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Similar immunogenicity of measles–mumps–rubella (MMR) vaccine administrated at 8 months versus 12 months age in children

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Hanqing He a,1 , Enfu Chen a,1 , Haiping Chen b , Zhifang Wang a , Qian Li a , Rui Yan a , Jing Guo a , Yang Zhou a , Jinren Pan a , Shuyun Xie a,∗ a b

Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, PR China China National Pharmaceutical Group Corporation, Beijing 100088, PR China

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Article history: Received 31 October 2013 Received in revised form 28 February 2014 Accepted 17 April 2014 Available online xxx

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Keywords: Measles–mumps–rubella vaccine Immunogenicity Safety

Two doses of measles–mumps–rubella (MMR) strategy has been recommended by World Health Organization and is also widely adopted in many countries. In order to provide the evidence for perfecting the immunization strategy of MMR, this study evaluated the safety and immunogenicity of MMR with different two-dose schedule in infants. 280 participants were enrolled and randomly allocated to Group 1 (first dose at 8 months) or Group 2 (first dose at 12 months), and both groups administered the second dose at 10 months later. Solicited local and general symptoms after each vaccination with MMR were mild and infrequent in all participants of two groups. After administration of the first dose of MMR, seropositive rates were 100% in both groups for measles, 89.3% in Group 1 and 87.1% in Group 2 for mumps (P = 0.578), 92.0% in Group 1 and 92.9% in Group 2 (P = 0.393). The seropositive rates of mumps decreased significantly (from >86% to 30 mm Any >30 mm ≥37.0 ◦ C ≥39.0 ◦ C

Group 1

8 months (n = 140)

18 months (n = 92)

12 months (n = 140)

22 months (n = 114)

6 (4.28%)a 0 6 (4.28%) 0 0 6 (4.28%) 1 (0.71%)

5 (5.43%) 0 5 (5.43%) 0 0 5(5.43%) 1 (1.09%)

4 (2.86%) 0 3 (2.14%) 0 0 4 (2.86%) 0

5 (4.38%) 0 4 (3.51%) 0 0 9 (7.89%) 0

Numbers in parenthesis indicate percentages.

3.2. Safety Solicited local and general symptoms after each vaccination with MMR were mild and infrequent in both groups. The most frequent complaints were fever with a mean prevalence of 4.28%, 5.43% in Group 1 and 2.86%, 7.89% in Group 2 during 1st and 2nd dose of MMR respectively (Table 1). There was no significant difference in frequency or timing between two groups or two doses. 3.3. Immunogenicity after 1st dose MMR The seropositivity and GMTs of specific antibodies against measles, mumps and rubella before and after the first vaccination are given in Table 2. There was no significant difference between the two groups with regard to seropositivity or GMTs before vaccination, with the exception of a higher rubella GMT in Group 1 (1.59 mIU/mL vs 1.15 mIU/mL, P < 0.001). After administration of the 1st dose of MMR, seropositive rates (SP%) was 100% in both groups for measles, 89.3% in Group 1 and 87.1% in Group 2 for mumps (P = 0.578), 92.0% in Group 1 and 92.9% in Group 2 for rubella (P = 0.393). Postvaccination GMTs of measles and mumps were both statistically higher in Group 1 (P = 0.007 and P < 0.001, respectively), and no significant difference was detected between two groups for postvaccination rubella GMT (P = 0.210) in the consideration of the baseline antibody level. The difference of seroconversion rate (SCR%) between the two groups for three antigens did not reach the significant value (P = 1, P = 0.714 and P = 0.410, respectively). The fold increase of GMTs (SCF mean) after vaccination was higher in Group 1 than in Group 2 (49.6 vs 45.8, P = 0.021). 3.4. Immune effects after 2nd dose MMR The results of immune effects before and after 2-dose MMR were shown in Table 3. The percentage of participants with positive antibodies for measles and rubella remained the same level in two groups 10 months later as compared to 1 month after given the first dose of MMR, but the seropositive rates (SP%) for mumps decreased about 20 percent (approximately from >85% to 65%) both in Group 1 (P < 0.001) and Group 2 (P < 0.001). There was no significant difference between two groups in GMTs after 10 months follow up before the second doses of MMR was given. Three seropositivities were all the same (100%) in two groups after vaccination with two doses MMR. Higher seroconversion rate (SCR%) was only found for mumps, and which did not show statistical difference between two groups (71.7% vs 77.2%, P = 0.370). The fold increase of GMTs (SCF mean) after the second dose MMR of Group 1 and Group 2 were 1.62 and 1.53 for measles, 13.4 and 15.8 for mumps, 1.61 and 1.30 for rubella, respectively. There was no significant difference between two groups with regard to SCF mean for the comparison of post-vaccination and pre-vaccination. The GMTs of antibodies against measles and mumps were higher in

Group 2 after two doses MMR, but the difference did not reach the statistical difference (P = 0.960 and P = 0.102, respectively). In comparison with Group 2, the GMT of antibodies against rubella was significantly higher in Group 1 (216 IU/mL vs 178 IU/mL, P = 0.017).

4. Discussion This is the first study to the best of our knowledge in China to evaluate the safety and immunogenicity of 2-dose MMR with two different time schedules (the first dose in children either at 8 months or at 12 months). We found that the MMR was well tolerated in general, regardless of varied immunization schedule. MMR vaccine generally is very safe and rarely associated with serious adverse events, therefore, MMR has been widely recommended for routine immunization and revaccination program all over the world [1,3]. The optimal immunization schedule of MMR is to maximize the time of protection against the diseases infection by minimizing the time between interference of maternal antibodies and vaccination of MMR vaccine [10]. The first dose of MMR is routinely recommended by WHO in children aged 12 months or later, mainly due to the possible primary vaccine failure with interference by maternal antibodies if vaccinated too early [11,12]. However, some evidence showed that almost none children from 6 months onwards had protective level of antibody against measles in Zhejiang province and many other places in China [13,14]. Recently, outbreaks investigation in Zhejiang demonstrated that children aged 8–11 months had the highest attack rate of measles among all age groups [15]. Early waning of maternal measles antibodies also has been found in some developed countries [16]. Moreover, infants are at higher risk for severe measles and more complications, and they are susceptible to measles because their maternal antibodies to measles have waned faster [17]. We demonstrated that earlier (8 months) vaccination of MMR has the similar immunogenicity against measles, mumps and rubella, as compared with immunization at 12 months of age in children. Vaccination of measles vaccine at age 6 months or before can provide the equivalent cell-mediated immune response [18,19]. Therefore, in countries with a high risk of measles infection, such as China, MMR can be administrated at the earlier age to close the gap of vulnerability for measles infection during infancy [20]. In addition, early two-dose measles vaccination is also associated with improved coverage [21]. Our findings indicate that a decreasing immunity of mumps 10 months after the first dose of MMR, and the seropositive rates of mumps were about 20 percent drop both in two groups. Same results had been reported that the mumps component of the MMR vaccine was the least effective of the three live, attenuated viruses [22,23]. We find the well booster effect in children after administration of the second dose MMR, and the fold increase of GMTs were detected for three antigens. In addition, higher seroconversion rate was found for mumps after the second dose MMR both in two groups (71.7% vs 77.2%, P = 0.370). Vaccine induced

Please cite this article in press as: He H, et al. Similar immunogenicity of measles–mumps–rubella (MMR) vaccine administrated at 8 months versus 12 months age in children. Vaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.04.044

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H. He et al. / Vaccine xxx (2014) xxx–xxx

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Table 2 Comparison of the immunization effects of the first dose MMR vaccination between two groups. Pa

Pre-1st vaccination Group 1 (n = 140)

Group 2 (n = 140)

Measles GMT (95% CI) SP% (95% CI) SCR% (95% CI) SCF mean (95% CI)

26.7 (24.8–28.8) 0.71 (0.02–3.92) – –

27.3 (25.3–29.6) 1.43 (0.17–5.07) – –

Mumps GMT (95% CI) SP% (95% CI) SCR% (95% CI) SCF mean (95% CI)

16.0 (15.1–17.0) 0.71 (0.02–3.92) – –

16.0 (15.3–16.7) 0 – –

Rubella GMT (95% CI) SP% (95% CI) SCR% (95% CI) SCF mean, (95% CI)

1.59 (1.43–1.77) 0.71 (0.02–3.92) – –

a

1.15 (1.06–1.24) 0.71 (0.02–3.92) – –

Pa

Post-1st vaccination b

Group 1 (n = 140)

Group 2 (n = 140)

0.729 1.00 – –

2790 (2590–3000) 100 98.6 (94.9–99.8) 118 (110–126)

2450 (2300–2600) 100 99.3 (96.1–100) 101 (94.3–109)

0.007& – 1.00 0.002&

0.989 1.00 – –

352 (309–400) 89.3 (82.9–93.9) 88.6 (82.1–93.3) 28.2 (25.1–31.3)

243 (212–278) 87.1 (80.4–92.2) 87.1 (80.4–92.2) 21.0 (18.0–24.0)