This study showed that more than 12% and 18% of the studied individuals were serologically susceptible to measles and rubella, respectively. The highest rates of susceptibility to measles and rubella (15.2% and 25% respectively) were observed among subjects in group B (15- 19 year old) who were born within 5 years before national MR immunization program and were vaccinated initially with two doses of mMV at the ages nine and 15 months, respectively. Two to five years later, they also received an additional dose of MMR vaccine right before entrance to school (age of 6 years). Moreover, the present results showed that 12.8% and 17.7% of subjects who were vaccinated with two doses of MMR vaccine after the age of 12 months (group C and group D), were serologically susceptible to measles and rubella, respectively. In this study the lowest rate of serosuseptibility to measles and rubella was detected among 20- 33- year- old adults who were MR revaccinated. Based on our findings, the main possible cause of susceptibility to measles and rubella in our vaccinated population was waning of acquired seroprotection with time (SVF), because of isolated lgG immunologic response to MMR revaccination in boosted susceptible individuals. Moreover, the results revealed that the levels of acquired MCA after revaccination of seroimmune subjects for both measles and rubella with MMR vaccine, did not improved specific immunity to these viruses.
The present result showed that 98% and 100% of subjects in group A (age 20-33 years) who were covered by the national program of MR immunization were serologically immune to measles and rubella, respectively. The long- term high- rate of protection could be attributed to MR vaccination or natural boosting in recent years. Years before the MR campaign the measles seroprevalence rates in the Iranian population were much lower(33-37) (40.7%33 - to 91.6%37) than the rates reported in this study. However, studies performed years after revaccination in different age groups indicated much higher levels of seroprotection: (63.2(29)% -to 91.7(28)% for measles and 87.4(28)%-to 99(24)% for rubella)(24-29). The relevant data are presented in Table 4. In a recent nationwide study conducted 13-14 years after the national MR campaign on girls above 15 years, the seroprotection rates to measles and rubella were investigated. Nearly 1573 sera were included from ten different provinces. The seroimmunity rates to measles and rubella were 80.7% (range 73.1%- to 89.8%) and 90.6% (range; 81.2- 95%) respectively (38). However, these rates varied greatly between provinces. The relatively high rate of seroprotection observed in our study as well as the mentioned studies, which were conducted years after national campaign could be attributed to the positive impact of MR revaccination and/or natural boosting in the immunized population.
In this study, the highest rate of measles and rubella susceptibility was observed in subjects of group B (age range: 15- 19 years), who were vaccinated not only with two- doses of mMV at the ages of nine and 15 months, but also received an additional dose of MMR vaccine upon school entrance (three doses of measles and one dose of rubella vaccine). These seronegativity to MR viruses in this age group detected nearly 13-15 years after the last dose of MMR vaccine, are unusual and raise some concern. Since, there is no information about immune responses to the primary measles immunization in this age group, the actual reasons for this rate of susceptibility and vaccine failure is unclear. However, waning of acquired seroimmunity over time may be influential, as the majority of boosted susceptible subjects in this group only showed IgG response to MMR revaccination.
The quality and durability of measles vaccine-induced immunity are dependent on a number of factors including the host and the vaccine status. The most important and well-studied host-related determinant is the age when the first dose of vaccine is administered(3-5,39). Studies on the immunogenicity and VE of MV administered before the age of 12 months, showed lower rates as compared to older ages(3-5, 39). In this regard, a prospective randomized trial by Redd et al(3), investigated the immunogenicity of measles component of MMR vaccine administered at the ages 9,12, and 15-18 months. They found a 98% seroconversion rate among 15 month-old vaccinees as compared to 95% in those vaccinated at the age of 12 months and 81% in those vaccinated at the age nine months(3). Moreover, a study by perez et al(4) revealed that measles vaccination at the age of < 12 months was associated with a higher risk of PVF. This negative effect persisted after vaccination with the second dose(4). These results were confirmed supported by a recent systematic reviews and meta-analysis(5, 39). Moreover, to determine the effects of age on the immunogenicity of measles vaccine a systematic review was recently performed. This study showed that earlier age of vaccination decreased the measles vaccine immunogenicity and protection after the first dose, and could influence VE after administering two-doses measles vaccine (39). However, in another review by Uzicanin et al(5) estimating the measles VE, they found that two-dose measles vaccine provide excellent protection. Nevertheless, in three out of eighth studies, VE was estimated at <90% relative to no vaccination(5).
On the other hand, some evidence suggests that antibody concentrations decline to low or undetectable levels over time(40-44). In this regard a study was conducted on different age groups of Iranian children who were vaccinated against measles at the age of nine and 15 months. The seroimmunity rates were 52.9% and 89.2% at five and three months after administering the first and second doses of MV, respectively. These rates decreased to 68% by the age six years and 40.5% by the age ten years. However, the seroimmunity rates increased to 96.8% at nine months after boosting with one dose of MV at the age of 14 years(40). Moreover, in a longitudinal study by Kremer et al(41), on the kinetic of measles and rubella antibodies, both antibodies waned over time, also, the rate of waning immunity was relatively faster for measles(41). Considering, the relatively high rates of measles and rubella susceptibility in group B in our study, this seronegativity could be attributed to both primary and secondary vaccine failure. To determine whether the seronegativity is related to PFV or SVF, there are two methods of assessment. These methods include IgG avidity test and IgM response to revaccination. In this study we used the IgM method, and found nobody positive response. These negative results are probably due to SVF. Possible delay in blood sampling for IgM detection and the lower sensitivity of the assay may be also influential. Nevertheless, this finding is most probably associated with SVF, due to isolated IgG seroconversion in boosted seronegative subjects.
The results of most study from developed countries have shown that approximately 90- 95% of children vaccinated at the age of ³12 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), although some studies have shown that the achieved seroprotection rate may decline over time or years after the initial immunization (42-44). In this study, nearly 12.8% and 17.7% of 7- 15-year-old subjects in group C and D (vaccinated with two doses of MMR vaccine administered after the age of 12 months) were serologically susceptible to measles and rubella, respectively, however, the exact cause of this lower unexpected rate is unknown. After revaccination, nearly all boosted serosusceptible subjects develop isolated IgG antibody response without IgM, and showed evidence of secondary immune response, besides waning of acquired immunity over time. Nevertheless, the present study waning of measles and rubella seroprotection rates after the primary vaccination occurred relatively earlier than expected time (1,5,6,39). Loss of acquired immunity after vaccination, particularly within a shorter period than expected time, is of concern(45,46). Therefore, vaccine- related factors such as lack of adequate potency of vaccine because of using more thermolabile strains, inadequate control of cold chain shipment/storage/ and use, and other probable factors may be responsible (45-47). Our assumption regarding the inadequate potency of vaccine is based on the results of studies that were designed to investigate the immunogenicity of MMR vaccine currently in used in Iran(48-53). The majority of these studies showed lower rates of seroconversion following the first and/or the second doses of MMR vaccine after the age of 12 months (Table 5).
The reduced levels of measles- rubella antibodies in the post- vaccinated period may result in the accumulation of potentially susceptible individuals to measles and/or rubella in the community. Several reports have described significant rates of SVF in population with a sustained high rates of vaccination coverage and long absence of measles virus transmission(40-44). In this regard, a prospective multicenter study performed by Smetana et al(43), evaluated the measles lgG antibody concentrations among vaccinated subjects ³ 18 years. Of 1911 sera, 83.3% were seropositive. When different age groups were compared, the seroprevalence rate decreased overtime: (18-29 years: 81.1%, and 30-39 years: 61.5%). The results of a similar study in Korea, also indicated a progressive decline in antibodies as well as the avidity of antibodies over time in 2- to 30-year-old vaccinated persons (44). Investigation of the measles outbreaks indicated the vaccine failure in 11- 49% of measles cases in several large outbreaks(11,54-57). Also, in an epidemic(56), up to 14%of cases had received at least two-doses of measles vaccine. These findings suggest SVF as the main cause of susceptibility which was mentioned earlier in group C and D of our study population. However, since the development of SVF was faster in these groups as compared to other studies, further investigations are recommended to evaluate the immunogenicity and long-term protection of measles vaccine in the Iranian population.
The WHO Regional Verification Commission of the Eastern Mediterranean region for measles and rubella elimination declared elimination of measles and rubella in Iran(31). In the present study among 7- to 33 year- old individuals, who were vaccinated at least with two-doses of measles vaccine with different schedules, nearly 87% and 81% were seroprotected to measles and rubella respectively. Considering a 95% coverage rate with two-doses of vaccine, immunity rates of 83% and 77.6% were estimated in the population respectively. This level of immunity is less than what is necessary to prevent measles and rubella virus transmission in the community and achieve disease elimination (93%- 95% and 88-90% for measles and rubella respectively) (1, 6). Also, phylogenetic analysis of the isolated measles viruses in the outbreaks of Iran showed major similarity with the measles viruses detected in neighbor countries. In some of these countries measles is still endemic(16,32), which can be an alarming sign for Iran. Therefore further long-term prospective studies are recommended to evaluate the immunogenicity of MMR vaccine and investigate the persistence of seroimmunity. If the present study are confirmed in further studies, additional dose of MMR vaccine is required as a national/regional supplementary immunization activity program for the age group of 10-25 year old individuals to sustain measles-rubella elimination in Iran (38).
One of the limitations of this study is the lack of information about the seroimmunity status after the primary vaccination which can differentiate between PVF and SVF. Also, the method used for the assessment of IgM response to revaccination may not be sensitive enough. Another limitation of this study is that it was not designed as a population based study, it was carried out in East of Mazandaran province, North of Iran with a modest number of participants which made the results less generalizable. Finally, there may be recall bias in group A regarding MR vaccination.