Advancing Rotavirus Vaccine Development (ARVAC) - BBIL Phase 3 Study

PATH?s Advancing Rotavirus Vaccine Development (ARVAC) project, the Indian Department of Biotechnology (DBT), and Bharat Biotech International, Ltd. (BBIL) conducted a Phase 3 efficacy study of BBILs 116E (ROTAVAC®) rotavirus vaccine, and an Expanded Program on Immunization (EPI) non?interference/clinical lot-to-lot consistency study has also been successfully completed. After the Phase 3 efficacy trial accumulated cases faster than expected by October 2012, the study?s Project Management Committee performed the primary analysis of efficacy and safety in February 2013, with approval of the study?s Data Safety Monitoring Board (DSMB). The DSMB determined that the trial met the highest standards for ethics and safety, the vaccine demonstrated an excellent safety profile, and efficacy was 56 percent against severe rotavirus gastroenteritis during the first year of life, meeting the pre-defined success criterion and falling within the same range of Rotarix® and RotaTeq® efficacy in developing-country populations. The data also demonstrated that ROTAVAC® did not interfere with immune responses to oral polio vaccine. The DSMB concluded that the clinical trial results warranted an application for early licensure with the Central Drugs and Standards Control Organization headed by the Drugs Controller General of India (DCGI). In January 2014, the DCGI approved licensure of ROTAVAC® for use among infants in India. The study partners published first-year efficacy data for ROTAVAC® in The Lancet in March 2013 and second-year efficacy data in Vaccine in August 2014 as part of a supplemental issue entitled ?Rotavirus in India: An update on epidemiology and vaccines.? The supplement also included an article on active surveillance for intussusception conducted during the Phase 3 study. In March 2015, the Government of India formally launched ROTAVAC® in the private market for India, at a ceremony led by the Indian Prime Minister. A year later, in March 2016, the Government of India introduced ROTAVAC® into the public sector immunization program of four states (Andhra Pradesh, Haryana, Himachal Pradesh, and Odisha) to initiate a phased national rollout. This marked a tremendous milestone resulting from a decades-long partnership between BBIL, PATH, the Government of India, local research institutions, and others to study, license, and ultimately introduce the vaccine in India. The Phase 3 EPI non-interference, lot-to-lot consistency study of ROTAVAC® which was launched in May 2014 at the Centre for Health Research and Development at SAS in New Delhi has been successfully completed. The study team enrolled a total of 1,356 infants in the trial, and laboratory analysis of samples was conducted at THSTI, Enterovirus Research Centre, and Super Religare Laboratory. Upon completion of the study, we worked with BBIL to provide significant input on the preparation of the clinical study report. The three Rotavac lots were proven to be not different as statistical clinical equivalence among them were established and Rotavac can be safety administered with pentavalent vaccine and oral polio vaccine without diminishing the serum antibody responses to each component of these vaccines. The results of the non-interference component of the study have been submitted to Vaccine Reports and is under review. BBIL submitted a prequalification dossier to WHO in February 2016, including files on the two ARVAC-P3-supported studies. Links to three most important published, peer reviewed articles are listed below: Article 1: Published in LANCET: Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind,placebo-controlled trial Link: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62630-6/abstract Article 2: Vaccine Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life Link: http://www.sciencedirect.com/science/article/pii/S0264410X14006185 Article 3: Vaccine Active surveillance for intussusception in a phase III efficacy trial of anoral monovalent rotavirus vaccine in India Link: http://www.sciencedirect.com/science/article/pii/S0264410X14004058

Each year, an estimated 1.8 million children worldwide die from severe, dehydrating diarrhea, and millions more are hospitalized. Diarrheal illness due to rotavirus causes more than 500,000 of these deaths each year, up to 85 percent of which are in the w orld?s poorest countries. Although two commercial rotavirus vaccines have been demonstrated to be safe and effective in certain populations, they are not yet widely available or affordable for the developing world. The forthcoming announcement of the reco mmendation by the World Health Organization?s (WHO?s) Strategic Advisory Group of Experts on Immunization (SAGE) for global use of rotavirus vaccines is expected to further increase demand, but these barriers to access will remain. To address this, it is critical that a mature market for rotavirus vaccines develop as quickly as possible, including manufacturers from both developed and developing countries. PATH will work closely with Bharat Biotech International Limited (BBIL) and the Department of Bio Technology (DBT) to complete late-stage clinical development of 116E, leading to licensure of the vaccine in India and WHO prequalification. The RCN-funded project will support the phase 3 efficacy trial at the New Delhi site conducted by Society for Appl ied Studies (SAS). There are two other sites in Pune and Vellore, supported by PATH and DBT. In addition to the efficacy trial, there are also complementary studies to determine: the vaccine?s non-interference with the Expanded Programme on Immunizatio n (EPI) schedule, consistency of the vaccine across three clinical lots, and the vaccine's safety at the highest titer at release.