Vaccines and Cancer Vaccines
Glycoprotein D Vaccine Adjuvant
Investigators at The Wistar Institute have developed a novel method for improving the immune response to vaccination by combining specific target antigens with a non-specific adjuvant. Wistar scientists have developed a new highly effective carrier protein adjuvant by fusing a Herpes simplex virus glycoprotein D (gD) sequence to the vaccine immunogen sequence. Glycoprotein D is a viral envelope protein that is normally expressed on the surface of cells infected with Herpes virus. The recombinant gD-antigen protein sequence preserves the structures responsible for interaction with an immune cell receptor, which is involved in controlling immune responses. The efficacy of recombinant gD as an adjuvant has been demonstrated with antigens from human papillomavirus (HPV), human immunodeficiency virus (HIV) and Influenza A virus.
In a mouse model of HPV-induced tumors, vaccination with a viral vector vaccine carrying HPV oncoproteins fused into the gD sequence induced strong immune response to the oncoproteins and resulted in significant tumor regression in mice with large tumor masses. Therefore, the gD adjuvant may be particularly useful for the development of a therapeutic HPV vaccine.
Unlike many carrier protein adjuvants that are targeted to intracellular compartments, the glycoprotein D-antigen proteins are expressed on the cell surface. This significantly reduces the likelihood of deleterious interaction with intracellular proteins such as those implicated in malignant transformation. The gD adjuvant may be applicable to multiple vaccine delivery methods. Vaccines in the form of naked DNA and viral vectors (adenovirus vectors and adeno-associated virus vectors) have been tested; testing of other vaccine delivery platforms are underway.
Novel Influenza Vaccine
There is a critical unmet need for new influenza vaccines that are easily produced and that induce protective immunity which is broadly cross-reactive with current and future epidemic virus strains. The external M2 protein (M2e) is highly conserved among human influenza type A viruses and M2e-specific antibodies have the potential to provide broad protective immunity across influenza A strains. However, the natural M2 protein is poorly immunogenic so that individuals exposed to influenza virus or immunized with current vaccines do not develop these broadly-protective antibodies.
Wistar researchers have developed novel multiple antigenic peptide constructs (MAPs) that induce M2e-specific antibodies in vivo. These MAPs consist of M2e and helper T cell determinants that are covalently linked. Mice immunized intranasally with MAPs exhibited significant production of M2e-specific antibodies as well as decreased morbidity after influenza virus infection. These MAPs, administered independently or in conjunction with whole virus, may be useful for developing an effective broadly protective influenza vaccine.
The RA 27/3 strain of rubella virus was developed at The Wistar Institute. The seed stock from RA 27/3 has been successfully used worldwide since the 1970's as a vaccine for the prevention of rubella infection. This vaccine has been administered alone and as part of a combination vaccine (e.g. MMR; measles, mumps, rubella vaccine).
The Wistar Institute has maintained seed stocks of the RA/ 27/3 strain of rubella for use in production of vaccines. These vaccines have been licensed to regional public health agencies and to for-profit companies who are developing vaccines for local distribution, particularly in Asia and South America.
Vaccine for Prevention of Rabies Infections in Humans
Researchers at Wistar have developed a new rabies vaccine that has the potential to produce the long-lasting immunity to rabies that is required for an effective prophylactic vaccine. This vaccine is derived from recombinant chimpanzee adenovirus (rAdC68) that contains the DNA sequence of the rabies glycoprotein.
In non-human primates, this adenovirus-based vaccine produces long-lasting immunity after just one intramuscular injection, even in the presence of pre-existing immunity to human adenovirus. In ongoing studies, primates immunized with one does of the rAdC68 rabies vaccine showed no decline in serum antibody levels after six months. Wistar is seeking a partner to develop this vaccine for prevention of human rabies infection, either as a single vaccine or in combination with the current human diploid cell rabies vaccine. The adenovirus-based vaccine is less expensive to produce, maintain, and distribute than the current human rabies vaccines. This new immunization approach may make it feasible and cost-effective to administer prophylactic rabies vaccines to children in areas where rabies still commonly infects dogs and other companion animals.
Vaccine to Treat Melanoma
Wistar scientists have developed novel peptides that mimic a BRAF mutation (BRAFV600E) which is expressed in a majority of melanomas. These mutated BRAF peptides stimulate T cell proliferation in melanoma patients who express HLA-2; this HLA type is expressed by about 50% of melanoma patients. Vaccines against BRAFV600E may induce both Class I and Class II-restricted lymphocyte responses and, as such, would be a useful tool for immunotherapy of melanoma.
In pre-clinical studies, 4 of 5 melanoma patients with BRAFV600E-positive lesions mounted a significant immune response (T cell proliferation) to stimulation with BRAFV600E peptide, thus demonstrating the feasibility of this immunotherapy in melanoma patients.
Method for Identifying Novel Cancer Antigens for Vaccine Development
A novel method for cloning MHC class II-dependent antigens from cancer cells has been developed for use in creating new cancer vaccines. Cancer antigens bound to MHC molecules on the surface of specialized antigen presenting cells (APCs) are recognized by CD4+ T-helper (Th) lymphocytes, which play a central role in providing protective immunity against cancer. New MHC class II-dependent cancer antigens therefore have significant promise as vaccine immunogens. They have previously been identified by artificially fusing libraries of cancer peptides with MHC molecules, expressing them in standard cell lines, and screening them for activation of CD4+ Th cells in culture. However, this method fails to recapitulate the complexity of antigen-MHC processing and presentation by APCs; requires prior knowledge of the MHC restriction element used by the Th cell and is very laborious. Wistar scientists have developed a phage method for expressing tumor cDNA libraries directly in APCs, without prior fusion to MHC. The APCs naturally process and present these tumor peptides on their surface, where they can be readily screened for CD4+ Th cell activation. The method has been used at Wistar to identify a novel Th cell antigen that is shared by melanomas and gliomas, and may be useful for the identification of other antigens for cancer vaccine development.
Rabies Vaccine - PM Seed Stock
The PM 1503 strain of rabies virus, developed at The Wistar Institute, has been successfully used worldwide to develop rabies vaccine for post-exposure treatment to prevent rabies infection of humans.
The Wistar Institute has seed stock of the PM 1503 strain of rabies for use in production of vaccines. The Wistar seed stocks were grown on Vero cells, however, they can be adapted to grow on human diploid cells. This rabies vaccine seed stock has been licensed to select regional public health agencies and to for-profit companies who are developing vaccines for local distribution in selected countries, particularly China and India.