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.
Journal of military pharmaco-medicine no8-2019 IMMUNOGENICITY OF MEASLES VACCINE OF MEASLES AND RUBELLA COMBINED VACCINE MANUFACTERING BY POLYVAC Nguyen Xuan Dong1; Dinh Hong Duong2; Nguyen Thuy Huong3 Ha The Tan2; Vu Tung Son2; Vu Ngoc Hoan2 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 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 - 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 Military Institute of Medicine Preventive Vietnam Military Medical Univerity 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 126 Journal of military pharmaco-medicine no8-2019 SUBJECTS AND METHODS + Lot number: MR-0115; production date: November 4, 2015; expiry date: November 4, 2017 Subjects * Volunteers: A total of 756 people in Hanam and Hoabinh provinces participated in the study, included 420 children from to years old, 168 people over 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 Control vaccine: MR vaccine produced by India Lot number: 012N4072; Production date: July 2014; expiry date: August 1, 2016 Methods * Research design: Randomized, controlled and singleblind 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 42 Collecting M0 blood sample 56 day Collecting M1 blood sample Figure 1: Vaccination and taking blood sample diagram 127 Journal of military pharmaco-medicine no8-2019 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: 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 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 In negative antibody group Table 1: Seroconversion rate of measles antibody Age group MRVAC Control vaccine n Number % n Number % - years 13 13 100 5 100 > to < 18 years 11 11 100 4 100 18 - 45 years 6 100 2 100 30 30 100 11 11 100 Total 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 Log2GMT (95%CI) GMT (95%CI) MRVAC (n = 30) Control vaccine (n = 11) 5.35 4.71 (5.05 - 5.65) (4.20 - 5.23) 40.79 26.17 (33.13 - 50.21) (18.38 - 37.53) p 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 128 Journal of military pharmaco-medicine no8-2019 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] 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 MRVAC Control vaccine Pre-vac (1) Post-vac (2) Pre-vac (3) Post-vac (4) (n = 458) (n = 458) (n = 234) (n = 234) p Log2GMT 4.52 5.55 4.58 5.14 (1;2): 0.001 (95%CI) (4.42 - 4.61) (5.49 - 5.60) (4.44 - 4.73) (5.03 - 5.24) (3;4): 0.001 22.94 46.85 23.92 35.26 (1;3): 0.382 (21.41 - 24.42) (44.94 - 48.50) (21.71 - 26.54) (32.67 - 37.79) (2;4): 0.001 GMT (95%CI) 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, postvaccination 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 Age group Post-vac/pre-vac antibody titer MRVAC n Number % 133 52.4 75 29.5 > fold 46 < fold < fold - years > to < 18 years Control vaccine - < fold - < fold > fold 254 100 n p Number % 90 68.7 26 19.8 18.1 15 11.5 32 32.0 33 67.3 36 36.0 14 28.6 32 32.0 4.1 131 49 0.004 0.001 129 Journal of military pharmaco-medicine no8-2019 < fold 18 years Total 45 79 76.0 11 10.5 > fold 14 < fold - < fold - < fold 46 85.2 14.8 13.5 0 244 53.3 169 72.2 122 26.6 48 20.5 92 20.1 17 7.3 104 458 > fold 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 fold-increase in antibody titer from pre- to post-vaccination accounting for the highest proportion of 53.3 and 72.2%, respectively, from to under 4-fold occupying 26.6 and 20.5%, from 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 fold-increase in the MRVAC group was lower, but from to under 4-fold and from and above-fold increase were higher than control group by overall and age group analysis The difference was statistically significant (p < 0.05, Chisquare 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 fold, from to under 4-fold and from and above-fold increase were 57.1%, 34.3% and 8.6%, respectively [3] CONCLUSION MRVAC vaccine achieved immunogenicity requirements to measles virus through 130 54 234 0.017 0.001 evaluation parameters such as seroconversion rate, high post-vaccination GMT, with a marked increase in antibody titer, postcompared to pre-vaccination GMT and immune response were stronger than the control vaccine REFERENCES Dang Thi Thanh Huyen, Duong Thi Hong Several epidemiological and clinical characteristics of measles in Vietnam, 2013 - 2014 Vietnam Journal of Preventive Medicine 2016, XXVI, (177), pp.98-106 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 and 3) Vietnam Journal of Preventive Medicine 2011, XXI, 4, pp.110-117 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, (143), pp.26-32 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 WHO Guidelines on Clinical Evaluation of Vaccines: Eegulatory Expectations 2016 ... Journal of Preventive Medicine 2016, XXVI, (177), pp.98-106 Doan Huy Hau, Dao Xuan Vinh, Dinh Hong Duong et al Evaluation of safety and immunogenicity of the measles vaccine MVVAC manufacturing by POLYVAC. .. 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 Age group... rate of less than fold, from to under 4-fold and from and above-fold increase were 57.1%, 34.3% and 8.6%, respectively [3] CONCLUSION MRVAC vaccine achieved immunogenicity requirements to measles