Adenovirus Vectors Are A Powerful Tool for Vaccine Development And Gene Therapy

In December 2022, the FDA granted marketing approval for Ferring Pharmaceuticals' bladder cancer drug Adstiladrin® (nadofaragene firadenovec-vncg). This is the first FDA-approved gene therapy for the treatment of bladder cancer. In this innovative gene therapy, non-replicating adenoviral vectors play an important role. It carries the human interferon-α 2b gene (IFNα2b). Under the synergistic effect of a surfactant excipient Syn-3, the adenoviral vector delivers IFNα2b to targeted bladder cancer cells, inducing apoptosis of human BCG-unresponsive bladder cancer (BLCA) cells.

Adenoviruses Overview

Adenoviruses are non-enveloped, double-stranded DNA viruses first discovered in human adenoid tissue in 1953. Adenoviruses usually cause mild, self-limited infections. In humans, adenoviruses usually cause mild respiratory and gastrointestinal infections. Therefore, adenovirus infections usually do not cause clinical symptoms. However, for those who are immunocompromised or have respiratory or heart disease, adenovirus infections can be life-threatening.

Adenoviruses express two types of genes: early genes and late genes. Early genes (E1A, E1B, E2, E3, and E4) are required to support viral replication in host cells; while late genes are required for host cell lysis, viral assembly, and virion release. Recombinant adenoviruses produced as vectors in the laboratory can be either replication-deficient or replication-competent. Replication-deficient adenoviruses can achieve the efficacy of using the adenovirus as a vector virus.

The adenovirus replication cycle is strictly controlled by the expression of the E1 protein, as the E1 gene is essential for viral replication. So-called E1-deleted viruses are generated by deleting E1 from the viral genome, which are able to infect host cells but cannot grow in large quantities due to replication defects. This modification of adenovirus provides the opportunity to generate replication-defective adenoviral vectors. In addition, the insertion of foreign DNA expressing one or more desired proteins has been successful under the control of a heterologous promoter located in the pre-E1 region. Therefore, it is now possible to easily achieve high expression of desired proteins in target cells using E1-deleted adenoviral vectors.

Features And Advantages of Adenoviral Vector Therapy

Adenoviruses have long been a popular viral vector for gene therapy because they are able to affect both replicating and non-replicating cells, accommodate large transgenes, and encode proteins without integrating into the host cell genome. More specifically, they are used as vectors to load recombinant DNA or protein therapeutics for targeted therapy by infecting targeted cells. This therapy is particularly useful in treating monogenic diseases (such as cystic fibrosis, α1-antitrypsin deficiency, etc.) and cancer.

Recombinant adenoviral vectors have been around for a long time, and the current adenoviral vectors are already their third generation. Active research around them has had a revolutionary impact on the field of gene therapy and vaccine production. People can now make conditionally replicating adenoviral vectors that only replicate in tumor cells, making adenoviral vectors a powerful tool for cancer treatment.

The advantages of adenoviral vector technology can be reflected in the following aspects:

(1) High transduction efficiency of dividing cells and quiescent cells

Adenoviral vectors can deliver genetic cargo to cells very efficiently, so therapeutic levels can be achieved with fewer viral particles.

(2) Persistence

The persistence of the vector is important for the delivery, transcription, and expression of the genetic payload as a therapeutic protein. Since adenoviral vectors do not integrate into the chromosomes of host cells, there is no risk of permanently altering the host's genetic composition.

(3) Broad tissue tropism

Many wild-type adenoviruses have been modified to create adenoviral vectors, providing a range of different tissue tropisms. By modifying the knob protein at the protruding end of the fiber capsid (this protein is the key to unlocking entry into specific cells through receptor-specific binding), adenoviral vectors that can precisely target specific tissues can be made.

(4) Scalable production

Adenovirus can achieve scalable industrial production.

Cat.No.	Product Name	Price
ONCOADV-001	Ad5-hTERT-E1A-E1B[GFP] Oncolytic Adenovirus	Inquiry
ONCOADV-002	Ad5/RGD-hTERT-E1A-E1B[GFP] Oncolytic Adenovirus	Inquiry
ONCOADV-003	Ad5-E1A(D24)-E1B[GFP] Oncolytic Adenovirus	Inquiry
ONCOADV-004	Ad5/RGD-E1A(D24)-E1B[GFP] Oncolytic Adenovirus	Inquiry
ONCOADV-005	Ad5-hTERT-E1A-E1B-mCMV-mGM-CSF Oncolytic Adenovirus	Inquiry
AD00007Z	LacZ adenoviral particles	Inquiry
AD00036Z	Human OCT4 adenoviral particles	Inquiry
AD00037Z	Human Sox2 adenoviral particles	Inquiry
AD00038Z	Human myc adenoviral particles	Inquiry
AD00040Z	Human OCT4,Sox2,KLF4 adenoviral particles	Inquiry
AD00043Z	Human E2F1 adenoviral particles	Inquiry
AD00044Z	Human hTERT adenoviral particles	Inquiry
AD00045Z	Human GPR6 adenoviral particles	Inquiry
AD00046Z	Human DRD1 adenoviral particles	Inquiry
AD00047Z	Human DRD2 adenoviral particles	Inquiry

Clinical Application of Adenovirus Vectors

(1) Vaccines

With regard to vaccine development, the main purpose of DNA vectors is to deliver epitopes from other viruses to host cells and ensure the production of such epitopes to enhance immune responses. Adenovirus vectors have demonstrated effective loading capacity (both in terms of the amount of load and the molecular weight of the load). In addition, the immunogenicity of some adenovirus vectors has been adjusted and exploited to stimulate the production of pro-inflammatory cytokines, thereby enhancing humoral and cellular immune responses.

AdHu5 (human type 5 adenovirus vector) vectors express three HIV antigens gag, pol, and nef, and are the most widely studied HIV vaccines in the world. However, this vaccine fails to reduce viral load in clinical practice and increases the risk of HIV infection in AdHu5 seropositive men. Another potential HIV vaccine candidate is the AdHu5 vector (replication-deficient) expressing the simian immunodeficiency virus gag protein, which has been shown to reduce viral load in preclinical settings.

Janssen has successfully developed an adenovirus vector-based Ebola vaccine. Clinical results have shown that the vaccine can induce a strong humoral immune response in the human body that lasts for more than a year. Adenovirus vectors can also be seen in vaccines against the SARS-CoV-2 virus. However, the two failed adenovirus vector-based Covid-19 vaccine developments (Phambili and STEP) have also raised concerns about the increased infection rate of HIV-1 virus in men. Despite this, adenovirus vectors remain the preferred vector for many different vaccine strategies, including HIV, Zika virus, malaria, and tuberculosis. In addition, adenovirus vectors are also widely used in the production of cancer vaccines. Current vaccine research focuses on prostate cancer, human papillomavirus, colorectal cancer, and pancreatic cancer.

(2) Gene therapy

In terms of gene therapy, adenovirus vectors have been very successful in the field of targeted therapy. The ability to modify fibrin and locally inject adenovirus vectors means that gene therapy can be strictly limited to specific areas of the body. Gene therapy for treating the eye and targeting specific tumors has been well established using adenovirus vectors. Another popular use is in ex-vivo therapy. In these areas, adenoviral vector therapy has very promising preclinical success rates.

References:

Lee C S, et al. Adenovirus-mediated gene delivery: potential applications for gene and cell-based therapies in the new era of personalized medicine. Genes & diseases, 2017, 4(2): 43-63.
Thacker E E, et al. A genetically engineered adenovirus vector targeted to CD40 mediates transduction of canine dendritic cells and promotes antigen-specific immune responses in vivo. Vaccine, 2009, 27(50): 7116-7124.
Buchbinder S P, et al. Use of adenovirus type-5 vectored vaccines: a cautionary tale. The Lancet, 2020, 396(10260): e68-e69.

* For research use only. Not intended for any clinical use.

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