5 Questions: Harry Greenberg on the rotavirus vaccine

Harry Greenberg

Rotavirus is a severe diarrheal disease that accounts for more than 500,000 deaths among children annually in the underdeveloped world. On June 16, the New England Journal of Medicine published results from a large study of a second-generation vaccine against rotavirus along with a commentary by Harry Greenberg, MD, senior associate dean for research at the Stanford University School of Medicine.

A professor of microbiology and immunology and of medicine, Greenberg was the lead inventor of the first-generation rotavirus vaccine, licensed for pediatric use in 1998. Although effective, that product was withdrawn from the market the following year, soon after reports surfaced indicating that about one in 10,000 vaccinated infants developed a serious, often life-threatening intestinal blockage called intussusception. The new study indicates that a second-generation rotavirus vaccine licensed about four years ago carries an intussusception risk between about one in 52,000 and one in 76,000 recipients. (Differences in how the vaccines were administered and the post-vaccination safety data preclude direct comparison of their risks.) Bruce Goldman, a science writer in the school’s communications office, asked Greenberg to explain the significance of the new study.

Q: What does the study of these newer vaccines tell us?

Greenberg: It tells us specifically that a second-generation rotavirus vaccine is associated with some intussusception risk shortly after the first or second dose. However, that serious side effect is very uncommon. Recent findings indicate that another second-generation vaccine, which was not part of this study, carries a similar risk.

Importantly, the new study also clearly indicates that this very small potential risk is greatly outweighed by very substantial and well-documented benefits. The vaccines’ pluses so outnumber the minuses that it’s almost immaterial to talk about the minuses. In places like the United States or Western Europe, the new vaccines substantially reduce hospitalizations and morbidity. They save hospital costs, plus the cost of work lost to parents who have to bring their child to the doctor or have the child hospitalized.

But in the less-developed world, these new vaccines save babies’ lives. Researchers have predicted that even a moderately efficacious vaccine would save close to 50,000 lives a year in India alone. So they do a lot of good.

The downside is that every therapeutic — or for that matter virtually every diagnostic — intervention has some risk associated with it. There are no free lunches. Do you have any idea how many people aspirin kills a year? A lot! But it sure makes headaches better.

It now seems clear that rotavirus vaccination increases the likelihood of intussusception in the short period immediately after vaccination. Intussusception can kill you if it’s not treated. But it is very rare. Meanwhile, it is absolutely not clear that the vaccines increase the total risk of intussusception. In fact, they may decrease the absolute risk of intussusception in those getting vaccinated, because the natural rotavirus infection appears to cause rare intussusceptions in and of itself. So, the vaccines may trigger some intussusceptions but prevent more of them down the road.

Q: You’re saying that something about rotavirus itself, and not just the vaccines against it, might cause intussusception?

Greenberg: Yes. We now have three rotavirus vaccines in which intussusception was associated with the administration of that vaccine, which makes one think that natural rotavirus infection itself probably causes intussusception at some low frequency, too.

Several lines of evidence support that idea. In a large safety study of one of the vaccines, the children who got vaccinated had statistically fewer intussusceptions over the following one-year period than the children who didn’t get vaccinations. Data just coming out of Australia now shows an increased rate of intussusception in that first week or two after vaccination among those vaccinated as compared with those who weren’t, but that increase evaporated over time. And a very large epidemiology study of the first-generation rotavirus vaccine detected no overall increase in intussusception rates.

Any way you cut it, though, the intussusception rate associated with the vaccine is way lower than the benefit rate.

Q: Were the fears about intussusceptions in the case of the first vaccine blown out of proportion?

Greenberg: I don’t think so. It is incumbent on us to understand, as best we can, the risks associated with all our medicines, interventions and vaccines. But the other side of this is that you can’t assess risk in the absence of assessing benefits. And I don’t think that was done thoroughly for the first-generation vaccine.

You can make a case that because of that initial lack of a careful risk/benefit assessment, many hundreds of thousands of babies died, almost entirely in less-developed countries. The first-generation vaccine was withdrawn in 1999, and the rollout of the second-generation vaccines into the Third World occurred in 2007. That’s eight years. Assuming a 50 percent reduction in mortality from rotavirus infection among vaccinated children, that comes out to several hundred thousand rotavirus-related deaths that might have been prevented, not a trivial number. In comparison, the number of deaths that would have occurred from intussusception with that first-generation vaccine is likely to have been minimal.

Q: How effective are the new vaccines?

Greenberg: Their efficacy rates vary. Several studies from parts of Africa and Asia show efficacy rates in the 45 percent to 50 percent range for both of those vaccines, as opposed to the 85-90+ percent range in the United States and Europe. Now, even at 50 percent efficacy you could save a boatload of lives in places like India and Africa. That’s why the World Health Organization is still recommending those vaccines, even though they don’t work as well in those places as they do in the United States. But there’s lots of discussion now about the possible need for a better vaccine for Asia and Africa than the two newer vaccines now in use.

The first-generation vaccine was only tested in the United States and Europe, so we don’t know its efficacy in less-developed places. We do know that it was very immunogenic in places like Bangladesh, where the second-generation vaccines are less efficacious. An entrepreneur, Leonard Ruiz, PhD, of the International Medica Foundation, picked up the patent for the first-generation vaccine and is just completing an efficacy trial in Ghana with it, the results of which should be out sometime this year.

Q: What’s the status of your effort to create an affordable vaccine for the developing world?

Greenberg: The current vaccines are expensive, although the manufacturers are talking about substantially lowering their price. In my opinion, the only way you’re going to get less-expensive vaccines in the Third World is to have the manufacturing done there.

There are a number of independent efforts going on. I’m involved in what is perhaps the most advanced effort, a collaboration among many groups. This vaccine is being manufactured in India by an Indian company. Enrollment is almost 30 percent complete. Thus far, a total of 1,996 babies have received at least one dose of this new Indian vaccine, headed toward a total of about 7,000. If the vaccine proves safe and effective, I think they plan to be able to market it at under $1 a dose.