Adenoviral vector vaccines have been in development for decades, but very few have been approved for use in humans. What does the history of adenoviral vector vaccine development tell us about their safety and their potential to alter DNA?
How Do Adenoviral Vector Vaccines Work?
Essentially, these types of vaccines . They use an adenovirus -- which has been engineered to be incapable of replicating and causing disease -- to deliver the genes for making the antigen; in this case, that's the SARS-CoV-2 spike protein. That in turn elicits an immune response and provides protection against the coronavirus.
are basically common cold viruses that can cause illnesses ranging from cold-like symptoms to bronchitis, gastroenteritis, and conjunctivitis.
"I think people are unfortunately familiar with adenoviruses ... [A]t far too many points, you know, you've had the sniffle. You've had the cough. You felt crummy. If it's a cold it's often adenovirus," Daniel Griffin, MD, PhD, said on a recent episode of 鶹ý's "Track the Vax" podcast. Griffin is chief of infectious disease at ProHEALTH Care, an Optum unit.
Humans are infected with multiple different types of adenoviruses throughout their lifetimes. Most serotypes cause mild illness, although has been associated with more severe illness. Older adults and people who are immunocompromised or have pre-existing respiratory or cardiac disease may have worse illness.
Precisely because adenoviruses are so common, one problem with using them in vaccines is that people may already have antibodies to them, overwhelming them before they can do their assigned work. Researchers get around that issue by using adenoviruses that humans are unlikely to have encountered before.
Currently, five adenovirus vector vaccines for COVID-19 are
Each works on the same basic principle, although delivery platforms differ. The AstraZeneca/Oxford vaccine , which is based on a modified version of a chimpanzee adenovirus.
The uses a proprietary , made up of a recombinant human adenovirus (adv26). It's the same platform used in the company's (which is approved in Europe) and its investigational Zika, RSV, and HIV vaccines.
uses recombinant human adenoviruses Ad26 and Ad5 for the first and second doses, respectively. Finally, China's CanSino vaccine uses the recombinant human adenovirus Ad5.
Adenoviral Vector Vaccines: 50 Years in Development
Research into adenoviral vector vaccines goes back decades. In the 1990s, scientists started studying adenoviruses for use in gene transfer therapy to treat diseases like cystic fibrosis. In 1993, researchers at the University of Iowa published the of cystic fibrosis gene therapy using an adenovirus vector in three patients. The results seemed promising, and suggested that gene transfer using this approach may compensate for the genetic defect in cystic fibrosis. Unfortunately, have failed to confirm these findings, showing only partial, transient correction.
One reason this approach fizzled is that adenoviruses induce strong T and B cell immune responses, quickly causing viral clearance and limiting their purpose in gene therapy. But the very fact that adenoviral vectors induce a robust immune response made them prime candidates for developing vaccines against infectious diseases, according to Lynda Coughlan, PhD, an adenovirus vaccine researcher at the University of Maryland.
Since then, scientists have worked on adenoviral vector vaccines against a , including Zika, RSV, HIV, influenza, tuberculosis, dengue, and MERS. During the Ebola outbreaks in West Africa and the Democratic Republic of the Congo, two adenoviral vector vaccines were quickly developed and deployed. Adenoviruses can also be genetically modified to target and kill cancer cells.
Earlier experience with adenovirus vector vaccines proved advantageous when the COVID-19 pandemic struck. Because these types of vaccines had been in development for so long, all scientists had to do was adapt them to COVID-19. For example, the platform used in the AstraZeneca/Oxford vaccine had been in clinical trials in humans for over 10 years for various other diseases. Going forward, that adaptability may also prove useful when updating vaccines to protect against new variants of COVID-19, according to Coughlan.
"What's attractive about adenoviruses is that you can use them almost like a plug-and-play system. The platform doesn't have to be changed but you can switch out the gene of interest for your disease," she told 鶹ý.
Another advantage: earlier work provided data on dosage and safety of adenoviral vector vaccines in humans.
"We already had quite a lot of information about how adenoviral vector vaccines work in other diseases, and roughly what dose we should give humans," said Coughlan. "Safety data from numerous clinical trials in humans showed that they are safe and induce good immune responses."
So far, phase III trials of adenoviral vector COVID-19 vaccines in humans bear this out. Both and have reported that their vaccines were well tolerated with no serious safety concerns. While serious adverse events were similar between vaccine and control arms of the AstraZeneca/Oxford vaccine phase III trial, three cases of transverse myelitis occurred (one in the control group, two in the vaccine group), prompting a study pause. Upon independent review, two cases were thought unrelated to the vaccine while the third was deemed possibly related to the vaccine.
Nonetheless, adenoviral vector vaccines generally have similar side effects as other types of vaccines like flu shots, said Coughlan, such as pain at the injection site, headache, or mild fever.
"Adenovirus vector vaccines have what I would consider to be normal reactogenicity. I don't see anything that would alarm me in terms of causing concern about receiving an adenoviral based vaccine," Coughlan said. "There might be individuals who may have higher grade reactions than others, but that would be the case with any vaccine or any therapy."
Potential to Change DNA?
Adenoviruses deliver DNA that can enter the cell nucleus, which brings up the question of whether they can alter DNA. That's an easy one -- no.
Adenoviruses -- even as they occur in nature -- just do not have the capacity to alter DNA. Unlike retroviruses such as HIV or lentiviruses, wild-type adenoviruses do not carry the enzymatic machinery necessary for integration into the host cell's DNA. That's exactly what makes them good vaccine platforms for infectious diseases, according to Coughlan.
And, engineered adenoviruses used in vaccines have been further crippled by deleting chunks of their genome so that they cannot replicate, further increasing their safety.
"The cell lines that are used for adenovirus vaccines are highly and well characterized cell lines. They are classified by the FDA as nonintegrating, meaning there has never been any evidence in humans and multiple animal models of vector-borne DNA integrating into a host," said Gregory Poland, MD, of the vaccine research group at the Mayo Clinic in Rochester, Minnesota.
Given this history, Coughlan says she has no personal worries about the current crop of vector-based COVID vaccines.
"I would be very happy to get an adenovirus vaccine," she said. "I think they're great vaccines, and I consider them safe. There's nothing I can really tell you that I would be concerned about administering nonreplicating adenoviral vectors in humans."