Parks: Replicating Viral Vaccine Vectors
Effective control of highly infectious viral diseases such as measles, mumps, rubella, polio, and smallpox, is due in large part to the fact that vaccines specific for these viral pathogens are based on live attenuated viruses. Vaccination causes a very mild or asymptomatic infection after administration and this 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 used to induce immunity that protects vaccinated macaques from disease caused by subsequent exposure to highly pathogenic SIV demonstrating that this approach is relevant to AIDS vaccine development. Unfortunately, such a strategy is not suitable for development of a HIV vaccine, thus the consortia led by Dr. Chris Parks at the International AIDS Vaccine Initiative (IAVI) plans to use unrelated viruses that do not cause serious human illness to construct replicating viral vectors that are modified to express multiple HIV proteins.
The rationale for developing HIV vaccines using this approach is that live vector replication will evoke immune responses naturally triggered by viral infections 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 tailored to fighting viral infections and are of greater magnitude and durability compared to those induced by non-replicating vaccines. Moreover, vector selection and vaccine design has been influenced by the simple concept that replicating vector-based HIV vaccines should mimic properties of the efficacious live attenuated SIV vaccines.
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 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 HIV 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 it incorporates the HIV Envelope (Env) glycoprotein on the surface of the virus particle and also uses functional Env to replicate. Consequently, replicating VSV vectors can be made that physically resemble an HIV particle and importantly present an authentic Env target 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, these animal viruses 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, one candidate will be prioritized to advance into clinical development.
1. Complete preclinical evaluation of VSV-SIV and CDV-SIV vaccines generating data to support advancement of one HIV vaccine candidate to clinical development.
2. Complete construction and in vitro characterization of VSV-HIV chimeric virus vaccines and backup candidates. Derive a VeroCD4/CCR5 cell line that is suitable for producing clinical trial material.
3. Complete construction and in vitro analysis of CDV-HIV vaccine vectors and backup candidates.
4. Evaluate CDV-HIV and VSV-HIV vaccine immunogenicity in nonhuman primates.
5. Evaluate CDV-HIV vaccine replication in ferrets to model vaccine safety.
6. Prepare CDV-HIV and VSV-HIV pre-Master Virus Seeds that will be used for cGMP Master Virus Seed production and vaccine manufacturing.