Summary Statement: ADARC Program Project on HIV/SIV Vaccine Development

PAGE 28

1 P01 AI43042-01 3 SEP
Ho, David D.
strategy to move forward to human testing in a timely manner. While the
construction of an env protein that stimulates antibodies to critical epitopes
is a worthwhile goal, it has -sued by many other investigators.
In addition, it is com y unclear from the applica i hich Principal
Investigator would be doing what making it nearly impossible to udge the
ability to make the n essary constructions.
Projects 1 was scored in the very good range, whereas Projects I and 3
received priority scores in the good range. Cores B and C were considered
appropriate, while Core A was rated as inappropriate. The overall application
consisting of projects 1, 2, and 3, and Cores B and C received a priority i
score in -thegood range with a numerical value of 330.
OVERALL DESCRIPTION (adapted from application): The major goal of this
application is to conduct preclinical and animal-model reseSch towards the
development of practical immunogens that may constitute, or contribute to, an
effective prophylactic vaccine against HIV-1 infection. The applicants plan
to carry out projects aimed at: (1) determining the correlates of protective
immunity elicited in rhesus macaques by a live, attenuated strain of SIV; (2)
characterizing a panel of HIV-1 strains to select an ideal viral strain for
use to construct candidate vaccines, to develop an appropriate SHIV-macaque
model, and to modify the envelope glycoprotein for enhanced immunogenicity;
(3) designing and evaluating vaccine strategies based on priming with either
recombinant vaccine or DNA vaccines, followed by boosting with pseudovirions
or different forms of the envelope glycoproteins. Furthermore, the applicants
intend to focus on the development and evaluation of immunogens based on HIV-1
clade C, the most prevalent subtype worldwide. They plan to conduct research
by an iterative process, in which th h l attempt to continually refine
laboratory-based r ch grams based upo the results of their animal
experiments. e a icants emphasize that- he are roposing not a basic
science progra, but one that is -y aI at the dev ment and
testing of vacc" e candidates ough no clinical evaluation is proposed in
the application, the applicant express their readiness to ex their
studies should results of preclin and animal stud rrant this, and
assess promising vaccine strategies in human populations, especially in
regions where subtype C is spreading rapidly, notably in southern Africa,
India, and southwestern China.
In Project 1, the applicants will attempt to identify the mechanisms by which
nef.-deleted SIVmac-immunized macaques are protected from infection after
challenge with homologous or heterologous pathogenic SIVs and SHIVs. In
observational studies, the investigators will try to identify the temporal
correlation between induction of various immune responses and the onset of
protection in macaques immunized with nef-deleted SIVmac. This will be done
by using archived specimens from an earlier project. Previous data from this
experiment showed no correlation between CTL or antibody responses measured at
the time of challenge and protection, so the investigators now intend to look
at ADCC, complement activation, the role of CTL, the immune responses, NK
activity, and non-specific immune factors, such as cytokines, beta-chemokines,

Continued