As I’ve noted various times on this blog, all vaccines have both benefits and risks. Much of the research focused on vaccines is aimed at ensuring that the former significantly outweigh the latter in routinely recommended immunizations. Then, additional studies, conducted after vaccines are licensed and recommended, continue looking for possible risks that might show up in large populations but which couldn’t have been detected in smaller clinical trial populations.
(It’s simply not possible to conduct clinical trials with millions of participants, so a reaction affecting one of every 1 million doses wouldn’t be detectable in a clinical trial. Real-world observational studies involving millions of doses are more likely to find and better estimate these risks.)
Two studies published in the New England Journal of Medicine today reported the findings of two large studies aimed at better understanding the risk of a serous bowel condition, called intussusception, with rotavirus vaccination. Briefly, intussusception is a condition in which part of the bowel “telescopes,” or slides into itself. It can require surgery to treat, and is estimated to occur to about 1,900 babies a year, independent of rotavirus vaccination. Meanwhile, rotavirus causes gastroenteritis, which involves severe diarrhea and potentially dehydration. It is a top killer of infants worldwide (nearly half a million deaths a year) and hospitalized 55,000-70,000 children a year in the US before widespread vaccination.
The two NEJM studies, one funded by the CDC and the other by the FDA through programs in the US Department of Health and Human Services, have taken more than seven years to complete because of the meticulous methodologies used and the need for enough participants that the researchers could appropriately estimate risks for such relatively recent vaccines.
Here’s the nutshell version: Both studies further confirmed what had been suspected for several years and reported in previous smaller studies — that both of the currently licensed rotavirus vaccines, RotaTeq and Rotarix, have a small increased risk of intussusception, approximately 1 to 5 additional cases of the condition per 100,000 children who receive the vaccine, depending on the vaccine and which dose it is.
These valuable findings confirm previous suspicions and greatly contribute to the knowledge of rotavirus vaccine risks, which helps with risk-benefit analyses of rotavirus immunization. In fact, the CDC had already advised in 2011 that children with a history of intussusception not receive rotavirus vaccines since those children would be more likely to develop the condition again. The studies’ results also match up with what the CDC already lists as possible serious risks of rotavirus vaccination, also included on the rotavirus Vaccine Information Statement. What I found remarkable was that the CDC’s estimate – “about 1 in 20,000 US infants to 1 in 100,000 US infants” — is spot on with these new findings.
Interestingly, the two studies appear at first to contradict each other, finding different vaccines to have the higher risk. But these kinds of discrepancies aren’t unusual or worrisome: the authors of the studies used different populations and slightly different methodologies, and their calculations must still take into account the possibility of chance findings. The differing findings actually reveal the value of having both large-sclae studies and emphasize the reality of scientific research: that it’s the accumulation of evidence that matters rather than this or that single study.
Before I explain the studies and results, it helps to know why this research was conducted in the first place. The first rotavirus vaccine licensed in the US, RotaShield, was pulled shortly after its approval in 1998 because of intussusception risk concerns, explained in the CDC’s history of RotaShield. As the current vaccines went through clinical trials, researchers specifically looked for intussusception risks and intentionally used larger populations than in RotaShield trials so that cases were more likely to show up.
The results of the clinical trials, also published in NEJM, found no increased risks in either RotaTeq, subsequently licensed as a three-dose vaccine in February 2006, or in Rotarix, subsequently licensed as a two-dose vaccine in April 2008. Both were added to the CDC schedule from ACIP recommendations shortly after their FDA approvals. But it was still possible an intussusception risk existed that was too small to be detected in the clinical trials; hence the initiation of these studies.
The CDC study assessed the risk of intussusception in babies aged 4 to 34 weeks who were vaccinated between April 2008 and March 2013 and participated in one of six health care organizations in the Vaccine Safety Datalink program. The data came from more than 1.3 million doses of RotaTeq and more than 200,000 doses of Rotarix. (There were more for RotaTeq because it had been available for longer.) The researchers found eight cases of intussusception a week after vaccination instead of the seven that would be expected (based on normal rates of the condition) among those receiving RotaTeq, a finding that could have been due to chance.
But among those who received Rotarix, instead of the 0.72 expected cases of intussusception they should have found if there was no increased risk, the researchers found 6 cases that developed within a week of vaccination. The increased risk therefore translated to about 5.3 extra cases of intussusception per 100,000 children receiving Rotarix.
But the FDA-funded study, led by researchers at Harvard, found RotaTeq to have the higher risk for intussusception. The children involved in this study, aged 5 to 40 weeks old, received more than 1.27 million total doses of RotaTeq (about a half million were first doses) and more than 100,000 doses of Rotarix (about 54,000 of which were first doses).
The researchers analyzed the data in two different ways, first comparing vaccinated children to themselves (looking at the weeks immediately after vaccination compared to the rest of the year) and then comparing vaccinated children to unvaccinated children. The authors found about 1.1 to 1.5 additional cases (depending on the analysis) of intussusception occurred per 100,000 doses within three weeks of RotaTeq vaccination, all in first doses only.
Meanwhile, the first analysis of Rotarix (comparing vaccinated children to themselves) did not find an increased risk of the condition (only one child experienced intussusception), but the second analysis did find an increased risk. However, the small number of total participants made it difficult to determine precisely what the increased risk was. (The risk has to be small since only one child had the condition and it would require at least a couple hundred thousands of participants to calculate the risk.)
Based on what they could calculate, the researchers determined the risk of intussusception to be approximately 1.5 additional cases per 100,000 across both vaccines.
So, together, the studies found what the CDC lists on its website: an increased risk of 1 to 5 extra cases of intussusception per 100,000 vaccine recipients that occurred as a result of the vaccine. The studies also conclude with very similar statements. The FDA study concludes, “The risks of intussusception must be considered in light of the demonstrated benefits of rotavirus vaccination.”
The CDC study concludes, “Since the start of the US rotavirus vaccination program, large declines in rotavirus disease and associated hospitalizations have occurred among US infants. Thus the benefits of rotavirus vaccination in infants have been found to outweigh possible small risks of intussusception.”
Indeed, before the vaccine was introduced, 8 in every 10 children in the US had had rotavirus by age 5, resulting in “approximately 410,000 physician visits, 205,000-272,000 emergency department visits and 55,000-70,000 hospitalizations” each year from the 1990s through the early 2000s, the CDC reported. The effects outside the US have been even more dramatic, such as a more than 50% drop in diarrhea-related deaths in Mexico after rotavirus vaccination was introduced, research covered by Skeptical Raptor a little over a year ago.
So, does the risk of the rotavirus vaccine, potentially causing an additional 50-60 cases of intussusception a year, outweigh its benefit, preventing approximately 50,000 hospitalizations a year from the disease? Both conditions, without prompt and appropriate treatment, can result in death. Rotavirus is scary less easily treated than intussusception, but that doesn’t negate the seriousness of intussusception (and the pain it can cause; familiarize yourself with intussusception symptoms).
The CDC’s Advisory Committee on Immunization Practices has determined, so far, that the benefits exceed the risks. I don’t expect to see them change their recommendations based on these findings, but there is still much to learn. As an editorial accompanying these studies notes, “Many questions remain to be resolved: Is the risk of intussusception similar with the two vaccines? What is the mechanism for the event? Can we identify a subgroup of infants who may be at increased risk?” More research will hopefully reveal some answers.
EDITED TO ADD: I was asked in a Facebook post what I thought about the risk-benefit analysis here. I provided my *personal* opinion , which is nothing more than my personal layman opinion, and I am not a doctor, nor do I have clinical experience. What I did was list what was known about the risks and benefits, and so I’m updating this post with what I said there.
There is definitely an increased risk of intussusception being observed among rotavirus recipients. The questions now are why and whether some kids are more susceptible than others. I can understand people who would want to skip it with that risk since rotavirus is one of the very few vaccines we protect against in the US that is unlikely to cause death *in the US*. (It’s a leading killer of kids worldwide, but that’s because of inability to get adequate medical care once they get the virus which most do. They die of dehydration usually, as with cholera.)
At the same time, consider the following:
–The risk of intussusception is still very low in rotavirus vaccine recipients.
–The risk of getting rotavirus without being vaccination (even now with high immunization rates) is higher than the risk of intussusception with the vaccine (in raw numbers).
–Intussusception has clear clinical symptoms and, as long as it is identified in a timely way, can be treated in one of three ways with good outcomes. (Also, the fact that occurs, if it’s going to occur, within the first three weeks after vaccination provides a clearly defined time period in which parents and doctors can watch for symptoms.)
–First-line treatment for intussusception does not require surgery; if that fails, it does require surgery (which rotavirus does not require).
–Rotavirus also has clear symptoms but can’t really be treated beyond providing fluids while it runs its course.
–Both rotavirus and intussusception often require hospitalization.
–Both rotavirus and intussusception can ultimately cause death if not treated or if complications develop. The rates of death for each one, in the US, are likely pretty similar and very rare for both. (In developing countries, the risk of death with rotavirus is likely considerably higher than the risk of death with intussusception.)
Given all those facts, I *personally* think the risk-benefit analysis leans toward getting the vaccine. My reasoning is that the danger, complications, hassle, pain, cost and mortality risks of both conditions are very comparable, but in raw numbers, a kid is much more likely to get rotavirus without the vaccine (it’s still common) than to get intussusception with the vaccine. So it comes down to a numbers game for me. Others may see it differently.