Adenoviruses seen via transmission electron microscopy.
Enlarge / Adenoviruses seen via transmission electron microscopy.

Out of an abundance of caution, US officials on Tuesday recommended pausing use of Johnson & Johnson’s COVID-19 vaccine. Officials linked the vaccine to six peculiar illnesses in which people developed life-threatening blood clots in combination with low levels of blood platelets, the cell fragments in blood that form clots. One person died from their condition and another is in critical condition.

It’s unclear if the vaccine caused the illnesses. Even if it did, the illnesses would represent an exceedingly rare side effect. The six cases occurred among more than 6.8 million people in the US who received the Johnson & Johnson vaccine. That would make it a side effect seen in fewer than one in a million. The risk of hospitalization and death from COVID-19, which the vaccine protects against, easily exceeds those odds. Without question, the benefits of the vaccine outweigh the potential risks.

Still, with robust supplies of vaccine from Moderna and Pfizer-BioNtech—neither of which have been linked to these unusual cases—US officials took the cautious route of pausing Johnson & Johnson’s vaccine while they investigate the cases further and inform clinicians about how to spot and treat any others that may arise. This latter point is critical, because if doctors try to use standard blood clot treatments in these vaccine-linked cases, the outcomes can be fatal.

Of course, the other critical aspect of this situation is that officials have seen these unusual cases before—linked to a similar COVID-19 vaccine developed by AstraZeneca and researchers at the University of Oxford. The AstraZeneca vaccine is not yet authorized for use in the US, but it has been authorized in many other countries, including those in the European Union. In recent weeks, regulators in the EU and the UK have investigated dozens of eerily similar cases, involving dangerous blood clots coupled with low platelets. Some estimates have pegged the reported case rate of one in 100,000 people vaccinated.

Trying now to connect all the dots and find answers, experts are eyeing the most obvious connection: both vaccines use an adenovirus vector, a viral delivery system used regularly in vaccine development.

At the moment, the adenovirus vector offers “the most straightforward explanation” for the possible side effects, says viral immunologist Hildegund Ertl, who develops adenovirus-based vaccines at the Wistar Institute in Philadelphia. Yet, the link to blood clots “took all of us by surprise,” she tells Ars. The situation has raised a slew of questions—as well as some doubts.

Vexing virus

Adenoviruses are a large family of very common viruses that cause a range of infections in humans, from mild colds and flu-like illnesses to pink eye, pneumonia, and gastroenteritis. Beyond humans, they can infect a range of animals, including pigs, cows, and chimpanzees. Researchers have been working with adenoviruses for decades. The Johnson & Johnson vaccine uses the adenovirus (Ad26), which was first identified in 1961 from anal swabs of children in Washington, DC. The AstraZeneca vaccine is based on an adenovirus that circulates in chimpanzees (ChAdOx1).

Over the years, researchers have considered adenoviruses useful delivery systems for vaccines and gene therapies. For starters, they’re easy to brew up in big batches in laboratory conditions. When engineered for vaccines, they can provoke potent immune responses in people against germs we want to fight. And they appeared relatively safe in humans, particularly since they’re often modified so they can’t replicate in our cells.

But adenoviruses have had a troubled past. Researchers all but abandoned their use in gene therapies in 1999 following the tragic death of 18-year-old Jesse Gelsinger. A team of researchers at the University of Pennsylvania had hoped to cure the teenager’s rare metabolic liver disease by correcting an underlying genetic mutation with new code—delivered in trillions of adenovirus vectors. The researchers used human adenovirus 5 (Ad5), which typically causes only a mild cold. In early tests, the therapy triggered only mild side effects and flu-like symptoms in animals and a human patient, The New York Times reported at the time. But in Gelsinger, the massive dose of virus vectors triggered a fatal immune response.

Researchers carried on with adenoviruses for vaccine development, where potent immune responses can be a plus instead of a peril. Programmed to be vaccine vectors, adenoviruses deliver key snippets of genetic code from dangerous viruses, bacteria, or parasites directly to human cells. From there, our cells translate the genetic code into protein, recognize it as foreign, and use it to train our immune systems to seek and destroy anything carrying the same protein. In the case of COVID-19, adenovirus-based vaccines carry the genetic code for the SARS-CoV-2 spike protein, which is the thorny protein that juts from the virus’s particle. The spike protein is what SARS-CoV-2 uses to enter human cells, and it's a key target for potent antibodies and other immune responses.

Vials of the AstraZeneca COVID-19 vaccine are seen during the opening of a vaccination center in Cyprus on March 22, 2021.
Enlarge / Vials of the AstraZeneca COVID-19 vaccine are seen during the opening of a vaccination center in Cyprus on March 22, 2021.

Shaky shots

Adenovirus-based vaccines have held a lot of promise over the years, but they have had notable stumbles, too. Nearly a decade after Gelsinger’s death, researchers halted a major trial of an Ad5-based HIV vaccine after data indicated that the vaccine increased the risk of becoming infected with HIV in people who had preexisting immune responses to Ad5. With the high-profile failure, many vaccine developers moved away from Ad5 to other adenoviruses—ones that people tend to have less preexisting immunity against, like chimpanzee adenoviruses.

Though researchers have been developing adenovirus-based vaccines against a slew of diseases—malaria, HIV, Zika, RSV (respiratory syncytial virus), and more—few have made it across the finish line and into use. Among the most successful is an Ad26-based Ebola vaccine made by Johnson & Johnson, which gained regulatory approval in Europe last year. The approval bolstered hopes for the company’s COVID-19 vaccine, which uses the same Ad26-based platform.

Early on in the pandemic, the adenovirus-based vaccines were often seen as front-runners, particularly AstraZeneca’s. Despite the checkered past of adenovirus vectors, the vaccine design was seen as a more established technology than the mRNA-based vaccines, which were completely unproven until the extraordinary success of COVID-19 vaccines from Moderna and Pfizer-BioNTech. Adenoviruses also have logistical advantages. They’re relatively cheap, easy to make, and easy to distribute. For instance, unlike the mRNA vaccines, which require ultra-cold storage conditions, AstraZeneca’s vaccine can handle normal refrigerator temperatures. Many experts and the World Health Organization have considered AstraZeneca’s vaccine to be the world’s go-to vaccine—a cheap, accessible vaccine that could be used in a variety of countries and settings.

But as the mRNA vaccines sprinted ahead in the pandemic, AstraZeneca seemed to lurch from problem to problem. The vaccine’s troubles hit a critical point last month when more than a dozen countries temporarily suspended its use amid concerns that it was causing extremely rare blood clots. On April 7, an investigation by the EU’s European Medicines Agency concluded that there was a strong association between the vaccine and peculiar illnesses involving both blood clots and low platelets. The agency determined that they should be listed as “very rare side effects” of the vaccine, but it still urged countries to continue using the vaccine.

“The reported combination of blood clots and low blood platelets is very rare,” the agency noted. “The overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects.”



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