Parks Vaccine Discovery Consortium

OVERVIEW:

Live attenuated viral vaccines, such as measles, mumps, rubella, rotavirus, canine distemper, and others that are used routinely for human and animal immunization, prime durable and protective immune responses after just 1-2 vaccinations. Consistent with the success of these live viral vaccines, some of the more effective experimental AIDS vaccines tested in the rhesus macaque model are based on live attenuated strains of SIV. Although all of the factors contributing to the efficacy of live vaccines are not understood, it is probable that their capacity to replicate and closely mimic an infection by a natural pathogen plays a crucial role in priming the immune system effectively. Unfortunately, this conventional and effective live attenuated viral vaccine strategy cannot be applied directly to development of an AIDS vaccine because there are significant safety risks associated with using a live attenuated HIV for routine vaccination.  Therefore, the Parks VDC is developing new live viral vectors that can safely deliver experimental SIV vaccines to rhesus macaques and determining which vaccine candidates can protect the animals from subsequent infection with a pathogenic strain of SIV.

RESEARCH OBJECTIVES:

The Parks VDC is developing live vaccine vector platforms that will test 4 concepts:

1. Vaccine delivery directly to mucosal tissues will prime immune responses that protect mucosal barriers from SIV infection. Three different vaccine vectors are in development to test this hypothesis. Canine distemper virus and Newcastle disease virus vectors are being developed for intranasal delivery, and mammalian orthoreovirus vectors will be administered orally to deliver vaccine to the gastrointestinal tract.
2. Vaccine delivery to lymphocyte populations will prime immune responses that protect organized lymphoid tissues from SIV infection. Modified canine distemper virus vectors are in development that will enhance delivery of vaccine to lymphoid cells.
3. Long-term persistent antigen expression is required to elicit efficacious immune responses against SIV.  The VDC initially used adeno-associated virus vectors to develop ‘persistent’ vaccines, but recently changed their emphasis to focus on rhesus cytomegalovirus vectors because of their natural ability to prime vigorous cellular immunity.
4. Live vaccines that produce progeny viral particles that closely resemble SIV/HIV will elicit a profile of immune responses that protects animals from subsequent SIV infection like a live attenuated SIV vaccine.  The researchers are developing two different RNA virus platforms to test this concept. The first is based on Venezuelan equine encephalitis virus and the second is based on vesicular stomatitis virus.

PROGRESS:

Vaccine vector construction and development of standardized immunologic testing procedures in the Parks VDC has progressed to the stage where they intend to commence several studies in rhesus macaques beginning in 2009.

The canine distemper virus vaccine is the most advanced of their vectors intended for delivery to mucosal tissues. A vector encoding SIV Gag currently is being tested in a small animal model, and we have made significant progress producing canine distemper virus vectors that will express the remaining SIV proteins (Pol, Nef, Env, and a fusion protein composed of Vif-Vpx-Vpr-Tat-Rev).  Importantly, canine distemper virus is lymphotropic and the researchers plan to exploit this characteristic to develop vaccines that can infect the gut associated lymphoid tissue to determine if targeted vaccination can improve regional immunity at this prominent site of SIV replication.

Progress also has been made constructing two other vectors they intend to test as mucosal vaccines. Researchers at the Parks VDC have cloned the genome of a Newcastle disease virus strain that will be used as our vector genetic background, and will commence production of vectors encoding SIV genes this year. Stable recombinant orthoreoviruses have been produced that expresses polypeptides derived from SIV Gag, and this year the VDC plans to develop vectors that contain increased quantities of SIV immunogen coding sequence.

The Parks VDC recently incorporated a new vector in their CAVD research program because recent results demonstrated that immunization with SIV vaccines based on live rhesus cytomegalovirus vectors protect animals from challenge (Hansen et al., Nat Med. 2009;15:293-9). Because rhesus cytomegalovirus establishes a persistent infection, they plan to initiate a study this year that will allow them to determine the character of the immune responses evoked by prolonged antigen exposure and search for correlates of immunity in vaccinated animals that are protected from SIV infection.

Finally, the VDC has produced a chimeric virus that is composed of the replication machinery of Venezuelan equine encephalitis virus packaged in SIV structural proteins. This chimeric virus is replication-competent but attenuated, and selectively replicates in CD4-positive cells. Moreover, the progeny viral particles produced by infected cells closely resemble SIV and should provide a very natural immunogen for priming the immune system. The researchers plan to commence a pilot rhesus macaque immunogenicity and safety study in this program year. They also have made progress constructing chimeric viruses based on vesicular stomatitis virus. The VDC has prepared prototype live vesicular stomatitis virus-SIV chimeras that selectively infect CD4-positive cells, which they are now modifying to increase its content of SIV protein coding sequence.