Parks: CDV and VSV Viral Vectors
The outstanding success of vaccination programs used to control highly infectious viral diseases such as measles, mumps, rubella, polio, and smallpox, is due in large part to the fact that these vaccines contain live attenuated viruses that cause a very mild or asymptomatic infection after vaccine administration. The mild, self-limiting infection prepares the immune system to respond specifically, quickly, and effectively against later natural exposure to the viral disease agents. Since such a strategy is not suitable for HIV, 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 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. Recent encouraging findings from Dr. Louis Picker lend support to this approach. An experimental SIV vaccine delivered by replication-competent rhesus cytomegalovirus (RhCMV) vector elicited immunity in macaques that dramatically suppressed replication of SIVmac239 in animals exposed to this virulent virus, and in fact, viremia was suppressed to low or undetectable levels in 50% of the infected animals.
To prevent sexual transmission of the AIDS virus, vaccination must establish adaptive immune responses that act swiftly at the site of HIV exposure. Accordingly, protective immunity will either block infection following vaginal or rectal exposure or prevent virus propagation and dissemination if HIV penetrates the mucosal surfaces at these sites. To elicit immunity that is best suited to protecting mucosal surfaces and the underlying tissues where HIV initially replicates, the vaccine must be designed to stimulate the type of immune responses that specifically fight viral infection at these locations. Therefore, the proposal focuses on developing replicating viral vectors based on viruses that naturally infect mucosal surfaces and are known to stimulate immune responses that can protect these vulnerable sites where viruses enter their hosts.
The objective of the work performed by Dr. Chris Parks’ team is to produce two new HIV vaccine candidates based on replication competent canine distemper virus (CDV) and vesicular stomatitis virus (VSV). Neither of these animal viruses is associated with human disease although exposed people are known to mount an immune response against these viruses. The CDV and VSV vectors are designed to produce HIV proteins needed to induce antibodies specific for the surface of the AIDS virus and evoke cellular immunity that attacks HIV-infected cells. By the end of the funding period, one candidate will be prioritized to advance to a Phase 1 clinical study.
The CDV-HIV and VSV-HIV vaccine candidates each are designed to test unique concepts. The VSV vector is designed to produce virus particles that physically resemble HIV. This will test the hypothesis that the VSV-HIV vaccine will elicit protective immunity similar to what has been observed with live attenuated experimental SIV vaccines. CDV and HIV infect a similar range of tissues and this biological property of CDV will be used to determine whether vaccine delivery to specific locations induces immune responses that are better adapted to fight the AIDS virus.
- Complete construction and in vitro characterization of VSV-HIV chimeric virus vaccines and backup candidates. Derive a VeroCD4/CCR5 cell line for production of these vaccines.
- Complete construction and in vitro analysis of CDV-HIV vaccine vectors and backup candidates.
- Evaluate CDV-HIV and VSV-HIV vaccine immunogenicity in nonhuman primates.
- Evaluate CDV-HIV vaccine replication in ferrets to model vaccine safety.
- Prepare CDV-HIV and VSV-HIV pre-Master Virus Seeds that will be used for cGMP Master Virus Seed production and vaccine manufacturing.