Parks: Replicating Viral Vaccine Vectors
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 specifically, 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 pathogenic 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 viruses developed as vectors also were selected because they had properties that could be used to mimic specific characteristics shared by efficacious live attenuated SIV vaccines and the AIDS virus.
Dr. Chris Parks’ team is developing live vaccine vectors based on canine distemper virus (CDV) and vesicular stomatitis virus (VSV). CDV was selected specifically because it preferentially replicates in lymphoid cells, which also is a prominent 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 better suited to protecting these vulnerable sites. VSV was selected based on a different characteristic. VSV can be manipulated such that the virus will incorporate significant amounts of HIV Envelope (Env) glycoprotein on its surface, which allows VSV vectors to be generated that physically resemble an HIV particle, and importantly, present authentic Env targets for eliciting antibody responses. 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 the vaginal and rectal mucosal barrier. Finally, CDV and VSV both naturally infect animals and were selected as vectors because they are not associated with serious human disease, but it is important to note that exposed individuals are known to mount an immune response against these viruses.
Currently, CDV and VSV vectors are being evaluated in rhesus macaques. By the end of the funding period, data will be available to evaluate their potential for advancement as vaccine candidates for clinical trial.
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 can 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 small animal models that can be used to assess vaccine safety.
4. Prepare CDV-HIV and VSV-HIV pre-Master Virus Seeds that comply with cGMP vaccine manufacturing