Study showed that nearly more than 12% and 18% of the studied individuals serologically were susceptible to measles and rubella respectively. The highest rates of susceptibility to measles and rubella with 15.2% and 25% was observed among subjects in the age group B (15–19 years old) who were born within 5 years just before national MR immunization and were vaccinated only with 2- dose of mMV at the age 9 and 15 months. Rubella immunity observed in this group was acquired by natural infection. Also, study showed that 12.8% and 17.7% of subjects that were vaccinated with 2- dose of MMR vaccine administered after the age of 12 (group C and D) months, were susceptible to measles and rubella, respectively. In this study the lowest rate of serosuseptibility to measles and rubella was detected among 20–33 years old adults that were MR revaccinated. Based on our findings, the main possible reasons for susceptibility to measles among our vaccinated population was SVF because of isolated lgG immunologic response to MMR revaccination in boosted susceptible individuals. Moreover, study revealed that revaccination of seroimmune subjects to measles and rubella with MMR vaccine did not resulted to enhanced specific immunity against both agents.
Our data showed that 98% and 100% of subjects of group A that were participated in the national program of MR immunization were serologically immune to measles and rubella, respectively. This long- term high- rate of protection could be attributed to MR vaccine boosting years earlier. Because, the reported prevalence rates of measles immunity among Iranian population studied years before MR campaign were much lower than observed in this study(36–40). 40.7%36; 54.7%37; 55.4%38; 72%39 and 91.6%40. However, years after revaccination, studies revealed much higher levels of seroprotection: one year after MR campaign among 6–29 years old subjects the rate were 87.5% (80.6% in younger age group) for measles and 91–99% for rubella(25). After 7 years among pregnant women; 81.7% and 96%(23), and after 10 years 79.2%(27) and 96.2% respectively. In a recent nationwide study among premarriage girl older than 15 years, (13–14 years after national MR camping), the seroprotection to measles and rubella was investigated. Nearly 1570 sera from 10 different provinces were included. Overall seroimmunity rate against measles,was 80.7% (range 73.1%- to 89.8%) and against rubella 90.6% (range; 81.2–95%)(41). However, these rates were varied greatly between provinces. The relative high rate of seroprotection observed in our study and in these mentioned studies carried out years after national campaign could be attributed to positive impact of MR revaccination among immunized population.
In this study, the highest rate of measles and rubella susceptibility was observed among group B (age range 15–19 years) that were vaccinated only with 2- doses of MV at the ages of 9 and 15 months without any history of rubella immunization. Because, there is not information about immune response to the initial measles immunization in this age group, the true reasons for this rate of susceptibility and vaccine failure is unclear. However, most probably it may be the result of SVF, because most of boosted susceptible subjects in this group only IgG responded to measles revaccination. The quality and durability of measles vaccine- induced immunity are dependent on a number of factors that relate both to the host and the vaccine. The most important and well-studied host- related determinant is the age that the first dose of vaccine administered(1,3−8). The results of studies on the immunogenicity and vaccine efficacy of MV administered before the age of 12 and 15 months was lower than those older ages(3–8, 41, 42). In this regard, in a prospective randomized trial by Redd etal(4), the immunogenicity of measles component of MMR vaccine given at the ages 9,12 and 15–18 months(4) was investigated. They found 98% seroconversion rate among 15 months vaccinees compared with 95% among those vaccinated at age of 12 and 81% at the age 9 months(4). Also, a study by perez etal(7) revealed that measles vaccination at the age < 12 months was associated with a greater risk of primary vaccine failure (PVF). The negative effects was persisted after the second dose(7). Similar to these data and conclusion were confirmed by a recent systematic review and meta-analysis(8).
Otherwise, there are evidences that antibody concentrations decline and fall to low or undetectable levels(43–45). Considering these evidences, the relative high rates of measles susceptibility observed among our study group B could be attributed to waning of acquired seroprotection over time (SVF) or possibly may be the result of PVF. However, due to IgG seroconversion detected among boosted seronegative subjects most probably are the results of SVF. Study finding also indicated that rubella infection was endemic in the country because 75% of studied subjects without history of rubella vaccination got immunity to rubella by natural rubella virus infection during their life time.
Most studies results from developed countries have shown that approximately 90–95% of children vaccinated at the age ≥ 12 months produce sufficient specific antibodies against measles and rubella. The protection rates will increase up to 95–98% after the second dose vaccination and persist for decades(1, 3, 6, 9), although, may decline over time years after initial immunization(43–45). In this study, nearly 12.8% and 17.7% of 7–15 years old subjects (group C and D) who were vaccinated with 2- dose of MMR vaccine administered after the age of 12 months were serologically susceptible to measles and rubella respectively. The exact reason for this lower rates than expected is not known. However, after revaccination nearly all boosted serosusceptible subjects by specific IgG antibodies seroconverted. This is an evidence of SVF. However, in this study waning of measles antibodies titer and seroprotection rates after vaccination occur more faster than expected(1, 3, 6, 9). The loss of acquired immunity within shorter duration of post- vaccination than that one would expect, based on published immunogenicity and vaccine efficacy reports is of concern(1, 3, 6, 9). Therefore, vaccine- related factors such as less potent vaccine because of more thermo labile strain, inadequate control of cold chain during shipment/ storage/ use/ and possibly other factors may be responsible(46– 48). The assumption of less potency of vaccine is based on the results of studies that were designed to investigate the immunogenicity of MMR vaccine currently in use in the Iran. Majority of these studies showed lower than expected sero-conversion rates following the first and/ or the second dose of MMR vaccine after the age of 12 months (Table 3).
Table 3
Immunogenicity and seroconversion rate to measles component of MMR vaccine currently in use in Iran.
Author/province | Years of study | No of Subjects | Age | Responses Rate |
MMR1 (%) | MMR2 (%) |
Saffar, Mazandaran30 | 2009 | 112 | 12.10 months of age | 84.8 | - |
Saffar, Mazandaran31* | 2011 | 249 228 | 18 m(6mo after) 6 years after MMR1 | 74 78.3 | 94 98.3 |
Shamsizadeh, Ahwaz32 | 2012 | 70 90 | 6 mo after first MMR1 6 year after MMR2 | 42.9 - | - 45.6 |
Tabatabaei, Tehran 33 | 2013 | 240 | 13.27 month | 75.8 | - |
Shakurnia, Ahwaz 34 | 2015 | 236 | ≤ 5 year | - | 87.3 |
Izadi, sistan-Bluchestan35 | 2015 | 663 | 30–54 month | - | 94.6 |
Zahrari, Kerman-Bluchestan28 | 2016 | 236 | > 12 month | 91.2 | - |
*: in these study seroconversion rates to rubella component of MMR vaccine after first dose of MMR was 75% VS 67%, and with MMR2 increased to 87% and 92.4%, respectively. These rates for mumps were 82.3% VS 68.4% and increase to 97% VS 94.4%, respectively.
Waning of measles- rubella antibodies concentration post- vaccination may result to accumulation of potentially susceptible individuals to measles and/ or rubella in the community. In this regard, several reports describe a significant proportion of SVF in population with sustained high vaccination coverage and long absence of measles virus transmission(43–45). In a prospective multicenter study by Smetana et al(43), measles lgG antibody concentrations among vaccinated subjects ≥ 18 years was evaluated. Of 1911 sera, 83.3% were seropositive. When individual age groups were compared, antibody titers decreased overtime; 18–29 year- 81.1%; 30–39 years; 61.5%. The results of similar study in Korea also indicated a progressive decline of antibody level and seroprotection rates over time among 2–30 years old vaccinated persons(45). Measles outbreaks investigation indicated that the vaccine failure was observed among 13–44% of measles cases in several large outbreaks, and in an epidemic up to 14% of cases had received at least 2- doses of measles vaccine(7). These data are in favor of SVF as the main cause of susceptibility among our studied subjects in the group C and D, however, because of faster development of SVF in these groups, further studies to evaluated the immunogenicity and long-term protection of measles vaccine in Iran are recommended.
The WHO Eastern Mediterranean Regional verification commission for measles and rubella elimination declared elimination of measles and rubella in Iran(29). In our study among 7–33 years- old, individuals who were vaccinated at least with 2- doses of measles vaccine with different schedule, nearly 87% and 81% were sero-protected to measles and rubella respectively. Considering 2- doses vaccine coverage 95%, a population immunity of 83% and 77.6% could be estimated. This levels of immunity is below than that is required (93%- 95%) and 88–90% to interrupt measles and rubella viruses transmission in the community and maintain achieved measles and rubella elimination(1, 3, 8). The point of concern is that the phylogenetic analysis of isolated measles virus in outbreaks in Iran showed major similarity with measles virus of neighbor countries that in some of these countries measles is endemic(17). These raise concern and potentially is alarming. To confirm our data, further long-term prospective studies to evaluate the immunogenicity of MMR vaccine in use and the persistence of seroimmunity are recommended. If these data were confirmed by further studies, to sustain measles-rubella elimination in Iran additional dose of MMR vaccine as an national and/or regional supplementary immunization activity program among age group of 10–25 years may be required(49).
The potential limitation of our study is lack of information about post-primary vaccination seroimmunity status to can differentiate PVF than SVF exactly. Another limitation include that study was done in East of Mazandaran province, north of Iran. Which made the results less generalizable. Also, recall bias about MR vaccination in group A may exist.