Biology Reference
In-Depth Information
expression in the non-antigen presenting cells (i.e. the myocyte) would
result in immune tolerance or non-responsiveness. Several groups
have demonstrated that antigen produced in the muscle can be
transferred into professional antigen-presenting cells by a method
known as cross-priming such that cytolytic T cells are generated.
14-16
Additional studies revealed that the vector backbone of the plasmid,
because it is bacterial DNA with a different methylation pattern than
mammalian DNA, stimulates the innate immune system via a Toll-Like
Receptor, thus potentially affecting the immunogenicity of the DNA
vaccine and increasing its potency.
17
Nevertheless, despite these novel mechanisms contributing to the
immunogenicity of the DNA vaccines, it became apparent that, while
robust in a variety of animal models, DNA vaccines require larger
doses or different adjuvants in non-human primates and humans at
least partly since their innate sensors are different.
4,5,9,10,18,19
These
observations have resulted in a variety of modifications to make the
DNA vaccines more potent.
Licensed Vèterinary DNA Vaccines
In 2005, the first veterinary DNA-based vaccines were licensed, for
salmon against infectious hematopioetic necrosis virus (Apex-IHN,
Novartis) and for horses against West Nile virus infection (Fort Dodge
Laboratories).
A first licensed DNA cancer vaccine for melanoma in dogs encodes
molecules from the tyrosine kinase family. Immunization with foreign
TYR DNA improved survival and even cured dogs with progressing
melanoma. In this case, the heterogenous tyrosinase was able to break
tolerance against the endogenous enzyme.
20
Antibodies appeared to
be the major effector molecules occurring in parallel with tumor
rejection. A similar approach has been initiated for human melanoma.
Patients with melanoma in stages 3-4 have received the murine tyrosi-
nase DNA followed by human TYR DNA. Half of the patients have
developed cytolytic CD8
+
cells directed against a TYR peptide. The
median survival time has not yet been reached, indicating a prolonged
survival.
21
