Safety of measles and rubella combined vaccine manufacturing by POLYVAC in Vietnamese volunteers

To evaluate safety of measles and rubella combined vaccine. Subjects and methods: Randomized, controlled and single-blind clinical trial study was conducted on 756 people aged 1 to 45 years old in Hanam and Hoabinh provinces. Results: Incidence of adverse events within the 30-minute and the 28-day follow-up in the two study groups were 5.6% and 9.5%; 7.5% and 7.5%. Conclusions: Measles and rubella combined vaccine was safely used on volunteers and not significantly different from the control group.

Journal of military pharmaco-medicine no6-2019 SAFETY OF MEASLES AND RUBELLA COMBINED VACCINE MANUFACTERING BY POLYVAC IN VIETNAMESE VOLUNTEERS Nguyen Xuan Dong1; Dinh Hong Duong2; Nguyen Thuy Huong3 Ha The Tan2; Vu Tung Son2; Vu Ngoc Hoan2 SUMMARY Objectives: To evaluate safety of measles and rubella combined vaccine Subjects and methods: Randomized, controlled and single-blind clinical trial study was conducted on 756 people aged to 45 years old in Hanam and Hoabinh provinces Results: Incidence of adverse events within the 30-minute and the 28-day follow-up in the two study groups were 5.6% and 9.5%; 7.5% and 7.5% Conclusions: Measles and rubella combined vaccine was safely used on volunteers and not significantly different from the control group * Keywords: Measles and rubella combined vaccine; Safety INTRODUCTION In our country, the epidemic situation of measles and rubella has changed positively with the trend of substantially decline morbidity and mortality after implementing vaccines in the expanded immunization programe However, measles is still circulating with a - year period of epidemic, rubella has an outbreak time, especially the congenital rubella syndrome in children increases the medical, economic and social burden every year [1, 2, 3] The goal of eliminating these two diseases in our country is still difficult due to the lack of vaccines The vaccine against rubella and rubella used previously was imported from India In fulfillment of a cost decrease in the expanded immunization programe and actively control, prevent 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 safety of MRVAC SUBJECTS AND METHODS Subjects * Volunteers: A total of 756 people in Hanam and Hoabinh provinces participated in the study, including 420 children from to 2, 168 people over to under 18 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 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: 25/06/2019 Date accepted: 05/08/2019 135 Journal of military pharmaco-medicine no6-2019 * Vaccines: Study vaccine: MRVAC vaccine produced by POLYVAC - Ingredients: Each bottle 10 doses of measles vaccine is reconstituted with 5.5 mL solvent Each dose 0.5 mL includes: - Lot number: MR-0115; production date: November 4, 2015; expiry date: November 4, 2017 Control vaccine: measles-rebella (MR) vaccine produced by India Lot number: 012N4072; production date: July 2014; expiry date: August 1, 2016 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; anamycin ≤ 12.5 µg Methods * Research design: A randomized, controlled and single-blind clinical trial study was conducted Local, systemic and serious adverse events within the 30-minute and the 28day follow-up were supervised, evaluated to collect data by questionnaires The safety of vaccines were assessed by the incidence of such events Vaccination AE, SAE supervision within the 30-minute 28 follow-up day Last check, questionnaires Figure 1: Vaccination and adverse events supervision diagram RESULTS AND DISCUSSION Adverse events occur within 30 minutes after vaccination Table 1: Adverse events within 30 minutes after vaccination in two study groups Adverse events within 30 minutes after vaccination Control vaccine (n = 504) (n = 252) p Number % Number % 28 5.6 24 9.5 0.042 Pain at the injection site 10 2.0 2.0 1.000 Red at the injection site 15 3.0 17 6.7 0.015 Swelling at the injection site 0.8 2.0 0.155 Subjects with events Events MRVAC Within 30 minutes after vaccination, the incidence of adverse events occurred in MRVAC group significantly lower than the control group, respectively: 5.6% and 9.5% 136 Journal of military pharmaco-medicine no6-2019 (p < 0.05, Chi-square test) In particular, mainly local events with redness at the injection site (p < 0.05, Chi-square test), pain at the injection site and swelling at the injection site No systemic events recorded The local events were mild and resolved after - days Adverse events occur within 28 day after vaccination Table 2: Adverse events within 28 day after vaccination in two study groups Adverse events within 28 day after vaccination Control vaccine (n = 504) (n = 252) p Number % Number % 38 7.5 19 7.5 1.000 Fever 33 6.5 13 5.2 0.451 Pain at the injection site 0.8 0.8 1.000 Red at the injection site 0.4 0.4 1.000 Swelling at the injection site 0.4 0.4 1.000 Headache 0.2 0.4 0.617 Arthralgia Chills 0.2 0.4 0.617 Diarrhea 0.2 1.2 0.076 Cough 13 2.6 2.0 0.613 Breathlessness 0.2 Sore throat 1.6 0.8 0.368 Other events 1.0 0.8 0.788 Subjects with events Events MRVAC Within 28 days after vaccination, the incidence of adverse events occurred in both MRVAC and control groups was 7.5% In particular, mainly fever (6.5% and 5.2%), cough (2.6% and 2.0%) Other events appeared at low rates Noted other events such as sore throat, VA inflammation, rash, predominantly occurs in children aged - years The incidence of events in the two study groups was not different (p > 0.05, Chi-square test) Except for two cases with severe and serious events, the rest were mild and self-resolved after - 0.479 days Local events prevailed within 30 minutes but within 28 days after vaccination, systemic events had a higher occurrence rate The incidence of adverse events in our study was higher than single and lower vaccine had the same formula produced in Japan and equivalent to some other MR combination vaccines The study by Doan Huy Hau et al with AIK-C measles strain did not record the rate of local events, fever rate was 3.1%, cough was 6.2% and diarrhea was 0.7% Yamane et 137 Journal of military pharmaco-medicine no6-2019 al’s research with rubella Takahashi did not found adverse events The study by Takeuchi Y et al showed that the prevalence of local events was 2.2%, fever was 25.1%, rash was 21.4% and lymphadenopathy was 3.0% The study by Kumagai T had only cases of mild erythema, case of diarrhea and case of headache, the study by Ozaki T et al only recorded case of mild fever, however the sample size of those studies were small [4, 5, 6, 7, 8] Table 3: Distribution of adverse events occurred within 28 days after MRVAC vaccination by province Hanam (n = 267) Adverse events within 28 day after vaccination % Number % 34 12.7 1.7 0.001 Fever 29 10.9 1.7 0.001 Pain at the injection site 1.5 0.059 Red at the injection site 0.7 0.182 Swelling at the injection site 0.7 0.182 Headache 0.4 0.346 Arthralgia Chills 0.4 0.346 Diarrhea 0.4 0.346 Cough 13 4.9 0.001 Breathlessness 0.4 0.346 Sore throat 3.0 0.007 Other events 1.1 The rate of events in Hanam province was 12.7%, which was significantly higher than Hoabinh province (1.7%), of which the majority of children were in the form of fever, cough, sore throat occupying high rate The cause of this difference may be due to the time of deployment in Hoabinh was from May to June, while in Hanam was from April to May, coinciding with the period of humid, hot-cold erratic in the North, and as a result, young children was 138 p Number Subjects with events Events Hoabinh (n = 237) 0.8 0.752 susceptible with respiratory diseases, contributing to making a difference Serious adverse event - The first case: Male, years old, MRVAC group He had sudden abnormal symptom from 6th day after vaccination with toxic infection syndrome (a fever of 390C, leukocytes were 17.4 x 109/l), gastrointestinal disorder, abdominal wall reaction (±), McBurney’ point (±) Journal of military pharmaco-medicine no6-2019 Preliminary and postoperative diagnosis: Acute appendicitis After surgery, subject recuperate well and was collected M1 blood sample according to the research schedule - The second case: Female, 27 years old, MRVAC group Subjects had variety manifestation from 3rd day after vaccination with moderate fever, severe and prolonged time swelling, redness, pain at the injection site Conclusion: Injection site abscess After taking antibiotics, anti-inflammatory and antipyretic drugs, subjects recuperated and completely cured after month Some serious adverse events associated with MRVAC have been recorded such as hypersensitivity reactions, acute and chronic arthritis, encephalitis, subacute meningitis, Guillain-Barré syndrome, seizures, thrombocytopenia and autism These serious adverse event cases could not relate to vaccines Immunization errors might be culprit of injection site abscess case [9, 10] CONCLUSION Measles and rubella combined vaccine achieved safety requirements with adverse events occurring within 30 minutes, 28 days after vaccination rate was 5.6% and 7.5%, equivalent to MR vaccine manufactured by India Two serious adverse events cases did not associate with vaccines 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, Vol XXVI, (177), pp.98-106 Dang Thi Thanh Huyen, Duong Thi Hong et al Epidemiology of rubella in Vietnam, 2008 - 2012 Vietnam Journal of Preventive Medicine 2015, Vol XXV, (168), pp.216-224 Tran Nhu Duong, Vu Hai Ha et al Epidemiological characteristics of cases of congenital rubella syndrome surveyed at Vietnam National Hospital of Pediatrics, 2011 - 2016 Vietnam Journal of Preventive Medicine 2016, Vol XXVI, 10 (183), pp.35-42 Doan Huy Hau, Dao Xuan Vinh, Dinh Hong Duong et al Evaluation of safety and immunogenicity of the MVVAC manufactering by POLYVAC (phase and 3) Vietnam Journal of Preventive Medicine 2011, Vol XXI, 4, pp.110-117 Yamane Y, Nagashima T, Asahara T et al Studies on the live attenuated rubella virus vaccine III Clinical trials with rubella virus (Takahashi strain) vaccine in children and women Kitasato Arch Exp Med 1974, 47, pp.89-100 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 Kumagai T, Ihara T, Nakayama T et al Reactogenicity and immunogenicity of measles-rubella combined vaccine in schoolentry-aged subjects with naturally acquired measles immunity Pediatr 2015, 57 (4), pp.597-602 Ozaki T, Nishimura N, Gotoh K et al Phases and immunization immunogenicity with combined measles-rubella vaccine Kansenshogaku Zasshi 2011, 85 (3), pp.250-255 WHO Supplementary information on vaccine safety Part 2: Background rates of adverse events following immunization 2000 10 WHO Global Manual on Surveillance of Adverse Events Following Immunization 2014 139 ...Journal of military pharmaco-medicine no6-2019 * Vaccines: Study vaccine: MRVAC vaccine produced by POLYVAC - Ingredients: Each bottle 10 doses of measles vaccine is reconstituted... CONCLUSION Measles and rubella combined vaccine achieved safety requirements with adverse events occurring within 30 minutes, 28 days after vaccination rate was 5.6% and 7.5%, equivalent to MR vaccine. .. trial of combined measles and rubella live attenuated vaccine Infectious Disease Magazine 2002, 76 (1), pp.56-62 Kumagai T, Ihara T, Nakayama T et al Reactogenicity and immunogenicity of measles- rubella