Rotavac 5D Mechanism of Action

Pharmacotherapeutic group: Rotavirus diarrhea vaccines. ATC code: J07BH01.
Pharmacology: Pharmacodynamics: Protective efficacy.
Efficacy: In total 12 clinical trials, approximately ~15000 subjects were vaccinated with different formulations of ROTAVAC vaccines consisting ORV116E as the active ingredient with a virus titer of NLT 10^5.0 FFU. These ORV116E strain containing ROTAVAC formulations (ROTAVAC, ROTAVAC 5C & ROTAVAC 5D) were tested for their Safety, Immunogenicity and Non-inferiority. The adverse reaction and immunogenicity profile observed in subjects administered with these three formulations were similar. ROTAVAC & ROTAVAC 5C formulations were tested for their Lot consistency and Non-interference with EPI vaccines and concluded that ROTAVAC formulations do not interfere with EPI vaccines and their manufacturing consistency was established. Since ROTAVAC 5D has also been evaluated for safety and immunogenicity in comparison to ROTAVAC while being co-administered with EPI vaccines, it is concluded that ROTAVAC 5D formulation is equally safe and immunogenic as ROTAVAC and ROTAVAC 5C. Efficacy, non-interference with EPI vaccines and manufacturing consistency of ROTAVAC and ROTAVAC 5C formulations can be extrapolated to ROTAVAC 5D formulation.
ROTAVAC (ORV 116E): A Multi-center clinical study was conducted in India to evaluate the efficacy of ROTAVAC to prevent severe rotaviral gastroenteritis. Data for vaccine efficacy has been presented for the first year and second year of life. The results of these two analyses were similar, suggesting that the vaccine efficacy persists into second year of life.
Vaccine efficacy (VE) for severe non-vaccine RVGE was 56.4% [95% CI 36.6, 70.1] and 34.6 [95% CI 19.7, 46.6] for non-vaccine RVGE of any severity, during the first year of life. In the same study, the VE against severe non-vaccine RVGE in the second year of life was 49% (95% CI 17.5, 68.4) and 35.0% [95% CI 19.1, 47.7] against non-vaccine RVGE of any severity. Non-vaccine RVGE requiring hospitalization and of any cause ROTAVAC prevented 47.7% (95% CI: 24.5, 63.8) of all hospitalization ≥24hrs due to severe non-ROTAVAC vaccine rotavirus gastroenteritis. ROTAVAC was also efficacious against severe GE of any etiology (VE=18.6% [95% CI 1.9, 32.3]).
EPI - noninterference study & Lot to Lot consistency: Post-vaccination, seroprotective level of antibodies against poliovirus type 1,2, and 3 were 98.2%, 99.4% and 92.4%, respectively, in infants receiving OPV along with ROTAVAC and 99%, 98.3% and 92.7%, respectively, in infants receiving OPV along with placebo. Difference in proportions between these groups was 0.8% (95% CI -1.1%, 2.2%) for type 1 strain, -1.2% (95% CI -3.3%, 0.2%) for type 2 strain and 0.3% (95% CI -3.5%, 3.6%) for type 3 strains of polio virus. Almost all infants, irrespective of the treatment group, developed protective antibody titre against diphtheria toxoid, tetanus toxoid and Hib (anti-PRP antibodies). Over 93% developed protective titre against HepB (anti-HBs antibodies).
The difference in proportion of infants who developed protective antibody titres was 0.5% (95% CI -1.3, 2.3) for diphtheria toxoid, 0.9% (95% CI -0.3, 2.4) for tetanus-toxoid, 2.2% (95% CI -1.7, 6.0) for anti-HBs antibodies and 0% (95% CI -1.3, 1.1) for anti-PRP antibodies. The ratio of GMCs between the placebo and ROTAVAC groups for pertussis toxin was 1.0 (95% CI: 0.8, 1.1).
The baseline and post 3^rd dose vaccination GMTs of IgA antibodies according to lot of ROTAVAC; Baseline GMT was similar across the three groups (2.7-2.8); post vaccination GMTs had a rise of 10.8 from 8.5.
ROTAVAC 5C (ORV 116E): There were no statistically significant differences in the pre- and post-vaccination IgA titers between the ROTAVAC 5C and ROTAVAC (mean baseline titer 22.3 and 24.2 U/mL respectively (p=0.84 comparing all arms); and post vaccination titer 59.1 and 76.0 U/mL, respectively (p=0.12)).
Seroconversion occurred by day 84 in 37.6% (95% CI: 31.1%, 44.2%) of the ROTAVAC 5C arm, and 41.3% (95% CI: 34.7%, 47.8%) of the ROTAVAC. There was no significant difference in seroconversion rates between the ROTAVAC and ROTAVAC 5C (p=0.489).
EPI - noninterference study & Lot to Lot Consistency: In the immunogenicity population, all three lots of ROTAVAC 5C were non-inferior to the ROTAVAC with the lower bound of the 95% confidence interval for the GMT ratio (ROTAVAC 5C/ROTAVAC) being greater than 0.5: Lot 1 GMT ratio 1.069 (95% CI 0.827 to 1.382; p<0.0001); Lot 2 GMT ratio 1.096 (95% CI 0.840 to 1.429; p<0.0001) and Lot 3 GMT ratio 1.129 (95% CI 0.867 to 1.471; p<0.0001). When all lots were combined, the GMT ratio was 1.097 (95% CI 0.888 to 1.357; p<0.0001).
There were no statistically significant differences in the pre- and post-vaccination IgA titers between the ROTAVAC 5C and ROTAVAC arms (mean baseline titer 24.0, 23.6, 21.5 and 28.5 for ROTAVAC 5C Lot 1, 2 and 3; and ROTAVAC, respectively; p=0.7275 ANOVA comparing the four arms).
There was no difference in the GMT titers between ROTAVAC 5C (all lots) and ROTAVAC -20°C for Bordetella pertussis, Diphtheria, Haemophilus influenzae type B, Hepatitis B or Tetanus (the lower limit for all was >0.50). There was no difference between lots for any of the vaccines. Thus, ROTAVAC 5C can be successfully co-administered with other childhood vaccines.
ROTAVAC 5D (ORV 116E): There were no statistically significant differences in the pre and post vaccination IgA titers between the ROTAVAC 5D and ROTAVAC (mean baseline titer 10.31 and 11.57 U/mL respectively (p=0.29 comparing all arms); and post vaccination titer 18.70 and 19.55 U/mL, respectively (p=0.77)).
Four-fold Seroconversion occurred by day 84 in 22.18% (95% CI: 17.01%, 27.35%) of the ROTAVAC 5D arm, and 21.25% (95% CI: 12.29%, 30.21%) of the ROTAVAC. There was no significant difference in seroconversion rates between the ROTAVAC and ROTAVAC 5D (p=0.86).
Post-marketing surveillance data: Post-marketing surveillance has been carried out for the Rotavirus 116E strain-based vaccine ROTAVAC and no significant safety signals of concern have been noted thus far.
Pharmacokinetics: Evaluation of pharmacokinetic properties is not required for vaccines.
Toxicology: Pre-clinical safety data: Repeated dose non-clinical toxicity study on oral rotavirus candidate vaccine 116E live strain was carried out in mice, rats and rabbits. These studies were initiated with 0.5 mL formulations and later on in continuation of developing formulations with buffer wherein the dose volume is 1.5 mL and 2.0 mL (ROTAVAC 5C) were subjected for pre-clinical toxicology studies. In both the cases, the excipients used were same except for concentration used. ROTAVAC 5D is having similar excipients as in ROTAVAC 5C but only difference is the concentration. Dose volume, concentration of buffer system and excipients were tested in animal model for toxicity and found to be safe. The pre-clinical safety data establish the safety of the vaccine for ROTAVAC 5D formulation.