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Review
. 2022 Dec 6;14(12):2727.
doi: 10.3390/v14122727.

Significance of Preexisting Vector Immunity and Activation of Innate Responses for Adenoviral Vector-Based Therapy

Wen-Chien Wang  1 , Ekramy E Sayedahmed  1 , Suresh K Mittal  1
Affiliations
Review

Significance of Preexisting Vector Immunity and Activation of Innate Responses for Adenoviral Vector-Based Therapy

Wen-Chien Wang et al. Viruses. .

Abstract

An adenoviral (AdV)-based vector system is a promising platform for vaccine development and gene therapy applications. Administration of an AdV vector elicits robust innate immunity, leading to the development of humoral and cellular immune responses against the vector and the transgene antigen, if applicable. The use of high doses (1011-1013 virus particles) of an AdV vector, especially for gene therapy applications, could lead to vector toxicity due to excessive levels of innate immune responses, vector interactions with blood factors, or high levels of vector transduction in the liver and spleen. Additionally, the high prevalence of AdV infections in humans or the first inoculation with the AdV vector result in the development of vector-specific immune responses, popularly known as preexisting vector immunity. It significantly reduces the vector efficiency following the use of an AdV vector that is prone to preexisting vector immunity. Several approaches have been developed to overcome this problem. The utilization of rare human AdV types or nonhuman AdVs is the primary strategy to evade preexisting vector immunity. The use of heterologous viral vectors, capsid modification, and vector encapsulation are alternative methods to evade vector immunity. The vectors can be optimized for clinical applications with comprehensive knowledge of AdV vector immunity, toxicity, and circumvention strategies.

Keywords: adenoviral gene therapy; adenoviral immunity; adenoviral innate immunity; adenoviral vector immunity; adenoviral vector vaccine; adenovirus capsid; adenovirus tropism; blood factor; circumvention of preexisting vector immunity; hepatic toxicity; preexisting immunity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Genome organization and structure of human adenovirus type 5. (A) Schematic representation of the adenoviral genome, transcription units, and major proteins. (B) Structural representation of adenovirus and its components. E, early region (shown as red arrows); L, late region (shown as black arrows); L’-ITR, left inverted terminal repeat; R’-ITR, right inverted terminal repeat; Ψ, packaging signal; AdPol, adenovirus DNA polymerase; TP, terminal protein; DBP, DNA-binding protein.
Figure 2
Figure 2
Transportation of human adenovirus type 5 or its genome within a host cell. The adenoviral knob domain binds to the CAR on the host cell surface. Following receptor binding, the fibers start to disassociate, exposing the RGD loop of the penton to interact with αv integrins, thereby initiating endocytosis. The endosome’s acidic environment results in the dissociation of the penton base and peripentonal hexon, followed by protein VI-mediated lysis of the endosome. The viral particle is transported to the nuclear membrane by microtubule motors. Finally, the adenoviral genome is transported to the nucleus through the nuclear pore complex. CAR, Coxsackievirus and adenovirus receptor; RGD, arginine–glycine–aspartic acid; GTPase; guanosine triphosphate hydrolase.
Figure 3
Figure 3
Activation of innate and adaptive immune responses in response to an adenoviral (AdV) vector. Following inoculation with an AdV vector, activation of innate immunity leads to the expression of proinflammatory chemokines and cytokines. Following antigen expression, processing, and presentation, humoral and cell-mediated immune responses develop. The resultant vector immunity will eliminate the vector, leading to a reduced duration of transgene expression. The development of vector-specific neutralizing antibodies (NAbs) and memory T cells provide long-term vector immunity and suppress subsequent inoculation with the same AdV vector. PAMP, pathogen-associated molecular patterns; TLRs, Toll-like receptors.
Figure 4
Figure 4
Circumventing strategies against preexisting vector immunity. (A) Inoculation with a rare human adenoviral (HAdV) or nonhuman AdV can evade the preexisting vector immunity. (B) Since most of the neutralizing antibodies (NAbs) target the capsid proteins, such as the fiber and hexon, exchanging the capsid and/or fiber proteins with a different AdV type can elude the preexisting vector immunity. (C) Chemical encapsulation can mask the AdV vector from antibody-mediated neutralization. (D) The use of different routes of inoculation or different vector platforms (prime–boost approach) can circumvent the preexisting vector immunity. ChAdV, chimpanzee adenovirus; PEG, polyethylene glycol.
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