Design of Adenovirus Based Vaccines for Cancer
The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for use as vaccines and therapeutics relatively straightforward in comparison with other viral vectors. Creative Biolabs is a world leader in the field of cancer vaccine development. With our extensive experience and advanced platform, we are therefore confident in offering the best development services for adenovirus-based vaccines. We guarantee the finest results for our customers all over the world.
Molecular Biology of Adenoviruses
Adenovirus is a non-enveloped double-stranded DNA virus. The 36 kbp genome accepts cDNA sequences up to 7.5 kbp. Replication of the genome occurs in the nucleus but remains extrachromosomal, minimizing the risk of insertional mutagenesis with this vector. Adenovirus can infect proliferating and resting cells and express transgenes with high efficacy. The majority of adenoviral vectors are replication-incompetent, following deletion of E1 and E3 viral genes. This limits their pathogenicity, while still allowing for the generation of a humoral and cellular response to transgenes. Adenoviral vectors are stable and easily propagated in laboratory settings, which allow researchers to easily modify the vector; this includes retargeting the virus’s tropism to enhance infection of DCs and target cells lacking the common Ad receptor, which is critical for infection. Adenovirus induces neutralizing antibodies in infected hosts, thus limiting the number of vaccinations.
Recombinant Adenoviruses as Vaccine Vectors
Adenoviruses have proven promising for vaccine vector development because they are capable of eliciting T and B cell responses to both self-antigens. The rationale underlying cancer vaccines is that they should enable the immune system to recognize cancer cells and influence their growth or lead to their eradication. One approach is immunization against tumor-specific antigens, which can be achieved via adenovirus-mediated delivery of tumor-associated antigens (TAAs) or immunomodulatory molecules. Adenoviruses as vaccine vectors are potentially as safe, or safer than live attenuated vaccines because the theoretical risk of reversion to virulence of the attenuated pathogen is extremely low, if not absent. Also appealing is that adenoviruses offer the possibility of targeting any antigen of interest.
There are several ways to create space for inserting foreign DNA (i.e., the antigen of interest) into adenoviruses. Most of the currently investigated recombinant adenovirus-based vaccine vectors are vectors of first and second generation where foreign DNA can be inserted into at least three regions of the adenoviral genome: the E1, E3, and the short region between E4 and right ITR.
Recombinant adenovirus vectors transduce both quiescent and actively dividing cells, can be produced at very high titers, have relatively high capacity for transgene insertion, and allow high expression of the recombinant protein. After entering the nucleus, adenoviruses do not integrate into the host genome, avoiding the risk of insertional mutagenesis and increasing the safety of these vectors. First-generation adenovirus vectors provide only transient transgene expression, and while this is of limited benefit for gene therapy, it is nonetheless adequate for cancer treatment and vaccination.
Our Strategies to Overcome Anti-Adenovirus Vector Immunity
Activation of host innate immune responses and preexisting immunity to common adenovirus serotypes may limit the efficacy of adenovirus-based vaccine vectors. Adenovirus vector-specific cytotoxic T cells and neutralizing antibodies may impede the induction of immune responses to the vaccine-encoded antigens, as they may reduce the dose and duration of exposure of target cells to the vaccine antigens. These features have forced the development of new strategies to evade undesired antivector host immune responses, including the search for other types of adenoviruses that occur at low prevalence in human populations.
- Different human and nonhuman adenovirus serotypes as a platform for vaccine development
- Capsid-modified adenovirus-based vaccine vectors
- Heterologous prime-boost regimens utilizing adenovirus vectors
Replication-Deficient Adenoviruses Expressing Tumor-Associated Antigens or Immunomodulatory Molecules
While CD4+ cytotoxic and helper T cells appear to be effective in de-bulking tumor mass in animal models, CD8+ cellular activation is considered to be equally important for successful immunotherapy. Skin or lymph node resident DC subsets are capable of cross-priming CD8+ cells through cross presentation of the exogenous antigens. Adenoviruses have been shown to generate antitumor immunity in animal models by transfer of TAA to DCs. TAA can be introduced to DCs either directly by infecting them with adenovirus, or by indirect TAA uptake from TAA-coding adenovirus infected cells. Melanoma specific antigen coding adenovirus-transduced DCs induced broader and stronger immunity against various peptides of the vaccinated antigen in comparison to a direct peptide loaded DC vaccine.
Oncolytic Adenovirus-Based Vaccines
Even though replication-competent OAds are rapidly cleared from the bloodstream and the tumor microenvironment, they still have potential to induce innate and adaptive immunity against tumors. Oncolytic adenoviruses offer multimodal mechanisms of tumor killing: an initial oncolytic event elicited by the virus resulting in cancer cell lyses, followed by induction of an antitumor immune response as a result of this oncolytic process, or OAd-mediated expression of therapeutic antigen. In this regard, the oncolytic virus can be considered as a vaccine.
Creative Biolabs is a leader in the field of vaccine development and has focused on the cancer vaccines for years. We have experienced experts and advanced platforms that are able to provide excellent services. If you are interested in our services, please contact us for more details.
Reference
- Majhen, D. (2014). “Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field.” Hum Gene Ther 25(4), 301-317.
All of our products can only be used for research purposes. These vaccine ingredients CANNOT be used directly on humans or animals.
