To assess immunogenicity of measles vaccine of measles and rubella combined vaccine. Subjects and methods: Randomized, controlled and single-blind clinical trial study was conducted on 756 people aged from 1 to 45 years old in Hanam and Hoabinh provinces, measured measles antibody titer by EIA technique, analyzed indexes to evaluate immunogenicity.
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IMMUNOGENICITY OF MEASLES VACCINE OF MEASLES
AND RUBELLA COMBINED VACCINE MANUFACTERING BY POLYVAC
Nguyen Xuan Dong 1 ; Dinh Hong Duong 2 ; Nguyen Thuy Huong 3
Ha The Tan 2 ; Vu Tung Son 2 ; Vu Ngoc Hoan 2
SUMMARY
Objectives: To assess immunogenicity of measles vaccine of measles and rubella combined
vaccine Subjects and methods: Randomized, controlled and single-blind clinical trial study was
conducted on 756 people aged from 1 to 45 years old in Hanam and Hoabinh provinces,
measured measles antibody titer by EIA technique, analyzed indexes to evaluate
immunogenicity Results: In negative antibody group, post-vaccination seroconversion rate was
100% In positive antibody group, measles and rubella combined vaccine, post-vaccination
geometric mean titer was 46.85 EIA units, significantly higher than pre-vaccination and control
vaccine, with a remarkable growth post-vaccination antibody titer
* Keywords: Measles and rubella combined vaccine; Immunogenicity
INTRODUCTION
In Vietnam, after implementing vaccines
in the expanded immunization program,
the epidemic situation of measles has
changed positively with the trend of
substantially decline morbidity and mortality
However, measles is still circulating with a
3 - 5 year period of epidemic, the number
of cases has still been high [1] The goal
of eliminating measles nationwide has
been continuously pushed back over time
and faced many difficulties and challenges,
partly due to the lack of vaccine sources
The vaccine against rubella and rubella used previously was imported from India
In fulfillment of a cost decrease in the expanded immunization program and actively control, prevent these measles, POLYVAC has successfully produced
measles and rubella combined vaccine
(MRVAC) according to technology transfer from Japan Before applying in community,
we conducted this study: To assess the
immunogenicity of measles vaccine of MRVAC vaccine
1 Military Institute of Medicine Preventive
2 Vietnam Military Medical Univerity
3 Center for Research and Production of Vaccines and Biologicals
Corresponding author: Nguyen Xuan Dong (nguyen.xuan.dong81@gmail.com)
Date received: 05/09/2019
Date accepted: 10/10/2019
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SUBJECTS AND METHODS
1 Subjects
* Volunteers:
A total of 756 people in Hanam and
Hoabinh provinces participated in the study,
included 420 children from 1 to 2 years
old, 168 people over 2 to under 18 years
old and 168 people from 18 to 45 years
old There were 504 subjects vaccinated
MRVAC and 252 subjects immunized
control vaccine Research time: from April
8, 2016 to July 27, 2016
* Vaccines:
- Study vaccine: MRVAC vaccine
produced by POLYVAC
+ Ingredients: Each bottle included 10
doses of measles vaccine is reconstituted
with 5.5 mL solvent Each dose 0.5 mL
included:
Live, further attenuated AIK-C measles
strain ≥ 1.000 PFU
Live, further attenuated Takahashi rubella
strain ≥ 1.000 PFU
Stabilizers: Lactose 2%; D-sorbitol 0.72%;
L-sodium glutamate 0.4%; hydrolized
gelatin 0.36%
Antibiotics: Erythromycin ≤ 12.5 µg;
kanamycin ≤ 12.5 µg
+ Lot number: MR-0115; production date: November 4, 2015; expiry date: November 4, 2017
Control vaccine: MR vaccine produced
by India Lot number: 012N4072; Production date: July 2014; expiry date: August 1,
2016
2 Methods
* Research design:
Randomized, controlled and single-blind clinical trial study was conducted M0 blood sample was taken immediately before vaccination, M1 sample was collected 42 - 56 days after immunization
to quantify pre- and post-vaccination measles antibody (figure 1) No sooner were M0 and M1 blood samples gathered at the commune health stations than they were transferred to Preventive Medicine Center
of Hanam province and Kimboi district to conduct on serum centrifugation Then serum samples were quantified antibody titer by enzyme immuno assay (EIA) technique at Vaccine Immunization Board, Department of Immunology and Molecular Biology, National Institute of Hygiene and Epidemiology, converting international units with the formula: EIA unit x 45 = milli-international units/mL (mIU/mL)
Vaccination
0 42 56 day
Collecting M0 blood sample Collecting M1 blood sample
Figure 1: Vaccination and taking blood sample diagram
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A total of 756 subjects had their blood
drawn for the first time, but when
collecting M1 blood samples, 23 subjects
withdrew from the study, including: 2
cases of identical serum code, someone
refused second blood sample collection
and other left the residence, so they could
not participate (although these subjects
had pledged that they did not leave the
locality within 2 months before entering
the study), only 733 blood samples were
quantified post-vaccination antibody titer
Immunogenicity of measles vaccine has been assessed by some major indexes: seroconversion rate, an antibody titre increase, pre- and post-vaccination geometric mean titre (GMT) follow in study and age groups
* Ethical issues in research:
This study complies with ethical principles
of Declaration of Helsinki and the revisions, current regulations of Ministry of Health
on Good Clinical Practice (GCP)
RESULTS AND DISCUSSION
1 In negative antibody group
Table 1: Seroconversion rate of measles antibody
Age group
Overall as well as separate analysis by age group, seroconversion rate of measles antibodies in both study groups was 100% Most of the participants in our study were vaccinated with at least one measles vaccine or were infected, so the number of subjects without antibodies was low After MRVAC vaccination, seroconversion rate was similar to study by Doan Huy Hau et al (100%), who clinical tried a single vaccine MVVAC containing AIK-C measles strain like MRVAC and Takeuchi Y (94.5%) who tried HF vaccines with the same formula on Japanese children [2, 4]
Table 2: Post-vaccination GMT of measles antibody follow in study groups
(5.05 - 5.65)
4.71 (4.20 - 5.23)
(33.13 - 50.21)
26.17 (18.38 - 37.53)
0.029
The post-vaccination GMT of two study groups were respectively 40.79 EIA units (1,835.6 mIU/mL) and 26.17 EIA units (1,177.7 mIU/mL) Log2GMT of MRVAC group
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was significantly higher than the control group (p < 0.05, independent sample t-test) Thus, in negative antibody group, immune response after MRVAC vaccination had been stronger than control vaccine and been equivalent to the study by Doan Huy Hau (5.31 Log2 EIA unit) [2]
2 In positive antibody group
With positive antibody group, the growth of antibody titer was not as strong as the negative group Measuring immune response after vaccination by indexes including the growth of GMT, multi-fold increase of antibody titer from pre- to post-vaccination [5]
Table 3: Pre- and post-vaccination GMT of measles antibody in two study groups
Pre-vac (1) (n = 458)
Post-vac (2) (n = 458)
Pre-vac (3) (n = 234)
Post-vac (4) (n = 234)
p
Log 2 GMT
(95%CI)
4.52 (4.42 - 4.61)
5.55 (5.49 - 5.60)
4.58 (4.44 - 4.73)
5.14 (5.03 - 5.24) GMT
(95%CI)
22.94 (21.41 - 24.42)
46.85 (44.94 - 48.50)
23.92 (21.71 - 26.54)
35.26 (32.67 - 37.79)
(1;2): 0.001 (3;4): 0.001 (1;3): 0.382 (2;4): 0.001
Pre- and post-vaccination GMT was
respectively 22.94 EIA units
(1,032.3 mIU/mL) and 46.85 EIA units
(2,108.3 mIU/mL) in the MRVAC group;
23.75 EIA units (1,068.8 mIU/mL) and
35.26 EIA units (1,586.7 mIU/mL) in the
control group Data analysis showed
that post-vaccination Log2 GMT was
significantly higher than pre-vaccination in
both study groups (p < 0.05, Wilcoxon
test) Thus, both vaccines even increased
measles antibody titer in possitive antibody group There was no significant difference between pre-vaccination Log2GMT in two study groups (p > 0.05, Mann-Whitney test) However, post-vaccination Log2GMT in MRVAC group was higher than control group (p < 0.05, Mann-Whitney test), which indicated that MRVAC vaccine increased measles antibody titer more remarkably than control vaccine
Table 4: The growth of post-vaccination measles antibody titer by study and age group
1 - 2 years
> 4 fold
254
131
0.004
> 2 to < 18
years
> 4 fold
100
49
0.001
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18 - 45
years
> 4 fold
104
54
0.017
Total
> 4 fold
458
234
0.001
The growth of measles antibody titer
had been also an important criterion for
evaluating immune response of vaccines
Data analysis in both study groups
showed that a less than 2 fold-increase in
antibody titer from pre- to post-vaccination
accounting for the highest proportion of
53.3 and 72.2%, respectively, from 2 to
under 4-fold occupying 26.6 and 20.5%,
from 4 and above-fold took up the lowest
with 20.1 and 7.3% Comparison between
the two study groups, the rate of a less
than 2 fold-increase in the MRVAC group
was lower, but from 2 to under 4-fold and
from 4 and above-fold increase were
higher than control group by overall and
age group analysis The difference was
statistically significant (p < 0.05,
Chi-square test) The MRVAC vaccine rosed
antibody levels more strongly than control
vaccine Measles antibody titer in our
study increased more remarkably than
study by Dang Thi Thanh Huyen et al,
who also conducted research on children
in Kimboi district, Hoabinh with the rate of
less than 2 fold, from 2 to under 4-fold
and from 4 and above-fold increase were
57.1%, 34.3% and 8.6%, respectively [3]
CONCLUSION
MRVAC vaccine achieved immunogenicity
requirements to measles virus through
evaluation parameters such as seroconversion rate, high post-vaccination GMT, with a marked increase in antibody titer, post- compared to pre-vaccination GMT and immune response were stronger than the control vaccine
REFERENCES
1 Dang Thi Thanh Huyen, Duong Thi Hong
characteristics of measles in Vietnam,
2013 - 2014 Vietnam Journal of Preventive Medicine 2016, XXVI, 4 (177), pp.98-106
2 Doan Huy Hau, Dao Xuan Vinh, Dinh Hong Duong et al Evaluation of safety and
immunogenicity of the measles vaccine MVVAC manufacturing by POLYVAC (phase 1 and 3) Vietnam Journal of Preventive Medicine
2011, XXI, 4, pp.110-117
3 Dang Thi Thanh Huyen, Pham Ngoc Dinh, Nguyen Van Cuong et al Immunogenicity of
second dose measles vaccine at 18 months of age in Kimboi district, Hoabinh province Vietnam Journal of Preventive Medicine
2013, XXIII, 7 (143), pp.26-32
4 Takeuchi Y, Togashi T, Sunakawa K et
al Field trial of combined measles and rubella
live attenuated vaccine Infectious Disease Magazine 2002, 76 (1), pp.56-62
5 WHO Guidelines on Clinical Evaluation
of Vaccines: Eegulatory Expectations 2016.