Annual and Interim Progress Report Summaries
Principal Investigator: Chris Parks
Project: A Research Consortium Dedicated to the Invention, Systematic Evaluation and Development of Novel AIDS Vaccine Candidates that Elicit Potent, Durable and Protective T Cell Responses
Submitted February 1, 2010 (Interim Report)
Live attenuated viral vaccines historically have made it possible to safely control many highly infectious human and animal pathogens, like smallpox, measles, polio and canine distemper viruses, because these replication-competent vaccines are able to prime durable and protective adaptive immune responses after just 1-2 vaccinations. Unfortunately, it is difficult to apply this conventional approach directly to an AIDS vaccine because it will be very difficult to produce a live attenuated HIV that is considered safe for use people. Therefore, our objective is to design and develop several specific types of replication-competent viral vector that can be used to deliver AIDS vaccines and then test the candidates in the rhesus macaque SIV/AIDS model to determine which evokes immunity that protects animals from experimental SIV infection.
We are developing live viral vectors that will be used to test 3 vaccine design concepts: 1) Vectors that provide persistent antigen expression are required to elicit and maintain immune responses that protect from SIV/HIV infection. For this purpose we are studying immune responses produced by vectors based on rhesus cytomegalovirus (RhCMV), which establishes persistent infection in macaques and stimulates vigorous T cell responses. A study will commence in early 2010 to determine whether RhCMV-SIV vaccine vectors evoke immunity that can protect animals from vaginal SIV infection. The nature of immune responses elicited by RhCMV-SIV vaccines will be evaluated comprehensively during this study. 2) Vectors that deliver vaccine directly to mucosal tissues will prime immune responses that better resist SIV/HIV infection at vaginal and rectal mucosal barriers. Three different vaccine vectors are in development to test this hypothesis. Canine distemper virus (CDV) and Newcastle disease virus vectors are being developed for intranasal vaccination and mammalian orthoreovirus vectors are designed for oral administration and delivery to the gastrointestinal tract. The attenuated CDV vector is most advanced and currently is being studied in a small animal model. The NDV and reovirus vectors are in the vaccine construction phase. a) Vectors that can infect mucosal surfaces and subsequently target lymphocytes for vaccine delivery will prime immune responses that protect organized lymphoid tissues from HIV/SIV infection. CDV vectors that are modified to enhance vaccine delivery to lymphocytes are in development. Experimental vaccines that encode SIV antigens will be produced in 2010. 3) Vectors that closely mimic the properties of a replication-competent attenuated SIV/HIV vaccine will elicit protective immune responses much like a traditional modified live viral vaccine. We are developing two different types of RNA virus vectors to test this concept. The first is based on Venezuelan equine encephalitis virus (VEEV) and the second is based on vesicular stomatitis virus (VSV). These novel vaccines are designed by removing parts of the vector and substituting elements of SIV to produce chimeric virus vaccines that will form virus particles that physically resemble SIV. Prototypes of both vectors have been produced and are being studied in the laboratory. We anticipate testing at least one of these vectors in macaques in 2010.