RNA and Codon-optimised Synthetic Genes in HIV specific DNA Vaccination: From epidemiology to clinical trials.
Ralf
Wagner1,2, Jens Wild1, Kurt Bieler1,
Ludwig Deml1, Frank Notka2, Hans Wolf1,
1Institute of Medical Microbiology, University of Regensburg,
Franz Josef Strauss Allee 11; 2GENEART GmbH, Josef-Engert-Straße
9, 93053 Regensburg, Germany
e-mail: ralf.wagner@klinik.uni-regensburg.de
As recently
demonstrated, extensive codon-usage modifications increases the overall GC
content of late HIV transcripts by almost 30% compared to wildtype genome,
enhanced the nuclear stability of viral RNAs and resulted in a constitutive
export of these RNAs into the cytoplasm. Besides that, codon-usage modifications
tremendously supported viral gene expression that turned out to be now independent
from cis acting sequences like RNA packaging elements, Rev and otherwise engaged
cellular RNA binding factors limiting nuclear translocation of HI-viral RNA.
As we
and others showed in immunisation studies in mice with clade B based vector
constructs, vaccination with codon optimised naked DNA induces Th1-type humoral
and cellular immune responses substantially higher than those obtained from
immunisation with the corresponding wt-constructs. Furthermore, those constructs
alone as well as in combination with protein- and MVA-booster immunisations
induced antiviral cellular immune responses in rhesus macaques leading to
stable CD4 cell counts, a containment of virus replication and protection
from disease progression after virus challenge (SHIV89.6P).
These
encouraging results justified extensions to human trials with analogous vaccine
constructs encoding GagPolNef and Env polygenes derived from a clade C molecular
clone (CN54) representing the prevalent virus circulating throughout China
as shown earlier by intensive epidemiological studies. Currently available
delivery systems (GMP grade materials) include plasmid DNA vaccines lacking
any antibiotic resistance gene as well as a replication deficient vaccinia
virus (NY strain) expressing the analogous set of antigens. Vaccination studies
with preGMP plasmid DNA alone as well as prime-boost regiments using NY-vaccinia
virus in Balb/c mice revealed the induction of cellular and humoral immune
responses.
Following
successful toxicology a first phase 1 clinical trial coordinated by the EUROVAC
network has started few weeks ago to test an initial set of immunogens in
human volunteers.