1 Epidemic Intelligence Service, Division of Applied Public Health Training, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA.
2 Measles Elimination Activity, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA.
3 Special Immunization Program, Dade County Department of Public Health, Miami, FL.
4 ABT Associates, Inc., Cambridge, MA.
5 Measles Virus Section, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
6 Laboratory of Pediatric and Respiratory Virus Diseases, Food and Drug Administration, Bethesda, MD.
7 Data Management Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
antibodies; immunity; infant; measles; measles vaccine; serologic tests; vaccines
Abbreviations: CDC, Centers for Disease Control and Prevention; EIA, enzyme immunoassay; MN, microneutralization; PRN, plaque reduction neutralization
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The early two-dose schedule has been implemented in the United States in communities with large outbreaks involving infants. After an outbreak of measles ended in 1987 in Dade County, Florida, health officials continued routine implementation of the early two-dose schedule that was initiated during the outbreak. We evaluated routine implementation of the schedule to 1) examine the population-based impact on vaccination coverage and disease incidence, 2) compare the serologic response with that of the standard schedule, and 3) determine vaccine effectiveness of the early two-dose schedule.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Early two-dose measles vaccination program in high-risk areas
During 19861987, Dade County experienced a large measles outbreak, primarily among preschool-aged children. Of the 257 outbreak-related cases of the disease reported in 1986, three quarters occurred in preschool-aged children, and 22 percent of these were in infants aged 611 months (17). Moreover, the incidence of disease (232/100,000 population) and the complication rates (33 percent) were highest among children younger than age 1 year compared with older persons. One measles-associated death was reported in an unvaccinated, young child with acquired immunodeficiency syndrome (18
).
Because of substantial morbidity among young children during the outbreak, the Dade County Department of Public Health began vaccinating infants as young as age 6 months and revaccinating them at age 1215 months. Children targeted for this early two-dose schedule lived in high-risk zip code areas, which were defined as those in which at least one case of measles was reported (figure 1). Providers receiving free vaccine from the health department were enlisted to implement the recommendation because they served children in the high-risk zip code area. These providers were public health department clinics (6 sites), a county hospital outpatient department, neighborhood health centers (13 sites), and private providers serving children enrolled in Medicaid (as many as 100 physicians).
|
After the outbreak, the early two-dose vaccination schedule was continued. Transmission of measles virus in the county was ongoing, and there was a potential threat of another outbreak.
Definition of the vaccination schedule
An early two-dose schedule was defined as administration of the first dose at age 611 months (2251 weeks) and a second dose at age 12 months (
52 weeks). A single, standard dose was defined as given at age
12 months (
52 weeks) and a single, early dose was defined as one given at age 611 months (2251 weeks). For the serologic survey, a more restrictive definition was used (as described in the Serologic Study section of this paper). For the present study, the routine second dose of measles vaccine administered at age 46 years (recommended after 1989) was not considered, because this requirement did not take effect in Dade County schools until the 19931994 school year. This policy was implemented at the end of the study period and is unlikely to have affected our results.
Population-based descriptive study
We conducted a descriptive epidemiologic study of the entire Dade County population from 1985 to 1996 to assess the impact of the early two-dose schedule for high-risk children on population-based vaccination coverage and disease. The 3-year period (19851987) before the early two-dose schedule was implemented routinely was defined as the preintervention period and was compared with the 9-year period (19881996), the postintervention period, after the routine schedule began. In the county, we examined the annual percentage of preschool-aged children vaccinated against measles as a process measure and the annual number of cases of measles as the outcome measure.
Measles vaccination coverage of preschool-aged children was measured in 19861996 by annual, cross-sectional population-based surveys of children aged 2 years. A random sample of 104114 children born in November of each year was selected from state-based birth certificates. This sample size enabled us to estimate a 95 percent confidence interval with a precision of ±10 percent. Parents or providers were interviewed by telephone or in person to determine the child's date of birth and dates of vaccination. Only dates (at least month and year) from a written record were accepted as evidence of vaccination. To assess how well the early two-dose schedule was implemented, we examined vaccination coverage of children aged 2 years surveyed in 1989 or later because they were eligible for the early two-dose schedule beginning in 1987.
Confirmed measles cases were ascertained from the National Notifiable Disease Surveillance System at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. A confirmed case had been confirmed serologically or met CDC's standard clinical case definition and was linked epidemiologically to another case that had either been confirmed serologically or met the case definition (19). Data collected on each case included the patient's age, sex, zip code of residence, exposure history, clinical information, laboratory results, and vaccination history. To further evaluate the impact on measles control in the county, we examined the epidemiology of confirmed cases for those persons targeted and those not targeted for the early two-dose schedule.
Serologic study
In FebruaryOctober 1995, to examine humoral immunity after an early two-dose schedule, we assessed the prevalence of measles antibody in high-risk children aged 46 years at least 3 years after the last dose of measles vaccine was administered. After the institutional review boards of CDC; ABT Associates, Inc., (Cambridge, Massachusetts); and each study site approved the study and informed consent was obtained from parents, children attending five pediatric clinics were enrolled consecutively in the study before receiving the school-entry dose of measles vaccine. Our target was to enroll at least 200 children who had received vaccine according to the early two-dose schedule and 200 children who had received a standard dose at age 12 months. In addition, we examined the small subset of children who had received only a single, early dose of measles vaccine. Antibody was measured by using three tests, as described previously: 1) an indirect enzyme immunoassay (EIA) that detects measles-specific immunoglobulin to the nucleoprotein antigen, 2) a microneutralization (MN) assay only if EIA antibody was not detected, and 3) a plaque reduction neutralization (PRN) assay (2023
). Any EIA or MN antibody is considered protective. We chose the EIA assay because it was widely used and highly practical. Neutralization assays were chosen because of their higher sensitivity (22
). The PRN assay was considered the most sensitive and was known to have a serologic correlate of protection against measles (titer > 1:120) (23
26
). A detectable PRN antibody titer was defined as
1:8.
For this component of the study, definitions of vaccination groups were more restrictive so we could precisely assess the serologic response to vaccination. An early two-dose schedule was defined as the first dose given at age 611 months (2551 weeks) and the second at age 1218 months (5282 weeks); a single, standard dose was defined as one given at age 1218 months (5282 weeks); and a single, early dose was defined as one administered at age 6 11 months (2551 weeks).
Vaccine effectiveness
To evaluate vaccine effectiveness among early two-dose recipients, we conducted a case-control study. Cases were defined as all preschool-aged children aged 1559 months with confirmed cases of measles reported to the National Notifiable Disease Surveillance System between 1989 and 1996. Unmatched controls were selected from the annual population-based survey of children aged 2 years in Dade County for vaccination status between 1989 and 1996, as outlined previously in the Population-based Descriptive Study section of this paper. Controls could not be matched to cases by age because the age of controls was limited by the study design; that is, the individual survey date was not available to compute the individual ages of controls. Controls were aged 2430 months at the time of the survey. Both cases and controls were residents of Dade County. Vaccine effectiveness was estimated by subtracting from 1 the exposure odds ratio for vaccinated cases versus vaccinated controls (1 odds ratio) (27). Because measles was exceedingly rare in preschool-aged children during the 8-year study period (annual average, 2 cases/100,000 population), the odds ratio approximated the relative risk.
Statistical methods
Differences in proportions were tested for significance by using either the chi-square or Fisher's exact test. A p value of < 0.05 was defined as statistically significant. PRN titers were log transformed (logarithm base 10) and were compared as reciprocal geometric mean titers by using the two-tailed, unpaired, Student's t test. Multiple logistic regression analysis was performed to estimate exposure odds ratios for vaccinated cases versus vaccinated controls for each vaccination group, adjusting for race/ethnicity. Most analysis was performed by using SAS version 6.12 software (SAS Institute, Inc., Cary, North Carolina). LogXact software (Cytel Software Corporation, Cambridge, Massachusetts) was used to estimate adjusted odds ratios.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Serologic study
The demographic characteristics of the 484 children in the serologic study were similar to those of children aged 46 years living in the high-risk areas of Dade County. Most were Latino or African American (88 percent), had mothers who were born outside of the United States (73 percent), and had mothers who were born in 1957 or later (86 percent). Nearly all children were born at term (97 percent) and had a normal birth weight (92 percent). In general, children in the early two-dose; the single, standard dose; and the single, early dose groups had similar characteristics. Minor differences were found among children in the early two-dose group, who were slightly younger than subjects in the other groups (mean age, 4.4 vs. 4.9 years), and those in the early, single dose group, who were more likely to be Latino than children in the other groups (54 vs. 61 percent). These differences were statistically significant (p < 0.05).
All 209 early two-dose recipients had detectable PRN antibody (titer 1:8), and 88 percent had EIA/MN antibody. A similar prevalence of detectable PRN antibody was found in the other vaccination groups (single, standard and single, early dose), although the prevalence of EIA/MN antibody in early two-dose recipients was statistically lower than that in the single, standard dose group (table 1). In addition, although the prevalence of a PRN antibody titer of >1:120 was similar in early two-dose recipients and 234 children vaccinated with a standard dose at age 1218 months, the reciprocal geometric mean titer was slightly lower in early two-dose recipients: 999 versus 1,440 (p < 0.05) (table 1). Most (84 percent) of the early two-dose recipients received the early dose between age 6 and 8 months. Of the small subset of 41 children who had received only a single dose at age 611 months, 98 percent had a detectable PRN antibody, 95 percent had EIA/MN antibody, and 93 percent had PRN titers of >1:120. More than one half (57 percent) of the 41 children who had received a single, early dose were vaccinated at age 68 months. Seroprevalence of infants aged 68 months was 91 percent with EIA/MN antibody, 96 percent with detectable PRN antibody, and 87 percent with a PRN titer of >1:120. Seroprevalence of infants aged 911 months was higher: all 18 infants had EIA/MN antibody and detectable PRN antibody at a titer of >1:120.
|
Vaccine effectiveness for children on the early two-dose schedule, after adjustment for race/ethnicity, was 99.5 percent (table 2). Similarly high vaccine efficacy estimates, adjusted for race/ethnicity, were found for children who received a single dose either at age 12 months (vaccine effectiveness, 99.7 percent) or age 611 months (vaccine effectiveness, 97.6 percent). Adjusted and unadjusted estimates were similar.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A direct impact of the early two-dose schedule on measles control is difficult to evaluate, because there was no similar county for comparison of both vaccination coverage data and occurrence of cases of measles during the study period. However, the shift from cases primarily among preschool-aged children to those in older persons, high seroprevalence, and high vaccine effectiveness all support the conclusion that this sustained program in Dade County was effective.
Other changes in the epidemiology of measles in Dade County that support the effectiveness of an early two-dose schedule included a disproportionately large decline in overall measles morbidity among infants aged 611 months as the distribution of cases of measles shifted from younger to older children. Moreover, no large outbreak occurred in Dade County during the national measles resurgence of 19891991, and endemic measles transmission reportedly ended after 1993. In contrast, three urban centers (Chicago, Illinois; Los Angeles, California; and New York City) that experienced large outbreaks among preschool-aged children in the mid-1980s (19851986), similar to Dade County, had another even larger outbreak during the resurgence and continued to report transmission of measles through 1998 (28, 29
).
While the high coverage achieved in the target population may not be attributed solely to the early two-dose schedule because new vaccination strategies in the county were also introduced during the postintervention period, high coverage with only an early dose suggests that the early two-dose schedule explains some of the improvement in coverage. The focus of new strategies was to improve access to vaccination services for all recommended vaccines and vaccine doses during the evenings and weekends in public health clinics and during routine hours in sites with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). The assumption that those receiving only a single, early dose would not have otherwise received measles vaccine is accurate because these children had no record of receiving other vaccines around the time that the second dose of measles vaccine could have been given. During the 8 years of routine implementation of the early two-dose schedule (1989 to 1996), an average of 20 percent of early-dose recipients each year received only that one dose. On the basis of that proportion, we determined that recipients of a single, early dose contributed a 6 percent increase in coverage among children aged 2 years (from 89 percent with any dose to 95 percent).
Recent studies in the United States and Canada found that 65100 percent of children will seroconvert after vaccination at age 6 months and 8590 percent will seroconvert after vaccination at age 9 months, particularly if their mothers were vaccinated and maternal antibody was low or not present when the child was vaccinated (8, 9
, 29
33
). In the present study, however, seroprevalence of measles antibody among those who received a single dose at age 68 months was higher (96 percent had PRN antibody, and 87 percent had a PRN titer of >1:120), and it was even higher among those who received it at age 911 months (all had detectable antibody at a titer considered protective). If we assume a 95 percent seroconversion rate among children vaccinated at age 12 months or older (89 percent of the population of children aged 2 years) and use a conservative estimate of an 80 percent seroconversion rate among children vaccinated once with an early dose at less than age 12 months (6 percent of the population of children aged 2 years), population immunity among children aged 2 years would have increased 5 percent (from 85 to 90 percent) because of those receiving only a single dose.
The high seroprevalence we found in all vaccination groups likely reflects the serologic response after vaccination, with little or no opportunity for boosting due to exposure to measles disease. During the study period in Dade County, vaccination coverage of children aged 2 years was more than 90 percent, and the occurrence of measles disease was exceedingly rare (annual average, 1 case/1,000,000 population). Thus, the measured humoral immunity among children approximately 3 years after measles vaccination was likely vaccine induced.
Although a lower seroprevalence of PRN antibody considered protective (titer > 1:120) was found among recipients of the early two-dose vaccination or a single, early dose compared with recipients of the standard dose at age 12 months, vaccine effectiveness was similar for all vaccination groups. These findings suggest no difference in clinical protection against measles based on vaccination status, which is supported by other vaccine efficacy studies in the United States that examined the effect of an early two-dose schedule relative to a single dose at age 12 months (13, 14
). These outbreak investigations among school-aged children, which occurred 10 years earlier (1980s), also found lower vaccine effectiveness among children given only a single, early dose.
While findings of very high vaccine efficacy can be biased in a case-control study with a very high attack rate in the vaccinated group, we did not observe such an attack rate (34). However, a potential bias in our study is differential exposure to measles among vaccinated and unvaccinated groups because we did not have a sufficient attack rate (5 percent) to assure that groups were composed of freely mixing populations (34
). This bias seems important only when the attack rate and vaccination coverage of the population are low but not when the attack rate is low and vaccination coverage is high, as was true in our study (34
). While differential exposure of the vaccinated and unvaccinated groups could have occurred, measles is a highly contagious disease, and the long study period of 8 years in which vaccination coverage was very high and attack rates were very low make significant differences in exposure unlikely. If anything, exposure to measles is probably still higher in high-risk areas than low-risk areas, which leads to underestimation of vaccine effectiveness. During the study period, large immigrant populations from endemic countries lived in the high-risk areas of the county, probably increasing the risk of exposure.
Another bias could have been ascertainment bias from differential reporting of cases of measles to the Dade County Department of Health. However, the public sector is one of the strongest components of the routine measles surveillance system in Dade County, and children in the public sector were most likely to have received the early two-dose schedule (35). More reported disease among vaccinated children would also underestimate vaccine effectiveness.
Finally, although we were unable to examine the effect of slightly different ages between preschool-aged cases and controls, and age is known to be associated with vaccination status, vaccine effectiveness is not known to vary by age among preschool-aged children. Thus, the difference in age is unlikely to have confounded the estimate of vaccine effectiveness.
When the effect of the early two-dose schedule and its current role are evaluated, there are many factors to consider, some of which are competing. The early two-dose schedule was effective in controlling measles in Dade County when the risk of measles in the United States was a problem and susceptibility to measles among preschool-aged children was considerable. Specifically, the Dade County program actually began when exposure to measles was high and vaccination coverage of preschool-aged children was suboptimal. Since 1995, vaccination coverage of preschool-aged children in the United States has been very high (90 percent or higher among children aged 2 years), leading to a reduction in overall susceptibility and very low measles incidence. However, susceptibility to measles among infants has increased because most infants are now born to vaccinated mothers and lose maternal antibody at an earlier age (36; National Center for Health Statistics, unpublished data). Susceptibility among young infants is of particular concern because infants have the highest rate of complications (26, 37
).
Measles transmission currently is not endemic in the United States, and the risks and benefits of an early two-dose measles vaccination schedule may differ from those in the past. In the United States and other countries, the optimal age for measles vaccination is based on weighing the benefit of vaccination and the risk of disease, complications of disease, and vaccine failures. For example, many countries in the Americas with a low incidence of measles have increased the age of the first routine dose of measles vaccine from 9 months to 12 months to increase the seroconversion rate. Our findings of the effect of an early two-dose schedule in Dade County strongly support the Advisory Committee on Immunization Practices recommendation to use this schedule when the risk of measles is high among infants (1).
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|