Structure of Human adenovirus 7 virus-like particles, a vaccine and nanotherapeutic platform

What is it about?

Adenovirus infections occur in eyes, respiratory, and the digestive system. Infections are especially dangerous to children and immunocompromised individuals. However, despite the significant clinical burden associated with adenovirus infections, there are currently no licensed adenovirus vaccines available for use in the general population. We recently made significant progress in this area by developing an adenovirus virus-like particle (VLP) platform as a vaccine candidate. These VLP lack genomic data, are not infectious, and induce an immune response capable of neutralizing adenovirus infection. Adenoviruses are large and morphologically complex viruses. Given this complexity, it is important to determine if the technology appropriately recapitulates the physical properties of the infectious virus to induce the ideal immune response. To this end, we determined the atomic structure of the VLP. The structure identifies important areas where additional protein engineering will improve the efficacy and stability of this vaccine.

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Photo by Giorgio Trovato on Unsplash

Photo by Giorgio Trovato on Unsplash

Why is it important?

There are over 100 types of adenovirus (AdV) that infect humans. Of these, types E4 and B7 are among the most prevalent and problematic strains. These two types rapidly spread through close contact, respiratory droplets (e.g. cough or sneeze), contaminated surfaces, and the fecal-oral route. They cause outbreaks that range from mild, cold-like illnesses to bronchitis and pneumonia. There is no approved specific antiviral treatment for their infection. Natural outbreaks of E4 and B7 have been particularly troublesome in military barracks. In the United States alone, approximately 80% of military recruits become infected, and 20% of the infected require hospitalization. This high rate of infection led to the development of a live virus oral vaccine specifically for military personnel; however, the vaccine is not available to the public as its administration results in rapid shedding and spreading of the virus through the barrack. Moreover, the live virus vaccine has the ability of exchanging genetic material with other AdV to generate more problematic subtypes. These concerns motivated us to develop an adenovirus virus-like particle (AdVLP) platform as an alternative for vaccination strategy -this platform can generate VLPs for multiple types of AdV. Earlier, we demonstrated that the AdVLPs of B7 (AdVLP-7) had the general shape of wild-type AdV-7. These VLP remained stable for months when stored in the refrigerator and retained their morphology after freeze-drying -a property important for long term storage and shipment. Immunogenicity studies in mice demonstrated that the AdVLPs elicited a potent, sustained, and protective neutralizing immune response specific to the desired type. Here we report the atomic structure of the AdVLP-7 and identify important protein-protein interfaces that could be engineered for improved vaccine efficacy and stability. We also identify important protein-protein interactions that change upon packaging of the AdV genome and maturation of the capsid to an infectious virion. The VLP platform represents a significant advancement for AdV vaccine production and next generation carrier for mRNA -a promising platform for novel gene therapy vectors. The VLP system is also a powerful tool for biophysical and structural studies aimed at elucidating the detailed mechanisms of AdV assembly and stability.

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