Biology Reference
In-Depth Information
to their widespread development and testing for prevention and
treatment of a variety of diseases.
DNA vaccines were a surprising development from efforts to for-
mulate bacterial plasmid DNA for uptake by cells
in vivo
. Because
viruses have evolved complex structures and mechanisms in order to
deliver their genetic material into cells, it was long thought that so-
called “naked,” unformulated DNA would not be useful as a means
to directly deliver genes into cells
in vivo
. Thus the observation by
Felgner and colleagues that bacterial plasmid DNA suspended simply
in saline could result in the uptake of the DNA (albeit relatively inef-
ficiently) by muscle cells
in vivo
— with the subsequent transcription
and translation of the encoded genes — came as a surprise.
1
Just as
unexpected was the ability of the DNA to result in the generation of
a cytotoxic T lymphocyte response that was effective at protecting
against a viral challenge,
2
because myocytes are not professional
antigen-presenting cells (APC), and presentation of antigen by a non-
professional APC usually results in tolerance or non-response rather
than activated cytolytic T cells. The effectiveness of the DNA for the
induction of immune responses was striking because the DNA was able
to induce both antibodies and T cells against the encoded antigen. And
as noted above, the cellular immune response was potent enough to
protect against death (but not disease) from a viral challenge.
Moreover, the challenge virus was of a strain different from the strain
from which the antigen gene had been cloned (i.e. it was heterosub-
typic). This type of cross-strain immunity is one of the great chal-
lenges of vaccine development for diseases such as influenza and HIV
where the virus mutates frequently and easily enough such that anti-
body responses against one strain are ineffective against another
strain. In the case of influenza this means that the vaccine must con-
tain several different strains of virus, and the vaccine composition
must be made new each year to provide the strains that are judged to
be the currently circulating strains. In the case of HIV, the tremen-
dous variability of the virus is one of the major reasons that no vac-
cine has been made to date.
A number of other rationales exist for delivery of proteins in the form
of genes rather than as proteins. For example, cytokine administration
