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Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors.
In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.
This research, funded by NIH, aims to test adenoviral recombinants based on simian serotypes for induction of immune responses to gag/pol/rev of HIV-1 or SIV-1 in a mouse model. Its goal is the development and characterization of novel vaccine carriers to HIV-1 antigens based on El-deleted adenoviral recombinants derived from chimpanzee serotypes in pre-clinical animal models. Such serotypes of adenovirus do not circulate in the human population. They should induce responses to the HIV-1 antigens that are unimpaired by pre-existing neutralizing antibodies to the vaccine carrier. Such antibodies are expected to reduce the efficacy of vaccines based on common human serotypes of adenovirus in a human target population.
The focus of this application is to develop an adenovirus-based vaccine against rabies virus that can provide rapid immunity following a single administration to achieve prophylactic status and as well as in response to a bioterrorism attack. The vaccines to be evaluated are based on an E1-deleted simian adenoviral vector derived from a chimpanzee isolate. In animal models, E1-deleted human adenoviral recombinants of the serotype 5 (AdHu5) have shown high efficacy as vaccine carriers. Humans are infected by common serotypes of human adenovirus such as AdHu5 and a significant percentage has neutralizing antibodies to this serotypes, which impair the efficacy of AdHu5 based vaccines.
To circumvent this problem, novel replication-defective adenoviral vaccine carriers based on El-deleted recombinants of chimpanzee-derived adenoviruses were developed. These viruses do not circulate in the human population and fail to carry neutralizing B cell epitopes that cross-react with the common serotypes of human adenoviruses. Lack of preexisting virus-neutralizing antibodies in the human population suggests that these novel adenoviral recombinants may provide improved vaccine carriers for use in humans. A simian adenoviral vector termed adenovirus C68 (AdC68) was generated as a molecular clone to express the glycoprotein of rabies virus. In mice, this vector induced after a single dose complete protection to rabies virus challenge. This vaccine also achieves long-term protection in non-human primates after a single dose.
The goal of this application is to further characterize immune responses that can cause the elimination of recombinant adeno-associated virus (rAAV) transduced cells. Most humans are naturally exposed to AAV-2 together with a helper virus and thus have immunological memory to AAV-2. Memory T cells can be triggered more readily than naive lymphocytes, which was not taken into account by pre-clinical animal experiments conducted thus far. Concerns about immunological consequences of rAAV-mediated gene transfer were substantiated by the outcome of a clinical trial in which human hemophilia B patients were infused into the liver with rAAV-2-F.IX vectors. Only one patient achieved therapeutic levels of F.IX, which were sustained for 4 weeks and then started to decline. At the same time the patient developed a transaminitis, which resolved after F.IX levels decreased to baseline levels. Overall, the patient's clinical course was compatible with immune-mediated destruction of rAAV-transduced hepatocytes.
Additional data generated since substantiated our hypothesis that AAV-2-specific T cells induced by a natural infection can cause elimination of rAAV-transduced hepatocytes. To further define immune responses to AAV and rAAV-encoded transgenes under conditions that mimic those of human hemophilia patients and to then devise informed strategies to circumvent such problems, we are to elucidate the effect of pre-existing AAV-2-specific T cell-mediated immunity on hepatic rAAV vector-mediated gene transfer in mice.
Costimulatory and coinhibitory pathways together with metabolic pathways orchestrate the fate of lymphocytes after antigenic stimulation. These findings lead to the hypothesis that impaired immune responses in the elderly to infection or vaccination reflects dysregulation of immunoregulatory pathways and metabolic pathways, which work in concert to orchestrate an effective immune response in young healthy individuals. We will test this hypothesis using an influenza virus model. Specifically, we will test samples from aged and, as a control, younger human subject before and after vaccination with the trivalent inactivated influenza vaccine (TIV) in an exploratory/confirmatory study design to assess age-related responsiveness to the vaccine. We will use functional studies combined with gene expression profiling to determine serological responses to the vaccine, enumerate responding T and B cell subsets, and validate the biological relevance of differential expression of genes involved in immunoregulatory and metabolic pathways.
Results obtained with human samples will be substantiated with experiments in mouse models, including models based on genetically modified mice. Studies in mouse models will permit extension of the human study to parameters that cannot be assessed with human samples, and enable selective analyses of antigen-specific T and B cells. These mouse models will help the interpretation of multi-parameter human studies which, in part, need to be conducted with mixed samples.
The microscope in the image belonged to William E. Horner, M.D., a collaborator with Caspar Wistar, M.D., in the early 1800s.
Dr. Horner, a lecturer at the University of Pennsylvania, was a pioneer of the use of microscopes in anatomical and medical research. He authored Special Anatomy and Histology, a seminal text on the subject.