Courtesy of Sam Jaffe
Angela Howard was concerned when her infant daughter stopped crying, despite repeated jabs with an IV needle. The child was dehydrated after three days of severe diarrhea and vomiting. A surgeon at the Philadelphia area hospital inserted an IV line into the child for fluid replenishment. Eight hours later, she was fully hydrated and almost back to normal.
Five thousand miles away in Janta Jeevan, India, 5-year-old Pooja also had sudden, severe diarrhea. Her grandfather spent the entire day filling out forms at the hospital, and the nurses weren't able to examine the child until the next day. He returned and handed his granddaughter to a doctor, who immediately recognized the severity of her dehydration. As the doctor inserted an IV into the girl's arm, her eyes rolled back in her head. She was dead.
While the two children on opposite ends of the world had different outcomes, both were fighting rotavirus. The circular virus enters epithelial cells lining the intestinal tract and causes severe diarrhea. It kills more than 600,000 children a year, most in developing countries such as India, and it is the number-one cause of infection-related deaths in infants worldwide. In the United States, the virus is mostly an economic threat, costing the health care system almost $2 billion a year in hospitalization costs. "In the developing world, rotavirus is a killer," says Roger Glass, head of the gastroenterological division of the US Centers for Disease Control and Prevention (CDC). "In the US, it's more a question of reducing hospital bills." In both worlds, the cheapest and most effective way to combat the disease is through vaccination.
A handful of rotavirus vaccines are in clinical trials, and some are closer to approval than others, particularly in developing nations. The first of the new vaccines, Rotarix, made by GlaxoSmithKline (GSK) Biologicals, was launched in Mexico in January. Merck's RotatEq may be ready for US Food and Drug Administration review by the second quarter of 2005. Three other vaccines are undergoing Phase II trials in India and could get regulatory approval there within three years. Another vaccine is already in use in China.
Getting final approval for the new vaccines won't be simple, but the stakes are high. Rotavirus vaccines are potentially a billion-dollar market. In 1999, less than a year after FDA approval, Wyeth pulled its RotaShield vaccine off the market after it was linked to an increased risk of intussusception, a rare but potentially life-threatening condition in which the bowel becomes blocked after it slides in on itself like a collapsing telescope. There were roughly 100 cases of intussusception associated with the vaccine according to the CDC, and the company had to write off more than $100 million in development costs. The newer vaccines each have their own unique histories and corporate or governmental shepherds. What they all need to show is that they are free from side effects.
"The tragedy of RotaShield is that it raised the bar for future approvals incredibly high," says Al Kapikian, who created RotaShield at the National Institutes of Health and has since created several other experimental vaccine candidates. "Maybe that's a good thing. Maybe we'll end up with the safest possible vaccine. Or it will cause some good vaccines to get lost in the regulatory machinery."
ROTARIX AND ROTATEQ
READY TO PRODUCE:
Courtesy of Bharat Biotechnologies International LTD
A biorefinery at Bharat Biotechnologies' new rotavirus vaccine manufacturing plant.
Rotarix is a two-dose live attenuated vaccine that contains elements of several human strains of the virus. The technology that GSK Biologicals used to make the vaccine isn't novel. What's new about Rotarix is that it will be rolled out without the approval of the FDA or the European Agency for the Evaluation of Medicinal Products. That's unusual, considering that major vaccines and drugs typically go through one of those two agencies. "I can't remember any medical treatment being done this way in the 30 years that I've been in this business," says Bruce Innis, a senior vice president at GSK Biologicals, who helped to oversee the vaccine's development.
Although some of the Phase III trials involving 60,000 infants were conducted in Finland, GSK hasn't asked Finnish authorities for approval. Instead, the trials were done under the auspices of the Mexican government, for approval in Mexico and other Latin American countries. GSK is trying to target an emerging middle class that supports a private healthcare industry. "There used to be only one choice: Charge the rich countries a lot to subsidize vaccine production for the poor countries," says Philippe Monteyne, a vice president for GSK Biologicals. "Now there's a whole new buyer which represents hundreds of millions of people in Latin America and Asia. They have the means to spend a moderate amount of money to improve the health of their children, and that's high on their list of priorities."
The strategy was successful in that the Phase III trial had promising results. Of the 30,000 infants given the vaccine in the trial, only six cases of intussusception were reported. Of the same number of children in the control group who were given a placebo, only seven cases of intussusception were reported. As a result, the Mexican government approved RotaRix and it went on sale in January of 2005 "We're now before review bodies in dozens of other countries in Latin America and Asia," says Monteyne. "Eventually we'll approach Europe for approval, but only after we've established ourselves in the countries with greatest need."
VACCINES IN DEVELOPMENT
GSK executives expect that Rotarix will be given to several hundred thousand children in Mexico in 2005. They won't reveal the price charged to the Mexican public health authorities or to private doctors.
Merck has taken a more traditional approach with RotaTeq and is focusing its efforts on the US market alone. Phase III trials for RotaTeq have concluded, and the preliminary results suggest that it prevents severe rotavirus infections without causing serious side effects such as intussusception. RotaTeq is a bovine reassortment vaccine consisting of a capsid shell derived from a bovine strain, and several proteins taken from human versions of the virus.
Merck recently accelerated its schedule for FDA approval of RotaTeq. It had been expecting to apply for approval by 2006, but in light of the positive trial results, it will submit its application in the second quarter of 2005, which means it could have a full rollout in the United States by the end of the year. It will still be several years after a US launch before the company launches the product in developing nations.
VACCINE DEVELOPMENT IN INDIA
Developers in India are trying a different type of vaccine, based on strains isolated from infants in the late 1980s. M.K. Bhan, then at the All India Institute of Indian Medical Sciences in Delhi, and C. Durga Rao, a microbiologist at the Indian Institute of Sciences in Bangalore, each isolated strains of a rotavirus that was sweeping through India. Babies infected with those strains tested positive for rotavirus but had no diarrhea.
Both teams found that large portions of the strains' genetic sequence were identical to a bovine form of the virus. "We immediately recognized that this could be an ideal vaccine candidate," says Rao. "Because it's a natural virus, it should be easy to manufacture. It immunizes the child against future severe bouts of rotavirus-related diarrhea without causing diarrhea in the first place." Bhan notes that they do not expect intussusception as a side effect, because no data have shown that the natural neonatal virus leads to increased risk of intussusception.
Despite the promise of the two strains, called 116E (Bhan's strain) and I321 (Rao's strain), the samples sat on lab shelves for a decade, because no company was willing to take a chance on the project. That changed in 1999, when Krishna Ella stood up at a medical meeting and announced that his company, Hyderabad-based Bharat Biotechnologies, would create a rotavirus vaccine. It was a bold move as the company was only two years old and had just begun to manufacture its first product, a hepatitis B vaccine. Ella had fewer than a hundred employees and no experience in live vaccine development.
Today, Bharat Technologies employs 350, and it has a $10 million factory dedicated to cranking out a live rotavirus vaccine. It will soon be producing three different vaccines, the two Indian strains and a third strain that Bharat recently licensed from the NIH. The vaccines are being used in clinical trials that have just begun (earlier safety trials had already been performed in the United States). Phase II trials have just begun in India for all three vaccine candidates. The best performer of those three will become Bharat's new rotavirus vaccine and could be a low-cost competitor to Rotarix and RotaTeq.
Both Bhan and Ella say they believe that a full rollout in India can begin within three years, assuming that at least one of the three candidates is successful in a Phase III trial. "There used to be no infrastructure for clinical trials in India," says Bhan. "Now that we've built that, we can complete all three rounds of trials in three years, where it takes a minimum of five years in the West. And we can do it at a fraction of the cost."
Cutting expenses is crucial when it comes to providing a vaccine for a country like India. Forty million newborns need to be vaccinated every year, and the government can afford to spend only a few dollars per inoculation. That's why Bhan hopes that Bharat and other homegrown biotechs can hit the threshold of $1 per dose. "Western countries can afford to spend $40 a dose," says Bhan. "We can't."
Although Bharat officials think they can hit the $1 mark, they don't have the same advantages that other Indian industries offer. "Yes, salaries are cheaper in India, but the real expense of making vaccines is in capital expenses – equipment and buildings – and we have no competitive edge over European or American companies there," says V.J.A. Harsha, director of the rotavirus effort at Bharat. Instead, Ella has devised a business plan to cut development costs by doing all the clinical trials in India and diluting the cost of equipment purchases by applying for grants from nonprofit organizations such as the Gates Foundation.
Once a rotavirus vaccine is rolled out in India, it could then be distributed in other Asian countries as well. "There's no reason that we can't become the global leader in this market," says Harsha. "Once we master the production techniques and prove that we have a safe and effective vaccine, we think we can compete with the biggest firms." The competition could drag prices down to historic lows. "Yesterday, we didn't have any rotavirus vaccines, " says the CDC's Glass. "Very soon we'll have a multitude from which to choose."