Made-in-India Rotavac: triumph of a 3-decade-long effort

The idea for an Indian rotavirus vaccine took birth in the mid-1980s when two independent groups of researchers spotted two unusual strains of rotavirus that infected newborns in hospital nurseries without making them sick. At the All India Institute of Medical Science, Delhi, M K Bhan discovered one of those strains (116E) during his routine testing of newborns. Down south, at the Indian Institute of Science, Bengaluru, C Durga Rao stumbled upon a similar strain (1321) at hospitals in Bengaluru and Mysuru.

The neonatal strains of 116E and 1321 showed much promise for use as vaccines because all of the infants naturally infected with these strains demonstrated a strong immune response to rotavirus when they were exposed to the pathogen again. None of them experienced severe diarrhoea. Both of these strains included genetic elements from human and bovine rotavirus strains. The disease-causing component of the human virus had been swapped with a strain of rotavirus that only infects cows, which is likely why the infants didn't experience any symptoms of illness.

Both teams roped in foreign partners for further research. Bhan brought in Roger Glass, a diarrhoeal expert working at the Atlanta-based Centre for Disease Control's rotavirus laboratory (he has since moved to the US National Institute of Health's (NIH) National Institute of Allergy and Infectious Diseases). Durga Rao sought out Stanford University's Harry Greenberg for collaboration.

For more than two decades, the two research teams worked in parallel under the Indo-US Vaccine Action Programme, initiated in 1987 by the Department of Biotechnology (DBT) and NIH/NIAID. The aim was to study the two different naturally occurring, weakened strains and develop new rotavirus vaccines for infants. In the absence of any industrial facility to produce clinical-grade vaccine, NIH contracted US-based DynCorp to produce pilot lots of the vaccine in 1997. The vaccine was evaluated on US adults and children before shipping to India. In 1998, the VAP looked for commercial partners in India and found a Hyderabad-based start-up Bharat Biotech that agreed to take up the next stage of development.

It's important to know the history behind the rotavirus vaccine because it is the first truly Made-in-India product. From research and product development, everything happened on home soil. Several scientists have compared it with the achievements of ISRO building a vibrant space programme from scratch.

In 2000, a consortium of partners, including Bharat Biotech, Centre for Disease Control, Atlanta, NIH, AIIMS, Stanford University and IISc, submitted a proposal to DBT and the non-governmental outfit PATH for support to move the two vaccine candidates through production, testing and surveillance. Three years later, the consortium decided to try both candidates in phase-1 trial, which began in May 2003 at AIIMS.

The institute completed the trial with children in May 2004 and with infants in May 2005. The results showed both vaccines had comparable safety and viral shedding profiles, but the 116E strain provided greater immunity to diseases (36.6% of 116E recipients as against 15.4% of 1321 recipients). Subsequently, the consortium decided to focus all efforts only on the 116E vaccine candidate.

The second phase of the trial was initiated in November 2006 with two different dosages on 369 infants. The results came in February 2008, with no safety concerns identified. The vaccine produced a robust immune response in 89% infants after the third dose at the higher dosage level. This paved the way for the third phase of the trial, which finally began in March 2011.

The last phase of trial involved 6,799 infants at three sites in Delhi, Pune and Vellore. A DBT institute (Translational Health Science and Technology Institute) was chosen for data analysis and there was a contract research organisation (Quintiles) to monitor the trial sites. Published in the Lancet in May 2015, the phase-III clinical trial demonstrated 55-60% efficacy, which the scientists said was good enough to go ahead with the commercialisation plan. The maximum efficacy was seen in the first year when babies are most vulnerable. Though the trial was not designed to check mortality reduction, a 20% drop was found in the group receiving the vaccine.

After nearly three decades of developmental journey, the vaccine Rotavac, finally entered the market in 2015. Within a year, it made an entry into the Union health ministry's Universal Immunisation Programme in four states, and in 2017, the ministry extended it to five more states. Soon, it will be introduced in the 10th state - Jharkhand.

The vaccine's footprint is set to expand outside India. In January, it received the World Health Organisation's pre-qualification certificate, making it eligible for purchase by global agencies like UNICEF and GAVI to tackle killer diarrhoea in other nations. African nations like the Democratic Republic of Congo and Angola can look at the Indian vaccine as a cheaper option to tackle the disease burden.

Rotavirus is the leading cause of severe diarrhoea and death among children less than five years of age around the world. According to a recent study, nearly 37% of 760,000 childhood diarrhoeal deaths in 2013 were due to rotavirus. India accounts for 20-25% of global deaths. Because of its strong public health impact, rotavirus vaccination has always been recommended by the WHO.

It's not that there are no other vaccines. There are currently two other licensed rotavirus vaccines that have been introduced in more than 40 countries. But these two vaccines - Rotarix (GSK) and RotaTeq (Merck), produced by two pharmaceutical giants - remain out of reach for many in the developing world. A second Indian vaccine from Serum Institute of India has also come out, though its efficacy is lower.

Bharat Biotech claimed it would supply the vaccine to the developing world at a cost of $1 per dose, with the feasibility of a further 30% price reduction, if the procurement is more than 100 million doses.

What remains to be seen is whether the Made-in-India vaccine can lead to another price war among vaccine manufacturers, similar to the battle witnessed on the Hepatitis-B vaccine almost two decades ago.

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