ABSTRACT
Within the past few years, several measles outbreaks have occurred in the southeast of Iran. To learn about the effectiveness of the immunization services for producing a serologic response against measles, this follow-up study was designed and implemented in the southeast of Iran. In Iran, all routine immunization services provided by the public sector are free of charge. The follow-up study was designed and implemented in 5 Urban Health Centers located in 3 districts of Sistan-va-BaluchestanProvince, Iran. In the pre-vaccination phase, 270 12-month-old babies were blood sampled; and in the post-vaccination phase, 4 to 7 weeks after Measles, Mumps, Rubella (MMR) vaccination, 236 of them were blood sampled (34 dropouts), and their sera were tested for IgG anti-measles antibodies, using indirect ELISA, in the National Reference Measles Laboratory. Out of the 236 participants, who had been blood sampled in the post-vaccination phase, 10 (3.7%) were excluded from the calculations of seroconversion rate, because they had protective levels of antibody before the vaccination. The seroconversion rate for the remaining 226 participants was 91.2% (95% confidence interval: 86.7 to 94.5). Among the variables studied, stunting (height-for-age z-score < −2) showed a strong relationship with the remaining seronegative after the vaccination (odds ratio = 5.6; 95% confidence interval: 1.7–18.2). The chance of seroconversion was inversely related to the mothers' levels of education (up to 9 y of education vs. above nine years) (odds ratio = 0.2; 95% confidence interval: 0.06–0.4). In the study population, the seroconversion rates for anti-measles antibodies after MMR vaccination are acceptable, even though in order to achieve the elimination goal, higher standards need to be achieved.
Introduction
Measles is one of the most contagious airborne diseases ever known which, thanks to an effective vaccine, is in the elimination stage in most developed countries; and global efforts are well under way in most of other countries to push it toward eradication.
Between the years 2000 and 2007, measles' deaths worldwide fell by 74%. In the Eastern Mediterranean region, measles deaths have been cut by a remarkable rate of 90% during the same period. In fact, by reducing measles deaths from 96,000 to 10,000, the region achieved the United Nations' goal to reduce measles deaths by 90% by 2010, 3 y earlier than expected.Citation1
In Iran, after the mass campaign of December 2003 in which all people between 5–25 y of age were vaccinated for measles and rubella, for a few years the disease was pretty under control; however, since 2006, the number of sporadic cases has begun to rise gradually and since 2009, scattered outbreaks have begun to surface here and there.Citation2,3 Based on measles surveillance system of Centre for Communicable Diseases Control of Iranian Ministry of Health and Medical Education, between 2009 and 2014, at least 26 measles outbreaks occurred in 8 provinces and 493 serologically confirmed cases were reported from all over the country.Citation3,4
Most of these outbreaks occur in Sistan-va-Baluchestan Province, located in the southeast of Iran and bordering with Afghanistan and Pakistan. Sistan-va-Baluchestan Province is a mountainous region extending from the edges of central deserts of Iran in the north to the coasts of the Oman Sea in the south, and it has a variety of climates from dry-temperate in the northern parts around Zahedan, the provincial capital, to subtropical climate at the coasts of the Oman Sea in Chabahar District. The average annual precipitations are highly variable on a yearly basis; and especially in the southern regions, drought cycles usually follow one another in 4-to-5-year cycles due to monsoon winds blowing from Southeastern Asia. This province has common cultural and economic ties with Afghanistan and Pakistan, and it is either the passage of illegal Afghan and Pakistani workers to other provinces of Iran or is their destination.
Within the last decade, the immunization schedule of measles vaccination has been changed several times in Iran. Before the mass campaign of 2003, measles vaccine was inoculated as a monovalent vaccine at the end of the ninth and 15th months of age; however, after the campaign, Measles, Mumps, Rubella (MMR) vaccine replaced the monovalent vaccine and would be prescribed once at the end of the first year of life and the second time before entering school at the age of 5 to 6. Since 2011, the schedule has been changed again and ever since the second dose is inoculated at the end of the 18th month of age. It is noteworthy that all immunization services in Iran are free of charge.
Based on surveillance data, the average vaccination coverage of measles in all districts is usually above 95%; however, in view of the fact that not all those who receive the vaccine necessarily do produce an immunologic response, there is always a gap between immunization coverage and the proportion of those thoroughly immune against the measles.Citation5 The extent of this gap is usually influenced by many factors, including the age of the vaccine receiver at the time of vaccination as well as the administrative procedures such as the cold chain regulations in the health centers.
Since 2007, Iran's Ministry of Health and Medical Education has started a new campaign against measles with the purpose of elimination. With a health service network as large and widespread as what is working in Iran, the goal of measles elimination should have been achieved by now; however, for reasons mostly unknown to local and ministerial health experts, this goal has not been realized yet. The Ministry of Health and Medical Education financed the present study, first and foremost, in order to learn about the seroconversion rate after vaccination with one of the domestically produced vaccines that was in routine use in the immunization system. To fulfill this goal, when designing and implementing this study, the researchers took into account all possible confounders, including children's characteristics.
Results
The study began on August 17th, 2013 simultaneously in 5 urban health centers located in 3 districts: 3 health centers in Zahedan, one in Khash and one in Sarbaz. The recruitment of participants ended on September 07th the same year. In pre-vaccination phase, 10 households refused to take part in the study because their children's fathers were not accessible to give the required permission for blood sampling, and since occurrence of non-response had already been foreseen in the sample size calculations, children of these 10 households were not replaced.
The post-vaccination blood sampling began on September 24th and ended on October 22nd, 2013. shows the final sampling scheme and shows some demographic and individual characteristics of the participants.
Table 1. The sampling scheme of participants at the beginning of the study by district.
Table 2. The comparison of the participants' characteristics at the time of the Pre- and Post-vaccination blood sampling.
270 and 236 participants were blood sampled in the pre-vaccination and post-vaccination phases respectively, i.e. 34 (12.6%) participants dropped out of the study. The main reasons for such a drop-out were the parents' refusal for taking part in post-vaccination blood sampling (24 cases) and the research teams' failure to find the households at the recorded addresses (10 cases). There were no statistically significant differences between those who dropped out of the follow-up and the children who remained in the study in terms of their mothers' levels of education (P-value = 0.8352; t-test, unequal variances) and their mothers' ages (P-value = 0.6542; t-test, unequal variances).
The minimum and maximum time intervals between pre-vaccination and post-vaccination blood samplings were respectively 29 and 49 days, and the mean and median time intervals were respectively 39.1 d (standard deviation = 3.8 days) and 39 d (Min: 29 days; Max: 49 days). Totally, 11 participants were sampled between the 29th and 34th day after the vaccination. The sampling intervals for the rest of the children were 35 to 49 d.
There were 4 participants younger than 365 days, all seronegative at baseline. These participants, the youngest one of whom was 349 d old, were allowed to remain in the study.
Out of a total of 270 participants who took part in the pre-vaccination blood sampling, 10 children (3.7%) who were 12.0 to 14.3 months old (mean = 12.5 months; SD = 0.6 months; median = 12.4 months) were categorized as seropositive (OD ≥ 0.1) in their baseline test before the vaccination. After the exclusion of these 10 children from the list of those 236 participants who took part in the post-vaccination blood sampling, the seroconversion rate for the remaining 226 participants who were seronegative before vaccination (OD < 0.1) was 91.2% (95% CI: 86.7 to 94.5).
There were totally 7 participants (from the initial 270 participants) with missing values for height (among them 3 participants with missing value for weight too); therefore, the calculating their anthropometric indices was not possible. Five of these participants were among the 226 participants who were seronegative in their pre-vaccination blood sampling and had taken part in the post-vaccination blood sampling. Considering the above-mentioned explanations, the rate of stunting (height-for-age z-score (HAZ) ≤ −2) among the participants of the pre-vaccination blood sampling was 11.4% (95% CI: 7.5% to 15.3%), i.e., 30 out of 263. The seroconversion rate for the 199 participants who were not malnourished based on HAZ < −2 and were seronegative in their first blood test (before the vaccination) was 93.0% (95% CI: 89.4% to 96.5%); and for the remaining 22 children with HAZ ≤ −2, it was 72.7% (95% CI: 52.5% to 92.9%), (mean difference = 20.2%; P-value = 0.0016; Z-test). The seroconversion rate for the 195 participants who were not wasted based on weight-for-height z-score (WHZ) and were seronegative in their pre-vaccination test was 90.2% (95% CI: 86.0 to 94.4); and for the remaining 26 children with WHZ ≤ −2, it was 96.2% (95% CI: 88.2 to 100.0), i.e. the seroconversion rate was better among participants affected with wasting (P-value = 0.3271, Z-test). It might be noteworthy that none of the participants with stunting were wasted simultaneously (and vice versa).
There was a negative relationship between the mother's level of education and seroconversion rate by a factor of 5, both in the univariate analysis and in the multivariate logistic regression analysis (), i.e., the chance of seroconversion in children whose mothers' levels of education were 9 y or less has been 5 times higher than in children whose mothers' levels of education were more than 9 y. It should be noted that the mean age of mothers in the 2 education categories, as reflected in , did not differ significantly (26.4 vs. 26.2 years; P-value = 0.8445). The other variable reported in the multivariate analysis () is HAZ. As it was mentioned before, it seems that HAZ is a better predictor of immune response to vaccination than WHZ, whose effect was not significant in the multivariate model and dropped out. All of the other variables (i.e. birth weight, type of feeding during the first 6 months of life (exclusive breast feeding against anything else), age of beginning of supplementary foods, father's level of education, and mother's age) in the multivariate analysis were checked, and none of them remained in the model.
Table 3. The effect of the participant's characteristics on the probability of seroconversion status using crude and adjusted odds ratio; Sistan-va-Baluchestan Province, I.R. Iran.
Discussion
The seroconversion rate of those participants who took part in the post-vaccination blood sampling and were seronegative before the vaccination was 91.2%. This seroconversion rate, albeit not the ideal possible target in vaccination activities against measles, might be considered acceptable. These results are similar to the findings in other countries with a similar situation. For instance, in a large study in Latin America on babies of 6 to 12 months, seroconversion rates were in the range of 70 to 90 percent.Citation6,7 In another study conducted in Turkey, the seroconversion rate for babies of 15 months of age was about 86.7%.Citation8 Based on a systematic review about the immunogenicity of MMR vaccines in 6 high-quality randomized clinical trials, seroconversion rates for measles range from 88.0% to 98.9%.Citation9 None of the participants in this study were sampled before the 29th day after the vaccination. In similar studies, the time interval between the vaccination and the post-vaccination blood sampling for the evaluation of immune response has usually been 4 to 6 weeks.Citation10-12
In the pre-elimination era, even in developed countries, the persistence of maternal antibodies even beyond 12 months of age had always been mentioned as one of the well-known mechanisms of measles vaccine failure.Citation13,14 As it was mentioned earlier, in the present study, 10 participants (3.7%) had protective levels of antibody before the vaccination, and they were not included in the calculations for seroconversion rates. In a study conducted in Turkey for determining the optimum age for measles vaccination using an ELISA method (Virotech diagnostic kits), the seropositive rate for anti-measles antibody among their participants of 7 to 9 months of age (19 out of 38 children) was 50%, and among their participants of 13 to 15 months of age (1 out of10 children), it was 10%.Citation15 In another study implemented in 2005 in the north of Iran, the seropositive rate of anti-measles antibodies before vaccination in 12-month-old babies was 6.2% (7 out of 112 children).Citation16 In the recently mentioned study, all the 7 children, who were seropositive before the vaccination had, been born to mothers who had a positive history of taking part in the nationwide anti-Measles-Rubella Vaccination Campaign of 2003, i.e., their mother immunity had been boosted before pregnancy. All the 28 children who had been born to mothers who did not take part in that campaign were seronegative before the vaccination. The mentioned Campaign of 2003 was a nationwide one and was also implemented in Sistan-va-Baluchestan Province (the present study's regions); however, the time interval between this study and the campaign was too long to be questioned and make a reliable valid recall.
The seroconversion rate for anti-measles antibody was significantly lower among participants affected with stunting (HAZ < −2) (mean difference = 20.2%; P-value = 0.0016); and based on logistic regression analysis, the chance of stunted children to remain seronegative is 4.9 times higher than normal children. At the first glance, these findings might be considered somehow contrary to the findings mentioned in some previous studies; i.e. based on most previous studies, malnourished children may respond with delay but adequately to measles vaccination; however, except our study, there are some other studies that have reported a significantly lower seroconversion rate for malnourished children; for instance, the one implemented in Uganda, which reported only 75% seroconversion rate among one-year-old children.Citation10,17,18 It is noteworthy that in almost all those studies, the authors' mean of malnutrition has been either wasting (i.e., WHZ < −2) or underweight (i.e. WAZ < −2), while the authors of the present paper found the main difference between the stunted children and the normal ones. In other words, it seems that stunting is a trait different from wasting in prediction of immunologic response to measles vaccination. The magnitude of the present study's findings in this regard is too large to be considered as accidental, even though they, like every other similar finding in similar situations, should be confirmed through repetition in other studies. It might be worth mentioning that in either group (seropositive or seronegative), none of the participants were both stunted and wasted simultaneously.
Another interesting finding of the study is a strong negative relationship between the mothers' levels of education and antibody response to measles vaccine (OR = 0.2) (). Explaining these findings in the context of the other results and relationships is not so easy. The authors do not think that education has anything to do with the biologic and immunologic response of the participants to immunization with measles vaccine; however, for the cutoff point of 9 y of education, the relationship, both in the univariate and in the multivariate analyses, was too strong to be considered a mere play of chance. Parents' education has been mentioned as an important risk factor for delaying the vaccination in several studies; however, we could not find any study in the literature in support of the relationship between seroconversion rate and mothers' levels of education.Citation19-22
When interpreting the results, it should be kept in mind that the study population was limited to the urban population and the results might not be generalized to rural areas and nomads. In addition, the setting where the study was implemented was a relatively controlled one, i.e., all the health workers were experienced vaccinators well accustomed with cold chain regulations and under supervision during the study. Considering these facts, it seems somehow unlikely that the real seroconversion rate in routine activities be as good as what was found in this study. As another matter of fact, the MMR vaccine used in this study was the one produced by Razi Institute of Serum and Vaccine Production (RIS), while at least half of the MMR vaccines used in routine immunization activities of Iran are usually the products of Serum Institute of India (SII). There are some differences between these 2 vaccines. The strain used in Iranian vaccines is AIC-HDC, which is a further attenuated AIK strain of live measles virus propagated in human diploid cells, while the vaccine produced by SII contains the Edmonston-Zagreb strain. These two stains show some differences with regard to immunogenicity.Citation12,23,24
As a conclusion, our findings showed that in the study region, after the MMR vaccination, the seroconversion rates for measles are in the acceptable range, even though compared with other countries, there is still room for more improvement. Also, considering the fact that with herd immunities below 95% achieving measles elimination would in fact be out of reach, this achievement is a necessity.Citation22,25 If we are going to eliminate measles in Iran and if we are going to get rid of recurrent outbreaks of measles here and there in the southeast of Iran, in addition to increasing the vaccination coverage as high as possible, we have to pay attention to the dilemma of the seroconversion rates, i.e. the dilemma of effectiveness of the immunization system. This dilemma might not be overcome except by retraining of our health staff, increasing our vigilance for cold chain regulations, and increasing the monitoring activities in the systems in every aspect for increasing the quality of immunization activities.
Materials and methods
Background
Zahedan with a population of around one million is the largest and most populated city of the province. There are 11 other districts in the province with population sizes from 70,000 to 200,000 and an urban/rural population ratio of around one.
Literature review
PubMed, World Health Organization site and Google Scholar were used in searching for related previous works and articles. The keywords, immunization, vaccination, seroconversion, measles, and Iran, were used in 2 rounds; the first time for preparing the protocol of the study, and the second time when writing the manuscript. In total, nearly 500 article abstracts were studied in the preliminary evaluations; and from among 192 full text articles finally 27 articles were used in the preparation of this paper. As one of the priorities in the selection of the relevant documents, the latest related works were selected for citation in every instance.
Study design
We used a follow-up study design for ascertaining the rate of seroconversion in the participants. The eligible participants were recruited consecutively from among the children who would be brought to health centers for the routine MMR vaccination at the end of their first year of life (according to the routine immunization schedule), and their immune status were evaluated using IgG capture ELISA for measuring IgG anti-measles antibody, once before the vaccination and the second time 4 weeks later.
A maximum of 5 mL of blood was taken from each participant immediately before the vaccination by using venipuncture and syringe. Sera were separated within a time interval of at most one hour in the nearest local laboratory and were frozen at −20 degrees centigrade and stored in the same reference laboratory of the same district until the whole collection could be taken to the National Reference Measles Laboratory in Tehran University of Medical Sciences, Tehran, Iran.
All of the MMR vaccines used in this study had been produced domestically by Razi Vaccine and Serum Research Institute (batch number: 00891035; expiry date: Jan. 2015), and the measles component of these products were an attenuated AIK strain of live measles virus propagated in human diploid cells, known as AIC-HDC strain. The vaccines were injected subcutaneously in fatty tissue over anterolateral thigh muscle, using standard needles 16 mm in length and by well-trained health workers. The Ethics Committee on Medical Research of Zahedan University of Medical Sciences has reviewed and approved the implementation of the study.
Study subjects
The study population was defined as all infants living in the urban regions of Sistan-va-Baluchestan Province, Iran. They were between 12 months and 12 months and 30 d of age, had not received any measles containing vaccine before, and did not have any history of exanthematic disease since birth.
Sample size
Most previous studies had estimated the seroconversion rates of about 95% or more; however, in order to get a higher sample size, we considered seroconversion rate to be about 90%, considering a 0.045 error estimate; and for a 95% confidence interval, the sample size came to 171.Citation23 Considering the design effect (for cluster sampling) to be about 50% and another 10% for non-response, the sample size came to 280.Citation27
Sampling
The main purpose of the study was to evaluate antibody response after the vaccination. To make certain that no problem with cold chain would affect the results and to make follow-up of the participants as feasible as possible, the study was implemented only in the urban areas. The complete list of all health centers (urban and rural) might be obtained from the province health center. With the help of a random number list (in the appendix section of a statistics reference book), totally 5 urban health centers were randomly selected from among 110 urban health centers in the province. In each center, the eligible participants were gradually and consecutively invited to enter the study from among those who were coming for MMR vaccination (convenient sampling). To make it certain that enough numbers of participants have been recruited, a health expert at the provincial level was following the number of the participants on a daily basis until the completion of the sample size.
Data collection methods, tools used, and measurements
There were totally 5 research teams, one team in each health center. Except Zahedan, which had 3 teams, the other districts each had only one team. The teams were composed of an interviewer, adept in the local language and trained for completing a questionnaire especially designed for the study, and a nurse, expert in blood sampling children and measuring anthropometric indices. Measuring the infants' head-toe length and weighting the participants with standard infant scales were performed according to standard methods approved by WHO.Citation28
All the health workers participating in the study took part in special training sessions for completing the questionnaire and doing the anthropometric measurements and blood sampling. In addition, all team members were supplied with an ‘instruction sheet', explaining how to complete the questionnaire and how to ascertain the eligibility criteria. In addition, 2 phone lines were available for answering any question or comment on the part of the team members during the field stage, just in case.
The questionnaire especially designed for the study was composed of 27 questions. The variables that were measured in the study were: mother and father's levels of education (years of successful education), age at the time of vaccination, mother's age at birth, type of feeding during the first 6 months of life, age at which supplementary feeding had begun, birth weight (in grams) and the vaccination history for any measles-containing vaccine. The heights of the participants were measured in supine position with an accuracy of half a centimeter. Weight was measured with mechanical baby scales (Seca) with an accuracy of 10 g. Age was calculated by subtracting the birth date from the date of vaccination (done by statistical software). Anthropometric indices (Height for Age Z-score (HAZ); Weight for Height Z-score (WHZ) and Weight for Age Z-score (WAZ)) were calculated using the Epinut 2.0 (EpiInfo library by Chris D. Smith; CDC Division of Surveillance and Epidemiology, USA; EpiInfo-6.04 software package). If a participant's height for age Z-score (HAZ) was 2 standard deviations below the reference median value, he/she was categorized as stunted. Similarly, ‘wasting’ was defined as participants below −2 standard deviation from the reference value for weight for height, and ‘underweight’ was defined as being −2 standard deviation below reference value for weight for age.
Laboratory methods
The sera were separated from the blood samples in a local laboratory at the district level and were kept at −20 degrees centigrade until they were delivered to the National Reference Measles Laboratory in the School of Public Health, Tehran University of Medical Sciences, Tehran, Iran, for the measurement of anti-measles IgG level. The laboratory is part of the WHO's network of laboratories.
In order to quantify the presence of IgG antibodies against the measles virus, indirect ELISA was used according to the manufacturer's instructions (Enzygnost® Anti-Measles Virus/IgG; Siemens, Marburg, Germany). Based on the manufacturer's descriptions with Enzygnost Anti-Measles Virus/IgG, the samples containing approximately 150 mIU/mL were found to be within the range of 0.100 to 0.200 ΔA. Specimens below 0.100 were considered as negative. Seroconversion rate was defined as the proportion of subjects initially seronegative, who developed post-vaccination antibody titers equal to or above 0.10 OD as the cut-off level.Citation5
Data management and analysis plan
The data collected through the questionnaires were transferred to a computerized data bank. After refining, the data were analyzed using Stata (ver. 11) and SPSS (ver. 15). Descriptive statistical tables and appropriate parametric and non-parametric statistics were used in the analysis. In all instances, the 95% confidence intervals were calculated; and where applicable, the statistics were reported as ‘mean ± standard deviation'.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
Our due thanks are to the hard-working health workers, at all levels, from the managerial levels to those on the front lines of providing health services in the districts involved in the study (Zahedan, Khash, and Sarbaz). In addition, the authors would like to appreciate the hard work of all employees and staff of the Reference National Measles Laboratory in the School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. The authors also wish to express their gratitude to Mr. Ali Beikian, the faculty member of English Language Department of Chabahar Maritime University, for editing the English text of this article.
Funding
This work was supported by the World Health Organization, Tehran Office, (WHO Registration: 2013/337702-0, Reg. File: EM-IRA-2013-APW-031).
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