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Adenovirus (AdV) vector-based vaccines

Adenovirus (AdV) is a member of the family Adenoviridae, whose name derives from their initial isolation from human adenoids in 1953 [42]. It is a medium sized (90-100nm) and non-enveloped virus with an icosahedral nucleocapsid containing a 36kb double stranded DNA genome (Fig. 7A). Hexon and penton structures form the capsid of AdV, and fiber protein mediates the binding of the virion to the cell surface and is a major determinant of viral tropism. Adenovirus transcription is a two-phase event, early and late, occurring before and after viral DNA replication, respectively (Figure. 7B). The early transcribed regions are E1A, E1B, E2A, E2B, E3, and E4, involved in viral transcription regulation, viral DNA replication, and the suppression of host immune response during infection. The late transcribed genes are L1-L5, encoding viral capsid components (Fig. 7B).

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Figure 7. Schematic of the adenovirus genome and adenovirus-based vectors. (A) Capsid crystal structure. (B) Adenovirus gene map. Top panel: a simplified map of the adenovirus serotype 5 genome showing the early genes (E1–E4) and the region from which the major late transcript is produced. Middle panel: general structure of an early region 1 (E1)-deleted Ad vector. Bottom panel: general structure of a helper-dependent Ad vector [43].

Principle

Principle of AdV entry into cells

For most serotypes, adenovirus infection is mediated by the high-affinity binding of the fiber-knob region to a receptor of target cell, named as the coxsackie-Ad receptor (CAR), which mainly determines the viral tropism [44]. Upon attachment, interaction between the penton-base Arg-Gly-Asp (RGD) and cellular αv integrins, which can stimulate actin polymerization, leads to internalisation of the virus into the endosome. Then the endosome acidifies, resulting in disassociation of capsid proteins and transportation of viral DNA into nucleus. Without integration into host genome, adenovirus genome remains in an episomal state, which guarantees the low risk of mutation (Fig. 8). Life cycle of adenovirus is separated by DNA replication process into two distinct phases: the early and late, occurring before and after viral DNA replication, respectively. After the synthesis of viral genome and capsid, they are assembled into viral products, releasing out of cell, and the infected cell starts lysis [45]. To prevent infected cell lysis, recombinant replication deficiency virus has been developed as a gene delivery tool to replace wild-type adenovirus (recombinant AdV in “application” part). Once packaged into a E1-complementing cell line, which provides the E1 products in trans, such as QBI 293A Cells, recombinant viral will be easily propagated. Picture loading failed.
Figure 8. Infection process of adenovirus. CAR receptor-fiber-knob adenovirus interaction and internalization process [46].

Immune responses induced by AdV

The entry of AdV into human body stimulates a wide spectrum of innate cellular responses, which might last a few minutes to hours and result in blood pressure changes, thrombocytopenia, inflammation, and fever [47]. AdV vector in blood activates vascular endothelial cells to release von Willebrand factor (vWF), induces platelets to expose the adhesion molecule P-selectin, and promotes the formation of platelet-leukocyte, ultimately leading to thrombocytopenia and bleeding [48]. Additionally, the hexon component of AdV capsid can bind to coagulation factor X (FX) to activate TLR4 on the surface of splenic macrophages and thereby stimulate NF-κB dependent activation of IL-1β, which may help recruit polymorphonuclear leukocytes to the marginal zone of the spleen and clear virus from the spleen rapidly [49, 50]. Besides binding to coagulation proteins, AdV in blood vessel can also bind to component C3 and natural [51-55]. Antibody-AdV complexes can provoke inflammatory cytokine and chemokine responses in macrophages via the intracellular antibody receptor TRIM21 [56-59].

In addition to innate immune responses in circulation, AdV virions can also be trapped by splenic macrophages (MFs) of the MARCO subset via the binding of fiber knob of the capsid to integrin b3 receptor [60]. This binding process leads to the release of IL-1α and activation of IL-1 receptor, promoting chemokines production and attracting other innate immune cells to kill AdV infected MFs [61]. AdV also activates the NLRP3 inflammasome to recruit proinflammatory caspases and promote IL-1β expression, thereby resulting in necrotic cell death [62]. Cytosolic sensing of AdV DNA via cyclic GMP-AMP synthase (cGAS) binds to stimulator of interferon genes (STING) to promote IRF3 phosphorylation to produce type I IFN [63, 64]. Moreover, AdV DNA is also sensed by the endosomal receptor TLR3, TLR7, and TLR9 to activate MyD88 signaling pathway. Nuclear sensing mechanisms of AdV DNA can also promote or inhibit immunity [65, 66]. These pathways cooperate to regulate the immune responses triggered by AdV vectors.

In the meantime, AdV also provoke highly effective adaptive immune responses, and the mechanism is similar to that of AAV. But contrary to AAV, AdV triggers a particularly strong CD8+ T cell responses, which is facilitated by potent induction of Th1 immunity [67]. Due to the induction of extremely strong immune responses, AdV vectors are a prerequisite vector for vaccine development. Picture loading failed.
Figure 9. Schematic principle of AdV-induced innate immune responses [15]. dsDNA: double-stranded DNA; NLPR3: NACHT, LRR and PYD domains-containing protein 3; ASC: Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD; Pro-casp 1: pro-caspase 1; IFNAR-1: interferon alpha/beta receptor 1; Jak1: Janus kinase 1; Tyk2: tyrosine kinase 2; Stat: signal transducer and activator of transcription; P: phosphoryl group; MDA5: melanoma differentiation-associated protein 5; dsRNA: double-stranded RNA; RIG-I: retinoic acid-inducible gene-I; MAVS: mitochondrial antiviral signaling protein; STING: stimulator of interferon genes; IRF: interferon response factor; cGAS: Cyclic GMP-AMP Synthase; TLR: toll-like receptor; ISG: interferon-stimulated genes; IFN: interferon; MyD88: myeloid differentiation primary response protein (88); NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ssRNA: single-stranded RNA.

Application

Recombinant AdV

Since wild-type adenovirus is associated with a wide range of illnesses and enlists a variety of immune responses, so recombinant replication deficiency virus has been an attractive vector for gene therapy [68]. To date, there have been many different generations of adenovirus vectors, differing in the extent to which the genome from wild-type adenovirus is attenuated. Based on human adenovirus type 5 (Ad5), recombinant adenovirus (Ad) a replication-defective adenoviral vector system, is widely used for gene delivery in most dividing and non-dividing cells based on its advantages in high transduction efficiency, high level of transgene expression, and broad range of viral tropism [69]. Traditionally, recombinant adenovirus vectors used in gene delivery were prepared with a plasmid containing the transgene flanked by inverted terminal repeats (ITRs), co-transfected with packaging plasmid pAd-BHGlox(delta)E1,3 (Fig. 10). Once packaged into a E1-complementing cell line, such as QBI 293A cells, recombinant viral will be easily propagated. Picture loading failed.
Figure 10. The two plasmids co-transfection system of recombinant adenovirus. pAd-EF1-MCS-CMV-EGFP: an adenovirus ITR-containing plasmid carrying multiple clone sites, which can be cloned into a transgene; pAd-BHGlox(delta)E1,3: a packaging plasmid.

AdV vector-based gene therapy

To date, more than 535 clinical trials have been carried out using adenovirus vectors for gene delivery [17], and promising gene therapy outcomes from recombinant adenovirus have been achieved from clinical trials for a great number of diseases, especially for cancer treatment, such as prostate cancer [70], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [71], non-small cell lung cancer (NSCLC) [72], melanoma [73], renal cell carcinoma [74].

AdV vector-based vaccine development

As a viral vector used for vaccine production, AdV induces strong immune responses and show better superiority than other viral vectors. In clinical trials, AdV vector-based vaccines have been used to prevent HIV-1 [75, 76], influenza [77], tuberculosis [78], and solid tumors [79]. Some of examples in clinical trials are listed in Table 4 [80]. However, there are also some reports with discouraging outcomes. For example, Ad5 vector with neutralizing antiserum against HIV contrarily significantly facilitated HIV infection besides the enhanced immune responses [81]. The pre-existing anti-AdV immunity against Ad5 is proved to be another limiting factor for the clinical application of Ad vector-based vaccines [82]. Therefore, although AdV vector exhibits some advantages over AAV vector in vaccine production, there are also some safety hazards and pre-existing anti-AdV immune responses needed for further exploration.

Table 4 - Examples of AdV vector-based vaccines [80]
Target Disease Status Clinical trials
Infectious diseasesHIVPhase I/II
NCT00865566;
NCT00413725

HIVPhase II
NCT00415649;
NCT00125970;
NCT00498056;
NCT00123968;
NCT00095576;
NCT00080106;
NCT00350623;
NCT01159990

MalariaPhase I/II
NCT00870987;
NCT00392015;
NCT01366534;
NCT01397227

MalariaPhase II
NCT01666925;
NCT01658696;
NCT00890760

Hepatitis C virusPhase I/IINCT02309086
Ebola virusPhase I/IINCT02289027
Ebola virusPhase IINCT02344407
TuberculosisPhase I/IINCT01017536
TuberculosisPhase IINCT01198366
RotavirusPhase IIINCT01305109
CancerColon/breast/lung/head/neck/renalPhase I/II
NCT00049218;
NCT00669136;
NCT00880464;
NCT00776295;
NCT00082641;
NCT00093548;
NCT01042535;
NCT00617409

Colon/breast/lung/head/neck/renalPhase II
NCT00589186;
NCT01147965;
NCT01924156

ProstatePhase II
NCT00583752;
NCT00583024

LymphomaPhase II
NCT00849524;
NCT00942409

Solid tumor/tissue sarcomaPhase I/II
NCT02285816;
NCT01898663

Leukemia/glioblastomaPhase II
NCT01773395;
NCT00589875

MelanomaPhase I/II
NCT00039325;
NCT00704938;
NCT00010309

MelanomaPhase IINCT00004025

Advantages and disadvantage

There are many advantages of AdV as a vector for clinical trials: ① well tolerated with no obvious influences on the cell viability after infection; ② great packaging capacity (up to 8kb); ③ broad range of infectivity, from dividing cells to non-dividing cells; ④ high infection efficiency; ⑤ no integration ability into the host genome, remaining epichromosomal in host cells, thus no oncogenicity; ⑥ inducing a wide variety of immune responses, including humoral and cellular immunity. These advantages make AdV as an excellent vector for vaccine development. 

Although adenovirus benefits a great deal of disease prevention, it does present some drawbacks: ① AdV-mediated gene delivery may not sustain for long time, just transient expression; ② pre-existing immunity and neutralizing antibodies (NAB) against AdV vectors might attenuate the preventive effects of AdV vector-based vaccines [83]; ③ despite reduced overall virulence, recombinant Ad5-based vectors exhibit a strong tropism for liver parenchymal cells due to the high expression level of CAR in hepatocytes, which increases hepatotoxicity and limits the clinical use of AdV vectors [84].

Optimization

Several measures were taken to improve the efficacy of AdV vector for vaccine development: ① modify the fiber protein to alter the tissue tropism and decrease the hepatic toxicity [85]; ② reduce viral vector-derived immune responses by changing virus gene expression, such as deleting E1 and E4 gene of AdV [86]; ③ modify the fiber protein to enhance the transduction of T cells and dendritic cells [87].

Genemedi got a rich experience in adenovirus packaging, you could find more information on https://www.genemedi.net/i/adenovirus-packaging.


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