Grants and Contracts Details
Description
During the past 30 years we have developed a comprehensive multidisciplinary research program using the
equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses
persist despite robust host immune responses and to evaluate experimental immunization strategies as
models for HIV-1 infection and vaccine development. In the previous grant period, we demonstrated for the first
time that Env variation is indeed a primary determinant of lentivirus vaccine efficacy that will need to be
addressed in the effort to develop broadly protective vaccines. In the current competitive renewal application
we propose to extend these studies to test our central hypothesis that EIA V Env is the primary determinant of
vaccine efficacy and that effective vaccines must elicit appropriate broadly reactive immunity against diverse
virus strains. Moreover, we suggest that Env antigen and its method of presentation need to be optimized to
elicit enduring broadly protective immunity. Thus, the following complementary specific aims are proposed: (i)
to define the Env determinants of vaccine protection and to characterize the specificity of vaccine immunity to
these critical determinants, (ij) to characterize the maturation of immune responses to attenuated EIAV
vaccines that is associated with the development of endurina protective vaccine immunity, and (iii) to develop
and evaluate novel immunization procedures using multivalent and consensus Env immunogens for their ability
to elicit broadly protective immunity to diverse EIAV strains. In the first specific aim, we will use selected
chimeric Env viruses derived from two defined variant Env species that differ markedly in vaccine protection to
map specific Env determinants of protection based on experimental challenge of ponies immunized with a
reference attenuated EIAV vaccine. In the second specific aim. we will perform a complementarv study to
define the immune correlates of vaccine efficacy bY characterizina the Env-specific antibody and cellular
immune reponses that distinauish nonprotective and protective vaccine immunity. In the third specific aim, we
will evaluate a series of vaccine modalities (attenuated virus, virus like particles, and adenovirus vectors)
expressing either a mixture of variant Env species or a consensus Env for their ability to produce broadly
reactive vaccine immunity and to protect against diverse Env strains of EIAV in experimentally immunized
ponies. It is anticiapated that the results of these studies will provide novel insights into the fundamental
mechanisms by which Env variation can circumvent protective vaccine immunity and determine the potential of
alternative vaccine strategies to overcome the challenge of Env diversity in vaccine development. Thus, these
EIAV studies address critical issues in AIDS vaccine research and can provide important information relevant
to the design of candidate human AIDS vaccines.
Status | Finished |
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Effective start/end date | 9/30/87 → 3/31/14 |
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