The US scientist Roger Glass.  Glass and M.K. Bhan got back with a glimmer of a road map for an affordable vaccine made in the country that could cut in half the 100,000-odd infant, diarrhoeal deaths in India. The work would stretch out over the rest of their careers and involve at least 10 research institutions across the world. Photo: Ramesh Pathania/Mint (Ramesh Pathania/Mint)
The US scientist Roger Glass. Glass and M.K. Bhan got back with a glimmer of a road map for an affordable vaccine made in the country that could cut in half the 100,000-odd infant, diarrhoeal deaths in India. The work would stretch out over the rest of their careers and involve at least 10 research institutions across the world. Photo: Ramesh Pathania/Mint

(Ramesh Pathania/Mint)

The making of Rotavac

Rotavac is effective in preventing severe rotavirus diarrhoea in low-resource settings in India

New Delhi: About 30 years ago, an American and an Indian, both scientists, weary after a day-long conference on diarrhoeal diseases, slipped out from the Kolkata convent they had been billeted in for a drink.

Roger Glass and M.K. Bhan got back with a glimmer of a road map for an affordable vaccine made in the country that could cut in half the 100,000-odd infant, diarrhoeal deaths in India. The work would stretch out over the rest of their careers and involve at least 10 research institutions across the world.

Glass credited Bhan, then an assistant professor at the All India Institute of Medical Sciences (AIIMS), with noting that in spite of a particularly widespread outbreak of rotavirus infections at the hospital, none of the children developed diarrhoea.

“That was an intriguing find for me because I was working with a group (in the US) studying similar strains found from four other continents and here was one more strain that infected children, but didn’t make them sick and that could mean a potential vaccine," Glass said.

The most common strain of the rotavirus is the so called strain A and there are six further sub-types that are commonly found in India. Rotaviruses, identified in 1973, are ubiquitous and so resilient that they cannot be eliminated even with exacting hygiene standards.

Though researchers at AIIMS and the US realized that there was something unusual about the Delhi strains, they couldn’t figure out what it was. After extensive tests at the US Centers for Disease Control and Prevention (CDC), it turned out that the strain defied smooth classification because it had a bizarre mutation, with a single segment of its genes containing a protein of bovine origin.

“It’s surprising because you rarely find such animal-sourced genes in rotavirus strains that infect humans and to think that such a re-assortment had happened naturally was unusual," said Bhan, who in 2012 stepped down as the secretary to the department of biotechnology, “That meant this particular strain was toxic to cows but not babies."

Rotavirus infections though well understood as a cause of severe diarrhoea aren’t usually lethal. However, they were a global health problem because they were a key contributor to hospitalization. That’s why they are of as much interest to developed as well as developing countries.

The Global Enteric Multicenter Study (GEMS) that enrolled more than 20,000 children from seven sites across Asia (including India) and Africa said in a study published in Lancet last week that rotavirus was the leading cause of diarrhoeal diseases among infants under 11 months across all sites and identified other top causes for which additional research is urgently needed. GEMS evaluated nearly 40 pathogens to map each one’s relative contribution to diarrhoeal disease. Combining data from all seven study countries, GEMS found that one in five children under the age of two suffers from so-called moderate-to-severe diarrhoea each year, which increased children’s risk of death 8.5 times and led to stunted growth over a two-month follow-up period.

According to the CDC website, rotavirus was responsible for more than 400,000 doctor visits each year in the US in the pre-vaccine period; more than 200,000 emergency room visits; 55,000 to 70,000 hospitalizations; and 20 to 60 deaths in children younger than five years of age.

Vaccines have been around since 1996, when three pharmaceutical multinationals launched products aimed at the rotavirus.

But while reducing deaths from 40 a year to less than 5 in developed countries, this has meant little for thousands of Indian children born to poor families, costing 2,000-2,500 for a course.

The government, which provides subsidized vaccines for polio, tuberculosis, diphtheria and tetanus and Hepatitis B, doesn’t include rotavirus vaccines as part of its immunization programme.

“Because we felt that the western vaccines weren’t going to be affordable for most Indians anytime, I was adamant that, because we had a promising strain, we had to get our own vaccine out," said Bhan.

After their Kolkata meeting, Bhan and Glass informally collaborated for three years and finally got funds from the Indo-US Vaccine Action Program (VAP) that was set up to develop products for dealing with infectious diseases relevant to India.

By 2000, not one but two promising strains from India—one independently discovered by a team of scientists at the Indian Institute of Science (IISc) from hospitals in Bangalore and Mysore—were ready to be made into potential vaccines by a massive network of institutions that also included Stanford University, Hyderabad-based Bharat Biotech, and international non profit PATH (Program for Appropriate Technology in Health). The two strains, 116e and I321 (the latter being the AIIMS one), were formulated as vaccines and tested in infants at AIIMS in 2003.

“It wasn’t extremely novel science but it was demanding and challenging," said Bhan. “What was important was that this was that rare occasion when a phase-1 trial for a potential vaccine was being done in India."

The traditional Indian approach to providing vaccines is to source tried and tested products from the West, manufacture them in government labs and then disseminate them through government hospitals and private channels.

“This was 1999. At that time we had never really made commercial grade vaccines before," said Krishna Ella, chairman and managing director, Bharat Biotech. “We were a little more familiar with the Hepatitis B vaccine, and that uses an entirely different approach, but this was a new thing for us."

Making the rotavirus vaccine involved the oldest, albeit still challenging, method—live attenuated vaccine manufacture. This involves developers taking the wild potent strain and growing it in specialized, living cells. These cells provide a hostile environment for the rotavirus and the principle is that the organism, in an effort to survive and adapt, is significantly weakened and loses its virulence. These attenuated cells are then kept in vials before being shipped for medical use.

“In fact they (Bharat) had a temporary disaster," recalled Glass. “It turned out that the vaccine strains they were preparing got contaminated with a bacterium called Mycoplasma and all that they had developed and prepared had to be thrown out."

A team of CDC scientists had to rush to Hyderabad, where they sought to revive the virus strains enough to make them fit for vaccine production, he added. “These are all the challenging parts of vaccine development and you couldn’t have improved your manufacturing techniques and processes if you haven’t had such experiences," said Bhan.

With two strains finally bottled as vaccine candidates, initial or Phase-1, trials began at AIIMS in May, 2003. By 2005, it was clear that one of the strains—116E, isolated by Bhan and his colleagues at AIIMS—had almost twice the protective effect than that of the IISc strain.

“After that we decided to concentrate all our resources on taking one strain forward and this was a big gamble because GSK and Merck were almost ready with their vaccines," said Bhan.

After a relatively quick phase-2 trial that finished in 2008 where the team determined the necessary quantity of vaccine that would be needed to generate an effective measure, a much larger group of scientists—from the Society for Applied Studies, Delhi, Christian Medical College, Vellore, and KEM Hospital, Pune—geared up for the most daunting challenge yet, the so-called Phase-3 trials.

In Phase-3 trials, medicines are tested on people at a scale that’s 10 or 100 times more than phase-2 trials—the comparable GSK trial involved 70,000 children—and these are placebo controlled. This meant that some of the children whose parents agreed to have them participate would get the vaccine and others wouldn’t. That would be the only way to determine whether the effect was solely due to the vaccine and not other reasons, such as say improved health care, better sanitation etc.

“Unlike most trials that are in hospital setting, in this case we had to go out to the communities, recruit appropriate volunteers, and monitor their progress. There aren’t many places that have stable populations, where you can recruit patients and where the populations trust the research groups and are willing to work with them," said Gagandeep Kang, a senior gastroenterologist at CMC and among the lead coordinators of the trial. “If you have somebody cold call you and ask if your child would be given an unknown solution, would you take it?"

Kang, who’d been preparing since 2005 for the phase-3 trial that would actually only begin in 2011, likened the exercise to “a military operation". Thus, across the three cities—Delhi, Pune and Chennai—7,000 or so participants were given mobile phones and connected to a dedicated call centre by which they could report sicknesses, complications etc almost immediately to the team of monitoring doctors.

“Usually trials are managed by the clinical trial companies," said Sai Prasad, vice-president, Bharat Biotech. “In our case, the tables were flipped. The doctors and academicians were at the frontline and the clinical trial company was involved with the monitoring, and quality control."

Kang added that the data was unquestionable. “As a template for how a clinical trial ought to be done, I don’t see how it can be done better."

So confident are the developers about the vaccine that the results of the Phase-3 trial were announced, unusually enough, at a widely publicized media event on 14 May, 2013 rather than published in a peer-reviewed journal.

“We thought about that long and hard," said Kang. “There’s no question that there will be a peer-reviewed paper but this was on the recommendation of the independent Data Safety Monitoring Board."

The board, according to a press statement by the DBT (Department of Biotechnology), said the vaccine, which was named Rotavac, had an “excellent" safety profile. It was efficacious in preventing severe rotavirus diarrhoea in low-resource settings in India and significantly reduced such diarrhoea by more than half or 56% during the first year of life with protection continuing into the second year. Moreover, the vaccine also showed impact against severe diarrhoea of any cause.

The board, according to Kang, said the findings were “extremely important" and ought to be publicised as soon as possible.

Rotavac would as effective as commercially available vaccines, Bhan said.

However, better healthcare and nutrition available in developed countries means that the vaccine appeared more efficient there than in developing countries, he added.

“That’s why rotavirus vaccines in the West have an efficacy of around 80%," said Bhan. “Were Rotavac administered in similar settings, it would show similar numbers (around 80%) than the 60% and 56% we’ve obtained in our clinical trials among poor colonies in India."

Given that the risk of secondary infections are the same, the extremely low cost of the vaccine ($1 per dose and, $3 for whole course) means that it is absolutely essential for India’s health programme, Bhan added.

However, a major side effect of rotavirus vaccines, bowel constriction, hasn’t been entirely detailed in the case of the indigenous Rotavac and will be known only in subsequent stages of monitoring, Bhan said.

Ella said his company will be approaching the Drug Controller General of India in July for approval to produce the vaccine. It would take at least a year for commercialization of the product, he said. “We’ve invested about 60 crore in this project and hopefully Rotavac will be popular not only in India but in several developing countries that face problems with diarrhoeal infections," Ella said.

Independent experts said that 60% efficacy was a promising enough result to go ahead with developing a vaccine, provided there were no additional side effects.

“It’s an encouraging number," said T.S. Balganesh, who leads a CSIR (Council of Scientific and Industrial Research) effort to develop new drugs for tuberculosis. “But that has to be seen in the light of the costs, side effects, ease of administering the vaccine etc."

He added that the presence of established vaccines could mean that doctors would rather recommend those than bet on a new one.

However Bhan said that such concerns were unlikely to arise.

“Globally, there’s a shortage in vaccine manufacturing supply and all that I, or this programme cares about, is that India’s poor must be able to access this medicine. That will happen come what may."

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