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 initially with 2- dose of mMV at the age 9 and 15 months. Rubella immunity observed in this group was acquired by natural infection. However, they received additional dose of MMR vaccine just before school entrance (6 years ), 1-5 years laater. 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 months (group C and D), 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 and rubella 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 the levels of MCA acquired after 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 (age group 20-33 years) were serologically immune to measles and rubella, respectively. This long- term high- rate of protection could be attributed to MR vaccine or natural boosting years earlier. Because, the reported prevalence rates of measles immunity The measles seroprevalence rate among Iranian population studied years before MR campaign were much lower than observed in this study and are presented in Table 3(38-42). 40.7%38; 54.7%39; 55.4%40; 72%41 and 91.6%42. However, years after revaccination seroprevalence, studies among different age groups population 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(24). The results of rubella seroprevalence studies indicated the majority of MR vaccinated subjects 84.7% to 99.6% acquired seroprotection (Table 3).After 7 years among pregnant women; 81.7% and 96%(26), and after 10 years 79.2%(27) and 96.2% respectively (Table 3). In a recent nationwide study among premarriage girl older than 15 years, (13-14 years after national MR camping), the seroprotection rates to measles and rubella was investigated. Nearly 1573 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%)(43). 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 and/or possibly natural boosting 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 not only with 2- doses of MV at the ages of 9 and 15 months without any history of rubella immunization also, they received one additional dose of MMR vaccine at school entrance (they received 3 doses of measles and one dose of rubella containing vaccine ). These rates of seronegative to MR detected in this age group nearly 10-13 years after last dose of MR vaccine are unusual and cumbersome and should raise concern. 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 showed an IgG response 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(3,4,44). 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(3-5,42-44). 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(3). Also, a study by perez etal(4) 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(4). Similar to These data and conclusion were confirmed by a recent systematic review and meta-analysis(5,44).
Otherwise, there are evidences that antibody concentrations decline and fall to low or undetectable levels over time(45-49). In a study among differentage groups of children vaccinated against measles at the age of 9 and 15 months, seroimmunity rate 5 and 3 months after injection of first and second dose were 52.9% and 89.2%, respectively. The rate decreased to 68% at the age 6 year and 40.5% at 10 years old. However, 9 months after boosting with one dose of measles vaccine at the age of 14 years, the rate increased to 96.8%. Further more, in a longitudinal study on the kinetic of measles and rubella antibodies , by Kremer et al, results showed that both antibodies wane with time but, measles relatively fast(45). Considering these evidences, the relative high rates of measles and rubella susceptibility observed among our study group B and other reported evidences, these seronegatively could be attributed to waning of acquired seroprotection over time (SVF) or possibly may be the result of PVF vaccine failure. Reduced vaccine effectiveness has been explained as due to primary or secondary vaccine failure. Vaccine failure may occur either because the immune response newer developed (PVF), or it waned overtime (SVF). To differentiate whether, the seronegatively developed either by PFV or SVF, two methods of assessment did exist. IgG avidity test and IgM immune response to revaccination . for this study we used IgM method, and no body showed positive response . this negative results most probably may be due to SVF. However, it may be to some late blood sampling or the result of a less sensitive assay. 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 study results from developed countries have shown that approximately 90- 95% of children vaccinated at the age 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 will persist for decades(1,3-6), although, achieved seroprotection rate may decline over time years after initial immunization(46-49). In this study, nearly 12.8% and 17.7% of 7- 15 years old subjects attributed to 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 responded and changed to seropositive. This is an evidence of SVF. However, in this study waning of measles and rubella antibodies titer and seroprotection rates after the initial course of vaccination occur more faster relatively shorter time than expected(1,5,6,42). The loss of acquired immunity within shorter duration of post- vaccination than that one would expected, based on published immunogenicity and vaccine efficacy reports is of concern(50,51). Therefore, vaccine- related factors such as less potent vaccine because of more thermolabile strain, inadequate control of cold chain during shipment/ storage/ use/ and possibly other factors may be responsible(50-52). The our 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 5).
Table 4. Measles and Rubella seroprevalence rates demonstrated among different studies before and after MR campaign in Iran.
Author/province
|
Relation to MR campaign 2003
|
Years of study
|
No of Subjects Age-groups
|
Tested method
|
Prevalence Rate
|
M
|
R
|
Emami-Naeini
Shiraz38
|
3-yr before
|
2000
|
241 medical students (19-25 yr)
|
ELISA
|
40.7%
|
|
Yekta Uremia 39
|
Months before
|
2002-3
|
835 (5-25 yr)
|
ELISA
|
54.7%
|
-
|
Saffar Sari40
|
Year before
|
2002
|
590(15-25yr)
|
ELISA
|
55.4%
|
-
|
Zam,ani Tehran 41
|
2 yr before
|
2001
|
1665 (6-11yr)
|
ELISA
|
72%
|
-
|
Salimi Tabriz42
|
Yr before
|
2002
|
225 (5-25 yr)
|
HI test
|
91.6%
|
-
|
Pourabbas Shiraz24
|
9 mo after
|
2004-5
|
909(6-26yr)
|
ELISA
|
6-10 yr 80.6%
11-15 yr 72.7%
16-20 yr 84.9%
21-25re 87.5%
|
91.0%
99.6%
99.6%
97%
|
Yekta Uremia 25
|
1 yr after
|
2004
|
624 (6-25yr)
|
ELISA
|
72.3%
|
-
|
Honarvar Shiraz26
|
7 yr aafter
|
2010-11
|
175 (16-24yr)
|
ELISA
|
81.7%
|
96%
|
Keshavarz Tehran 27
|
10 yr after
|
2014
|
53 (19-26 yr)
|
ELISA
|
79.2%
|
96.2%
|
Izadi Southeast 28
|
12-13 yr after
|
2015
|
1056 (16-20 yr)
|
ELISA
|
91.7%
|
87.4%
|
Kaarami Hamadan29
|
13 yr after
|
2016
|
272 (1-40 yr)
|
ELISA
|
63.2%
|
-
|
Yr: year, mo: months
Table 5. Immunogenicity and seroconversion rate to measles and rubella component of MMR vaccine currently in use in Iran.
Author/province
|
Years of study
|
No of Subjects
|
Age
|
Responses Rate MMR
|
MMR1 (%)
|
MMR2 (%)
|
M
|
R
|
M
|
R
|
Saffar, Mazandaran Razi-Iran31
|
2007
|
112
|
12.10 mo
|
84.8% ELISA
|
53%
|
-
|
-
|
Saffar, Mazandaran
Razi-Iran33*
|
2011
|
249
228
|
18m (6mo after MMR1)
6 yr (5 yr after MMR1)
|
74% ELISA
78.9%
|
75%
66%
|
94.4%
|
92.6%
|
One mo after MMR2
|
98.2
|
87%
|
One mo after MMR2
|
Shamsizadeh, Ahwaz Karaj-Iran Razi Iran34
|
2010-2011
|
70
90
|
18 mo(6 mo after MMR1)
6.5 yr A*
|
42.9% ELISA
-
|
90%
-
|
-
45.6%
|
-
87.8%
|
Tabatabaei, Razi-Iran 35
|
2011-2012
|
240
|
13.27 mo (12-15)
|
75.8% ELISA
|
73.8% ELISA
|
-
|
-
|
Izadi, Bluchestan –Kerman-Hormozgan Razi-Iran37
|
2015
|
663
|
30-54 mo
|
-
|
-
|
94.6%
|
-
|
After revaccination dose of MMR
|
Zahrari, Bluchestan –Kerman-Hormozgan Razi-Iran36
|
2016
|
236
|
>12 mo
|
91.2% ELISA
|
B*
|
-
|
|
*: in these study seroconversion rates to rubella component of MMR vaccine after first dose of MMR was 75% among younger VS 67% older age groups, and with MMR2 increased to 87% and 92.4%, respectively.
A*: one dose of MMR vaccine in addition to 2 dose MV at age 9 and 15 month.
B*: Based on strict control of vaccination administration by researchers.
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(45-49). In a prospective multicenter study by Smetana et al(47), measles lgG antibody concentrations among vaccinated subjects ³ 18 years was evaluated. Of 1911 sera, 83.3% were seropositive. When individual age groups were compared, antibody titers seroprevalence rate decreased overtime; 18- 29 year- 81.1%; and 30- 39 years; 61.5%. The results of similar study in Korea also indicated a progressive decline of antibody level and seroprotection rates as well as the avidity of antibodies over time among 2- 30 years old vaccinated persons(49). Measles outbreaks investigation indicated that the vaccine failure was observed among 11- 49%(11,52-55) of measles cases in several large outbreaks, and in an epidemic up to 14%(53) of cases had received at least 2- doses of measles vaccine(11,43,44,52,53). 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(30). 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(1,6). 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(16,31). 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(43).
The potential limitation of our study is lack of information about post-primary vaccination seroimmunity status to can differentiate PVF than SVF exactly. Also, the assessment method of IgM response to revaccination probably was less sensitive. Another limitation include that study was done not designed as a population based study in East of Mazandaran province, north of Iran with a modest number 0f participants which made the results less generalizable. Also, and finally recall bias about MR vaccination in group A may exist.