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Protection after Two Doses of Measles Vaccine Is Independent of Interval between Doses [1]

['De Serres', 'Public Health Research Unit', 'Chul Research Center', 'Department Of Social', 'Preventive Medicine', 'Laval University', 'Sciberras', 'Ontario Ministry Of Health', 'Toronto', 'Naus']

Date: 1999-07-01  

Abstract

The protection provided by one or two doses of measles vaccine was compared, as was the effect of the timing of delivery of the doses on the protection provided. A total of 5542 measles cases occurred in Ontario, Canada, between January 1990 and December 1996. Three controls per case were matched for age and residence. Children who received a single dose at age 15 months and older were 5 times more likely to contract measles than were children who received two doses of vaccine after their first birthday. Among children given two doses of vaccines, the risk of measles was 3 times greater in those who had their first vaccination at age 11 months compared with children who first received vaccine after age 1 year, but the protection was independent of the interval between doses. Delaying the second dose >6 months after the first does not increase protection.

Despite high vaccine coverage, single-dose measles immunization programs have been unsuccessful in eliminating measles. Primary vaccine failures caused by the interference of maternal antibody have been a primary cause of continued circulation of the virus [1]. Levels of maternal antibody in the child decline with age, with a corresponding decline in the probability of primary vaccine failure. In contrast to most Canadian jurisdictions, where measles vaccine has been given routinely at 12 months of age, some other countries have long recommended measles vaccination at 15 months of age (e.g., USA) or later (e.g., Sweden) in an attempt to minimize this type of vaccine failure. However, even delay of the initial vaccination has not been sufficient to eliminate measles. Based on the results of serologic studies that showed that most children who do not respond to the first dose of measles vaccine will develop a good antibody response to a second dose [1], many countries (e.g., Canada, UK, and USA) have decided to switch to two-dose immunization schedules.

The improved protection afforded by two doses of measles vaccine is well documented in countries where two-dose schedules have been implemented for many years and where measles has been virtually eliminated [2]. However, epidemiologic data comparing the protection of children afforded by a single dose with two doses of measles vaccine during a period of high transmission are still lacking. There are also no epidemiologic data about the effect of the timing of delivery of the two doses on the protection provided against measles. For logistic reasons, some jurisdictions in Canada provide both doses prior to age 2 years (at 12 and 18 months); others provide both doses prior to school entry (at 12–15 months and 4–6 years).

In Ontario, Canada, >11,000 cases of measles were reported between 1 January 1990 and 31 December 1996. We used the data from this period of high transmission to quantify the improved protection provided by the second dose of vaccine, the influence of age at first dose, and the effect of the duration of the interval between the first and second doses of vaccine. Control measures for measles during this period included the routine administration of a single dose of measles vaccine to children as soon as possible after their first birthday and during outbreaks, and suspension of unimmunized children from school. During 1990–1993, outbreak control activities after a case of measles occurred in a school included administration of a second dose of measles vaccine to all single-dose recipients to prevent additional cases. A two-dose schedule was introduced in Ontario in February 1996, with the second dose administered at school entry.

Methods

A case-control study was conducted utilizing data from two information systems at the Ontario Ministry of Health. Measles cases were selected from the Reportable Diseases Information System (RDIS) and matched controls were selected from the Immunization Record Information System (IRIS). RDIS was implemented 1 January 1990 in Ontario to record all cases of reportable diseases meeting the national case definition for that disease [3]. The IRIS was implemented in 1993 and contains records of 2 million children up to age 17 years who were enrolled in licensed day nurseries or schools in Ontario. Both databases contain the following variables for each individual: date of birth, postal code, and vaccination status. For each case, we selected 4 controls matched for year of birth and the first three characters of the six-character postal code. The vaccination status of a case was assessed as of 21 days prior to the date of onset of measles symptoms. The date was also used to assess the vaccination status of the matched controls.

Cases for this study selected from RDIS had to meet the following criteria: onset of measles between 1 January 1990 and 31 December 1996, date of birth between 1 October 1976 and 30 September 1990, and administration of the first dose of a measles-containing vaccine between 11 and 23 months of age. Cases and controls were excluded from the study if one or more of these critical dates were missing from the record, if the postal code was not on the record, or if an invalid postal code had been entered. For the purposes of analysis, cases and controls were also excluded if they received their second dose of vaccine after age 83 months, <30 days after the first dose, or <21 days prior to date of onset of measles. Those who received more than two doses of measles-containing vaccines were also excluded from the study.

The relative risk (RR) of measles was estimated from odds ratio (OR). Both matched and unmatched analyses were done. However, because these analyses provided similar results, only unmatched results are presented below. To separate the influence of age at first vaccination and delay between the first and the second dose, a multivariate logistic regression analysis was done with age at first vaccination divided into three categories (11 months, 12–14 months, and ⩾ 15 months), and the delay between the first and the second dose was also distributed into three categories (<6 months, 6–11 months, and ⩾12 months).

Results

Of the 11,427 cases included in RDIS during the study period, 5691 occurred among children born between 1 October 1976 and 30 September 1990 who received their first dose of measles vaccine between 11 and 23 months of age. The following cases were excluded: 142 children who received their second dose after age 83 months, 2 children whose second dose was given within 30 days of the first dose, and 5 children whose second dose was given ⩽21 days prior to onset of measles; 5542 cases of measles were used in the analysis. Of the 22,764 controls initially selected, 16,587 were used in the analysis. We excluded 6177 for the following reasons: unknown vaccination status (2069), first dose given at <11 months (88) or >23 months (3196), second dose given at <12 months (3) or >83 months (791) or within 30 days of the first (15), and receipt of more than two doses (15). The final case:control ratio was 1:3.

Protection against measles improved incrementally with age at vaccination up to 14–15 months (table 1). After that age, the risk of measles stabilized. The changes in point estimates after 15 months are likely due to random variation rather than to real changes in protection. Children who received a single dose at 15 months and older were 5 times more likely to sustain measles than those with two doses administered after their first birthday (P < .001).

Table 1 Open in new tabDownload slide Odds ratio (OR) of measles, comparing children who received a single dose of vaccine given at different ages (months) with those who received two doses after their first birthday.

Among children who received two doses, those who received their first dose before the first birthday were at significantly greater risk of measles than those who had their first dose after their first birthday (RR, 3.1; 95% confidence interval [CI], 1.5–6.9). In children who received their first dose between age 12 and 14 months, the risk of measles was not significantly greater in univariate analysis if the second dose was given before rather than after 24 months of age (OR, 4.9; exact 95% CI, 0.86–27.2) (table 2). In multivariate logistic regression analysis, the age at first dose, but not the delay from the first to second dose, significantly changed the risk of measles.

Table 2 Open in new tabDownload slide Distribution of cases and controls who received two doses of measles vaccine, according to age at first and second dose.

The risk of measles with a first vaccination given at 11 months was greater than that with one given at 12–14 months (RR, 3.5, P = .005) or at 15–23 months (RR, 2.7, P = .06). For the interval between the first and the second dose, the risk with an interval <6 months was smaller but not significantly so compared with an interval of 6–11 months (RR, 0.5, P = .52) or ⩾12 months (0.68, P = .62).

Discussion

The analysis of this data set from a very large number of measles cases and matched controls supports the assertion that a second dose of measles vaccine confers protection among those who experienced vaccine failure after the first dose of vaccine and is consistent with results from serologic studies [1].

As expected, the protection induced by a single dose of vaccine increased with older age at vaccination but reached a plateau at age 15 months. Delaying the administration of the first dose to later than 15 months of age did not improve protection to a level similar to that afforded by two doses delivered after age 12 months. If interference of maternal antibody with measles vaccine and immaturity of humoral immune response [4] were the only explanations of primary vaccine failure, protection should improve continuously with older age at vaccination. In fact, protection given by a single dose is maximal when the vaccine is administered at age 15 months. This strongly suggests that other mechanisms are involved in primary vaccine failures.

All of the cases reported to the RDIS met the national measles surveillance case definition. Although reporting may not be complete, it is unlikely that the completion rates varied significantly by whether the case received one or two doses of measles vaccine in the past. Controls were matched for age and residence, to increase the likelihood of comparable exposures to measles infection. In addition, matching for residence would to some extent control for regional differences between epidemic and nonepidemic areas or from year to year. The results obtained from the matched and unmatched analyses were similar, suggesting that these factors did not induce confounding.

Children who received their first dose of measles vaccine at 11 months of age and their second dose after age 12 months had a significantly greater risk of measles than those who received both doses after their first birthday (OR, 3.2). This finding supports the recommendation that children who receive a first dose of measles vaccine prior to their first birthday should be given two additional doses after that birthday [5, 6]. Long-term protection against measles in children vaccinated in early infancy (<12 months old) is unclear. Several investigators have demonstrated relatively poor and transient antibody response to revaccination in these children [7–12]. Once early vaccination has occurred, the protection afforded by a third dose (i.e., the second and the third doses, given after the first birthday) is unknown.

Based on 10 twice-vaccinated cases, Paunio et al. recently reported that an interval of 2.5 years between the two doses was more protective than a shorter interval [13]. In contrast, in our data, even when both doses of measles vaccine were delivered after age 1 year, there was no improvement in protection from measles when the interval between the first and second doses increased from <6 months to more than that. Although the power of this study to detect such a difference was very limited, it is reassuring that the risk of measles in subjects who received their second dose 1–6 months after their first was about half that of those who received their second dose later. This observation supports the concept that schedules in which the second dose is administered before the second birthday (e.g., age 18 months) and those in which the second dose is given at school entry are equally protective [5, 6] as long as the risk of acquiring measles between these ages is minimal. The benefit and risk of selecting a particular age for the second dose should be based on the local programmatic constraints and on the results of mathematical modeling of the epidemiology in that particular jurisdiction.

In conclusion, although a small percentage of children remained unprotected after two doses of measles vaccine, our data demonstrate that the second dose of vaccine greatly reduced the risk of measles. These findings reinforce three important concepts: first, two doses of measles-containing vaccine are necessary to eliminate measles; second, the first dose should not be given before the first birthday; and third, delaying the second dose >6 months after the first does not increase protection.

Acknowledgments

We are grateful to Martin Sargent, who processed the IRIS database, and to Brian Ward, who reviewed the manuscript.

References

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© 1999 by the Infectious Diseases Society of America

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