NOVEL METHODOLOGIES FOR VACCINE DEVELOPMENT

Background:

UCSF researchers have developed a panel of novel, live-attenuated bacterial and viral vectors with a view to their use in vaccine development. Vaccines have long been a crucial component of the arsenals used to combat diseases such as measles, tetanus, polio and tuberculosis. Continuing research into the vaccine field is required to develop improved compositions of current vaccines as well as to develop novel vaccines for diseases such as HIV and cancer.

Current vaccine technologies have several shortfalls. DNA vaccines do not target the mucosum or undergo rounds of replication in the host cell. RNA self-launching replicons only undergo one round of replication and also fail to target the mucosum although increased antigen expression is achieved. In summary, both systems induce only a limited immune response. In contrast, live vaccines induce long-lived, multi-faceted immunity and augment the immune response by infecting neighboring cells with progeny for systemic effects, but these vaccines also do not target the mucosae of the immune system. What is needed is an improved live-attenuated viral vector system and/or a vaccine delivery vector that targets the mucosal immune system, inducing a more complete response whilst also producing a long-lasting response that is propagated to neighboring cells.

The panel of live-attenuated vectors developed by the UCSF group exploits the advantageous aspects of RNA, DNA and live virus vaccines and fulfills this need. A wide variety of exogenous sequences can be expressed by these new systems including those encoding microbial pathogens, proteins with therapeutic activity and tumor-associated antigens. In addition, one vector within the panel enables the delivery of exogenous sequence primarily to mucosae and epithelial cells. Such targeting is crucial in the development of vaccines to HIV.

Vaccine vector 1

Novel, live-attenuated flavivirus providing for delivery and expression of an exogenous sequence in a host cell.

Vaccine vector 2

As for vector 1 but with the addition of an IRES, thus causing transcription of the exogenous sequence independently of viral components.

Vaccine vector 3

Novel, live-attenuated bacterial vector that enables the delivery of recombinant viral RNA sequence to the host cell, primarily cells of the mucosal immune system, and releases the RNA virus to infect neighboring cells.

Scientific Results:

All three vectors have been characterized in in vitro systems to determine their ability to trigger transcription of inserted test genes and retain the inserted exogenous sequence for a large number of replication rounds. In addition, vector 1 has been shown to induce protective immunity in vivo via a variety of administration routes. Its administration also caused regression of established tumors and immuno-therapy of metastases. Vector 3 has similarly been characterized in vivo, via oral administration route, and shown to deliver and launch recombinant virus infection permitting the expression of foreign antigen.

Competitive Advantages Offered by These Vectors:

Vectors 1, 2 & 3:

• Live-attenuated vectors will continue to propagate until the intervention of host’s immune system, therefore inducing a systemic response with longer durability than many current vaccine vectors.
• Low toxicity in vivo, non-pathogenic.
• Delivery of proteins of many sizes.
• Double copies of sequence of interest can be inserted to cause an increase in protein production.
• Exogenous polypeptide is expressed independently of the vector polyprotein precursor and thus does not interfere with the vector protein-folding or function.
• Exogenous polypeptide undergoes intracellular co-translational and post-translational modifications in a manner substantially identical to the processing it undergoes in its native environment.

Specific to Vector 3:

• Plasmids are low or single copy number; therefore, the risk of integration into the host genome resembles simple naked-DNA immunization.
• With regard to HIV vaccine potential, this vector combines the advantages of a bacterial-DNA delivery vector with that of a recombinant live-attenuated RNA virus; delivery to mucosal immune system for a better response, long-term memory, systemic immunity
• Oral route of administration.

Potential Applications of this Technology:

• Vaccines for diseases such as HIV.
• Gene therapy.

Patent Status

Vector 1(SF99-054)
The Regents of the University of California’s issued US. Patent (6,589,531) can be found at the following link.

Vector 2 SF01-052)
The Regents of the University of California has filed patent applications. The PCT publication can be found at the following link.

Vector 3 (SF04-021)
The Regents of the University of California has filed a patent application.

If you would like to receive further information about this technology and potential licensing opportunities, please contact:

Karin Immergluck, Ph.D.
Senior Licensing Officer
(415) 353-4469 phone
(415) 348-1579 fax
Karin.Immergluck@ucsf.edu

Reference: OTM Case #SF04-021