CCR5 Ligand Levels and Immune Response to HIV Vaccines [Revised Proposal]

ZRG1 VACC (01) 5 1 RO1 A1052038-01A1
GARZINO-DEMO, A
This study simply proposed to refine the methodology for measuring chemokines without significant
analysis to evaluate the relevance of these chemokines in protection.
Whereas the majority of the preliminary data showing chemokine generation was generated only on
fresh cells, frozen cells will be available for Phase I and II studies. The reviewers expressed a concern
that these, like other cellular immunity measurements (CTL and proliferative responses), would not be
very accurate when using frozen cells, raising questions about the interpretation of any results.
In the response, the authors argued that the PA only asked for development of sensitive, standardized
assays of clinical HIV vaccine studies, and any significance will be evaluated when Phase II trials are
underway. In this study, they will be measuring correlates of immunity rather than mechanisms of
immunity, which is outside the scope of this work. Although it is understandable the true significance of
these measurements can not be known until the results of Phase II and ultimately Phase II studies are
completed, there is insufficient basis for believing this information will add significant new
understanding to the immune response or correlate with protection from immunity.
Additional data was provided about comparisons of cellular responses from fresh vs. frozen samples.
Although encouraging, the high background and high CVs observed make it difficult to conclude that
reliable data can be collected from frozen samples. Additional validations are planned and
arrangements have been made with the new HVTN study to collect fresh blood samples for this
purpose as well.
INNOVATION: The proposed measurement of chemokine activity in vaccinees is important in
understanding immune response and may be valuable in predicting vaccine outcome. However, only
standard methods and approaches are proposed with not much innovation. This work will add yet
another measurement of immune status, but it is not clear that the results of these studies will add
significantly to our understanding of responses to vaccine or predictability of immune status over
current assays.
INVESTIGATOR: Dr. Garzino-Demo is well qualified to carry out the proposed work. He is very familiar
with the design and evaluation of chemokine assays and was a member of the original team that
discovered the CCR5 ligands and their role in protection from infection. Several strong letters of
support are included in the proposal and further demonstrate that he is well regarded in the scientific
community and capable of leading this effort.
ENVIRONMENT: The work environment for design and evaluation to the chemokine assays is
excellent. The UMD Institute of Human Virology is well equipped to carry out the proposed studies.
HUMAN SUBJECTS: No concerns.
THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW
ADMINISTRATOR TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW
COMMITTEE ON THE FOLLOWING ISSUES:
PROTECTION OF HUMAN SUBJECTS (Resume): ACCEPTABLE.
lNCLUSION OF WOMEN PLAN (Resume): ACCEPTABLE.
INCLUSION OF MINORITIES PLAN (Resume): ACCEPTABLE.
INCLUSION OF CHILDREN PLAN (Resume): ACCEPTABLE.

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested.