The structure of the Human Adenovirus 7 virus-like particles reveals that pentons and core-genome promote hexon-pIIIa interactions during capsid maturation

Members of the Adenoviridae family routinely infect humans, exhibit significant genetic diversity, and are associated with a variety of illnesses. Types 4 and 7 frequently circulate in the United States and are major causes of respiratory disease. Infections can result in hospitalization and, in severe cases, death. Although a live wild-type-virus vaccine targeting these two types exists, its use is restricted to military personnel due to concerns about viral-shedding and the potential for genetic recombination. To overcome these limitations, we recently developed a virus-like particle (VLP) platform as an alternative vaccination strategy. These VLPs are stable, lack genomic material, and elicit a potent humoral immune response in mice, effectively neutralizing adenoviral infection. Here, we describe the cryo-EM structure of these VLPs at near atomic resolution. Structural insights are essential to ensure that the neutralizing antigens displayed on the VLPs accurately mimic those of the infectious virion, guide the design of particles with improved stability and efficacy, and enable engineering of VLPs with antigenic properties targeting multiple adenovirus types. The structure confirms that the key epitopes capable of eliciting neutralizing antibodies are appropriately displayed for antibody recognition. It also reveals previously unobserved interactions critical for capsid maturation. The penton base adopts multiple conformations when interacting with hexons, and its proper positioning is necessary to facilitate hexon-pIIIa interactions that stabilize the capsid. A comparison of the VLP with immature and mature adenovirus structures shows that core-genome packaging strengthens interaction between cementing proteins pIIIa and pVIII and the hexon shell.