The Expanded Program on Immunization (EPI) of the WHO had a worldwide aim to reduce reported measles incidence by 90% and mortality by 95% from prevaccination levels by 1995.1
Measles vaccine was introduced in Córdoba City, Argentina, in 1971, in children 1 to 4 years of age, as a discontinuous program of immunization, reaching low overall vaccination coverage (between 50 and 70%). The current vaccination program started in 1978 and only in 1993 was a mass immunization available to subjects 1 to 14 years of age.
Currently in Argentina the one dose measles vaccine is given at 12 months of age. This strategy was based on studies in the 1970s that reported a drop in immunogenicity of measles vaccine in infants vaccinated before 12 months.2 This was thought to be a result of the presence of maternally acquired antibodies.3 When these studies were conducted women derived their immunity from natural infection, whereas currently the majority of women of child-bearing age develop measles vaccine-induced immunity. Because measles vaccine induces lower antibody titers than does natural infection, lower titers of passively acquired maternal measles antibody would be expected among infants whose maternal immunity is vaccine-related. Several reports support this notion in developed countries.4, 5
The present investigation was carried out to compare measles protective neutralizing antibody titers among cohorts of pregnant women born during and before the measles vaccine age, in Córdoba City, Argentina. Data are unavailable in our country and in other developing areas regarding measles immunity in infants and children in relation to the maternal source of infection. The aim of this report is to provide local data to facilitate a policy review of measles immunization for the Argentine Expanded Program on Immunization.
Materials and methods.Study population. Sera from pregnant women seen for pregnancy care during 1997 in the General Direction of Medical Specialities (Northern area) in Córdoba City were used to measure measles antibody. The women came from a predominantly lower middle class, urban population. The authorities of the Medical Center were told about the nature and purpose of the study and their approval was granted.
A cohort of 401 pregnant women ages 14 to 41 years and in their first 5 months of pregnancy was enrolled in the study. Only one serum sample from each one was obtained and sera were stored at −20°C. Maternal birth date was used as a proxy for maternal immunity and women were assigned to three groups: Group A (n = 79), mothers born before 1967 (>30 years old), presumed to have naturally acquired measles infection given that most people in Argentina age 5 or older in 1971 were infected by live measles virus; Group B (n = 225), mothers born between 1967 and 1978 (19 to 30 years old), who were considered to be a mixed group because some had experienced measles infection and some developed immunity after immunization; Group C (n = 97), mothers born after 1978 (<19 years old) and presumed to have acquired immunity after measles immunization. This population was reimmunized during the mass immunization in 1993.
Serologic assay. A seroneutralization assay (Nt) was performed as described by Nates et al.6 The highest dilution of serum that completely inhibited the cytopathic effect was regarded as the end point of antibody titration. Titers equal to or higher than 1:2 were considered positive. Measles virus control and an international reference preparation of measles antibody were used in every 96-well microculture plate and diluted in the same manner as the test samples. Results were converted to milli-International Reference Units per ml of serum (mIRU/ml) based on parallel assay results. Titers ≥32 mIRU/ml were defined as seropositive based on the test sensitivity at the first serum dilution of 1:2.
Data analysis. Geometric mean titers (GMTs) (95% confidence intervals) were calculated only for pregnant women with detectable antibodies. The reciprocals of measles neutralization titers were logarithmically converted and GMTs were calculated. Differences in antibody titers were determined by Tukey-high significant difference test, with statistical significance at P < 0.05.7
Results. Among the total pregnant female population studied, 79 (19.7%) mothers were born before 1967 (A), 225 (56.1%) between 1967 and 1978 (Group B) and 97 (24.2%) after 1978 (Group C), corresponding to the normal distribution of infants' births in our country regarding maternal age. There were no significant differences in measles antibody detection among the three groups studied: Group A 70 of 79 = 88.6% [95% confidence interval (CI), 79.5 to 97.9%]; Group B 186 of 225 = 82.7% (95% CI 89.1 to 75.7%); and Group C 85 of 97 = 87.6% (95% CI 96.0 to 79.4%). By comparison the GMT in pregnant women in Group A (165, 95% CI 67 to 869) was significantly larger than those in Group B (95, 95% CI 42 to 441), and Group C (81, 95% CI 41 to 357) (P < 0.05). In contrast no significant difference in GMTs was found between Groups B and C. As shown in Figure 1 the GMTs declined with decreasing age of the women. Geometric mean Nt titer in women born before 1967 was 3.6-fold higher than that in younger pregnant women.
Discussion. The optimal schedule of measles vaccination of infants should take into consideration the source for maternal immunity and the persistence of antibody titers during the first year of life.
This study is the first to document a significant association between antibody titers, as a marker of immunity, and probable exposure to measles vaccine or live measles virus in pregnant women in Córdoba City, Argentina. Our results show that the decline in maternal measles antibody titers matches the implementation of routine measles vaccination. It is also possible that younger mothers were exposed to measles virus during measles epidemics in the mid-1970s, 1980s and 1990s, thereby boosting their measles titers as a result of an anamnestic antibody response. Likewise mothers from Group C were also revaccinated during the mass campaign of 1993. Nevertheless our results show that in vaccinated pregnant women neither reexposure to the wild-type measles virus nor revaccination produced titers as high as those induced by the natural infection. Others have reported similar findings.8, 9 Our results are in agreement with the data of Rouderfer et al.10 who used a mathematical model to show that reexposure to live measles virus in vaccinated individuals was not an important factor in determining optimal measles vaccination schedules. However, those studies have been conducted in developed countries, where measles infection were uncommon for the last 30 years.
Our study indicates that even in developing countries many infants today received less antibody at birth and were both susceptible to measles infection and potentially responsive to the vaccine at an earlier age than a decade ago. This finding suggests that early infant immunization might be more appropriate, although the immunogenicity of measles vaccine in seronegative infants younger than 12 months needs further assessment.
Silvia V. Nates, Ph.D.
Andrea Cumino, M.S.
María B. Isa, M.S.
Laura C. Martínez, M.S.
Elizabeth Naretto, M.S.
Silvia I. Medeot, Ph.D.
Miguel O. Giordano, B.T.E.C.
Cristina D. de Wolff, Ph.D.
Instituto de Virología "Dr. J. M.Vanella"; Facultad de Ciencias Médicas; Universidad Nacional de Córdoba; Agencia 4; Ciudad Universitaria (SVN, AC, NBI, LCM, SIM, MOG)
Dirección de Especialidades Médicas; Municipalidad de Córdoba (EN)
Ministerio de Salud y Acción Social de la Nación (CDW); Buenos Aires
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