Comparison of Vaccination with Measles-Mumps- Rubella Vaccine at 9, 12, and 15 Months of Age

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1 SUPPLEMENT ARTICLE Comparison of Vaccination with Measles-Mumps- Rubella Vaccine at 9, 12, and 15 Months of Age Stephen C. Redd, 1 Gail E. King, 1,a Janet L. Heath, 2 Baghar Forghani, 3 William J. Bellini, 2 and Lauri E. Markowitz 1 1 National Immunization Program and 2 National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 3 California State Department of Health Services, Viral and Rickettsial Disease Laboratory, Richmond, California To determine seroconversion rates with measles-mumps-rubella vaccine administered to children at 9, 12, or 15 months of age, we undertook a prospective randomized trial. Among children vaccinated at 15 months of age, 98% seroconverted to measles, compared with 95% of those vaccinated at 12 months of age and 87% of those vaccinated at 9 months of age. In each age group, children of mothers born in or before 1963 had lower rates of seroconversion against measles, with the lowest rate in children vaccinated at 9 months. The seroconversion rate of rubella paralleled that of measles, with the lowest seroconversion rates in children vaccinated at 9 months of age whose mothers were born in or before The response to mumps varied little by age of the child or birth year of the child s mother. These results support the recommended age for first vaccination with measles-mumps-rubella at months. Selecting the appropriate age to vaccinate children against measles has challenged policy makers since the licensure of measles vaccine in 1963 [1, 2]. Transplacentally acquired maternal IgG antibody protects young children from measles but also can block or attenuate the response to measles vaccination [3, 4]. During gestation, children acquire IgG from their mothers through what begins as a passive process but later in gestation becomes an active and selective process [5]. The appropriate age for measles vaccination must balance the risk of acquiring measles after maternal antibody has declined to less-than-protective levels with the risk of vaccine failure if vaccination takes place before maternal antibody has declined sufficiently. Although differences in the efficiency of transport of maternal measles antibody across the placenta vary by the geographic residence and possibly by ethnicity of the mother, the most important determinant is the amount of maternal IgG [2]. Maternal levels of IgG are determined by the The trade name MMR II (Merck) is used for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the US Public Health Services, or the US Department of Health and Human Services. a Deceased. Reprints or correspondence: Dr. Stephen C. Redd, Centers for Diseases Control and Prevention, 1600 Clifton Rd., Mailstop E-17, Atlanta, GA (scr1@cdc.gov). The Journal of Infectious Diseases 2004; 189(Suppl 1):S by the Infectious Diseases Society of America. All rights reserved /2004/18909S1-0019$15.00 mother s history of exposure to measles. Mothers who have had natural measles virus infection have higher antibody titers than do mothers who have been vaccinated, and mothers who have not had measles and have not been vaccinated have no antibody [6]. In the United States, the numerous changes in the recommended age for measles vaccination reflect changes in the epidemiology of measles the risk of acquiring wild-type infection and in the understanding of the response to measles vaccination. When measles vaccine was first licensed in 1963, the potential for maternally derived antibody to interfere with vaccination of infants was recognized, but available data indicated that such antibody was no longer present by 7 months of age [7]. Children aged 9 months were recommended to receive measles vaccine [8]. By 1965, additional data had accumulated indicating more prolonged persistence of maternally derived measles antibody; many 9-month-old children still had maternal measles antibody, and policy makers raised the recommended age for vaccination to 12 months [9, 10]. In 1976, the higher rate of vaccine failure among children vaccinated between 12 and 15 months of age led to the recommendation that children be vaccinated at 15 months of age [11]. As vaccination coverage increased in the United States through the 1960s and 1970s, fewer and fewer children contracted measles. By the late 1980s, more S116 JID 2004:189 (Suppl 1) Redd et al.

2 women of childbearing age in the United States had vaccination-induced immunity to measles and fewer had disease-induced immunity than did women in the 1960s and 1970s. Consequently, mothers born in the United States since 1963 have lower titers of antibody to measles than do women born earlier, and lower titers of antibody in newborns decline to nonprotective levels more quickly than do higher titers [12, 13]. One consequence of the shorter duration of passive antibody protection was an increase in the proportion of measles cases among children!12 months old during the measles resurgence to 14.3% of total cases. Furthermore, one study has shown that children of mothers born since 1963 are more likely to respond to measles vaccination at 9 months than are children of women born before 1963 [13]. To determine whether measles, mumps, and rubella (MMR) vaccination could be recommended for younger children, we compared the immune response to measles-mumps-rubella vaccine (MMR II; Merck) in children aged 9 months, 12 months, and 15 months. METHODS Study setting and patients. Children were enrolled in 1992, 1993, and 1994 from 19 different freestanding clinics that were part of Group Health Incorporated, a staff model health maintenance organization (HMO) in Minneapolis and St. Paul. Each clinic served as a site for primary health care for a defined patient population; subspecialists were available at several of the clinics. Study procedures. A database of children enrolled in the Group Health HMO was used to identify children who were 7 months old. A letter was mailed to the parents of each 7- month-old child describing the study and inviting participation; a copy of a consent form was also included. This mailing was followed by a telephone call to answer questions, to determine whether the parents wished to give permission for the child to participate in the study, and to obtain informed consent. If the parent gave informed consent, an enrollment questionnaire was completed during the telephone interview; requested data included demographic information on the child and mother and details of the mother s history of natural measles or measles vaccination. After the parents had given consent and children were enrolled, children were randomly assigned to receive vaccination at 9 months, 12 months, or 15 months of age. Before the study began, a computer generated a random list of group assignments. Each group assignment was individually placed in a sealed, opaque envelope that was opened at the time of randomization. Neither the telephone interviewer nor parents of enrolled children were aware of the contents of the envelope until it was opened. After randomization, parents of enrolled children were asked to schedule an appointment for MMR vaccination. A reminder postcard was mailed 10 days before the scheduled vaccination visit, and parents of enrolled children who did not come to clinic for the scheduled appointment were telephoned within a few days of the missed appointment. At the time of the visit for MMR vaccination, a 5-mL blood specimen was collected from the mother and a 0.75-mL blood specimen was collected from the child. These blood specimens were centrifuged; serum was decanted and refrigerated. Serum specimens were shipped to the central laboratory for Group Health Incorporated each day and frozen at 20 C. The enrolled child was vaccinated with 0.5 ml of MMR vaccine and observed for 30 min. Five weeks after vaccination, a postcard was mailed to parents asking them to take the child to the laboratory at the clinic where the child had been vaccinated, for a postvaccination blood draw. At the return appointment, a 0.75-mL blood specimen was obtained, centrifuged, transported to the central laboratory, and frozen, as with the prevaccination serum specimen. All serum specimens were tested in pre- and postvaccination pairs. Parents of children who failed to respond to vaccination were contacted and advised to schedule an appointment for revaccination. After revaccination, serum specimens before and after vaccination were collected as at the initial vaccination. Because an interim analysis showed a lower rate of seroconversion to measles among children vaccinated at age 9 months, enrollment in this study arm was halted 14 months after enrollment began. Children who initially had been randomized to receive MMR vaccine at 9 months of age but had not yet been vaccinated were re-randomized to be vaccinated at 12 or 15 months of age. In addition to examining seroconversion immediately after vaccination, we investigated seroconversion 24 months after vaccination by contacting parents of children enrolled in the study and requesting that they participate in a follow-up assessment of antibody levels at 24 months. Laboratory studies. At 1-month intervals, collections of frozen serum specimens were shipped to the Centers for Disease Control and Prevention (CDC) for serological testing. Serum specimens were tested by an indirect EIA that measured IgG antibody to measles virus nucleoprotein [14]. Specimens that yielded negative results were tested by a microneutralization assay [15]. Specimens lacking detectable antibody before vaccination that had antibody after vaccination were considered to indicate seroconversion. If antibody was detected in the prevaccination serum specimen, the postvaccination specimen had to have a 4-fold rise in titer to be considered indicative of seroconversion. A postvaccination serum specimen yielding negative results (microneutralization titer of!10) was considered to reflect vaccine failure. An aliquot of serum was shipped to the Viral and Rickettsial Disease Laboratory, Richmond, California, for testing of rubella Vaccination at 9, 12, and 15 Months JID 2004:189 (Suppl 1) S117

3 Table 1. Characteristics of children enrolled in a study comparing measles-mumps-rubella vaccination at 9, 12, and 15 months of age. Randomization age group at vaccination Characteristic 9 months 12 months 15 months Proportion male 59.7 (170/285) 50.3 (180/358) 53.9 (187/347) Mean age at vaccination, months (SD) 9.6 (0.54) 12.3 (0.44) 15.2 (0.41) Median birth year of mother Breast-fed Race/ethnicity (n p 990) White African American Hispanic Other/unknown Attending day care Mother with a history of measles Mother with measles IgG detected by EIA NOTE. Unless indicated otherwise, data are % or % (no./total). and mumps antibody by EIA [16]. Children were considered to have seroconverted to these antigens when prevaccination specimens had no detectable antibody and postvaccination specimens had detectable antibody. Children with rubella or mumps antibody that was detectable in both prevaccination and postvaccination specimens were considered to have an uninterpretable response to vaccination and were excluded from analysis. Specimens obtained from children examined 24 months after vaccination were collected as above; antibody levels were tested by means of the same methods. Analyses. Rates of seroconversion to measles, mumps, and rubella in children who were vaccinated at 9 and 12 months of age were compared with rates in children vaccinated at 15 months of age. Maternal birth year, as a surrogate for the risk of the mother having had natural measles, was examined as a determinant of seroconversion. A logistic regression model was constructed comparing vaccination at 9 and 12 months with vaccination at 15 months. The model included age at vaccination and mother s birth year; an assessment for interaction between these 2 covariates was undertaken. All statistical analyses were conducted with SAS [17]. Ethical approvals. The protocol for this study was approved by the Institutional Review Boards of the CDC and Group Health Incorporated. RESULTS Nine hundred ninety children were enrolled over a 24-month enrollment period and completed the study; 285 children were vaccinated at age 9 months, 358 were vaccinated at age 12 months, and 347 were vaccinated at age 15 months. Characteristics of the 990 enrolled children who completed the study did not differ significantly by randomization group (table 1). Similar proportions of children had mothers with histories of measles and mothers with IgG antibody to measles as measured by EIA. An additional 36 children (3.5% of total whose parents gave informed consent) were randomized to receive vaccination but then dropped out of the study. Children who did not complete the study had younger mothers (28.5 years old vs years old at the start of the study; P p.003, t test) than did children who did complete the study. Randomization group assignment was not associated with failing to complete the study. A higher proportion of children randomized to receive MMR at 15 months of age than of children receiving MMR at 9 or 12 months of age seroconverted to measles (table 2). Response to rubella in the 9-month group was also lower than in the 12- or 15-month group, although there was only a non statistically significant 1.4% difference between the 12- and 15- Table 2. Seroconversion by vaccine antigen, age group vaccinated, and birth year of mother among children vaccinated with measles-mumps-rubella vaccine at 9, 12, or 15 months of age. Vaccine antigen, birth year of mother Randomization age group 9 months 12 months 15 months Measles, overall 249/285 (87.4) 341/358 (95.3) 341/347 (98.3) 1963 or earlier 147/176 (83.5) 209/221 (94.6) 219/224 (97.8) After /109 (93.6) 132/137 (96.4) 122/123 (99.2) Rubella, overall 249/273 (91.2) 335/353 (94.9) 319/331 (96.4) 1963 or earlier 148/167 (88.6) 208/218 (95.4) 206/213 (96.7) After /106 (95.3) 127/135 (94.1) 113/118 (95.8) Mumps, overall 251/272 (92.3) 318/354 (89.8) 307/330 (93.0) 1963 or earlier 154/167 (92.2) 196/219 (89.5) 197/213 (92.5) After /105 (92.4) 122/135 (90.4) 110/117 (94.0) NOTE. Data are no/total (%). S118 JID 2004:189 (Suppl 1) Redd et al.

4 month groups. The rate of seroconversion to mumps was nearly identical in each of the 3 groups. The birth year of the mother affected the rate of seroconversion to measles, with children of more recently born mothers having higher seroconversion rates (table 2). Although this trend was noted in each randomization group, it affected the group vaccinated at 9 months of age particularly. The seroconversion rate among children vaccinated at 9 months of age whose mothers were born after 1963 was 93%, compared with 83% among similarly aged children whose mothers were born in 1963 or earlier. In a stratified analyses, children vaccinated at 9 months of age were less likely to respond than were children vaccinated at 15 months of age ( P!.001 for mothers born in or before 1963 and P!.03 for mothers born after 1963). In a similar stratified analysis comparing children vaccinated at 12 months with children vaccinated at 15 months of age, the differences in seroconversion rate were not statistically different. The seroconversion rate to rubella showed a similar, although not statistically significant, trend in 9-month-old vaccine recipients, with higher rates seen in those with more recently born mothers; this was not detected in children vaccinated at 12 or 15 months of age. No trend with maternal age was noted for the response to mumps vaccine. Mothers who had antibody to measles, a characteristic common in all 3 age groups of study children, were more likely to have a child who did not respond to vaccination. Nearly onethird of mothers (32.2%) had an unknown history of measles. As with mother s year of birth, the effect of mother s history of measles and measles antibody status differed depending on the age of vaccination of the child, with younger children having a lower seroconversion rate when the mother had either antibody to measles or a history of measles. The seroconversion rate among children who were vaccinated at 9 months of age whose mothers had a history of measles was 76.3% (58/76), compared with 95.6% (109/114) among children vaccinated at 9 months of age whose mothers had a history of not having measles; comparable seroconversion rates for 12-month-old children were 93.8% (91/97) versus 96.6% (140/145) and for 15-month-old children were 95.6% (86/90) versus 99.3% (133/ 134). Other variables were assessed for possible association with seroconversion to measles, including sex of the child, clinic of enrollment, whether the child was attending day care, whether the child had ever been breast-fed, and race or ethnicity of the child; none was associated with increased or decreased risk of seroconversion to measles. In a logistic regression model that included age of the child and birth year of the mother, both terms were associated with seroconversion to measles vaccination. Compared with children vaccinated at 15 months of age, the adjusted odds ratio for vaccination failure among those vaccinated at 9 months of age was 8.33 and among those vaccinated at 12 months of age was The Hosmer-Lemeshow goodness-of-fit statistic had a P of.92, indicating that the model fit the data well. An assessment for interaction between birth year of the mother and age of the child at vaccination showed that there was no interaction. Lack of seroconversion to measles vaccine was not associated with lack of seroconversion to rubella or mumps vaccine. Among 904 who responded to the first dose of measles vaccine and for whom sera were available for rubella and mumps testing, 855 (94.6%) responded to rubella vaccine and 830 (91.8%) responded to mumps vaccine. Among children not responding to the first dose of measles vaccine, 48 (90.6%) of 53 responded to rubella vaccine and 46 (88.5%) of 52 responded to mumps vaccine. Only 2 children failed to respond to all 3 antigens. Of the 59 children who failed to seroconvert to measles, 41 were revaccinated (28 in the 9-month group, 10 in the 12- month group, and 3 in the 15-month group) a median of 24.3 weeks after the initial vaccination, and 35 (85.4%) responded to revaccination. By age group, 26 of 28 revaccinated 9-montholds responded, 7 of 10 revaccinated 12-month-olds responded, and 2 of 3 revaccinated 15-month-olds responded. The median number of weeks between the first and second vaccination did not differ among the 3 groups of children. A total of 749 children participated in the 24-month followup, 217 (76%) of the children initially vaccinated at 9 months of age, 284 (79%) of the children initially vaccinated at 12 months of age, and 248 (71%) of the children initially vaccinated at 15 months of age. Children who were initially vaccinated at 9 months of age were more likely to be have negative results of testing for antibody 24 months after initial vaccination than were children initially vaccinated at 12 or 15 months of age (table 3). Children who experienced failure of first vaccination at 9 months and were revaccinated (and developed antibody after revaccination) were more likely to have negative results for antibody at the 24-month follow-up assessment than were children who did not have failure of the initial vaccination ( P p.03). This higher proportion of antibody-negative results occurred despite the high seroconversion rate after revaccination among children who experienced failure of first vaccination. DISCUSSION The results of this study show that the likelihood of seroconversion to measles after a child is vaccinated with MMR depends on the age of the child and the birth year of the child s mother. Birth year of the mother is likely acting as a surrogate for risk of the mother having disease-induced rather than vaccination-induced immunity to measles. Older children responded better than did younger children, and children of mothers with more recent birth years responded better than did children with older mothers. The analysis for interaction between these effects showed that they were independent of Vaccination at 9, 12, and 15 Months JID 2004:189 (Suppl 1) S119

5 Table 3. Serological evidence of immunity to measles 24 months after initial vaccination with measles-mumps-rubella (MMR) in children vaccinated at 9, 12, or 15 months. Randomization age group Antibody response 9 months 12 months 15 months Without detectable antibody 19/217 (8.8) 7/284 (2.5) 1/248 (0.4) No detectable antibody after responding to initial vaccination 14/195 (7.2) 7/280 (2.5) 1/246 (0.4) No detectable antibody after failing to respond to initial vaccination 5/22 (22.7) 0/4 0/2 NOTE. Children were excluded from this analysis for any of 3 reasons: not providing a serum specimen 24 months after initial vaccination, failing to respond to the first dose of MMR and not receiving a second dose, or failing to respond to the first dose of MMR and also failing to respond to a second dose. Data are no./total (%). each other. Regardless of the birth year of the mother, older children responded better; and regardless of the age at vaccination, children with more recently born mothers responded better. This study showed a significantly lower rate of seroconversion to measles among children vaccinated at 9 or 12 months of age compared with 15-month-old children. This effect was most marked in 9-month-old children whose mothers were born in or before 1963, years when most women would have been expected to have had immunity to measles as a result of disease rather than vaccination. Studies comparing vaccination at 9 and 12 months have produced similar findings [8, 9]. Although the effect of the mother s birth year was most evident in children who were vaccinated at 9 months of age, it was also observed in children vaccinated at 12 and 15 months. The most likely explanation for the effect of maternal birth year is the decreased risk of the mother having had measles, but we cannot rule out some other age-related effect that would render children of older mothers less susceptible to vaccination than are children of younger mothers. The mother s history of measles, which would have resulted in a higher titer of measles antibody than would result from vaccination, was associated with a lower rate of response to MMR vaccination, but more than one-third of mothers could not remember whether they had had measles. In situations in which a reliable history of measles or absence of disease can be obtained, this information could be used to predict the likelihood of a child responding to measles vaccination. Because the reliability of a history of measles may vary among different populations, the findings of the current study are insufficient as a basis for a change in national policy. The response to the rubella antigen in MMR in 9-monthold children was similar to the response to the measles antigen in MMR, although the seroconversion rate in children with mothers born in or before 1963 was not statistically different from the seroconversion rate in those whose mothers were born later. The lack of an association of the mother s birth year with the response to rubella vaccination in 12- and 15-month-old children may reflect less interference of maternally derived rubella antibody, a more rapid rate of decline of maternally derived antibody in infants than for measles antibody, or an effect of age of the child separate from the decay of maternally derived antibody. Rubella vaccination recommendations were implemented later than those for measles, but additional analyses using different maternal ages as thresholds did not document an effect of later maternal birth year on rates of seroconversion to rubella in 12- or 15-month-old children (data not shown). The possible reasons that the response to mumps vaccination was not affected by the age of the child or by the birth year of the mother must be speculative. The mother s vaccination or wild-type infection could induce immunity that crosses the placenta and interferes with vaccination similarly. Alternatively, waning of maternal antibodies to wild-type mumps virus infection may not have the same effect on response to mumps vaccination as appears to be the case with measles and rubella. The lack of effect of mother s birth year, with 1963 as threshold, may be attributable to the relatively recent introduction and initially incomplete coverage of mumps vaccine; few mothers in the study may have had vaccine-induced immunity to mumps. However, later birth year was not associated with improved response to mumps vaccine (analyses not shown). Several studies have examined the effect of age at vaccination on response to the Urabe strain of mumps vaccine [18 20]; 1 study found a reduction in seroconversion rate [19] and 2 did not [20, 21]. No data are available on the Jeryl Lynn strain of mumps vaccine used in the United States. The high rate of response to revaccination among children who failed to respond to the measles component of the first vaccination is reassuring and suggests that current recommendations for a second dose of MMR will protect children who do not respond to the first dose [21]. However, at the 24- month follow-up, nearly 10% of the children vaccinated at 9 months of age were without detectable antibody. Others have S120 JID 2004:189 (Suppl 1) Redd et al.

6 documented rapid decline in antibody levels among some second-dose recipients, and the potential for a modified immune response to revaccination after early vaccination has been debated [22 24]. Ward et al. [23] found a dissociation between humoral and cellular immunity to measles; a substantial proportion of children who lost antibody after responding to revaccination retained evidence of cell-mediated immunity. Although a measles antibody titer of 11:120 in the plaque reduction neutralization assay has been shown in 1 study to be protective against measles, whereas lower titers were not [25], the response to revaccination may be more complex than that following primary vaccination, and cellular immunity may be a more important determinant of long-term immunity than is humoral immunity after revaccination. Several outbreak investigations have found similar levels of protection among 2- dose measles vaccine recipients among children initially vaccinated before 12 months of age and those initially vaccinated after 12 months of age [26, 27]. The results of primary vaccination in this study suggest that measles vaccination will become increasingly effective overall and increasingly effective among younger children as the proportion of mothers with vaccination-induced rather than disease-induced immunity to measles increases. The trend for rubella vaccination appears similar to that for measles, and the trend for mumps, the most recently introduced vaccine, is unclear. In the future, lowering the recommended age for measles vaccination below 12 months would probably not substantially lower the serological response to vaccination. However, the current very low risk of exposure to measles in the United States does not indicate a need to lower the age for measles vaccination. The policy of administering a second dose of MMR vaccine to children at school entry ensures that a very high level of population immunity against measles will be maintained; the 2-dose policy has similar implications for mumps and rubella. The number of reported measles cases is at record low levels, with strong evidence that measles virus transmission has been interrupted in the United States [28, 29]; all measles in the United States is likely the result of international importations. In this situation, children below the recommended age for vaccination may be susceptible but are at very low risk for acquiring measles. Given the current low risk of exposure to measles, the slightly higher response to vaccination at older ages is of greater benefit than the protection that an earlier dose would provide. 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