Parks: HIV Vaccine Clinical Candidates based on Replication-Competent Viral Vectors that Preferentially Replicate in Lymphoid Tissues
Highly contagious viral diseases such as measles, mumps, rubella, and polio are controlled by immunization with live attenuated viral vaccines. Vaccination causes a very mild or asymptomatic infection that prepares the immune system to respond speci cally, quickly, and effectively against later natural exposure to the viral disease agents. Importantly, experimental live attenuated SIV vaccines also have been shown to induce immunity that protects vaccinated macaques from disease caused by subsequent exposure to highly patho- genic virus demonstrating that this approach is relevant to AIDS vaccine development. Unfortunately, using a similar live attenuated strain of HIV to vaccinate people is too risky, thus the program led by Dr. Chris Parks at the International AIDS Vaccine Initiative (IAVI) is using unrelated viruses that do not cause serious human illness to generate replicating viral vectors that express multiple HIV proteins.
The rationale for this approach is that live vector replication will evoke immune responses naturally triggered by viral infection while also delivering HIV proteins that will elicit immune responses that are directed specifically against the AIDS virus. Exposing the immune system to a replicating vector also is expected to induce immune responses that are more durable compared to those induced by non-replicating vaccines. The virusesdeveloped as vectors were selected because they had properties that could be used to mimic speci c characteristics shared by ef cacious live attenuated SIV vaccines and the AIDS virus. Vaccine vectors based on canine distemper virus (CDV) and vesicular stomatitis virus (VSV) are being developed. CDV was selected because it preferentially replicates in lymphoid cells, which also is a feature of SIV or HIV infection. Thus,a CDV-HIV vaccine vector will deliver HIV antigens to lymphoid tissues naturally infected by the AIDS virus perhaps inducing immunity that is suited to protecting these vulnerable sites. VSV was selected because this vector can be manipulated to incorporate signi cant amounts of HIV Envelope (Env) glycoprotein on its surface; creating VSV vectors that physi- cally resemble an HIV particle. Both VSV and CDV will infect through contact with mucosal surfaces; therefore, mucosal vaccination also is being investigated to determine if this delivery route enhances immunity at mucosal barriers. Finally, CDV and VSV infect animals and although neither is associated with serious human disease, exposed individuals are known to mount an immune response against these viruses.
1. Complete preclinical evaluation of VSV-SIV and CDV-SIV vaccine prototypes in rhesus macaques and determine if they induce immunity that prevents or substantially controls SIV infection.
2. Generate CDV and VSV vectors that deliver a trimeric HIV Env immunogen and determine if they induce anti-Env antibodies in vaccinated macaques.
3. Evaluate VSV-HIV and CDV-HIV vaccines in animal models that can be used to assess vaccine safety.
4. Prepare VSV-HIV pre-Master Virus Seeds that complies with cGMP vaccine manufacturing