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Weighing the risks and benefits of vaccines

April 26, 2021 by Laura Edison Kallen

All medical interventions carry risks and benefits. Scientists from PATH’s Center for Vaccine Innovation and Access apply insights from rotavirus to COVID-19.

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A health worker prepares a vaccine for administration during a Japanese encephalitis vaccination campaign. In most cases, the lifesaving benefits of vaccines vastly outweigh the risks. Photo: PATH/Aaron Joel Santos.

When the US Food & Drug Administration recommended a pause on the Johnson & Johnson vaccine due to six recipients developing blood clots, it felt like déjà vu to scientists at PATH. For decades, PATH has worked alongside partners to advance, evaluate, and inform decisions related to rotavirus vaccines, another vaccine with a very rare side effect.

“Evidence has shown time and again that the benefits of rotavirus vaccines significantly outweigh the known low-level risk of adverse reaction, and the vaccines’ use continues to save lives today,” says David C. Kaslow, MD, head of PATH’s Center for Vaccine Innovation and Access.

“The experience we’ve gained with rotavirus offers important insights for assessing the benefits and risks of COVID-19 vaccines going forward—whether Johnson & Johnson, Oxford-AstraZeneca, or new formulations yet to be developed.”

Rotavirus vaccines and intussusception

About 15 years ago, another virus was circulating around the world out of control, striking fear into families. This wasn’t a novel virus—it was rotavirus, which causes severe, rapidly dehydrating diarrhea in young children.

At that time, rotavirus was responsible for around half a million child deaths each year, mostly in countries with limited access to health care. In countries with robust health systems, rotavirus still caused hundreds of thousands of hospitalizations and sleepless nights for parents and children.

The development and licensure of two rotavirus vaccines, ROTARIX® and RotaTeq®, began to change things in 2006, but these weren’t the world’s first attempts at vaccines against rotavirus. An earlier vaccine, RotaShield®, had been taken off the US market in 1999 due to a rare and unanticipated side effect called intussusception: a life-threatening intestinal condition where the bowel folds in on itself cutting off blood supply and interrupting the passage of food and fluid. The risk of intussusception with RotaShield was estimated at 1 in 10,000 vaccinated children.

Before new rotavirus vaccines could be licensed, regulatory authorities required manufacturers to perform large clinical trials—with more than 60,000 infants—specifically to evaluate the potential risk of intussusception associated with rotavirus vaccine administration. These studies detected no risk, so countries began to license and introduce the vaccines.

As countries began introducing the new rotavirus vaccines, post-licensure surveillance continued to watch for intussusception. With the vaccines being given to millions of children, some post-vaccination intussusception did start to show up—but at a far lower rate.

The new rotavirus vaccines had an estimated risk of intussusception between 1 in 20,000 and 1 in 100,000. This is in addition to the rate of naturally occurring intussusception in the general population, which occurs in about 1 in 2,000 children every year. The new rotavirus vaccines had a significantly lower risk—approximately one-half to one-tenth—of intussusception compared to that observed for RotaShield.

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The risk of intussusception with ROTARIX® and RotaTeq® is significantly smaller than with an earlier vaccine or the risk of naturally occurring intussusception. Each box shows the scale needed to produce one case of intussusception. Image: PATH.

With all the surveillance coming in, another observation became clear: rotavirus vaccines work very well.

Countries that have introduced rotavirus vaccines have seen swift and significant reductions in rotavirus hospitalizations—a median reduction of 59 percent—in children under 5 years of age. Given the overwhelming evidence in favor of the vaccines, the World Health Organization recommended in 2009 that rotavirus vaccines be included in all national immunization programs for infants.

In the decade since, more than 100 countries have added rotavirus vaccines into routine immunization. Real-world vaccine effectiveness has ranged from 45 to 90 percent. Scientists have continued to monitor intussusception over the years and maintain the recommendation that the vaccines’ benefits heavily outweigh the risks.

Miren Iturriza-Gomara, head of PATH’s rotavirus vaccine initiative, observes, “Rotavirus vaccines are a runaway public health success story. They are saving children’s lives and saving parents from heartache all over the world.”

“If regulators had removed rotavirus vaccines because of the 1 in 100,000 risk of intussusception, about 900,000 children would not be alive today.”

“If regulators had removed rotavirus vaccines because of the 1 in 100,000 risk of intussusception, about 900,000 children would not be alive today.”
— Miren Iturriza-Gomara, PATH’s rotavirus vaccine initiative

COVID-19 vaccines and blood clots

With the Johnson & Johnson COVID-19 vaccine, the stakes are even greater. The pandemic continues to claim hundreds of thousands of lives every day, and the threat of new variants makes vaccination an urgent priority.

However, the Johnson & Johnson vaccine’s use in the United States was paused after six women developed blood clots with low levels of blood platelets after receiving the vaccine. While research is ongoing, this risk so far appears to be less than 1 in a million.

A risk of blood clots with low platelet counts, which may or may not be caused by the same mechanism of action as in the Johnson & Johnson vaccine, also appears to exist for the Oxford-AstraZeneca COVID-19 vaccine. This vaccine has been in use throughout Europe and much of the world through the COVAX initiative. After countries started seeing a small increase in blood clots—estimated at 4 in a million—several countries paused or limited the vaccine’s use.

“Monitoring vaccine safety is paramount to any vaccination program,” notes Dr. Kaslow.

“The rapid identification of these blood clot cases with low levels of blood platelets underscores the importance of reporting any adverse events and quickly determining if there is a plausible link to the vaccine. At the same time, every medical intervention comes with some level of risk, and an essential role of public health officials is to assess the balance and to effectively communicate both the benefits and the risks to the public.”

Applying lessons from rotavirus for COVID-19

In the case of rotavirus vaccines, public health officials carefully analyzed the evidence before affirming that the lifesaving benefits of the vaccines outweighed the low-level risk of intussusception. Officials continue to communicate the risk to health care workers so they can warn parents to look out for intussusception in the rare chance that it does occur.

Additionally, because they knew the risk was small due to data from the clinical trials, officials did not pause rotavirus vaccine usage during post-licensure surveillance. This decision allowed children to continue being protected from life-threatening diarrheal disease while they continued to gather more data on rare side effects.

As scientists and officials weigh the risks and benefits of COVID-19 vaccines, the success of rotavirus vaccination is an important lesson to keep in mind.

“The risks of life-threatening blood clots with low blood platelet levels now reported for the Johnson & Johnson and Oxford-AstraZeneca vaccines appear to be rare, and we know that currently in many countries the individual and public health risks of not being vaccinated are extraordinarily high,” says Dr. Kaslow.

“Rotavirus vaccines are an instructive example of the importance of balancing rare-frequency risks with lifesaving benefits, and of the importance of carefully communicating the benefit-risk balance to health care providers and, most importantly, to the public.”