As a medical student in 1999, when I first learned about rotavirus, it was the most common cause of severe gastroenteritis (vomiting and diarrhea) in the world. This included the United States where it resulted in hundreds of thousands of doctor visits each year, with 55 to 70 thousand hospitalizations and 20 to 60 deaths. During my 3rd and 4th year pediatric rotations, I saw several cases of severely dehydrated kids who required IV fluids, and came to know the fairly unique smell of rotavirus diarrhea intimately.
20 to 60 deaths a year was bad, but certainly paled in comparison to the death and mayhem caused by this virus in developing regions of the world. As many as half a million children were dying worldwide every year from dehydration and malnutrition caused by the infection, and 2 million were hospitalized. The vast majority of these severe presentations occurred in children under the age of 5 years, not because older children and adults were immune but because we develop immunologic protection from prior exposure so recurrences tend to be asymptomatic or mild. Certain immune deficiencies put patients of any age at risk for severe disease, however.
Back then, virtually every child in the world became infected with rotavirus at some point in the first few years of life. The virus is spread from person to person via the fecal-oral route rather easily because it doesn’t take much of it to make you sick. Though only requiring a relatively brief exposure to stool containing about 100 colony forming units per gram, stool from someone acutely ill might contain 106 to 109 times that amount. And shedding of the virus can continue well past the resolution of symptoms, even up to 3 weeks, meaning that adorable and well-appearing toddler you just met at the park might be the index case for your family.
The first rotavirus vaccine
In 1998, the first oral vaccine against rotavirus was licensed in the United States. RotaShield, which I must admit is a pretty cool name for a vaccine, was produced using a combination of human and rhesus monkey rotavirus strains because human rotavirus doesn’t grow well enough in cultures for mass production. It was very effective, reducing severe infection risk by close to 100%, and it sailed through phase 3 trials without evidence of significant adverse events. Unfortunately, the following year it was withdrawn by the manufacturer.
In a stellar example of one of the most important aspects of vaccine safety, post-licensure surveillance data raised the concern that the vaccine may be to blame for a small, but real, increase in the risk of a form of intestinal blockage known as intussusception. This is when a proximal segment of bowel, usually small intestine, is pulled into a distal segment, usually large intestine, like one of those handheld, collapsible telescopes or spyglasses. The increased risk was ultimately found to be about 20 times the typical rate during the week after a child received the vaccination, or about one extra case for every 10 to 12 thousand vaccinated babies.
Intussusception can be caused by a variety of intestinal infections, anatomical abnormalities, and even cancer. The link between the first vaccine and intussusception was, theoretically, that the live, but weakened, virus caused inflammation in the gut in susceptible children who were at increased risk of developing the condition with any intestinal infection. Overall, the vaccine was shown to actually reduce the risk of intussusception after that first week. Furthermore, the risk was likely strain specific because newer vaccines using different strains do not have the same issue.
It wasn’t until 2006, just as I was completing my pediatric residency training and starting work as a newborn hospitalist, that we finally got another vaccine against rotavirus here in the United States. RotaTeq (less cool but what are you gonna do?) was co-invented by the amazing Paul Offit, a friend of the blog and my guest on episode 74 of The Prism Podcast. This is a guy who can legitimately claim to be responsible for saving hundreds of lives every day because of his work.
Right on its heels in 2008, a second live, attenuated, oral rotavirus vaccine, Rotarix, was licensed. While Offit’s baby is a reassortant vaccine produced with a bovine strain and 5 human strains, Rotarix contains just one human strain that provides partial cross-protection against most others. There are two additional rotavirus vaccines licensed for use in India and China, and a couple more in the pipeline.
The efficacy of the newer vaccines is on par with that of the original, reducing the risk of severe infection by 80-90% in many of the regions where they have been introduced. In the United States, there are about 50,000 fewer hospitalizations every year compared to when I was just starting out in the late 90’s. After 3 years seeing only newborns, I returned to general pediatric hospitalist work in 2009 and was amazed at the change. I can now say that I have not admitted a suspected rotavirus infection in many years.
In some resource-poor regions the benefit is still significant but has been less robust, with severe disease reduction closer to 50%. This is likely because of difficulty achieving high enough vaccination rates for herd immunity to begin to play a role. In regions with high uptake of the vaccine, we see much less rotavirus in adults and in children who cannot be vaccinated because of certain immune system disorders.
With the reduction in severe disease, visits to emergency departments, and hospitalizations, it was expected that mortality associated with rotavirus would also decrease. It did…a lot. Though still the most common cause of severe gastroenteritis worldwide, rotavirus associated deaths have decreased by close to 50%. That is hundreds of thousands of lives saved every single year. Hundreds of thousands of infants and toddlers who do not die. I am not a religious man, but that is a Goddamn miracle if ever there was one.
You are probably wondering about the risk of intussusception with the new vaccines. There appears to be a very slight increase in the first 2-3 weeks after dosing, so we don’t recommend the vaccine in children who have already had that type of obstruction. But the risk is significantly lower than it was with RotaShield, and it is considerably lower than the risk of severe rotavirus infection in children who are not vaccinated. Overall, the vaccine reduces the risk of intussusception in vaccinated kids because natural infection is a likely cause.
Wait, it gets better…probably
Late last month, a study out of Australia published in JAMA Pediatrics found a 14% reduction in the diagnosis of type 1 diabetes in rotavirus vaccinated children through age 4 years. They compared the rate of this diagnosis during the 8 years before and after introduction of the vaccine in May of 2007. Unfortunately, they did not see a decrease in older children.
This isn’t as out of left field as it might seem. There is a plausible expectation that reduction in the rates of rotavirus infection would also prevent some cases of type 1 diabetes in susceptible children. While we don’t understand the exact cause, we believe that a combination of genetic and environmental factors, most likely viral infections, result in the body’s immune system attacking the cells of the pancreas that produce insulin.
Rotavirus infection has been shown in murine data to injure the pancreas and to exacerbate diabetes, although it is not considered to be a common cause of pancreatitis in humans. There is also data showing molecular mimicry between certain rotavirus proteins and human T cells implicated in attacking pancreatic islet cells. The potential protective benefit would likely only be in children with a genetic risk factor and during a key period of immune system maturation when the complicated process of learning self from foreign invader is more prone to error.
Conclusion: More data is needed, but in the meantime please vaccinate your babies
This data is interesting but it should be considered preliminary. It warrants further investigation. But just imagine if it pans out. This is pretty exciting stuff! In the meantime, it’s not like we really need another compelling reason for babies to be vaccinated against rotavirus. It’s a safe, effective, and lifesaving vaccine regardless of whether or not it reduces the risk of diabetes. So what are you waiting for?