CD40L and GITRL adjuvants for anti-HIV Ad5 vector vaccines

Geoffrey W. Stone and Richard Kornbluth, Veterns Medical Research Foundation

Adenovirus-based vaccines are among the most promising candidates for both a prophylactic and therapeutic HIV vaccine. However, there remain concerns that this vaccine platform may still not be strong enough or produce responses that are durable enough to make a major impact upon the HIV pandemic. This IDEA project follows upon our recent finding that DNA vaccines can be markedly improved by incorporating within them novel, multimeric forms of soluble CD40L and GITRL. The central hypothesis to be tested is that including these new molecular adjuvants in an adenoviral vaccine will significantly improve the resulting immune responses in a mouse model.

Three Specific Aims are proposed: (1) To construct six adenoviral 5 (Ad5) vectors for testing: Ad5/membrane CD40L; Ad5/1-trimer soluble CD40L; Ad5/4-trimer soluble CD40L; Ad5/membrane GITRL; Ad5/1-trimer soluble GITRL; and Ad5/4-trimer soluble GITRL. (2) To determine if these molecularly adjuvanted adenoviral vectors are more effective than regular Ad5 for activating dendritic cells in vitro. (3) To determine if these molecularly adjuvanted adenoviral vectors induce stronger, broader, and longer-lasting responses than regular Ad5 in an Ad5/Gag HIV vaccine mouse model.

When these studies are complete, they will establish if adding CD40L or GITRL makes Ad5 a stronger vaccine. The improved vaccine construct would then be used for additional vaccine development research in animal and clinical trials. Because adenoviral vectors have many other potential vaccine uses, these studies have broad public health significance for California.