Adenoviruses as vaccine vectors

Abstract

Adenoviruses have transitioned from tools for gene replacement therapy to bona fide vaccine delivery vehicles. They are attractive vaccine vectors as they induce both innate and adaptive immune responses in mammalian hosts. Currently, adenovirus vectors are being tested as subunit vaccine systems for numerous infectious agents ranging from malaria to HIV-1. Additionally, they are being explored as vaccines against a multitude of tumor-associated antigens. In this review we describe the molecular biology of adenoviruses as well as ways the adenovirus vectors can be manipulated to enhance their efficacy as vaccine carriers. We describe methods of evaluating immune responses to transgene products expressed by adenoviral vectors and discuss data on adenoviral vaccines to a selected number of pathogens. Last, we comment on the limitations of using human adenoviral vectors and provide alternatives to circumvent these problems. This field is growing at an exciting and rapid pace, thus we have limited our scope to the use of adenoviral vectors as vaccines against viral pathogens.

Fig. 1

Organization of the adenovirus genome. The different early and late transcription units and the orientation of transcription are shown.

Fig. 2

Generation of an E1-deleted adenovirus vector from a molecular viral clone.

Fig. 3

CD8⁺ T cell responses to Ad vectors. The graphs show the frequencies of transgene product-specific CD8⁺ T cells induced by adenoviral vectors of the human serotype 5 (bottom) and chimpanzee serotype 68 (top). Mice were injected intramuscularly with 10¹⁰ vp of vector. Ten days later, splenocytes were cultured for 5 h with the peptide carrying the immunodominant epitope of the transgene product (right) or an unrelated peptide (left) in presence of brefeldin. Cells were then stained with a FITC-labeled antibody to CD8 and, upon permeabilization of the membrane, with a PE-labeled antibody to interferon (IFN-γ). Cells were analyzed by two-color flow cytometry; data were analyzed by WimnDi software. Events were gated onto live cells. The percentages of double-positive cells (CD8 cell producing IFN-γ) over FITC-positive cells (CD8⁺ cells) were determined and are displayed in the upper right quadrants.