Phase III randomized clinical studies to evaluate the immunogenicity, lot-to-lot consistency, and safety of ROTAVAC? liquid formulations (ROTAVAC 5C & 5D) and non-inferiority comparisons with licensed ROTAVAC? (frozen formulation) in healthy infants

The WHO pre-qualified rotavirus vaccine, ROTAVAC (R), is derived naturally from the neonatal 116E rotavirus strain, and stored at -20 degrees C. As refrigerator storage is preferable, immunogenicity and safety of liquid formulations kept at 2-8 degrees C, having excipients to stabilize the rotavirus, with or without buffers, were compared with ROTAVAC (R) in different clinical studies. Study-1, the pivotal trial for this entire product development work, was a randomized, single-blind trial with two operationally seamless phases: (i) an exploratory phase involving 675 infants in which two formulations, ROTAVAC 5C (LnHRV-1.5 mL and LnHRV-2.0 mL) containing buffer and excipients to stabilize the virus against gastric acidity and temperature, were compared with ROTAVAC (R). As the immune response of ROTAVAC 5C (LnHRV-2.0 mL) was non-inferior to ROTAVAC (R), it was selected for (ii) confirmatory phase, involving 1,302 infants randomized 1:1:1:1 to receive three lots of LnHRV-2.0 mL, or ROTAVAC (R). Primary objectives were the evaluation of non-inferiority and lot-to-lot consistency. The secondary objectives were to assess the safety and interference with the concomitant pentavalent vaccine. As it was separately established that buffers are not required for ROTAVAC (R), in Study-2, the safety and immunogenicity of ROTAVAC 5D (R) (with excipients) were compared with ROTAVAC (R) and lot-to-lot consistency was assessed in another study. All lots elicited consistent immune responses, did not interfere with UIP vaccines, and had reactogenicity similar to ROTAVAC (R). ROTAVAC 5C and ROTAVAC 5D (R) were immunogenic and well tolerated as ROTAVAC (R). ROTAVAC 5D (R) had comparable immunogenicity and safety profiles with ROTAVAC (R) and can be stored at 2-8 degrees C, leading to WHO pre-qualification.Clinical Trials Registration: Clinical Trials Registry of India (CTRI): CTRI/2015/02/005577CTRI/2016/11/007481 and CTRI/2019/03/017934.