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Adenovirus infections are normally mild, and no adenovirus has ever caused a distressing pandemic. So why are adenoviruses among the most important and thoroughly studied pathogens in human history? Read on to learn more about these fascinating viruses and how they are being used to fight COVID-19 and other human diseases.

Adenovirus infections
Adenoviruses infect a wide variety of vertebrates. In humans, adenoviruses typically cause mild infections (common cold symptoms) that resolve without treatment. Children account for over 80% of cases. However, the typical infection tells an incomplete story, as over 100 types of human adenoviruses have been identified and divided into seven species, with different types capable of infecting different parts of the body¹. Infections occur in the respiratory tract, stomach, intestines, eyes, and urinary tract and can even spread from the site of infection to other parts of the body. As a result, adenoviruses cause a broad spectrum of symptoms beyond a mere cough, sore throat, or runny nose. Other illnesses include conjunctivitis (pink eye), tonsillitis, ear infection, croup, gastroenteritis (resulting in diarrhea and vomiting), pneumonia, viral meningitis, and encephalitis. While infections can be severe and sometimes lead to death, these cases are rare and overwhelmingly occur in people with weakened immune systems and young children.

Adenovirus epidemics in closed settings
Adenovirus epidemics have been described in healthy populations in closed settings. One such setting is the military. The confined spaces and stress of basic training have led to repeated outbreaks amongst military recruits in countries worldwide. The problem was pervasive enough that the United States military began vaccinating all recruits with live, unweakened adenovirus type 4 and type 7 in 1971. The vaccine was an oral tablet designed to pass undissolved through the stomach and release the virus in the intestine.

The vaccinations decreased adenovirus illnesses, but the program stopped in 1999 after the manufacture of the vaccine ended production, and the stock ran out. Infections rebounded, eventually leading to a new manufacturer making an adenovirus vaccine with the same formulation as the original, allowing vaccinations to return to the US military in 2011. The vaccine has not been tested for use in the general public and remains solely for military personnel.

Adenovirus vaccines are considered low priority
Bringing an effective adenovirus vaccine to a broader population is low on the list of priorities in science. Especially considering the more threatening outbreaks caused by other viruses in recent decades, including multiple coronaviruses, Ebola virus, H1N1 Influenza, Dengue virus, and Zika virus. Nonetheless, adenoviruses remain a thriving component of vaccine research. But what is the link? The answer lies in the long, rich history of adenovirus research.

Adenovirus research
Adenovirus was first isolated in 1953 from human adenoids², the patch of germ-fighting tissue at the back of the nasal cavity that inspired the name adenovirus. Since then, adenoviruses have been rigorously studied, and scientists have chronicled their structure, functions, and interactions with living cells in fine detail. Indeed, we owe large swathes of our knowledge of the molecular biology of life to their study.

Adenoviral vectors
As is often the case in science, adenovirus researchers have not been content to simply learn about their subject and its environment. Science craves new tools for more research, medicine, and human advancement. In this role, as a tool of science, adenoviruses have flourished, most notably as viral vectors. Viral vectors are viruses that scientists use to introduce genetic material of their choosing into cells. Components of the virus can then prompt infected cells to make protein based on the delivered genetic material. This might be done to study or produce a protein of interest in cell culture, or a viral vector might be used in a living organism for gene therapy or as a vaccine.

Adenoviruses are easy to work with within the laboratory, and the wealth of knowledge accumulated about them made them well-positioned to be repurposed as viral vectors. They have proved well-equipped for the task because they grow to high titers, can accommodate large gene insertions, and affect many types of dividing and non-dividing cells with high efficiency. Furthermore, unlike viral vectors made from lentiviruses and other retroviruses, adenoviruses do not integrate their genetic material into the host genome. As you can imagine, this is something to generally avoid when treating a person! The downside to not becoming part of the target cell’s genome is that the gene of interest will only be expressed for a limited time. Adenoviral vectors also typically cause a strong immune response in living organisms, destroying the infected cells and losing the target protein. However, this immune response can be advantageous in vaccination, as well as in cancer therapy.

Adenovirus gene therapy & vaccines
Viruses engineered to selectively kill cancer cells are called oncolytic viruses. The oncolytic adenovirus known as Oncorine, or H101, was approved in 2005 in China as a treatment for head and neck cancer, making it the first approved oncolytic virus medicine. In 2017, China licensed an Ebola virus vaccine made using adenovirus technology, making it the second country to approve a vaccine against the deadly Ebola virus disease.

Adenovirus in the fight against COVID-19
If you have heard adenoviruses mentioned in the news in recent years, it is likely due to their use in COVID-19 vaccines. Coronavirus disease 2019, or COVID-19, is the disease caused by the virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A common goal of many COVID-19 vaccines is to introduce the surface protein of SARS-CoV-2, called spike, into the human body in hopes of eliciting an immune response capable of protecting against SARS-CoV-2 infection. One way to do that is to package the spike protein DNA into an adenoviral vector. These modified viruses can enter a person’s cells and coerce them to make spike protein from the delivered genetic material, but they cannot replicate to make a new virus.

This strategy is used by numerous COVID-19 vaccines, including by Oxford-AstraZeneca’s AZD1222 and Janssen’s Ad26.COV2.S. Interestingly, these two vaccines rely on different adenoviral vector technologies, with Oxford-AstraZeneca choosing a chimpanzee adenovirus vaccine vector known as ChAdOx1 and Janssen employing a modified human adenovirus type 26. Alternatively, the Gam-COVID-Vac COVID-19 vaccine, commonly known as Sputnik-V, uses a vector-based on human adenovirus type 26 for the first immunization and one based on human adenovirus type 5 for the subsequent booster. This strategy of using different virus types counteracts the immunity people can develop to adenoviral vectors themselves, sometimes making subsequent booster shots ineffective.

An often-heralded advantage of the Oxford-AstraZeneca COVID-19 vaccine is its storage stability, a beneficial trait typical of adenovirus vaccines. AZD1222 keeps for longer than 6 months while transported and stored at normal refrigerated temperatures of 2°C to 8°C. Contrast that with the Pfizer-BioNTech COVID-19 vaccine, which uses mRNA-based technology rather than an adenovirus delivery system. For stability, the Pfizer product requires transport and storage at ultra-low temperatures of -60°C to -86°C.

Although some adverse events have been reported -mostly in young women- related to thrombosis and other atypical coagulation events, a clear mode of action has yet to be defined, and it is currently unclear how much of this phenomenon is due to the expression of the SARS-CoV2 Spike protein vs the vector itself.

Adenovirus stability
Adenoviruses are stable; they are more resistant to destruction by physical and chemical means than most viruses and can survive for unusually prolonged periods outside the body, even under dry conditions that are typically unfavorable. This is in large part because adenoviruses are non-enveloped. An enveloped virus is most simply described as being surrounded by a lipid coat. This outermost layer, or envelope, derives from host cell membranes made of a lipid bilayer mixed with proteins and other molecules. Viral proteins are also included in the envelope. Adenoviruses lack this lipid cover and instead have as their outer shell a tough protein coat, called a capsid, that is more resistant to degradation. Even their core genetic material, made of double-stranded DNA, is more stable than the RNA genomes found in some viruses.

The ruggedness of adenoviruses makes them particularly valuable to our work at VRS. We regularly test the virucidal activity of a broad range of compounds, fabrics, and surface materials provided by our clients. Given the COVID-19 pandemic, people naturally want to demonstrate that their samples are effective against the pandemic agent, SARS-CoV-2. But coronaviruses are enveloped and not particularly robust. So, keep in mind that testing against adenovirus is a great way to present a stiff challenge to the virucidal might of your product.

Another reason not to overly fixate on coronaviruses is that scientists cannot predict with any certainty what type of virus might cause the next pandemic that, unfortunately, almost surely will occur. What we do know is that whatever future viral disease comes our way, adenoviruses will be one of the first weapons scientists use to fight it.

References

1. Lynch JP 3rd, Kajon AE. 2021. Adenovirus: Epidemiology, global spread of novel types, and approach to treatment. Semin Respir Crit Care Med. 42:800-821.
2. Rowe WP, Huebner RJ, Gilmore LK, Parrott RH, Ward TG. 1953. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proc Soc Exp Biol Med. 84:570-3.

Blog by Farrell MacKenzie
Edited by Reckon Better Scientific Editing