another look at phase iia results

Reading though the paper:

http://www.virax.com.au/downloads/Scientific_Papers/Influence_of_IFNy_Co_Expression_1.pdf

It's interesting to see that the small sample size (n=10 on full construct vaccine) produced lower viral load with p=0.06. Given the current Phase II trial in Africa is using a dose 10 times higher than the IIa trial, and that patients are receiving the vaccine monthly (rather than one off) it's going to be very interesting looking at the in depth results. Is anyone else excited, or is it just me?

"Both rFPV‑based vaccines (PC and FC) were shown to be safe and
well tolerated when given to subjects who previously received three
doses of the construct in a previous trial.14
The primary study endpoint (mean time‑weighted change from
baseline in viral load) was approximately one log lower in those
receiving the FC compared to those that received either the PC
or placebo. This suggestion of an effect of the FC was consistently
demonstrated across a variety of analytical approaches including
covariate analysis although not attaining statistical significance,
This is possibly due to the small study size. In the multivariate
modelling age was the only covariate other than vaccine associated
with differential effect on viral load. There was a statistically
significant reduction in time to pVL 10,000 and when adjusted
for age, multivariate analysis demonstrated that PC recipients were
approximately 4.5 times more likely to reach pVL 10,000 than FC
recipients.
The major effect of FC seems to be a blunted recrudescence of
pVL. This recrudescence appears to follow very similar patterns in
the placebo and the PC groups. In both groups, after the initial rise
there is a consistent pattern of equilibration to a variable set‑point
that appears relatively stable thereafter. In the FC group, there appear
to be two discernable patterns of pVL recrudescence. Two patients
(20%) experienced a rapid increase in pVL within the first 5C7 weeks
of ceasing CART, while the remainder (80%), appeared to exert
varying degrees of control over HIV replication throughout the period
of study with some patients experiencing negligible recrudescence.
In addition, and potentially important to our understanding of the
immunopathology in this group, is a small transient peak within
two weeks of cessation of antiretroviral drugs during which, pVL
levels increased to about 200C300 copies/mL before dissipating.
Thereafter the rate of increase of these curves was highly variable
but appeared to be consistently lower than the experience of subjects
in the other two groups.
The observed antiretrovirological effect of FC was manifest over
the 20 week period of the clinical study. It is therefore unclear if
vaccination with FC had only a transient antiretrovirological effect
which would manifest in no long term clinical benefits for vaccinated
individuals. Future studies should evaluate potential long term
clinical benefits of vaccination by employing longer ATI periods.
In addition it will be critical to ascertain if boosting with FC during
ATI prolongs the period of viral suppression.
No clear immunological correlate could be detected between
arms to explain these results on the basis of the measures of T‑cell
immunity or down stream effects of IFNg or innate immunity
performed on PBMC. Importantly, although these experiments and
their analysis do not provide an immune correlate of this effect,
the data presented here exclude the premise that the improved
response seen in the FC arm could be explained by host factors
associated with good or poor viral control across the treatment
arms.
The reason for the failure to measure an immunologic correlate
in this study is unclear. The FC was designed to induce a strong
cell‑mediated immune response, as previously observed in macaques.13
There remains the possibility that FC vaccination has primed the
immune system appropriately prior to the Analytical Treatment
Interruption (ATI), the treatment interruption effectively boosting
other unmeasured responses to autologous virus.12 Alternatively as
fowlpox persists for greater than a week, IFNg expression may be
affecting viral replication directly via modulation of the immune
response upon uptake of the FC by antigen presenting cells and
release of the wildtype HIV upon ATI.
It is interesting to compare these results with those of previous
studies where ATI was performed after therapeutic vaccination.
In the Quest study patients who had commenced ART very soon
after primary infection were vaccinated with either the canarypox
vector vCP1452 alone or in combination with Remune (Inactivated
HIV Immunogen). There was no significant difference between
placebo and active groups in their ability to control HIV viral replication
in the ATI.11 Comparable results were observed upon
vaccination of a similar patient group with vCP1452 + gp160.25
Despite measurable immune responses being induced in both trials
Figure 4. Time to plasma HIV RNA >10,000 copies/mL for each treatment
group upon discontinuation of antiretroviral therapy (ART) in the analytical
treatment interruption as summarised using Kaplan Meier plots.
266 Human Vaccines 2007; Vol. 3 Issue 6
www.landesbioscience.com Human Vaccines 267
Recombinant Fowl Pox Vector Vaccine for HIV Infection
upon vaccination there was no correlation between immunogenicity
and viral control during ATI.11,25 Contrary to these results upon
vaccination of chronically HIV‑infected patients with the canarypox
vector vCP1433 and the lipopeptides HIV‑LIPO‑6T followed by
three cycles of IL‑2 enhanced viral control of the vaccinated group
was observed that correlated with the measured immune response.26
In summary the FC was demonstrated to be safe and well
tolerated in patients with HIV‑1 infection. Results suggest that the
FC may have the potential to control viral replication during ATI.
It is noted that these studies have been conducted in a small number
of patients and a further study of these constructs is required in
broader populations with HIV disease. Such studies could include a
dose ranging design with an expanded array of assays of the innate
and adaptive immune system so as to further probe the virological
effect and mechanism of action of this promising immunotherapeutic
vaccine. To support further late stage development of FC such trials
would have to demonstrate significant viral load reduction relative
to the placebo arm that might retard decline in CD4 cell count.
A promising application for a HIV therapeutic vaccines possessing
such characteristics would be the lengthening the time between
primary HIV infection and the need to commence CART."