153 pregnancies in 59 patients. Epilepsia 16:99-110, 1975. 33. Goodwin JF, Lawson CW: Status epilepticus complicating pregnancy. Br Med J 2:332-333, 1947. 34. McClure JH: Idiopathic epilepsy in pregnancy: Summary of the literature and clinical study of 20 patients. Am J Obstet Gynecol 70:296\x=req-\ 301, 1970. 35. Klein MD, Goodfriend MJ, Shey IA: Status epilepticus and pregnancy. Am J Obstet Gynecol 72:188-190, 1956. 36. Suter C, Klingman WO: Seizure states and pregnancy. Neurology 7:105-118, 1957. 37. Orringer CE, Eustace JC, Wunsch CD, et al: Natural history of lactic acidosis after grandmal seizures. N Engl J Med 297:796-799, 1977. 38. McCrann DJ, Schifrin BS: Fetal monitoring in high-risk pregnancy. Clin Perinatol 1:229\x=req-\ 252, 1974. 39. Ramsay RE, Strauss RG, Wilder BJ, et al: Status epilepticus in pregnancy: Effects of phenytoin malabsorption on seizure control. Neurology 28:85-89, 1978. 40. Dimsdale H: The epileptic in relation to pregnancy. Br J Med 2:1147-1150, 1959. 41. Brown GW: Berkson fallacy revisited: Spurious conclusions from patient surveys. Am J Dis Child 130:56-60, 1976.
Immunity After
Rubella and Measles Viral Vaccines
the early stages of clinical trials with live attenuated rubella vaccines about a decade ago, two
During
important questions
were
paramount
in the minds of those responsible for those trials. The first was concerned with the possible communicability of the vaccine virus and the second with the duration of immunity. It must be accepted that any new vaccine poses problems, both general and specific, but as far as rubella vaccines were
concerned, these
importance.
were
of
special
The first question arose from the original trials in a small group of susceptible children carried out by Parkman et al1 and Meyer et al2 with their high passage virus (HPV-77) prepared in monkey kidney cell cultures. They had shown that intermittent excretion of rubella vaccine virus occurred in the majority of vaccinated individuals. The question was simple.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
If vaccinees excreted virus in the
nasopharynx, could infection be transmitted to susceptible contacts and, more important, if the contact was a pregnant virus
woman, could the vaccine damage to the fetus?
cause
Fortunately, for one reason or another, possibly due to the fact that the vaccine virus in the nasopharynx was usually excreted in low titer, transmission of infection to suscepti¬ ble contacts could not be detected.
This fact was fully confirmed by the extensive trials of other live rubella vaccines between 1967 and 1969.M Nevertheless, at the time it was the most important potential drawback to the licensure of live rubella vaccines which, although attenuated in the sense that they produced very little clinical disease, had the propensity of spreading and could by no yardstick be regarded as attenuated or nonteratogenic for the human fetus that they
designed to protect. All current immunization programs against ru¬ bella are based on the fact that the vaccine is safe to administer to chil¬ dren and young adults and that no restrictions need be placed on them for fear of transmitting infection to their mothers or others with whom they might come into contact. The second question, that of the duration of immunity, was, and still is, a far more difficult one to answer. Many natural infections, including were
smallpox, yellow fever, poliomyelitis, measles, and rubella, give rise to a life-long immunity in that clinically and virologically proved second at¬
tacks are very rare events. It used to be taught that live attenuated vac¬ cines, such as smallpox and yellow fever, were to be preferred to inacti¬ vated vaccines because they gave rise
life-long immunity (which they clearly did not). Revaccination against smallpox was a statutory requirement to
for travellers for many years so that immunity could be maintained. Draw¬ ing a distinction between life-long and long-term immunity is not just a matter of semantics, there is an important difference. Only careful and continued surveillance of immu¬ nized populations can answer the question as to whether vaccines cur¬ rently in use against poliomyelitis, measles, and rubella for example, can confer the same effective immunity that follows natural infection. The present success with measles vaccine in the United States reported by Krugman" is encouraging, but it would be foolhardy to assume that success with a measles vaccine is necessarily going to be the same as with a rubella vaccine. First of all, the two viruses are different, the vaccines are different and the two diseases are
different. Measles is essentially a disease of early childhood capable of causing severe disease, particularly in the presence of malnutrition, whereas rubella is a disease of older children and adolescents in whom it causes little serious disease unless it occurs in pregnancy. The purpose for which measles and rubella vaccines are administered is therefore all impor¬ tant. Measles vaccine is administered to confer direct protection to the indi¬ vidual; rubella vaccine is administered to confer protection indirectly to an unborn fetus at some later stage in the life of the individual. The two vaccines do not necessarily have to be administered together, though it may be convenient to do so if combined vaccines are available. The procedure now recommended in the United States is to offer rubella vaccine to all children, both boys and girls from approximately 15 months of age to puberty.7 This would have the dual objective of conferring immunity on a large proportion of the childhood population before they ac¬ quired natural infection and also of suppressing or otherwise controlling the reservoir of infection. In theory, elimination of wild virus from the community by mass vaccination would remove the main source of the cause of congenital rebella defects, but it would also remove the most effective means of maintaining immunity in vaccinated communities. Unless there is a very high acceptance-rate of vaccine, rubella will continue to occur in vaccinated communities. This has already been reported in several areas in the United States with outbreaks of rubella occurring mainly in unvaccinated susceptible individuals.8 In Brit¬ ain and many European countries, selective immunization is used for
schoolgirls aged 11 to 14 years, leaving boys unvaccinated. Most countries
recommend immunization of ado¬ lescent girls and women if serological tests indicate that they are suscepti¬ ble. This then is the essential differ¬ ence between the so-called American and British schemes to control con¬ genital rubella defects—for this after all is what rubella immunization is all about. The crucial question to be answered now
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Manitoba User on 06/04/2015
with respect to rubella is whether vaccine-induced immunity is as effec¬ tive and durable as immunity from the natural disease. On this depends the whole question of the age at which the vaccine is best administered. As for natural immunity, there is good evidence that primary infection in childhood leads to immunity lasting for many years but it is not known with certainty how immunity is main¬ tained. It could be that humoral immunity persists for prolonged peri¬ ods after the primary stimulus to the immune mechanism, or that periodic reinfection occurs producing a booster or reinforcing effect to immunity. In this situation, one would expect the secondary type response to be asso¬ ciated with the rapid appearance of antibody of the IgG type. Horstmann and her colleagues9 have shown that reinfection occurs much more fre¬ quently after vaccination than after natural infection. In one study in mili¬ tary recruits,9 the reinfection rate after administration of Cendehill vac¬ cine was 80% compared with 3.9% in naturally immune individuals. Rein¬ fection was entirely asymptomatic and it is generally assumed that viremia does not occur in a reinfec¬ tion. Several reports have recently ap¬ peared that indicate that immunity after vaccination may not be as longlasting as originally anticipated. Dr Dorothy Horstmann carried out a surveillance of rubella vaccines on several hundred children immunized in 1968, with the HPV-77 duck embryo vaccine (HPV-77 DE5).1" Several im¬ portant points emerged from the study. First, the number of children with low antibody titers (1:8 to 1:16) was higher in the vaccinated group (30%) than in those naturally immune and a further 60% of the vaccinated group had hemagglutination inhibi¬ tion antibody levels in the median range. Second, there was a noticeable difference in the number of children who had lost antibody after vaccina¬ tion when tested three to five years later. Of the vaccinated group, 26% had no detectable antibody and this was mainly in the group that showed a poor initial response. Of these, asymp¬ tomatic reinfection developed in 12%,
whereas none of those who were natu¬ rally immune or who had high initial titers did so. In the original trial, it seemed that there was rather a large number of "vaccine-failures"; 118 children were so classified because there was no detectable antibody two months postvaccination. However, it is now well known that if the first postvaccination sample is collected too early, that is to say six to eight weeks after vaccination, then the percentage of seroconverters will be lower than when the second sample is collected eight to 12 weeks after vaccination. The percentage of seroconverters will then be in the region of 959c to 98%. Of the children designated as vaccinefailures, and retested,1" 82% were found to have detectable antibody three years after, and from the type of antibody response, it looked as if these had in fact responded to the administration of the vaccine rather than a naturally acquired immune response having developed. A later report published in a recent issue of the Journal (132:573-577, 1978) by Doctors Balfour and Amren from the University of Minnesota, Minneapolis, has shown a substantial¬ ly high serological failure rate in chil¬ dren given rubella, measles, and mumps vaccines, either as a monoval¬ ent vaccine or in a combined form. It is difficult to be certain that these were true vaccine-failures or nonseroconverters since antibody tests were not carried out after vaccination in as much as this was part of a routine primary health care program. It is possible that some children labelled as vaccine-failures had lost antibody, possibly in cases, as Horstmann found, where the initial antibody response was low. On the other hand, the number of seronegative children was higher in those groups immunized between 11 and 13 months than in the 14- to 16-month group, suggesting that residual amounts of maternal antibody could have the same suppressive effect as occurs when measles vaccine is administered at too early an
age."
Altogether, 58 of 159 children (36%) had no detectable rubella hemaggluti¬ nation inhibition antibodv at a mean
age of 4.7 years postvaccination. With measles vaccine, the same pattern was observed; the overall serological fail¬ ure rate was 18% (31/168 children) and here again, the age of immunization seemed to be a determining factor in
achieving sion
a
satisfactory
seroconver-
The failure-rate with vaccine was only 9%. It could mumps be that some of these children had very low levels of rubella antibody undetectable by standard tests and who were in fact immune. Krugman" found this to be the case in a study of a number of children in whom measles antibody had declined after a period of 11 years. When given a second inoculation 14 years later, a typical booster response with rapid appear¬ ance of antibody developed. Balfour and Amren have considered various possibilities to explain these unusual events. Loss of potency in the vaccine is one possibility, but several batches of vaccine were used over a period of time. Although this cannot be ruled out, it is well known that measles and rubella vaccines are labile products sensitive to heat and light and unless meticulous attention is paid to the details of storage, particu¬ larly when reconstituted, potency can be rapidly lost. This might occur more frequently when large numbers of children are being immunized in clin¬ ics as opposed to the somewhat differ¬ ent setting of a clinical trial. In a sense, these findings are not dissimilar from those of Horstmann1" from which two supplementary ques¬ tions arise. If such a high proportion of children are found to be seronega¬ tive four to five years after rubella vaccination, whatever the cause, what will be the position 20 to 25 years later when these vaccinated children will have reached the age of child-bearing? Will they continue to respond to rein¬ fection with an asymptomatic, nonviremic illness? After passage of time, will the effect of the primary antigen¬ ic stimulus cease to be effective, in which case could reinfection be asso¬ ciated with symptomatic disease, viremia, and a risk to the fetus? One way to answer this question is to revaccinate a group of these seronega¬ tive children to determine the type of immune response. This would seem rate.
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more reasonable than to challenge them with wild virus to try and deter¬ mine the presence or absence of viremia which would be an extremely difficult procedure to evaluate. These are questions that require urgent answers and until they are evaluated, the question of reimmunization of children vaccinated in early childhood will have to be kept open. In any case, there does seem to be an important message of practical impor¬ tance that reinforces the recommen¬ dation of the American Academy of Pediatrics that measles and rubella vaccines should not be given before the age of 15 months (except in the case of measles vaccine where indi¬ cated in the first year of life). But are 15 months and early childhood still too early for rubella vaccination, bearing in mind that the threat to be averted lies many years in the future? J. ALASTAIR DUDGEON, MD Department of Microbiology Hospital for Sick Children Great Ormond Street London WC1N 3JH, United
Kingdom References 1. Parkman PD,
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HM Jr, Kirschstein
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Med 275:569-574, 1966. 2. Meyer HM Jr, Parkman PD, Panos TC, et al: Clinical studies with attenuated rubella virus, in First International Conference on Vaccines Against Viral and Rickettsial Diseases of Man. Pan American Health Organization Scientific Publication No. 147, 1967, pp 390-398. 3. International symposium on rubella vaccines, Proceedings of the 23rd symposium organized by the Permanent Section of Microbiological Standardization, Nov 18-20, 1968, in Immunobiological Standardization. New York, S. Karger, vol 11, 1969. 4. Dudgeon JA, Marshall WC, Peckham CS: Rubella vaccine trials in adults and children. Am J Dis Child 118:237-242, 1969. 5. Krugman S (ed): International conference of rubella immunization. Am J Dis Child 118:2\x=req-\ 400, 1969. 6. Krugman S: Present status of measles and rubella immunization in the United States: A medical progress report. J Pediatr 90:1-12, 1977. 7. Steigman AJ (ed): Report of the Committee on Infectious Diseases, ed 18. Evanston, Ill, American Academy of Pediatrics, 1977. 8. Center for Disease Control Rubella Surveillance, No 3. Atlanta, Center for Disease Control, October 1971. 9. Horstmann DM, Liebhaber H, Le Bouvier GL, et al: Rubella: Reinfection of vaccinated and naturally immune persons exposed in an epidemic. N Engl J Med 283:771-778, 1970. 10. Horstmann DM: Controlling rubella: Problems and perspectives. Ann Intern Med 83:412\x=req-\ 417, 1975.
